Objective Regenerating genes express mainly in gastrointestinal tissues and the injured regenerating pancreatic tissues,which can promote the regeneration of pancreatic β cells and other tissue cells.In recent years,researches on Reg family mainly involved the gene structure of various subtypes of Reg,and its role in diabetes,gastrointestinal cancer,inflammation,anti-microbial and the related mechanisms.Among the various subtypes of Reg,regenerating geneⅢ(Reg3) plays a particularly crucial role in these diseases.Therefore,Reg3 is a promising target for the treatment of these diseases.Based on the relationships of Reg3 with a variety of diseases,our group devote to the role of Reg3 [human REG3A,and mouse Reg3γ(Reg3g)] in type 1 diabetes,inflammation-linked pancreatic carcinogenesis,and the immunological changes participated in these processes.Hence,this review will summarize serial studies on Reg3 and the feasibility of it as drug targets.
Reg于1988年首次在大鼠胰岛中发现,并且从大鼠再生性胰岛cDNA库中首次分离,在再生性胰岛β细胞中表达[5]。Reg与组织修复有关,尤其与胰岛β细胞再生密切相关[6]。Reg蛋白主要在胃肠等消化道组织中表达,也存在于心脏和再生性神经元中 [7-8]。基于基因编码蛋白的结构,Reg家族主要分为4个亚型:RegⅠ、Ⅱ、Ⅲ、Ⅳ。小鼠RegⅢ包括RegⅢα、RegⅢβ 和RegⅢγ。人有5个REG基因,包括REG Ia、REG Ib、人肝癌-肠-胰腺或者人胰腺炎相关蛋白(human hepatocarcinoma-intestine-pancreas or human pancreatitis-associated protein,HIP/PAP)、REGⅢ和REGIV[9]。笔者所在课题组主要研究小鼠RegⅢγ(Reg3g)和人REG3A,REG3A即 HIP/PAP[10-12]。RegⅢγ和REG3A为同源物,Reg3g的cDNA全长774 bp,编码174个氨基酸分子,包含6个外显子和5个内含子。REG3A也有6个外显子和5个内含子[9],包括一个结构域——LECTIN C和一个基序——SP。LECTIN C是REG3A的功能域,位于第40~172个氨基酸区域,具有钙依赖的碳水化合物结合功能。基序SP是REG3A的保守序列,位于第1~27个氨基酸区域,其功能在于体现结构域的生物学作用。
2 Reg3促进β细胞修复和治疗糖尿病的作用及相关机制
淋巴细胞浸润会导致1型糖尿病患者胰岛β细胞凋亡[13]。笔者给予非肥胖型糖尿病(non-obese diabetic,NOD)小鼠慢病毒载体包装的Reg3g,发现其诱导调节性T细胞(regulatory T cells,Tregs)分化,抑制树突状细胞(dendritic cell,DC)成熟,减少胰岛淋巴细胞浸润,从而减弱自身免疫反应[14]。基于相关报道[15-16],笔者推测Reg3g过度表达可能通过促进β细胞的再生,抑制炎症反应,在1型糖尿病自身免疫中重建免疫耐受,改善1型糖尿病。蛋白质免疫印迹结果表明,Reg3g在胰腺尤其是胰岛中高效表达,从而促进β细胞的再生,恢复胰岛素分泌水平。除此之外,笔者还确定了Reg3g对内源性抗胰蛋白酶(α-1-antitrypsin,AAT-1)表达的影响。AAT-1是肝脏来源多功能丝氨酸蛋白酶抑制剂[17-18],具有抗炎和抗凋亡特性。在给予Reg3g的小鼠体内,AAT-1血清水平最高,这与AAT-1抑制β细胞凋亡结果相符。笔者的研究还表明,Reg3g可以通过激活酪氨酸蛋白激酶2/信号转导与转录激活因子3(janus kinase 2/signal transducer and activators of transcription 3,JAK2/STAT3)通路一定程度上增加AAT-1产生[14]。此外,激活JAK2/STAT3 通路能诱导β细胞再生,恢复胰岛素水平[19-20]。说明Reg蛋白在体内可能参与β细胞再生。笔者还发现Reg3g会显著上调Tregs比例,进而显著增加Th2型细胞因子分泌[14]。Reg3g通过增加Tregs比例和诱导耐受性DCs,促进β细胞再生,并且保护β细胞免受自身免疫攻击,在体内改善1型糖尿病紊乱的免疫调节过程,从而对β细胞提供保护作用。Reg3g极有可能成为预防和逆转1型糖尿病的有效基因治疗方法。
REG3A是一个相对分子质量为19×103、具有促进生长功能的胰腺分泌蛋白。正常胰腺组织中缺乏REG3A,急慢性胰腺炎时则显著上调。笔者研究发现,REG3A在胰腺癌细胞以及组织样本中均显著高表达,而在REG3A的下游发挥作用的负调控因子细胞因子信号抑制因子3(suppressor of cytokine signaling,SOCS3)在3/5的胰腺癌细胞系和11/36的胰腺癌组织样本中呈现异常甲基化[15]。去甲基化剂(5’-杂氮-2’-脱氧胞嘧啶)能显著抑制胰腺癌细胞增殖,并且诱导其凋亡。笔者临床研究也发现,在人胰腺癌样本中,REG3A信使RNA的表达水平更高,同时也存在SOCS3甲基化。多项研究表明,SOCS3甲基化与多种人类癌症相关[22-27]。有研究表明SOCS3甲基化与胰腺癌的发展有关。体外评估SOCS3与REG3A的关系表明,SOCS3在REG3A的下游发挥作用,调节REG3A促癌功能的发挥。利用干扰RNA在正常胰腺上皮细胞中敲低SOCS3的表达,以及运用质粒在胰腺癌细胞中过表达SOCS3,分别促进和抑制REG3A诱导的肿瘤细胞增殖。基于SOCS3负调控REG3A介导的胰腺癌的发展,笔者研究表明,SOCS3甲基化失活后协同REG3A过表达可促进胰腺癌细胞生长,且可能参与慢性胰腺炎相关癌变。此外,该研究也揭示了JAK/STAT3/NF-κB在胰腺细胞生长过程中可能也与SOCS3-REG3A相互作用有关[15]。
WU等[55]研究了REG3A介导糖尿病皮肤损伤性炎症的过程及机制。研究表明,REG3A与皮肤损伤后Toll样受体3(toll like receptor,TLR3)介导的炎症有关,这个效应与SHP-1蛋白相关。糖尿病情况下,高血糖通过葡萄糖糖化作用下调IL-17诱导的IL-33表达,从而下调REG3A表达,REG3A表达下降减少SHP-1蛋白的产生,活化TLR3诱导的JNK2磷酸化,增加TLR3诱导的促炎细胞因子例如TNF-α、IL-6的产生,增强皮肤损伤中的炎症反应,延缓伤口修复,导致糖尿病中皮肤损伤的恶化。
8 Reg3在其他消化系统肿瘤发展中的作用及机制
除了胰腺癌以外,REG3A也被报道与多种人类癌症相关,如结肠直肠癌、胃癌、肝癌[56-58]。YE等[59]研究了REG3A在结肠直肠癌(colorectal cancer,CRC)中的生物学功能和潜在的分子机制。研究发现,相比于正常组织,REG3A在CRC中的表达水平增加。而且,REG3A的过度表达与肿瘤体积增大、癌症恶性程度增高以及生存率降低有关。当在CRC的两个细胞系——LOVO和PKO中敲低REG3A的表达时,将会显著抑制细胞增殖,诱导G1期阻滞和细胞的凋亡,同时显著抑制细胞迁移和侵袭。此外,研究还发现REG3A表达水平与AKT和EPR1/2磷酸化程度呈正相关。这表明REG3A过表达将会通过激活AKT和ERK1/2通路促进CRC发生。功能分析和基因探针富集分析(genome set enrichment analysis,GSEA)也表明REGA3A可能通过激活AKT和ERK通路调节细胞增殖、凋亡、迁移和侵袭,作为一个致癌基因发挥作用。因此,REG3A可能是CRC潜在的治疗靶点。
WANGY,JACOVETTIC,LIB,et al.Coordinated age-dependent and pancreatic specific expression of mouse Reg2,Reg3α,and Reg3β genes[J].Growth Factors,2011,29(2-3):72-81.
Reg family proteins such as Reg1 and islet neogenesis-associated protein (INGAP) have long been implicated in the growth and/or neogenesis of pancreatic islet cells. Recent reports further suggest similar roles to be played by new members such as Reg2, Reg3αα, and Reg3ββ. We have studied their age-, isoform-, and tissue-specific expressions. RNA and protein were isolated from C57BL/6 mice aged 7, 30, and 90 days. Using real-time polymerase chain reaction, the levels of gene expression in the pancreas were 20--600-fold higher than that in other tissues (6262duodenum>stomach>liver); gene expression of , , and was age dependent as it was hardly detectable at day 7, increased drastically at day 30, and significantly decreased at day 90; the levels of pancreatic proteins displayed similar age-dependent variations. Using dual-labeled immunofluorescence, , , and were abundantly expressed in most acinar cells of the pancreas, in contrast to INGAP which exhibited stepwise increases from day 7 to day 90 and colocalized with the αα-cells. These new genes were mainly expressed in the pancreas, with clear age-dependent and isoform-specific patterns.
GIGOUXV,CLERCP,SANCHEZD,et al.Reg genes are CCK2 receptor targets in ElasCCK2 mice pancreas[J].Regul Pept,2008,146(1-3):88-98.
We previously demonstrated that expression of the gastrin receptor, CCK2R, in pancreatic acini of transgenic ElasCCK2 mice induced alteration of acinar morphology and differentiation, increased sensitivity to a carcinogen and development of preneoplastic lesions and tumours. Reg proteins are suggested to be involved in pancreatic cancer and in regeneration of endocrine pancreas. Reg I gene is a known target of gastrin. We examined whether an expression of CCK2R in the pancreatic acini of ElasCCK2 mice is linked to induction of Reg proteins expression. We analyzed Reg expression by Western-blot and immunohistochemistry in pancreas from ElasCCK2 and control mice. Islet neogenesis, glucose homeostasis, insulin secretion and content were also evaluated. Reg I is exclusively produced in acini in ElasCCK2 and control mice. In tumoral pancreas, Reg I and Reg III proteins are expressed in duct-like cells in preneoplastic lesions or in the periphery of tumours and in adjacent acini. The expression of Reg III proteins is increased in ElasCCK2 pancreas before the development of preneoplastic lesions in a subpopulation of islet cells and in small islet-like cell clusters dispersed within the acinar tissue. Several criteria of an enhanced neogenesis are fulfilled in ElasCCK2 pancreas. Moreover, ElasCCK2 mice have an improved response to glucose load, an increased insulin secretion and a doubling of insulin content compared to control mice. We show that Reg proteins are targets of CCK2R activation and are induced during early steps of carcinogenesis in ElasCCK2 mice pancreas. Alterations of exocrine tissue homeostasis in ElasCCK2 pancreas concomitantly activate regenerative responses of the endocrine pancreas possibly linked to paracrine actions of Reg III proteins.
YANGJ,LIL,RAPTISD,et al.Pancreatic stone protein/regenerating protein(PSP/reg):a novel secreted protein up-regulated in type 2 diabetes mellitus[J].Endocrine,2015,48(3):856-862.
Type 2 diabetes mellitus (T2DM) has insulin resistance (IR) or reduced -cell mass, partially due to an increased -cell apoptosis rate. Pancreatic stone protein/regenerating protein (PSP/reg) is a secretory protein produced in the pancreas and up-regulated dramatically during pancreatic disease. Recent studies revealed that -cells undergoing apoptosis induce PSP/reg expression in surviving neighboring cells. Further experiments demonstrated that PSP/reg was elevated during disease progression in type 1 diabetes mellitus (T1DM). However, the association between PSP/reg and T2DM patients is unknown. The aim of this pilot study was to investigate PSP/reg in different clinical stages of T2DM and evaluate its correlation with chronic complications of diabetes. A total of 1,121 participants (479 males, 642 females; age range 23-80years) were enrolled in this study. PSP/reg serum values were measured by a newly developed enzyme-linked immunosorbent assay (ELISA). We analyzed its correlation with clinical and biochemical parameters in subjects with T2DM at different clinical phases. Statistical analyses were conducted using SPSS 17.0 software. Correlations of PSP/reg and clinical parameters were performed using Spearman's rank correlation coefficient. Differences between groups were determined by Nemenyi test. PSP/reg was elevated in high-risk and impaired glucose regulation (IGR) patients (p<0.05). PSP/reg was significantly up-regulated in newly diagnosed T2DM patients and long-term diabetes patients with complications (p<0.001). PSP/reg levels correlated with the duration of diabetes (p<0.001). The area under the curve (AUC) for presence of diabetes-onset and its chronic complications was 0.640 and 0.754, respectively. PSP/reg is significantly up-regulated in T2DM patients, and PSP/reg levels are related to the duration of diabetes. Therefore, PSP/reg might be useful as a predictor of T2DM and disease progression.
