中国科技论文统计源期刊 中文核心期刊
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
, 陈秋月, 韩勇
, CHEN Qiuyue, HAN Yong
目的 用生物信息学一致性相关系数(CCC)法预测非小细胞肺癌一线化疗方案NP方案(长春瑞滨+顺铂)药物敏感性基因。方法 使用5种统计学方法:Pearson相关分析、Spearman相关分析、Welch's t-test、ANCOVA和rank-based ANCOVA,从NCI 60数据库筛选药物敏感性基因,通过CCC筛选非小细胞肺癌患者化疗药物敏感性基因。利用在线数据库DAVID进行KEGG通路富集分析。结果 筛选出可能应用于预测非小细胞肺癌化疗药物敏感性基因:顺铂的药物敏感性基因主要富集在蛋白聚糖、细菌侵袭上皮细胞通路中;长春瑞滨的药物敏感性基因主要与癌症信号通路、蛋白聚糖有关。结论 生物信息学CCC法可应用于筛选出预测非小细胞肺癌化疗药物敏感性的基因,可能为将来构建NP方案精准化疗模型提供研究基础。
Objective The concordance correlation coefficient (CCC) method of bioinformatics is used to predict the drug sensitivity genes of the NP scheme(vinorelbine and cisplatin) in the first-line chemotherapy regimen for non-small cell lung cancer. Methods Five statistical methods (Pearson correlation analysis,Spearman correlation analysis,Welch's t-test,ANCOVA and rank-based ANCOVA) were used to screen drug sensitivity genes from the NCI 60 database,and screened biomarkers of chemotherapeutic drug sensitivity in patients with non-small cell lung cancer by concordance correlation coefficient (CCC).The online database DAVID was used for enrichment analysis of KEGG pathway. Results The selection of genes that may be used to predict the sensitivity of chemotherapy drugs of non-small cell lung cancer chemotherapy drugs:the drug sensitivity genes of cisplatin were mainly enriched in proteoglycans and bacterial invasion of epithelial cells;The drug sensitivity genes of vinorelbine were mainly related to cancer pathways,and proteoglycans. Conclusion The CCC method of bioinformatics can be applied to screen out genes that predict the sensitivity of non-small cell lung cancer chemotherapy drugs,which can provide a research foundation for the construction of the NP scheme precision chemotherapy prediction model in the future.
开放科学(资源服务)标识码(OSID)
肺癌是全球常见的恶性肿瘤之一。肺癌包括两种主要的组织学类型:小细胞肺癌(small cell lung cancer,SCLC)和非小细胞肺癌(non-small cell lung cancer,NSCLC)。其中,NSCLC是常见的组织学类型,占肺癌总病例的80%[1]。NSCLC是一种高度异质性疾病,患者对化疗敏感性个体差异较大。近年来有很多研究通过筛选生物标志物(如CTR1、ABCB1等)能够预测NSCLC患者化学治疗(化疗)的生存情况[2,3,4,5,6]。但这些生物标志物基于较少临床样本量的检测与验证,且每项研究用于检测和分析的备筛选生物标志物数量有限。由于NSCLC在早期无典型症状,患者确诊时多以中晚期为主[7]。长春瑞滨+顺铂序贯化疗治疗方案(NP方案)是晚期NSCLC的一线化疗方案,临床研究表明,NP 方案可显著延长晚期患者的生存期(
从美国国家癌症研究所网站(http://discover.nci.nih.gov)下载使用HG-U133A GeneChip阵列分析的NCI 60细胞系数据(Affymetrix)。从NCI数据库获得(http://dtp.nci.nih.gov)NCI 60细胞系50%生长抑制(GI50)的药物敏感性数据。从基因表达数据库 GEO 数据库中下载NSCLC患者数据GSE3593(Potti198,198个NSCLC样本)[11]。平台信息:GPL96[HG-U133A]Affymetrix Human Genome U133A Array。
1.2.1 筛选药物敏感性基因 使用5种统计学方法,包括Pearson相关分析、Spearman相关分析、Welch's t-test、协方差分析(ANCOVA)和rank-based ANCOVA,以GI50为临界值,比较两个化疗药物(顺铂和长春瑞滨)对同一细胞系各个基因的不同作用,筛选出这两种药物的敏感性基因。这些基因与体外药物敏感性高度相关或在每种药物的敏感和耐药细胞系之间明显存在差异表达。示意图见
1.2.2 筛选CCC基因 使用CCC进行相关分析[10,12-13]。本研究检索GEO和ArrayExpress数据库,限定检索条件“NSCLC;Homo sapiens;Expression profilling by array”筛选出所需NSCLC数据库,选择样本量最大的 Potti198作为研究对象[11]。具体过程简化为3步:①将NCI 60数据库里面的每个基因与剩余其他基因的spearman相关系数定义为CR
1.2.3 DAVID通路分析 将5种统计学方法筛选出的基因取合集,导入DAVID 6.8分析工具(https://david.ncifcrf.gov),进行KEGG通路富集分析,条件设定为
NCI 60细胞系数据用于药物敏感性基因的筛选。筛选出的化疗