ZHENGY,VALDEZ PA,DANILENKO DM,et al.Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens[J].Nat Med,2008,14(3):282-289.
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TERAZONOK,YAMAMOTOH,TAKASAWAS,et al.A novel gene activated in regenerating islets[J].J Biol Chem,1988,263(5):2111-2114.
Administration of poly(ADP-ribose) synthetase inhibitors such as nicotinamide to 90% depancreatized rats induces regeneration of pancreatic islets, thereby ameliorating the surgical diabetes (Yonemura, Y., Takashima, T., Miwa, K., Miyazaki, I., Yamamoto, H., and Okamoto, H. (1984) Diabetes 33, 401-404). In screening the regenerating islet-derived cDNA library, we came across a novel gene encoding a 165-amino acid protein. The gene was expressed in regenerating islets but not in normal pancreatic islets, insulinomas, or regenerating liver. In 90% depancreatized and nicotinamide-injected rats, the expression of the gene was increased 1 month after the partial pancreatectomy and reached a peak 3 months after the operation. The increase in expression of the gene was temporally correlated with the increase in size of regenerating islets and the decrease in urinary glucose level. The gene was also found to be activated in hyperplastic islets of aurothioglucose-treated mice. Thus, the expression of the gene in both regenerating and hyperplastic islets suggests possible roles for this gene in replication, growth, and maturation of islet beta-cells. We also found that a human pancreas-derived cDNA library contained a homologue to the gene.
HUANGJ,YANGY,YANGJ,et al.Regenerating gene family member 4 promotes growth and migration of gastric cancer through protein kinase B pathway[J].Int J Clin Exp Med,2014,7(9):3037-3044.
Regenerating gene family member 4 (REG4), a secreted protein, is overexpressed in several cancers, including gastric cancer. The present study was undertaken to determine the roles of REG4 in the growth of gastric cancer in the nude mice and in the proliferation and migration in human gastric cancer cell line and its downstream signaling pathway. Gastric cancer models were elicited by intraperitoneally injecting MKN45 human gastric cancer cells and the tumor size was measured every other day. The expressions of REG4 mRNA and protein were increased in the gastric cancer tissues from gastric cancer patients. REG4 increased the gastric tumor weight and size in the nude mice, and promoted the proliferation and migration of gastric cancer cells MKN45. Adeno-associated viral (AAV)-mediated knockdown of REG4 decreased the gastric tumor weight and size in the nude mice, and suppressed the proliferation and migration of MKN45 cells. REG4 increased the expression of phosphorylated protein kinase B (Akt). Triciribine hydrate (TCN), the inhibitor of Akt, decreased the gastric tumor weight and size in the nude mice and abolished REG4-induced weight and size increase of the tumor. TCN also inhibited proliferation and migration and abolished REG4-induced proliferation and migration increase of human gastric cell line MKN45. These results indicate that REG4 promotes the growth, proliferation and migration of gastric cancer through Akt pathway.
VANDERLAAGK,WANGW,FAYADAT-DILMANL,et al.Regenerating islet-derived family member,4 modulates multiple receptor tyrosine kinases and mediators of drug resistance in cancer[J].Int J Cancer,2012,130(6):1251-1263.
Regenerating islet-derived family member, 4 (Reg IV) is a secreted protein and member of the C-type lectin superfamily. Expression analyses have characterized Reg IV as a prognostic marker for certain cancers; however, the functional role of Reg IV in cancer, including downstream signaling, has only begun to be elucidated. To investigate the biological role of Reg IV in cancer, phosphorylation events were studied in cancer cell lines in the context of either Reg IV stimulation (HCT116 cells) or knockdown of endogenous Reg IV (PC3 and KM12 cells). In addition to the previously observed impact on epidermal growth factor receptor and Akt phosphorylation, we observed modulation in the phosphorylation of multiple additional receptor tyrosine kinases (RTKs), including insulin receptor, insulin-like growth factor receptor as well as their downstream effectors, mitogen-activated protein kinase and phosphatidylinositol-3-kinase pathways. Furthermore, knockdown of Reg IV impacted the ability of insulin and EGF to stimulate downstream tyrosine phosphorylation. Knockdown of Reg IV in cancer cell lines inhibited anchorage-dependent and anchorage-independent (both soft-agar and spheroid assays) cell growth and induced cell cycle arrest. This was accompanied by upregulation of p21 and p27. Transiently silencing Reg IV in cancer cells induced apoptosis and downregulated Bcl-2. Conversely, stimulation of HCT116 cells with recombinant Reg IV induced Bcl-2. Hsp27, a molecule implicated in drug resistance, was similarly modulated by Reg IV. Consistent with our observations with Reg IV siRNA-mediated knockdown, monoclonal antibodies directed against Reg IV inhibited PC3 and KM12 cell growth. Collectively, Reg IV plays an important role in cancer by modulation of key signaling molecules including Hsp27, Bcl-2 and multiple RTKs.
NAMIKAWAK,FUKUSHIMAM,MURAKAMK,et al.Expression of Reg/PAP family members during motor nerve regeneration in rat[J].Biochem Biophys Res Commun,2005,332(1):126-134.
In this study, we examined the expression of mRNAs for Regenerating gene (Reg)/pancreatitis-associated protein (PAP) family members following hypoglossal nerve injury in rats. In addition to four rat family members (RegI, Reg-2/PAP I, PAP II, and PAP III) that had been identified, we newly cloned and sequenced a type-IV Reg gene in rats. Among these five family members, the expression of Reg-2/PAP I mRNA was predominantly enhanced in injured motor neurons after axotomy. Furthermore, a marked induction of PAP III mRNA was observed in the distal part of the injured nerve. A polyclonal antibody was raised against PAP III, and a Western blotting analysis using this antibody confirmed an increased level of PAP III protein in the injured nerve. These results suggest that Reg family members would be new mediators among injured neurons and glial cells, and may play pivotal roles during nerve regeneration.
NATAK,LIUY,XUL,et al.Molecular cloning,expression and chromosomal localization of a novel human REG family gene,REG Ⅲ[J].Gene,2004,340(1):161-170.
Regenerating gene ( Reg ), first isolated from a regenerating islet cDNA library [J. Biol. Chem. 263 (1988) 2111], encodes a secretory protein with a growth stimulating effect on pancreatic β cells that ameliorates the diabetes of 90% depancreatized rats [Proc. Natl. Acad. Sci. USA 91 (1994) 3589] and non-obese diabetic mice [Diabetes 51(Suppl. 3) (2002) S478]. Reg and Reg -related genes have been revealed to constitute a multigene family, the Reg family, which consists of four subtypes (types I, II, III, IV) based on the primary structures of the encoded proteins of the genes [Diabetes 51(Suppl. 3) (2002) S462]. Plural type III Reg genes were found in mouse and rat. On the other hand, only one type III REG gene, HIP/PAP (gene expressed in hepatocellular carcinoma-intestine-pancreas/gene encoding pancreatitis-associated protein), was found in human. In the present study, we found a novel human type III REG gene, REG III . This gene is divided into six exons spanning about 3 kilobase pairs (kb), and encodes a 175 amino acid (aa) protein with 85% homology with HIP/PAP. REG III was expressed predominantly in pancreas and testis, but not in small intestine, whereas HIP/PAP was expressed strongly in pancreas and small intestine. IL-6 responsive elements existed in the 5′-upstream region of the human REG III gene indicating that the human REG III gene might be induced during acute pancreatitis. All the human REG family genes identified so far ( REG Iα , REG Iβ , HIP/PAP , REG III and REG IV ) have a common gene structure with 6 exons and 5 introns, and encode homologous 158–175-aa secretory proteins. By database searching and PCR analysis using a yeast artificial chromosome clone, the human REG family genes on chromosome 2, except for REG IV on chromosome 1, were mapped to a contiguous 140 kb region of the human chromosome 2p12. The gene order from centromere to telomere was 5′ HIP/PAP 3′-5′ RS 3′-3′ REG Iα 5′-5′ REG Iβ 3′-3′ REG III 5′. These results suggest that the human REG gene family is constituted from an ancestor gene by gene duplication and forms a gene cluster on the region.
GRANLUNDA,BEISVAGV,TORP SH,et al.Activation of REG family proteins in colitis[J].Scand J Gastroentero,2011,46(11):1316-1323.
To do a genome-wide gene expression study of active and inactive ulcerative colitis and Crohn's disease (inflammatory bowel disease--IBD) and examine the most differentially expressed genes. As the study showed an extreme upregulation of all regenerating islet-derived genes (REG proteins) in active IBD, we further studied the expression of REGs on protein level in active and inactive IBD, as well as in non-IBD (pseudomembranous) colitis.Microarray analysis was done on a total of 100 pinch biopsy samples from healthy controls and patients with Crohn's disease or ulcerative colitis. Tissue samples from IBD and pseudomembranous colitis were examined with routine histology and immunohistochemical analysis for REGI伪, REGIV, DEFA6, and serotonin.REG mRNAs were up to 83 times overexpressed in diseased mucosa compared with mucosa from healthy individuals. REGI伪 and REGIV were overexpressed at immunohistochemistry and located to different mucosal cell types. REGI伪 was expressed in basal half of crypts, REGIV in mid and outer parts of crypts and in surface epithelium and seems to be stored in, and secreted from, goblets. Pseudomembranous colitis samples showed similar staining patterns, and some IBD samples stained REG positive without inflammation on routine histology.All REG family mRNAs are upregulated in IBD. REGI伪 and REGIV have different cellular localization, possibly reflecting different biological functions. REG protein expression also in pseudomembranous colitis shows that REG family proteins are regulated in inflammatory injury and repair, not specifically for IBD as previously thought.
DUSETTI NJ,FRIGETIO JM,FOX MF,et al.Molecular cloning,genomic organization,and chromosomal localization of the human pancreatitis-associated protein(PAP) gene[J].Genomics,1994,19(1):108-114.
Abstract Pancreatitis-associated protein (PAP) is a secretory pancreatic protein present in small amounts in normal pancreas and overexpressed during the acute phase of the pancreatitis. In this paper, we describe the cloning, characterization, and chromosomal mapping of the human PAP gene. The gene spans 2748 bp and contains six exons interrupted by five introns. The gene has a typical promoter containing the sequences TATAAA and CCAAT 28 and 52 bp upstream of the cap site, respectively. We found striking similarities in genomic organization as well as in the promoter sequences between the human and rat PAP genes. The human PAP gene was mapped to chromosome 2p12 using rodent-human hybrid cells and in situ chromosomal hybridization. This localization coincides with that of the reg/lithostathine gene, which encodes a pancreatic secretory protein structurally related to PAP, suggesting that both genes derived from the same ancestral gene by duplication.
SAKKINENH,AROJ,KAIKKONENL,et al.Mitogen-activated protein kinase p38 target regenerating islet-derived 3 gamma expression is upregulated in cardiac inflammatory response in the rat heart[J].Physiological Reports,2016,4(20):1-12
Regenerating islet‐derived 3γ(Reg3γ) is a multifunctional protein, associated with various tissue injuries and inflammatory states. Since chronic inflammation is characteristics also for heart failure, the aim of this study was to characterize Reg3γexpression in cardiac inflammatory conditions. Reg3γexpression was studied in experimental rat models of myocardial infarction (MI) and pressure overload in02vivo. For cell culture studies neonatal rat cardiac myocytes (NRCMs) were used. In addition, adenovirus‐mediated gene transfer of upstream mitogen‐activated protein kinase (MAPK) kinase 3b and p38αMAPKin02vivo and in02vitro was performed. Reg3γmRNA(12.8‐fold,P<020.01) and protein (5.8‐fold,P<020.001) levels were upregulated during the postinfarction remodeling at day 1 afterMI, and angiotensin II (AngII) markedly increased Reg3γmRNAlevels from 602h to 202weeks. Immunohistochemistry revealed that the AngII‐induced expression of Reg3γwas localized into the cardiac fibroblasts and myofibroblasts of the proliferating connective tissue in the heart. Stretching and treatments with endothelin‐1, lipopolysaccharide (LPS), and fibroblast growth factor‐1 increased Reg3γmRNAlevels inNRCMs.SB203580, a selective p38MAPKinhibitor, markedly attenuatedLPSand mechanical stretch‐induced upregulation of Reg3γgene expression. Moreover, combined overexpression ofMKK3bE andWTp38αincreased Reg3γgene expression in cultured cardiomyocytes in02vitro and in the rat heart in02vivo. Our study shows that cardiac stress activates Reg3γexpression and p38MAPKis an upstream regulator of Reg3γgene expression in heart. Altogether our data suggest Reg3γis associated with cardiac inflammatory signaling.
ZHANGB,LUY,CAMPBELL-THOMPSONM,et al.Alpha 1-antitrypsin protects beta-cells from apoptosis[J].Diabetes,2007,56(5):1316-1323.
Beta-cell appears to represent a key event in the of . Previous studies have demonstrated that administration of the () prevents in and prolongs islet allograft survival in ; yet the mechanisms underlying this therapeutic benefit remain largely unclear. Herein we describe novel findings indicating that significantly reduces cytokine- and ()-induced beta-cell . Specifically, strong antiapoptotic activities for (Prolastin, ) were observed when cells (MIN6) were exposed to -alpha. In a second model system involving -induced beta-cell , treatment of MIN6 cells with similarly induced a significant increase in cellular viability and a reduction in . Importantly, in both model systems, treatment with completely abolished induced caspase-3 activity. In terms of its activities in vivo, treatment of C57BL/6 with prevented -induced and, in agreement with the in vitro analyses, supported the concept of a mechanism involving the disruption of beta-cell . These results propose a novel biological function for this molecule and suggest it may represent an effective candidate for attempts seeking to prevent or reverse .
XIAF,CAOH,DUJ,et al.Reg3 goverexpression promotes beta cell regeneration and induces immune tolerance in nonobese-diabetic mouse model[J].J Leukoc Biol,2016,99(6):1131-1140.
The regenerating islet-derived gene was first isolated in regenerated pancreas tissues, greatly contributing to β cell regeneration. It is an anti-inflammatory in response to cellular stress. This encouraged us to investigate the exact role of a novel member of Reg family, regenerating islet-derived gene γ, in type 1 diabetes of nonobese-diabetic mice. For this, Reg3g gene was overexpressed in pancreatic islets, and conferred beneficial effects on β cell regeneration through activating the Janus kinase 2/signal transducer and activator of transcription 3/nuclear factor κB signaling pathway. Lentiviral vector-encoding regenerating islet-derived gene γ treatment also decreased lymphocyte infiltrates of the intra-islet and peri-islet by inducing both differentiation of regulatory T cell and immature dendritic cells of tolerogenic properties, which attenuated autoimmunity. This treatment further contributed to rebalanced levels of type 1/2 helper T cell cytokines and elevated α1-antitrypsin levels in the serum. These results were not observed in phosphate-buffered saline-treated mice or in lentivirus-control mice. We have shown, for the first time, to our knowledge, that regenerating islet-derived gene γ promotes β cell regeneration and preserves β cells from autoimmunity damage by increasing regulatory T cell differentiation and inducing tolerated dendritic cells. This regenerating islet-derived gene γ infusion could probably be developed into an optimal gene therapy for the prevention and reversal of type 1 diabetes.
WANGJ,ZHOUH,HANY,et al.SOCS 3 methylation in synergy with Reg3 A overexpression promotes cell growth in pancreatic cancer[J].J Mol Med(Berl),2014,92(12):1257-1269.
Abstract Pancreatic cancer (PaC) is the fifth leading cause of cancer death in the world, but the molecular mechanisms for its development remain unclear. Regenerating islet-derived protein 3-alpha (Reg3A) has been reported overexpressed in pancreatic inflammation and associated with PaC malignancies, thus believed as a potential target in inflammation-linked pancreatic carcinogenesis. Silencing of suppressor of cytokine signaling SOCS3, a well-known feedback inhibitor of cell proliferation, has been found in many human cancers. Here, we identified that SOCS3 was aberrantly methylated in its CpG island in 3/5 human PaC cell lines and 11/36 cancer tissue samples. SOCS3 restoration by a demethylating agent, 5-aza-2 -deoxycytidine, remarkably suppressed cell proliferation and induced apoptosis of methylated PaC cells. Moreover, we also have shown that Reg3A was highly expressed in PaC cells and tissue samples. Assessment of potential relationship between SOCS3 and Reg3A aberrations in vitro revealed that SOCS3 worked downstream of Reg3A and modulated Reg3A-linked pro-tumor functions. siRNA -mediated SOCS3 knock-down in normal pancreatic epithelial cells and plasmid-transfected SOCS3 overexpression in PaC cells, respectively, resulted in the obvious promotion and inhibition of Reg3A-induced cell proliferation, thereby suggesting SOCS3 negatively regulating Reg3A-mediated PaC progression. In addition, our findings also revealed that JAK/ STAT3 / NF- B appear involved in the effect of SOCS3-Reg3A interaction on pancreatic cell growth. In summary, SOCS3 inactivation by methylation was demonstrated to act in synergy with Reg3A overexpression to promote PaC cell growth and maybe the progress of inflammation-linked pancreatic carcinogenesis. Key messages Reg3A overexpression promoted cell growth in pancreatic cancer. SOCS3 is a key target in cancer by inhibiting cell growth and inducing apoptosis. SOCS3 negatively regulated Reg3A-mediated cell growth in pancreatic cancer. SOCS3 methylation act in synergy with Reg3A overexpression to promote pancreatic cancer cell growth.
CUIW,DEJESUSK,ZHAOH,et al.Overexpression of Reg3 alpha increases cell growth and the levels of cyclin D1 and CDK4 in insulinoma cells[J].Growth Factors,2009,27(3):195-202.
Regenerating gene (Reg) family protein Reg3alpha is normally expressed in pancreatic acinar and endocrine cells. In order to explore its effect on islet beta-cell replication, insulinoma MIN6 cells were stably transfected with murine Reg3alpha cDNA. Determined using real-time PCR and Western blots, the levels of Reg3alpha mRNA and protein in Reg3alpha-transfected clones were increased 10- and 6-fold, respectively. Western blots also revealed that the protein was released into the culture medium, consistent with an endocrine effect. In MTT cell proliferation assay, Reg3alpha-overexpressing cells exhibited a 2-fold increase in the rate of cell growth. In order to investigate the intracellular mechanism, we studied cell cycle regulatory proteins. In Reg3alpha-expressing cells, we detected 2.2- and 2.5-fold increased levels of cyclin D1 and CDK4, respectively, which paralleled a 1.8-fold increase in the rate of Akt phosphorylation. It is established that beta-cell replication is associated with increased cyclin D1 and CDK4 levels; deficiency in CDK4 or cyclin D2 results in reduced beta-cell mass and diabetes. Our results suggest that Reg3alpha stimulates beta-cell replication, by activating Akt kinase and increasing the levels of cyclin D1/CDK4.
SUMIDAM,OHTAS,ATSUMIS,et al.Geographic variability in expression of the sex-linked AAT-1 gene of the bell-ring frog,Buergeria buergeri[J].J EXP Zool B Mol Dev Evol,2004,302(2):182-194.
Cytological observation and artificial crossing experiments were used to examine the geographic differences in the sex-determining mechanism and mode of inheritance of the sex-linked AAT-1 gene in the bell-ring frog, Buergeria buergeri. The AAT-1 phenotypes were also examined by allozyme analysis using field-caught females and males collected from 19 populations from the Honshu, Shikoku, and Kyushu islands of Japan, in order to comprehensively elucidate the geographic variability in the expression of the sex-linked AAT-1 gene of B. buergeri. The results showed that the Aomori population of B. buergeri from the northern end of Honshu was female heterogametic in sex determination, that chromosome No. VII was a sex chromosome of the ZZ/ZW type, and that the sex-linked AAT-1 gene was expressed on both the Z and W chromosomes. This mode of AAT-1 expression in the Aomori population was different from that in the Hiroshima population from western Honshu, in which the AAT-1 gene was expressed on the Z chromosome but not on the W chromosome. The results also showed that there was no differentiation among populations in the expression of the AAT-1 genes on the Z chromosome, whereas two populations, the Hiroshima and Aomori frogs, exhibited distinct modes of expression of the AAT-1 gene on the W chromosome. These two modes of expression may be widely distributed in western and eastern Japan, and coexist in the central part of Honshu.
YEJ,LIAO YT,JIAN YQ,et al.Alpha-1-antitrypsin for the improvement of autoimmunity and allograft rejection in beta cell transplantation[J].Immunol Lett,2013,150(1-2):61-68.
Islet transplantation offers hope for patients with type 1 diabetes, which is an autoimmune disease. However, islet transplant recipients must overcome two obstacles in both allograft rejection and autoimmune reaction. Alpha-1-antitrypsin (a1-proteinase inhibitor, AAT) possesses anti-inflammatory properties, reduces cytokine-mediated islet damage, and induces specific immune tolerance. In this study, an insulinoma cell line, NIT-1, was transfected with human AAT (hAAT), named NIT-hAAT, and was transplanted to the left renal subcapsular spaces of 7-week-old female non-obese diabetic (NOD) mice (n=22). Cyclophosphamide(CY) was administered to synchronize and accelerate the development of diabetes. Thus, the immunosuppressive and cytoprotective activity of hAAT in -cell transplantation was investigated. NIT-hAAT has immunomodulatory properties, which delay the onset of autoimmune diabetes, reduce diabetes incidence, inhibit insulitis and -cell apoptosis, and dampen transplant site inflammation. We propose that NIT-hAAT has a dual function by improving islet autoimmunity and protecting transplanted -cells from allograft rejection. However, the low expression of hAAT in vivo results in the inability of NIT-hAAT to induce long-term specific immune tolerance and to completely block allograft rejection.
YAMAUCHIA,ITAYA-HIRONAKAA,SAKURAMOTO-TSUCHIDAS,et al.Synergistic activations of REG I alpha and REG I beta promoters by IL-6 and glucocorticoids through JAK/STAT pathway in human pancreatic beta cells[J].J Diabetes Res,2015,2015:173058.
ABSTRACT Reg (Regenerating gene) gene was originally isolated from rat regenerating islets and its encoding protein was revealed as an autocrine/paracrine growth factor for β cells. Rat Reg gene is activated in inflammatory conditions for β cell regeneration. In human, although five functional REG family genes (REG Iα, REG Iβ, REG III, HIP/PAP, and REG IV) were isolated, their expressions in β cells under inflammatory conditions remained unclear. In this study, we found that combined addition of IL-6 and dexamethasone (Dx) induced REG Iα and REG Iβ expression in human 1.1B4 β cells. Promoter assay revealed that a signal transducer and activator of transcription- (STAT-) binding site in each promoter of REG Iα (TGCCGGGAA) and REG Iβ (TGCCAGGAA) was essential for the IL-6+Dx-induced promoter activation. A Janus kinase 2 (JAK2) inhibitor significantly inhibited the IL-6+Dx-induced REG Iα and REG Iβ transcription. Electrophoretic mobility shift assay and chromatin immunoprecipitation revealed that IL-6+Dx stimulation increased STAT3 binding to the REG Iα promoter. Furthermore, small interfering RNA-mediated targeting of STAT3 blocked the IL-6+Dx-induced expression of REG Iα and REG Iβ. These results indicate that the expression of REG Iα and REG Iβ should be upregulated in human β cells under inflammatory conditions through the JAK/STAT pathway.
DORON-MANDELE,FAINZILBERM,TERENZIOM.Growth control mechanisms in neuronal regeneration[J].FEBS Lett,2015,589(14):1669-1677.
Neurons grow during development and extend long axons to make contact with their targets with the help of an intrinsic program of axonal growth as well as a range of extrinsic cues and a permissive milieu . Injury events in adulthood induce some neuron types to revert to a regenerative state in the peripheral nervous system (PNS). Neurons from the central nervous system (CNS), however, reveal a much lower capacity for regenerative growth. A number of intrinsic regeneration-promoting mechanisms have been described, including priming by calcium waves, epigenetic modifications, local mRNA translation, and dynein-driven retrograde transport of transcription factors (TFs) or signaling complexes that lead to TF activation and nuclear translocation. Differences in the availability or recruitment of these mechanisms may partially explain the limited response of CNS neurons to injury.
SIDDIQUET,AWAN FR.Effects of Reg3 delta bioactive peptide on blood glucose levels and pancreatic gene expression in an alloxan-induced mouse model of diabetes[J].Can J Diabetes,2016,40(3):198-203.
Abstract OBJECTIVE: The endocrine regeneration of the pancreas holds great potential for stable diabetes therapy. The Regeneration (Reg) family of proteins has been associated with pancreas regeneration. Hence, the Reg3 delta bioactive peptide from a mouse was evaluated to see whether it can reverse hyperglycemia in a mouse model of diabetes with any effects on pancreatic gene expression. METHODS: In this study, we administrated the synthetic Reg3 delta bioactive peptide to healthy mice and to alloxan-induced mouse models of diabetes for 30 days, with weekly measurements of body weight and blood glucose levels. After 1 month, pancreatic gene profiling of these mice was performed for the Ngn-3, Pdx-1, MapK8, IGF-1, IGF2bp2, Reg3 beta and Reg3 delta genes. RESULTS: The glycemic levels in mice with diabetes were decreased significantly, restored almost to normal. Furthermore, the gene expression levels measured by quantitative polymerase chain reaction (qPCR) showed that messenger RNA (mRNA) levels of 2 important transcription factors (Ngn-3 and Pdx-1) were increased during the Reg3 delta peptide treatment. CONCLUSIONS: This study shows that Reg3 delta has the potential to reverse hyperglycemia by modulating gene expression in pancreatic endocrine precursor markers Pdx-1 and Ngn-3, which require further investigation at the protein and immunohistology levels. Copyright 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.
LIY,DE HAARC,CHENM,et al.Disease-related expression of the IL6/STAT3/SOCS3 signalling pathway in ulcerative colitis and ulcerative colitis-related carcinogenesis[J].Gut,2010,59(2):227-235.
BACKGROUND: models have shown that interleukin (IL)6 stimulates survival, proliferation and progression to of intestinal epithelial cells via activation of signal transducers and activators of 3 ().: To investigate the expression of /phosphorylated (p-)/suppressor of cytokine signalling 3 () in biopsy specimens from patients with (UC) and UC-related () progression.: Biopsy specimens from patients with inactive UC (n=18), active UC (n=28), UC with (LGD) (n=9), UC with () (n=7), UC-(n=11) and sporadic (n=14) were included. Biopsy specimens (n=9) from patients without colonic abnormalities served as control. The protein expression of , p-and was determined immunohistochemically.: Patients with active UC had significantly more and p--positive epithelial cells than both patients with inactive UC and controls (strong positive : 53.6%, 11.1% and 0%, respectively; p-: 64.3%, 22.2% and 11.1%, respectively; all p<or=0.012). -positive cells were significantly increased in colonic epithelium of both inactive and active UC compared with controls (strong positive: 94.4%, 96.4% and 11.1%, respectively; both p<0.001). In and , significantly more epithelial cells expressed and p-compared with controls (strong positive : 72.7% and 0% respectively; p-: 54.5% and 11.1%, respectively; both p<0.05), whereas the proportion of -positive cells in this progression reduced (LGD 33.3%; 14.3%; UC-9.1%). In addition, methylation of the gene was detected in epithelial cells from UC-biopsy specimens.: The importance of /p-in patients with inflammation-induced was demonstrated. Moreover, may be involved in UC and the absence of seems critical for progression.
LIN YC,LIN CK,TSAI YH,et al.Adenovirus-mediated SOCS3 gene transfer inhibits the growth and enhances the radiosensitivity of human non-small cell lung cancer cells[J].Oncol Rep,2010,24(6):1605-1612.
The Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway is one of the most important components of cytokine signaling cascades. JAK-STAT signaling pathway modulates various fundamental biological processes and cancer pathogenesis. JAK-STAT is controlled by negative regulators that include suppressors of cytokine signaling (SOCS) proteins. Failure of feedback suppression by SOCS proteins may result in activated JAK-STAT signaling. Methylation-mediated silencing of SOCS3 has been reported in non-small lung cancer (NSCLC) and other human cancers. In this study, we restored SOCS3 expression using adenovirus-mediated gene transfer in NSCLC cells. Infection with a SOCS3-expressing vector inhibited the growth of lung cancer cells, with or without SOCS3 expression, at 2-3 days after infection. The growth inhibition of lung cancer cells was associated with suppressing entry into the S-phase. Restoration of SOCS3 expression induced apoptosis of NSCLC cells that did not express SOCS3. In addition, overexpression of SOCS3 by adenoviral transfer enhanced the radiosensitivity of treated NSCLC cells. In conclusion, our findings may provide insights into the development of applications of SOCS3 gene therapy for lung cancer and, possibly, other human cancers.
MOLAVIO,WANGP,ZAKZ,et al.Gene methylation and silencing of SOCS3 in mantle cell lymphoma[J].Br J Haematol,2013,161(3):348-356.
Summary Top of page Summary Design and methods Results Discussion Acknowledgements References The significance of loss of SOCS3, a negative regulator of signalling pathways including those of STAT3 and NF -κ B , was examined in mantle cell lymphoma (MCL). The protein expression and gene methylation status of SOCS3 were detected using immunohistochemistry/Western blots and methylation-specific polymerase chain reaction, respectively. To evaluate its functional importance, SOCS3 was restored in two SOCS3-negative MCL cell lines using a lentiviral vector. Loss of SOCS3 protein expression was found in 3/4 MCL cell lines and 18/33 (54·5%) tumours. SOCS3 was found consistently methylated in cell lines (3/4) and tumours (7/7) negative for SOCS3, and was unmethylated in all SOCS3-positive cell line (1/1) and tumours (5/5) examined. Treatment of all three SOCS3-negative cell lines with 2′-deoxy-5-azacytidine restored SOCS3 expression. SOCS3 is biologically important in MCL, as lentiviral transfer of SOCS3 in SOCS3-negative cell lines increased their apoptotic activity, downregulated nuclear factor (NF) -κ B-p65, cyclin D1 (CCND1), BCL2 and BCL-XL (BCL2L1), and substantially dampened interleukin 10-induced STAT3 activation. In 19 patients aged ≤69years at time of diagnosis, we found that those that carried SOCS3-negative tumours showed a trend toward a worse outcome ( P =0·1, log-rank).
GREER JB,WHITCOMB DC.Inflammation and pancreatic cancer:an evidence-based review[J].Curr Opin Pharmacol,2009,9(4):411-418.
There is a growing awareness that inflammation plays a contributory role in numerous pathologies, including pancreatic carcinogenesis. Inflammatory states are characterized by the creation of reactive oxygen species and the induction of cell cycling for tissue growth and repair. The initiation, promotion and expansion of tumors may be influenced by numerous components that function in the inflammatory response. Recognized risk factors for pancreatic cancer include cigarette smoking, chronic/hereditary pancreatitis, obesity and type II diabetes. Each risk factor is linked by the fact that the inflammatory state significantly drives its pathology. This article will outline how inflammatory mechanisms are etiologically linked to pancreatic adenocarcinoma.
DEER EL,GONZALEZ-HERNAADEZJ,COURSEN JD,et al.Phenotype and genotype of pancreatic cancer cell lines[J].Pancreas,2010,39(4):425-435.
The dismal prognosis of pancreatic adenocarcinoma is due in part to a lack of molecular information regarding disease development. Established cell lines remain a useful tool for investigating these molecular events. Here we present a review of available information on commonly used pancreatic adenocarcinoma cell lines as a resource to help investigators select the cell lines most appropriate for their particular research needs. Information on clinical history; in vitro and in vivo growth characteristics; phenotypic characteristics, such as adhesion, invasion, migration, and tumorigenesis; and genotypic status of commonly altered genes (KRAS, p53, p16, and SMAD4) was evaluated. Identification of both consensus and discrepant information in the literature suggests careful evaluation before selection of cell lines and attention be given to cell line authentication.
NAGARAJ NS,SMITH JJ,REVETTAF,et al.Targeted inhibition of SRC kinase signaling attenuates pancreatic tumorigenesis[J].Mol Cancer Ther,2010,9(8):2322-2332.
ABSTRACT Elevated Src expression correlates with malignant potential and metastatic disease in many tumors including pancreatic cancer. We sought to characterize the molecular effects of Src kinase inhibition with dasatinib (BMS-354825), a novel, multitargeted kinase inhibitor that targets Src family kinases in pancreatic ductal adenocarcinoma (PDA). We identified sensitive and resistant PDA cell lines to dasatinib treatment and tested the molecular effects of Src inhibition in vitro and in vivo. We show for the first time that cellular localization of Src expression affects survival in patients with PDA. Pancreatic tumors with increased membranous expression of Src resulted in decreased survival compared with tumors that had increased cytoplasmic Src expression. Src kinase inhibition with dasatinib markedly inhibits cell proliferation, migration, invasion, cell cycle progression and anchorage-independent growth, and stimulates apoptosis. This was accompanied by decreased phosphorylation of Src, focal adhesion kinase, paxillin, AKT, signal transducers and activators of transcription 3 (STAT3), extracellular signal-regulated kinase, and mitogen-activated protein kinase (MAPK), as well as decreased cyclin D1 expression in a time- and concentration-dependent manner. Furthermore, small interfering RNA to Src results in a significant decrease in cell proliferation, invasion, and migration of pancreatic cancer cells. Dasatinib treatment also inhibits in vivo pancreatic tumor growth. Mechanisms of resistance to Src inhibition seem to be related to a lack of inhibition of STAT3 and MAPK signaling. These results establish a mechanistic rationale for Src inhibition with dasatinib as a therapeutic target in the treatment of pancreatic cancer and identify potential biomarkers of resistance to Src inhibition.
LIUX,WANGJ,WANGH,et al.REG3A accelerates pancreatic cancer cell growth under IL-6-associated inflammatory condition:involvement of a REG3A-JAK2/STAT3 positive feedback loop[J].Cancer Lett,2015,362(1):45-60.
Regenerating gene protein (REG) 3A is a 1965kD secretory pancreas protein with pro-growth function. Previously we demonstrated that overexpression of REG3A, acting as a key molecule for up-regulation of the JAK2/STAT3 pathway, contributed to inflammation-related pancreatic cancer (PaC) development. However the exact network associated with REG3A signaling still remains unclear. Here we determined that exposure of human PaC cells to cytokine IL-6 activated the oncogenic JAK2/STAT3 pathway, which directly upregulated REG3A expression, accelerated cell cycle progression by promoting CyclinD1 expression, and enhancing the expression of the anti-apoptosis Bcl family. Importantly, the activation of REG3A would instead enhance the JAK2/STAT3 pathway to constitute a REG3A–JAK2/STAT3 positive feedback loop, which leads to the amplification of the oncogenic effects of IL-6/JAK2/STAT3, a classic pathway linking to inflammation-related tumorigenesis, ultimately resulting in PaC cell over-proliferation and tumor formation both in vitro and in vivo . Moreover, EGFR was found to mediate the REG3A signal for PaC cell growth and JAK2/STAT3 activation, thus functioning as a REG3A receptor. Collectively, our results provide the first evidence for the presence of the synergistic effect of REG3A and IL-6 on PaC development via a REG3A–JAK2/STAT3 positive feedback loop.
XUQ,FUR,YING,et al.Microarray-based gene expression profiling reveals genes and pathways involved in the oncogenic function of REG3A on pancreatic cancer cells[J].Gene,2016,578(2):263-273.
We previously reported that regenerating islet-derived protein 3 alpha (REG3A) exacerbates pancreatic malignancies. The mechanism of this effect has not been clearly elucidated. Here we first identified key differentially expressed genes (DEGs) and signal pathways in the pancreatic cancer cell line SW1990, compared to two control cell lines, by microarray analysis. We then identified key genes and pathways regulated by REG3A or the cytokine IL6 in SW1990 cells. Afterwards, these DEGs induced by REG3A or IL6 were subjected to KEGG pathway enrichment analysis and GO function analysis by the DAVID online tool. Ultimately, we constructed protein rotein interaction networks among the DEGs by Cytoscape. Among the three pancreatic cell lines, SW1990 exhibited highly deterioration with the activation of genes and pathways related to proliferation, survival, angiogenesis, and invasion. As a result, 50 DEGs enriched in 11 pathways were identified in REG3A-treated SW1990 cells, and 28 DEGs enriched in 9 pathways were detected in IL6-treated cells. Overall, results of microarray analysis followed by qRT-PCR and Western blotting suggest that REG3A regulates pancreatic cell growth by increasing the expression of at least 8 genes: JAK1 , STAT3 , IL10 , FOXM1 , KRAS , MYC , CyclinD1 , and c-fos ; and activation of at least 4 signal pathways: TGF , PDGF, angiogenesis and RAS. Similar results were obtained with IL6 treatment. Regulation network analysis confirmed the cell growth related DEGs, and further uncovered three transcription factor families with immune functions regulated by REG3A.
MANTOVANIA,SOZZANIS,LOCATIM,et al.Macrophage polarization:tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes[J].Trends Immunol,2002,23(11):549-555.
Mononuclear phagocytes are versatile cells that can express different functional programs in response to microenvironmental signals. Fully polarized M1 and M2 (or alternatively activated) macrophages are the extremes of a continuum of functional states. Macrophages that infiltrate tumor tissues are driven by tumor-derived and T cell-derived cytokines to acquire a polarized M2 phenotype. These functionally polarized cells, and similarly oriented or immature dendritic cells present in tumors, have a key role in subversion of adaptive immunity and in inflammatory circuits that promote tumor growth and progression.
CHINETTI-GBAGUIDIG,BARONM,BOUHLEL MA,et al.Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARgamma and LXRalpha pathways[J].Circ Res,2011,108(8):985-995.
A crucial step in atherogenesis is the infiltration of the subendothelial space of large arteries by monocytes where they differentiate into macrophages and transform into lipid-loaded foam cells. Macrophages are heterogeneous cells that adapt their response to environmental cytokines. Th1 cytokines promote monocyte differentiation into M1 macrophages, whereas Th2 cytokines trigger an "alternative" M2 phenotype. We previously reported the presence of CD68(+) mannose receptor (MR)(+) M2 macrophages in human atherosclerotic plaques. However, the function of these plaque CD68(+)MR(+) macrophages is still unknown. Histological analysis revealed that CD68(+)MR(+) macrophages locate far from the lipid core of the plaque and contain smaller lipid droplets compared to CD68(+)MR(-) macrophages. Interleukin (IL)-4-polarized CD68(+)MR(+) macrophages display a reduced capacity to handle and efflux cellular cholesterol because of low expression levels of the nuclear receptor liver x receptor (LXR) and its target genes, ABCA1 and apolipoprotein E, attributable to the high 15-lipoxygenase activity in CD68(+)MR(+) macrophages. By contrast, CD68(+)MR(+) macrophages highly express opsonins and receptors involved in phagocytosis, resulting in high phagocytic activity. In M2 macrophages, peroxisome proliferator-activated receptor (PPAR) activation enhances the phagocytic but not the cholesterol trafficking pathways. These data identify a distinct macrophage subpopulation with a low susceptibility to become foam cells but high phagocytic activity resulting from different regulatory activities of the PPAR -LXR pathways.
YING,DUJ,CAOH,et al.Reg3g promotes pancreatic carcinogenesis in a murine model of chronic pancreatitis[J].Dig Dis Sci,2015,60(12):3656-3668.
Regenerating islet-derived 3 (Reg3) is abnormally expressed in several human digestive system diseases, including chronic pancreatitis (CP) and pancreatic cancer (PC).The purpose of this study was to clarify the mechanism of the enhanced expression of Reg3 in inflammation-induced PC.C57BL/6 mice were treated with caerulein for 6weeks to induce CP and then injected with pReg3g-a lentivirus system encoding formurine Reg3g-accompanied by dimethylbenzanthracene to induce PC. We detected pancreatic histopathological characteristics, tumor-relatedgeneexpression, inflammation-associated pathway activation, serum biochemical indicators, and immunological cell activities.The mice that developed CP after caerulein treatment were marked by pronounced histologic lesions, elevated serum amylase levels, and activation of inflammation-related pathways. Mice given a high dose of pReg3g developed PC by 16weeks, with recognizable tumors in the pancreas. While, both the low and high doses of pReg3g produced higher transcription of c-fos, k-ras, cytokeratin-19, and proliferating cell nuclear antigen, and a lower expression of caspase-3 compared to pNEG controls. Additionally, the higher dose of pReg3g increased the expressions of pSTAT3, NF B (p65), and SOCS3 methylation during PC development.In addition, mice treated with pReg3g displayed higher levels of serum IL10 and TGF and suppressed T lymphocyte proliferation and DC function.The comprehensive analysis suggests enhanced Reg3g expression exacerbates PC in inflammation-associated cancer progression. Reg3g appears to promote CP-related PC in mice through multiple mechanisms, involving enhancedtranscription of pancreatic tumor markers,repression of anti-tumor immunity, and activation of STAT3/p65 signal transduction pathways.
HIROOKAY,ITOHA,KAWASHIMAH,et al.A combination therapy of gemcitabine with immunotherapy for patients with inoperable locally advanced pancreatic cancer[J].Pancreas,2009,38(3):69-74.
Dendritic cell (DC) therapy frequently induces a measurable immune response. However clinical responses are seen in a minority of patients, presumably due to insufficient expansion of antigen-specific cytotoxic T lymphocytes (CTLs) capable of eradicating tumor cells. To increase therapeutic efficacy of DC-based vaccination, we have undertaken the first clinical trial involving a combination therapy of gemcitabine (GEM) with immunotherapy for patients with inoperable locally advanced pancreatic cancer.Patients (n = 5) received the treatment course, which consisted of intravenous GEM administration at 1000 mg/m (day 1) and the endoscopic ultrasound-guided fine-needle injection of OK432-pulsed DCs into a tumor, followed by intravenous infusion of lymphokine-activated killer cells stimulated with anti-CD3 monoclonal antibody (CD3-LAKs) (day 4), at 2-week intervals.No serious treatment-related adverse events were observed during the study period. Three of the 5 patients demonstrated effective responses to this clinical trial; 1 had partial remission and 2 had long stable disease more than 6 months. In the patient with partial remission, it has been shown that DC-based vaccination combined with GEM administration induces tumor antigen-specific CTLs.This combined therapy was considered to be synergistically effective and may have a role in the therapy of pancreatic cancer for inducing tumor antigen-specific CTLs.
PATERSONY.Rational approaches to immune regulation[J].Immunol Res,2003,27(2-3):451-462.
Our studies are mainly focused on developing strategies of immune regulation. In the case of infectious and neoplastic disease, our approach is to upregulate cell-mediated immunity to viral of tumor antigens using an intracellular bacterium as a vector for targeting these antigens to the major histocompatibility complex (MHC) class I and class II pathways of antigen processing, in addition to exploiting the adjuvant properties of the vector to stimulate innate immunity. In the area of autoimmunity, we are attempting to downregulate the immune response by specific immune intervention directed against autoreactive T cells. In these studies we use murine models for multiple sclerosis. Our approach is to use both rationally designed T cell receptor (TCR) peptide analogs and recombinant viral vectors that express TCR components to regulate the disease.
MAY,ADJEMIANS,MATTAROLLO SR,et al.Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells[J].Immunity,2013,38(4):729-741.
The therapeutic efficacy of anthracyclines relies on antitumor immune responses elicited by dying cancer cells. How chemotherapy-induced cell death leads to efficient antigen presentation to T cells, however, remains a conundrum. We found that intra-tumoral CD11c(+)CD11b(+)Ly6C(hi) cells, which displayed some characteristics of inflammatory dendritic cells and included granulomonocytic precursors, were crucial for anthracycline-induced anticancer immune responses. ATP released by dying cancer cells recruited myeloid cells into tumors and stimulated the local differentiation of CD11c(+)CD11b(+)Ly6C(hi) cells. Such cells efficiently engulfed tumor antigens in situ and presented them to T lymphocytes, thus vaccinating mice, upon adoptive transfer, against a challenge with cancer cells. Manipulations preventing tumor infiltration by CD11c(+)CD11b(+)Ly6C(hi) cells, such as the local overexpression of ectonucleotidases, the blockade of purinergic receptors, or the neutralization of CD11b, abolished the immune system-dependent antitumor activity of anthracyclines. Our results identify a subset of tumor-infiltrating leukocytes as therapy-relevant antigen-presenting cells.
CASH HL,WHITHAM CV,BEHRENDTCL,et al.Symbiotic bacteria direct expression of an intestinal bactericidal lectin[J].Science,2006,313(5790):1126-1130.
The mammalian intestine harbors complex societies of beneficial bacteria that are maintained in the lumen with minimal penetration of mucosal surfaces. Microbial colonization of germ-free mice triggers epithelial expression of RegIIIgamma, a secreted C-type lectin. RegIIIgamma binds intestinal bacteria but lacks the complement recruitment domains present in other microbe-binding mammalian C-type lectins. We show that RegIIIgamma and its human counterpart, HIP/PAP, are directly antimicrobial proteins that bind their bacterial targets via interactions with peptidoglycan carbohydrate. We propose that these proteins represent an evolutionarily primitive form of lectin-mediated innate immunity, and that they reveal intestinal strategies for maintaining symbiotic host-microbial relationships.
MUKHERJEES,PARTCH CL,LEHOTZKY RE,et al.Regulation of C-type lectin antimicrobial activity by a flexible N-terminal prosegment[J].J Biol Chem,2009,284(8):4881-4888.
Members of the RegIII family of intestinal C-type lectins are directly antibacterial proteins that play a vital role in maintaining host-bacterial homeostasis in the mammalian gut, yet little is known about the mechanisms that regulate their biological activity. Here we show that the antibacterial activities of mouse RegIIIgamma and its human ortholog, HIP/PAP, are tightly controlled by an inhibitory N-terminal prosegment that is removed by trypsin in vivo. NMR spectroscopy revealed a high degree of conformational flexibility in the HIP/PAP inhibitory prosegment, and mutation of either acidic prosegment residues or basic core protein residues disrupted prosegment inhibitory activity. NMR analyses of pro-HIP/PAP variants revealed distinctive colinear backbone amide chemical shift changes that correlated with antibacterial activity, suggesting that prosegment-HIP/PAP interactions are linked to a two-state conformational switch between biologically active and inactive protein states. These findings reveal a novel regulatory mechanism governing C-type lectin biological function and yield new insight into the control of intestinal innate immunity.
LEHOTZKY RE,PARTCH CL,MUKHERJEES,et al.Molecular basis for peptidoglycan recognition by a bactericidal lectin[J].Proc Natl Acad Sci U S A,2010,107(17):7722-7727.
RegIII proteins are secreted C-type lectins that kill Gram-positive bacteria and play a vital role in antimicrobial protection of the mammalian gut. RegIII proteins bind their bacterial targets via interactions with cell wall peptidoglycan but lack the canonical sequences that support calcium-dependent carbohydrate binding in other C-type lectins. Here, we use NMR spectroscopy to determine the molecular basis for peptidoglycan recognition by HIP/PAP, a human RegIII lectin. We show that HIP/PAP recognizes the peptidoglycan carbohydrate backbone in a calcium-independent manner via a conserved "EPN" motif that is critical for bacterial killing. While EPN sequences govern calcium-dependent carbohydrate recognition in other C-type lectins, the unusual location and calcium-independent functionality of the HIP/PAP EPN motif suggest that this sequence is a versatile functional module that can support both calcium-dependent and calcium-independent carbohydrate binding. Further, we show HIP/PAP binding affinity for carbohydrate ligands depends on carbohydrate chain length, supporting a binding model in which HIP/PAP molecules "bind and jump" along the extended polysaccharide chains of peptidoglycan, reducing dissociation rates and increasing binding affinity. We propose that dynamic recognition of highly clustered carbohydrate epitopes in native peptidoglycan is an essential mechanism governing high-affinity interactions between HIP/PAP and the bacterial cell wall.
BRANDLK,PLITASG,SCHNABLB,et al.MyD88-mediated signals induce the bactericidal lectinRegⅢ gamma and protect mice against intestinal Listeria monocytogenes infection[J].J Exp Med,2007,204(8):1891-1900.
Abstract Listeria monocytogenes is a food-borne bacterial pathogen that causes systemic infection by traversing the intestinal mucosa. Although MyD88-mediated signals are essential for defense against systemic L. monocytogenes infection, the role of Toll-like receptor and MyD88 signaling in intestinal immunity against this pathogen has not been defined. We show that clearance of L. monocytogenes from the lumen of the distal small intestine is impaired in MyD88(-/-) mice. The distal ileum of wild-type (wt) mice expresses high levels of RegIII gamma, which is a bactericidal lectin that is secreted into the bowel lumen, whereas RegIII gamma expression in MyD88(-/-) mice is nearly undetectable. In vivo depletion of RegIII gamma from the small intestine of wt mice diminishes killing of luminal L. monocytogenes, whereas reconstitution of MyD88-deficient mice with recombinant RegIII gamma enhances intestinal bacterial clearance. Experiments with bone marrow chimeric mice reveal that MyD88-mediated signals in nonhematopoietic cells induce RegIII gamma expression in the small intestine, thereby enhancing bacterial killing. Our findings support a model of MyD88-mediated epithelial conditioning that protects the intestinal mucosa against bacterial invasion by inducing RegIII gamma.
VAISHNAVAS,YAMAMOTOM,SEVERSON KM,et al.The antibacterial lectin RegⅢ gamma promotes the spatial segregation of microbiota and host in the intestine[J].Science,2011,334(6053):255-258.
Abstract The mammalian intestine is home to ~100 trillion bacteria that perform important metabolic functions for their hosts. The proximity of vast numbers of bacteria to host intestinal tissues raises the question of how symbiotic host-bacterial relationships are maintained without eliciting potentially harmful immune responses. Here, we show that RegIII纬, a secreted antibacterial lectin, is essential for maintaining a ~50-micrometer zone that physically separates the microbiota from the small intestinal epithelial surface. Loss of host-bacterial segregation in RegIII纬(-/-) mice was coupled to increased bacterial colonization of the intestinal epithelial surface and enhanced activation of intestinal adaptive immune responses by the microbiota. Together, our findings reveal that RegIII纬 is a fundamental immune mechanism that promotes host-bacterial mutualism by regulating the spatial relationships between microbiota and host.
ISMAIL AS,BEHRENDT CL,HOOPER LV.Reciprocal interactions between commensal bacteria and gamma delta intraepithelial lymphocytes during mucosal injury[J].J Immunol,2009,182(5):3047-3054.
The intestinal mucosal surface is in direct contact with a vast beneficial microbiota. The symbiotic nature of this relationship is threatened when the surface epithelium is injured, yet little is known about how mucosal surfaces maintain homeostasis with commensal microbes following damage. Gammadelta intraepithelial lymphocytes (gammadelta IEL) reside at the gut epithelial surface, where they stimulate mucosal healing following acute injury. A genome-wide analysis of the gammadelta IEL response to dextran sulfate sodium-induced colonic damage revealed induction of a complex transcriptional program, including coordinate regulation of cytoprotective, immunomodulatory, and antibacterial factors. Studies in germfree mice demonstrated that commensal microbiota regulate key components of this transcriptional program, thus revealing a dialogue between commensal bacteria and gammadelta IEL in injured epithelia. Analysis of TCRdelta-deficient mice indicated that gammadelta T cells are essential for controlling mucosal penetration of commensal bacteria immediately following dextran sulfate sodium-induced damage, suggesting that a key function of gammadelta IEL is to maintain host-microbial homeostasis following acute mucosal injury. Taken together, these findings disclose a reciprocal relationship between gammadelta T cells and intestinal microbiota that promotes beneficial host-microbial relationships in the intestine.
KEILBAUGH SA,SHIN ME,BANCHEREAU RF,et al.Activation of RegⅢbeta/gamma and interferon gamma expression in the intestinal tract of SCID mice:an innate response to bacterial colonisation of the gut[J].Gut,2005,54(5):623-629.
The mechanisms by which commensal bacteria provoke intestinal inflammation in animal models of inflammatory bowel disease (IBD) remain incompletely defined, leading to increasing interest in the innate immune response of the colonic mucosa to bacterial colonisation.Using gene expression profiling of colonic RNA from C.B17.SCID germ free mice and those colonised with altered Schaedler's flora, we investigated the innate immune response to bacterial colonisation in vivo. The two most consistently induced gene groups were RegIIIbeta and gamma as well as interferon gamma (IFN-gamma) response genes.Using quantitative reverse transcription-polymerase chain reaction, we showed that RegIIIbeta, RegIIIgamma, and IFN-gamma were constitutively expressed in the colon of conventionally housed SCID mice compared with either germ free SCID or conventionally housed BALB/c mice. Induction of these genes was reproduced by chronic monoassociation of germ free SCID mice with either of two separate gut commensal bacterial species-segmented filamentous bacteria and Schaedler's Escherichia coli. The cellular source for IFN-gamma on monoassociation of SCID mice with Schaedler's E coli was localised to a subset of intraepithelial natural killer (IENK) cells that express asialo-GM1. In vivo IFN-gamma immunoneutralisation studies failed to demonstrate any alteration in RegIIIbeta or gamma expression.Thus bacterial colonisation of the colon independently activates two distinct innate immune cell types at the mucosal interface with the colonic lumen, intestinal epithelial cells, and IENK cells, a response that may be regulated by the adaptive immune system. These innate immune responses may play a role in the pathogenesis of colitis in SCID adoptive transfer models in mice and possibly in patients with IBD.
MATSUMOTOS,KONISHIH,MAEDAR,et al.Expression analysis of the regenerating gene(Reg) family members Reg-Ⅲbeta and Reg-Ⅲgamma in the mouse during development[J].J Comp Neurol,2012,520(3):479-494.
Abstract The regenerating gene/regenerating islet-derived (Reg) family is a group of small secretory proteins. Within this family, Reg type-III (Reg-III) consists of: Reg-IIIα, -β, -γ, and -δ. To elucidate the physiological relevance of Reg-III, we examined the localization and ontogeny of Reg-IIIβ and Reg-IIIγ in mice at different time points spanning from embryonic day 13.5 to 7 weeks old, using in situ hybridization and immunohistochemistry. Our results showed that Reg-IIIβ was expressed in specific subsets of primary sensory neurons and motor neurons, and that expression was transient during the embryonic and perinatal periods. Reg-IIIβ expression was also observed in absorptive epithelial cells of the intestine. In contrast, Reg-IIIγ expression was mainly observed in epithelial cells of the airways and intestine, but not in the nervous system, and expression levels showed a gradually increasing pattern along with development. In the airways Reg-IIIγ was expressed in goblet and Clara-like cells, whereas in the intestine Reg-IIIγ was expressed in the absorptive epithelial cells and Paneth cells, and was found to be expressed in development before these organs had been exposed to the outside world. The present findings imply that Reg-IIIβ and Reg-IIIγ expression is regulated along divergent pathways. Furthermore, we also suggest that expression of Reg-IIIγ in the airway and intestinal epithelia may occur to protect these organs from exposure to antigens or other factors (e.g., microbes) in the outer world, whereas the transient expression of Reg-IIIβ in the nervous system may be associated with the development of the peripheral nervous system including such processes as myelination. Copyright 08 2011 Wiley-Liss, Inc.
NATIVIDAD JM,HAYES CL,MOTTA JP,et al.Differential induction of antimicrobial REGⅢ by the intestinal microbiota and Bifidobacteriumbreve NCC2950[J].Appl Environ Microbiol,2013,79(24):7745-7754.
The intestinal microbiota is a key determinant of gut homeostasis, which is achieved, in part, through regulation of antimicrobial peptide secretion. The aim of this study was to determine the efficiency by which members of the intestinal microbiota induce the antimicrobial peptide REGIII and to elucidate the underlying pathways. We showed that germfree mice have low levels of REGIII-γ in their ileum and colon compared to mice with different intestinal microbiota backgrounds. Colonization with a microbiota of low diversity (altered Schaedler flora) did not induce the expression of REGIII-γ as effectively as a complex community (specific pathogen free). Monocolonization with the probiotic Bifidobacterium breve, but not with the nonprobiotic commensal Escherichia coli JM83, upregulated REGIII-γ expression. Induction of REGIII-γ by B. breve was abrogated in mice lacking MyD88 and Ticam1 signaling. Both live and heat-inactivated B. breve but not spent culture medium from B. breve induced the expression of REGIII-α, the human ortholog and homolog of REGIII-γ, in human colonic epithelial cells (Caco-2). Taken together, the results suggest that REGIII-γ expression in the intestine correlates with the richness of microbiota composition. Also, specific bacteria such as Bifidobacterium breve NCC2950 effectively induce REGIII production in the intestine via the MyD88-Ticam1 pathway. Treatment with this probiotic may enhance the mucosal barrier and protect the host from infection and inflammation.
LOONEN LM,STOLTE EH,JAKLOFSKY MT,et al.REG3gamma-deficient mice have altered mucus distribution and increased mucosal inflammatory responses to the microbiota and enteric pathogens in the ileum[J].Mucosal Immunol,2014,7(4):939-947.
Mucosal Immunology is the official publication of the Society of Mucosal Immunology (SMI). It aims to provide a forum for both basic and clinical scientists to discuss all aspects of immunity and inflammation involving mucosal tissues. The journal reflects the interests of scientists studying gastrointestinal, pulmonary, nasopharyngeal, oral, ocular, and genitourinary immunology through the publication of original research articles, scholarly reviews, and timely commentaries, editorials and letters.
MUKHERJEES,HOOPER LV.Antimicrobial defense of the intestine[J].Immunity,2015,42(1):28-39.
The mammalian gastrointestinal tract is home to a dense community of resident bacteria and is also exposed to microorganisms from the external environment. The epithelial surface of the intestine plays a critical role in host protection by producing a diverse repertoire of antimicrobial proteins that directly kill or hinder the growth of microorganisms. Here we discuss the general principles that govern the mechanisms of action of epithelial antimicrobial proteins, regulation of antimicrobial protein expression and activity, and in vivo functions of intestinal antimicrobial proteins. We also consider how altered antimicrobial protein expression and function can contribute to disease and how these endogenous antibiotics might be harnessed for the benefit of human health.
MIKIT,HOLSTO,HARDT WD.The bactericidal activity of the C-type lectin RegⅢ beta against Gram-negative bacteria involves binding to lipid A[J].J Biol Chem,2012,287(41):34844-34855.
RegIIIβ is a member of the C-type lectin family called RegIII. It is known to bind peptidoglycan, and its bactericidal activity shapes the interactions with commensal and pathogenic gut bacteria. However, little is known about its carbohydrate recognition specificity and the bactericidal mechanism, particularly against Gram-negative bacteria. Here, we show that RegIIIβ can bind directly to LPS by recognizing the carbohydrate moiety of lipid A via a novel motif that is indispensable for its bactericidal activity. This bactericidal activity of RegIIIβ could be inhibited by preincubation with LPS, lipid A, or gentiobiose. The latter is a disaccharide composed of two units of β-(1→6)-linked d-glucose and resembles the carbohydrate moiety of lipid A. Therefore, this structural element may form a key target site recognized by RegIIIβ. Using point-mutated RegIIIβ proteins, we found that amino acid residues in two structural motifs termed "loop 1" and "loop 2," are important for peptidoglycan and lipid A binding (Arg-135, Asp-142) and for the bactericidal activity (Glu-134, Asn-136, Asp-142). Thus, the ERN motif and residue Asp-142 in the loop 2 are of critical importance for RegIIIβ function. This provides novel insights into the carbohydrate recognition specificity of RegIIIβ and explains its bactericidal activity against Gram-negative bacteria.
WANGL,FOUTS DE,STARKELP,et al.Intestinal REG3 lectins protect against alcoholic steatohepatitis by reducing mucosa-associated microbiota and preventing bacterial translocation[J].Cell Host Microbe,2016,19(2):227-239.
Approximately half of all deaths from liver cirrhosis, the tenth leading cause of mortality in the United States, are related to alcohol use. Chronic alcohol consumption is accompanied by intestinal dysbiosis and bacterial overgrowth, yet little is known about the factors that alter the microbial composition or their contribution to liver disease. We previously associated chronic alcohol consumption with lower intestinal levels of the antimicrobial-regenerating islet-derived (REG)-3 lectins. Here, we demonstrate that intestinal deficiency in REG3B or REG3G increases numbers of mucosa-associated bacteria and enhances bacterial translocation to the mesenteric lymph nodes and liver, promoting the progression of ethanol-induced fatty liver disease toward steatohepatitis. Overexpression of Reg3g in intestinal epithelial cells restricts bacterial colonization of mucosal surfaces, reduces bacterial translocation, and protects mice from alcohol-induced steatohepatitis. Thus, alcohol appears to impair control of the mucosa-associated microbiota, and subsequent breach of the mucosal barrier facilitates progression of alcoholic liver disease.
LAIY,LID,LIC,et al.The antimicrobial protein REG3A regulates keratinocyte proliferation and differentiation after skin injury[J].Immunity,2012,37(1):74-84.
Epithelial keratinocyte proliferation is an essential element of wound repair, and abnormal epithelial proliferation is an intrinsic element in the skin disorder psoriasis. The factors that trigger epithelial proliferation in these inflammatory processes are incompletely understood. Here we have shown that regenerating islet-derived protein 3-alpha (REG3A) is highly expressed in keratinocytes during psoriasis and wound repair and in imiquimod-induced psoriatic skin lesions. The expression of REG3A by keratinocytes is induced by interleukin-17 (IL-17) via activation of keratinocyte-encoded IL-17 receptor A (IL-17RA) and feeds back on keratinocytes to inhibit terminal differentiation and increase cell proliferation by binding to exostosin-like 3 (EXTL3) followed by activation of phosphatidylinositol 3 kinase (PI3K) and the kinase AKT. These findings reveal that REG3A, a secreted intestinal antimicrobial protein, can promote skin keratinocyte proliferation and can be induced by IL-17. This observation suggests that REG3A may mediate the epidermal hyperproliferation observed in normal wound repair and in psoriasis.
DONGC.Diversification of T-helper-cell lineages:finding the family root of IL-17-producing cells[J].Nat Rev Immunol,2006,6(4):329-333.
Abstract CD4+ T helper 1 (T(H)1) and T(H)2 cells have long been regarded as two sides of a coin in terms of adaptive immune responses. However, as I discuss here, this concept needs to be reconsidered. In particular, recent data indicate that interleukin-17 (IL-17) is produced by T(H) cells that are distinct from the traditional T(H)1- and T(H)2-cell subsets. Furthermore, the generation of these IL-17-producing CD4+ T cells from naive precursors during immune responses is not dependent on the cytokines and transcription factors that mediate T(H)1- and T(H)2-cell development. Given that IL-17 has crucial roles in regulating tissue inflammation and the development of disease in several animal models of autoimmunity, I propose that IL-17-producing CD4+ T cells represent a distinct inflammatory T(H)-cell lineage.
INFANTE-DUARTEC,HORTON HF,BYRNE MC,et al.Microbial lipopeptides induce the production of IL-17 in Thcells[J].J Immunol,2000,165(11):6107-6115.
Naive Th cells can be directed in vitro to develop into Th1 or Th2 cells by IL-12 or IL-4, respectively. In vivo, chronic immune reactions lead to polarized Th cytokine patterns. We found earlier that Borrelia burgdorferi, the spirochaete that causes Lyme disease, induces Th1 development in alpha beta TCR-transgenic Th cells. Here, we used TCR-transgenic Th cells and oligonucleotide arrays to analyze the differences between Th1 cells induced by IL-12 vs those induced by B. burgdorferi. Transgenic Th cells primed with peptide in the presence of B. burgdorferi expressed several mRNAs, including the mRNA encoding IL-17, at significantly higher levels than Th cells primed with peptide and IL-12. Cytometric single-cell analysis of Th cell cytokine production revealed that IL-17 cannot be categorized as either Th1 or Th2 cytokine. Instead, almost all IL-17-producing Th cells simultaneously produced TNF-alpha and most IL-17(+) Th cells also produced GM-CSF. This pattern was also observed in humans. Th cells from synovial fluid of patients with Lyme arthritis coexpressed IL-17 and TNF-alpha upon polyclonal stimulation. The induction of IL-17 production in Th cells is not restricted to B. burgdorferi. Priming of TCR-transgenic Th cells in the presence of mycobacterial lysates also induced IL-17/TNF-alpha coproduction. The physiological stimulus for IL-17 production was hitherto unknown. We show here for the first time that microbial stimuli induce the expression of IL-17 together with TNF-alpha in both murine and human T cells. Chronic IL-17 expression induced by microbes could be an important mediator of infection-induced immunopathology.
LANGRISH CL,CHENY,BLUMENSCHEIN WM,et al.IL-23 drives a pathogenic T cell population that induces autoimmune inflammation[J].J Exp Med,2005,201(2):233-240.
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KOBAYASHIS,AKIYAMAT,NATAK,et al.Identification of a receptor for reg(regenerating gene) protein,a pancreatic beta-cell regeneration factor[J].J Biol Chem,2000,275(15):10723-10726.
Reg (regenerating gene) was isolated as a gene specifically expressed in regenerating islets (Terazono, K., Yamamoto, H., Takasawa, S., Shiga, K., Yonemura, Y., Tochino, Y., and Okamoto, H. (1988) J. Biol. Chem. 263, 2111-2114). Rat and human Reg gene products, Reg/REG proteins, have been demonstrated to stimulate islet beta-cell growth in vitro and in vivo and to ameliorate experimental diabetes. In the present study, we isolated a cDNA for the Reg protein receptor from a rat islet cDNA library. The cDNA encoded a cell surface 919-amino acid protein, and the cells into which the cDNA had been introduced bound Reg protein with high affinity. When the cDNA was introduced into RINm5F cells, a pancreatic beta-cell line that shows Reg-dependent growth, the transformants exhibited significant increases in the incorporation of 5'-bromo-2'-deoxyuridine as well as in the cell numbers in response to Reg protein. A homology search revealed that the cDNA is a homologue to a human multiple exostoses-like gene, the function of which has hitherto been unknown. These results strongly suggest that the receptor is encoded by the exostoses-like gene and mediates a growth signal of Reg protein for beta-cell regeneration.
LEVETAN CS,UPHAM LV,DENGS,et al.Discovery of a human peptide sequence signaling islet neogenesis[J].Endocr Pract,2008,14(9):1075-1083.
To identify triggers for islet neogenesis in humans that may lead to new treatments that address the underlying mechanism of disease for patients with type 1 or type 2 diabetes.In an effort to identify bioactive human peptide sequences that might trigger islet neogenesis, we evaluated amino acid sequences within a variety of mammalian pancreas-specific REG genes. We evaluated GenBank, the Basic Local Alignment Search Tool algorithm, and all available proteomic databases and developed large-scale protein-to-protein interaction maps. Studies of peptides of interest were conducted in human pancreatic ductal tissue, followed by investigations in mice with streptozocin-induced diabetes.Our team has defined a 14-amino acid bioactive peptide encoded by a portion of the human REG3a gene we termed Human proIslet Peptide (HIP), which is well conserved among many mammals. Treatment of human pancreatic ductal tissue with HIP stimulated the production of insulin. In diabetic mice, administration of HIP improved glycemic control and significantly increased islet number. Bioinformatics analysis, coupled with biochemical interaction studies in a human pancreatic cell line, identified the human exostoses-like protein 3 (EXTL3) as a HIP-binding protein. HIP enhanced EXTL3 translocation from the membrane to the nucleus, in support of a model whereby EXTL3 mediates HIP signaling for islet neogenesis.Our data suggest that HIP may be a potential stimulus for islet neogenesis and that the differentiation of new islets is a process distinct from beta cell proliferation within existing islets. Human clinical trials are soon to commence to determine the effect of HIP on generating new islets from one's own pancreatic progenitor cells.
WUY,QUANY,LIUY,et al.Hyperglycaemia inhibits REG3A expression to exacerbate TLR3-mediated skin inflammation in diabetes[J].Nat Commun,2016,7:13393.
Abstract Dysregulated inflammatory responses are known to impair wound healing in diabetes, but the underlying mechanisms are poorly understood. Here we show that the antimicrobial protein REG3A controls TLR3-mediated inflammation after skin injury. This control is mediated by REG3A-induced SHP-1 protein, and acts selectively on TLR3-activated JNK2. In diabetic mouse skin, hyperglycaemia inhibits the expression of IL-17-induced IL-33 via glucose glycation. The decrease in cutaneous IL-33 reduces REG3A expression in epidermal keratinocytes. The reduction in REG3A is associated with lower levels of SHP-1, which normally inhibits TLR3-induced JNK2 phosphorylation, thereby increasing inflammation in skin wounds. To our knowledge, these findings show for the first time that REG3A can modulate specific cutaneous inflammatory responses and that the decrease in cutaneous REG3A exacerbates inflammation in diabetic skin wounds.
CAVARDC,TERRISB,GRIMBERG,et al.Overexpres-sion of regenerating islet-derived 1 alpha and 3 alpha genes in human primary liver tumors with beta-catenin mutations[J].Oncogene,2006,25(4):599-608.
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YUAN RH,JENG YM,CHEN HL,et al.Opposite roles of human pancreatitis-associated protein and REG1A expression in hepatocellular carcinoma:association of pancreatitis-associated protein expression with low-stage hepatocellular carcinoma,beta-catenin mutation,and favorable prognosis[J].Clin Cancer Res,2005,11(7):2568-2575.
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CHOIB,SUHY,KIM WH,et al.Downregulation of regenerating islet-derived 3 alpha(REG3A) in primary human gastric adenocarcinomas[J].Exp Mol Med,2007,39(6):796-804.
Experimental & Molecular Medicine is an open access journal that publishes the highest quality articles in translational research and biomedical studies.
YEY,XIAOL,WANG SJ,et al.Up-regulation of REG3A in colorectal cancer cells confers proliferation and correlates with colorectal cancer risk[J].Oncotarget,2016,7(4):3921-3933.
Colorectal cancer (CRC) is one of the most common malignancies in the world. Previous studies have investigated the altered expression of regenerating islet-derived 3 alpha (REG3A) in various cancers. We aimed at exploring the biological function and the underlying molecular mechanism of REG3A in CRC. In this study, REG3A was found elevated in CRC compared with normal tissues. Further, high REG3A expression level was correlated with bigger tumor size, poorer differentiation, higher tumor stage and lower survival rate. Knockdown of REG3A in two CRC cell lines, LOVO and RKO, significantly inhibited cell proliferation, and increased cells population in G1 phase and cell apoptotic rate. We also found that down-regulation of REG3A in CRC cells notably inhibited cell migration and invasion. Gene set enrichment analysis on The Cancer Genome Atlas dataset showed that Kyoto Encyclopedia of Genes and Genomes (KEGG) DNA replication and base excision repair (BER) pathways were correlative with the REG3A expression, which was further confirmed in CRC cells by Western blot. Moreover, we confirmed the interaction of REG3A and fibronectin in CRC cells. We also found that there was a positive correlation between REG3A expression level and the AKT and ERK1/2 phosphorylation status. These collective data indicated that REG3A overexpression promotes CRC tumorigenesis by activating AKT and ERK1/2 pathways. REG3A may serve as a promising therapeutic strategy for CRC.
DINGY,XUY,SHUAIX,et al.Reg 3 alpha overexpression protects pancreatic beta-cells from cytokine-induced damage and improves islet transplant outcome[J].Mol Med,2014,20(1):548-558.
The process of islet transplantation for treating type 1 diabetes has been limited by the high level of graft failure that may be overcome by locally delivering trophic factors to enhance engraftment. Regenerating islet-derived protein 3 alpha (Reg3α) is a pancreatic secretory protein, which functions as an antimicrobial peptide in control of inflammation and cell proliferation. In this study, to investigate whether Reg3α could improve islet engraftment, a marginal mass of syngeneic islets pretransduced with adenoviruses expressing Reg3α or control EGFP were transplanted under the renal capsule of streptozotocin-induced diabetic mice. Mice receiving islets with elevated Reg3α production exhibited significantly lower blood glucose levels (9.057 ± 0.59 mmol/l vs 13.48 ± 0.35 mmol/l, P < 0.05) and improved glucose-stimulated insulin secretion (1.80 ± 0.17 ng/ml vs 1.16 ± 0.16 ng/ml, P < 0.05) compared with control group. The decline of apoptotic events (0.57% ± 0.15% vs 1.06% ± 0.07%, P < 0.05) and increased beta-cell proliferation (0.70% ± 0.10% vs 0.36% ± 0.14%, P < 0.05) were confirmed in islet grafts overexpressing Reg3α by morphometric analysis. Further experiments showed that Reg3α production dramatically protected cultured islets and pancreatic beta-cells from cytokine-induced apoptosis and the impairment of glucose-stimulated insulin secretion. Moreover, exposure to cytokines led to the activation of MAPKs in pancreatic beta-cells, which was reversed by Reg3α overexpression in contrast to control group. These results strongly suggest that Reg3α could enhance islet engraftments through its cytoprotective effect and advance the therapeutic efficacy of islet transplantation.
TAKEHARAA,EGUCHIH,OHIGASHIH,et al.Novel tumor marker REG4 detected in serum of patients with resectable pancreatic cancer and feasibility for antibody therapy targeting REG4[J].Cancer Sci,2006,97(11):1191-1197.
Abstract Top of page Abstract Materials and Methods Results Discussion Acknowledgments References Pancreatic ductal adenocarcinoma (PDAC) shows the worst mortality rate among common malignancies, with a 5-year survival rate of only 4%, and the majority of PDAC patients are diagnosed at an advanced stage in which no effective therapy is available at present. Although the proportion of curable cases is still not so high, surgical resection of early stage PDAC is the only way to cure the disease. Hence, establishment of a screening strategy to detect early stage PDAC by novel serological markers is required urgently, and development of novel molecular therapies for PDAC treatment is also eagerly expected. We here report overexpression of REG4, a new member of the regenerating islet-derived (REG) family, in PDAC cells on the basis of genome-wide cDNA microarray analysis as well as reverse transcription olymerase chain reaction and immunohistochemical analysis. We also detected significant elevation of REG4 in the serum of some patients with early-stage PDAC using our enzyme-linked immunosorbent assay system, indicating the possibility of REG4 as a new serological marker of PDAC. Furthermore, we found that knockdown of endogenous REG4 expression in PDAC cell lines with small interfering RNA caused a decrease in cell viability. Concordantly, addition of recombinant REG4 to the culture medium enhanced growth of a PDAC cell line in a dose-dependent manner. A monoclonal antibody against REG4 neutralized its growth-promoting effects and attenuated significantly the growth of PDAC cells. These findings indicate that REG4 is a promising tumor marker to screen early-stage PDAC, and also that neutralization of REG4 by the antibody may offer novel potential tools for the treatment of PDAC. ( Cancer Sci 2006; 97: 1191 1197)
... Reg于1988年首次在大鼠胰岛中发现,并且从大鼠再生性胰岛cDNA库中首次分离,在再生性胰岛β细胞中表达[5].Reg与组织修复有关,尤其与胰岛β细胞再生密切相关[6].Reg蛋白主要在胃肠等消化道组织中表达,也存在于心脏和再生性神经元中 [7-8].基于基因编码蛋白的结构,Reg家族主要分为4个亚型:RegⅠ、Ⅱ、Ⅲ、Ⅳ.小鼠RegⅢ包括RegⅢα、RegⅢβ 和RegⅢγ.人有5个REG基因,包括REG Ia、REG Ib、人肝癌-肠-胰腺或者人胰腺炎相关蛋白(human hepatocarcinoma-intestine-pancreas or human pancreatitis-associated protein,HIP/PAP)、REGⅢ和REGIV[9].笔者所在课题组主要研究小鼠RegⅢγ(Reg3g)和人REG3A,REG3A即 HIP/PAP[10-12].RegⅢγ和REG3A为同源物,Reg3g的cDNA全长774 bp,编码174个氨基酸分子,包含6个外显子和5个内含子.REG3A也有6个外显子和5个内含子[9],包括一个结构域——LECTIN C和一个基序——SP.LECTIN C是REG3A的功能域,位于第40~172个氨基酸区域,具有钙依赖的碳水化合物结合功能.基序SP是REG3A的保守序列,位于第1~27个氨基酸区域,其功能在于体现结构域的生物学作用. ...
Molecular cloning,genomic organization,and chromosomal localization of the human pancreatitis-associated protein(PAP) gene
1994
Mitogen-activated protein kinase p38 target regenerating islet-derived 3 gamma expression is upregulated in cardiac inflammatory response in the rat heart
1
2016
... Reg于1988年首次在大鼠胰岛中发现,并且从大鼠再生性胰岛cDNA库中首次分离,在再生性胰岛β细胞中表达[5].Reg与组织修复有关,尤其与胰岛β细胞再生密切相关[6].Reg蛋白主要在胃肠等消化道组织中表达,也存在于心脏和再生性神经元中 [7-8].基于基因编码蛋白的结构,Reg家族主要分为4个亚型:RegⅠ、Ⅱ、Ⅲ、Ⅳ.小鼠RegⅢ包括RegⅢα、RegⅢβ 和RegⅢγ.人有5个REG基因,包括REG Ia、REG Ib、人肝癌-肠-胰腺或者人胰腺炎相关蛋白(human hepatocarcinoma-intestine-pancreas or human pancreatitis-associated protein,HIP/PAP)、REGⅢ和REGIV[9].笔者所在课题组主要研究小鼠RegⅢγ(Reg3g)和人REG3A,REG3A即 HIP/PAP[10-12].RegⅢγ和REG3A为同源物,Reg3g的cDNA全长774 bp,编码174个氨基酸分子,包含6个外显子和5个内含子.REG3A也有6个外显子和5个内含子[9],包括一个结构域——LECTIN C和一个基序——SP.LECTIN C是REG3A的功能域,位于第40~172个氨基酸区域,具有钙依赖的碳水化合物结合功能.基序SP是REG3A的保守序列,位于第1~27个氨基酸区域,其功能在于体现结构域的生物学作用. ...
Alpha 1-antitrypsin protects beta-cells from apoptosis
1
2007
... 淋巴细胞浸润会导致1型糖尿病患者胰岛β细胞凋亡[13].笔者给予非肥胖型糖尿病(non-obese diabetic,NOD)小鼠慢病毒载体包装的Reg3g,发现其诱导调节性T细胞(regulatory T cells,Tregs)分化,抑制树突状细胞(dendritic cell,DC)成熟,减少胰岛淋巴细胞浸润,从而减弱自身免疫反应[14].基于相关报道[15-16],笔者推测Reg3g过度表达可能通过促进β细胞的再生,抑制炎症反应,在1型糖尿病自身免疫中重建免疫耐受,改善1型糖尿病.蛋白质免疫印迹结果表明,Reg3g在胰腺尤其是胰岛中高效表达,从而促进β细胞的再生,恢复胰岛素分泌水平.除此之外,笔者还确定了Reg3g对内源性抗胰蛋白酶(α-1-antitrypsin,AAT-1)表达的影响.AAT-1是肝脏来源多功能丝氨酸蛋白酶抑制剂[17-18],具有抗炎和抗凋亡特性.在给予Reg3g的小鼠体内,AAT-1血清水平最高,这与AAT-1抑制β细胞凋亡结果相符.笔者的研究还表明,Reg3g可以通过激活酪氨酸蛋白激酶2/信号转导与转录激活因子3(janus kinase 2/signal transducer and activators of transcription 3,JAK2/STAT3)通路一定程度上增加AAT-1产生[14].此外,激活JAK2/STAT3 通路能诱导β细胞再生,恢复胰岛素水平[19-20].说明Reg蛋白在体内可能参与β细胞再生.笔者还发现Reg3g会显著上调Tregs比例,进而显著增加Th2型细胞因子分泌[14].Reg3g通过增加Tregs比例和诱导耐受性DCs,促进β细胞再生,并且保护β细胞免受自身免疫攻击,在体内改善1型糖尿病紊乱的免疫调节过程,从而对β细胞提供保护作用.Reg3g极有可能成为预防和逆转1型糖尿病的有效基因治疗方法. ...
Reg3 goverexpression promotes beta cell regeneration and induces immune tolerance in nonobese-diabetic mouse model
3
2016
... 淋巴细胞浸润会导致1型糖尿病患者胰岛β细胞凋亡[13].笔者给予非肥胖型糖尿病(non-obese diabetic,NOD)小鼠慢病毒载体包装的Reg3g,发现其诱导调节性T细胞(regulatory T cells,Tregs)分化,抑制树突状细胞(dendritic cell,DC)成熟,减少胰岛淋巴细胞浸润,从而减弱自身免疫反应[14].基于相关报道[15-16],笔者推测Reg3g过度表达可能通过促进β细胞的再生,抑制炎症反应,在1型糖尿病自身免疫中重建免疫耐受,改善1型糖尿病.蛋白质免疫印迹结果表明,Reg3g在胰腺尤其是胰岛中高效表达,从而促进β细胞的再生,恢复胰岛素分泌水平.除此之外,笔者还确定了Reg3g对内源性抗胰蛋白酶(α-1-antitrypsin,AAT-1)表达的影响.AAT-1是肝脏来源多功能丝氨酸蛋白酶抑制剂[17-18],具有抗炎和抗凋亡特性.在给予Reg3g的小鼠体内,AAT-1血清水平最高,这与AAT-1抑制β细胞凋亡结果相符.笔者的研究还表明,Reg3g可以通过激活酪氨酸蛋白激酶2/信号转导与转录激活因子3(janus kinase 2/signal transducer and activators of transcription 3,JAK2/STAT3)通路一定程度上增加AAT-1产生[14].此外,激活JAK2/STAT3 通路能诱导β细胞再生,恢复胰岛素水平[19-20].说明Reg蛋白在体内可能参与β细胞再生.笔者还发现Reg3g会显著上调Tregs比例,进而显著增加Th2型细胞因子分泌[14].Reg3g通过增加Tregs比例和诱导耐受性DCs,促进β细胞再生,并且保护β细胞免受自身免疫攻击,在体内改善1型糖尿病紊乱的免疫调节过程,从而对β细胞提供保护作用.Reg3g极有可能成为预防和逆转1型糖尿病的有效基因治疗方法. ...
Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARgamma and LXRalpha pathways
Activation of RegⅢbeta/gamma and interferon gamma expression in the intestinal tract of SCID mice:an innate response to bacterial colonisation of the gut
REG3gamma-deficient mice have altered mucus distribution and increased mucosal inflammatory responses to the microbiota and enteric pathogens in the ileum
Hyperglycaemia inhibits REG3A expression to exacerbate TLR3-mediated skin inflammation in diabetes
1
2016
... WU等[55]研究了REG3A介导糖尿病皮肤损伤性炎症的过程及机制.研究表明,REG3A与皮肤损伤后Toll样受体3(toll like receptor,TLR3)介导的炎症有关,这个效应与SHP-1蛋白相关.糖尿病情况下,高血糖通过葡萄糖糖化作用下调IL-17诱导的IL-33表达,从而下调REG3A表达,REG3A表达下降减少SHP-1蛋白的产生,活化TLR3诱导的JNK2磷酸化,增加TLR3诱导的促炎细胞因子例如TNF-α、IL-6的产生,增强皮肤损伤中的炎症反应,延缓伤口修复,导致糖尿病中皮肤损伤的恶化. ...
Overexpres-sion of regenerating islet-derived 1 alpha and 3 alpha genes in human primary liver tumors with beta-catenin mutations
1
2006
... 除了胰腺癌以外,REG3A也被报道与多种人类癌症相关,如结肠直肠癌、胃癌、肝癌[56-58].YE等[59]研究了REG3A在结肠直肠癌(colorectal cancer,CRC)中的生物学功能和潜在的分子机制.研究发现,相比于正常组织,REG3A在CRC中的表达水平增加.而且,REG3A的过度表达与肿瘤体积增大、癌症恶性程度增高以及生存率降低有关.当在CRC的两个细胞系——LOVO和PKO中敲低REG3A的表达时,将会显著抑制细胞增殖,诱导G1期阻滞和细胞的凋亡,同时显著抑制细胞迁移和侵袭.此外,研究还发现REG3A表达水平与AKT和EPR1/2磷酸化程度呈正相关.这表明REG3A过表达将会通过激活AKT和ERK1/2通路促进CRC发生.功能分析和基因探针富集分析(genome set enrichment analysis,GSEA)也表明REGA3A可能通过激活AKT和ERK通路调节细胞增殖、凋亡、迁移和侵袭,作为一个致癌基因发挥作用.因此,REG3A可能是CRC潜在的治疗靶点. ...
Opposite roles of human pancreatitis-associated protein and REG1A expression in hepatocellular carcinoma:association of pancreatitis-associated protein expression with low-stage hepatocellular carcinoma,beta-catenin mutation,and favorable prognosis
2005
Downregulation of regenerating islet-derived 3 alpha(REG3A) in primary human gastric adenocarcinomas
2
2007
... 除了胰腺癌以外,REG3A也被报道与多种人类癌症相关,如结肠直肠癌、胃癌、肝癌[56-58].YE等[59]研究了REG3A在结肠直肠癌(colorectal cancer,CRC)中的生物学功能和潜在的分子机制.研究发现,相比于正常组织,REG3A在CRC中的表达水平增加.而且,REG3A的过度表达与肿瘤体积增大、癌症恶性程度增高以及生存率降低有关.当在CRC的两个细胞系——LOVO和PKO中敲低REG3A的表达时,将会显著抑制细胞增殖,诱导G1期阻滞和细胞的凋亡,同时显著抑制细胞迁移和侵袭.此外,研究还发现REG3A表达水平与AKT和EPR1/2磷酸化程度呈正相关.这表明REG3A过表达将会通过激活AKT和ERK1/2通路促进CRC发生.功能分析和基因探针富集分析(genome set enrichment analysis,GSEA)也表明REGA3A可能通过激活AKT和ERK通路调节细胞增殖、凋亡、迁移和侵袭,作为一个致癌基因发挥作用.因此,REG3A可能是CRC潜在的治疗靶点. ...
, 许倩倩, 向明
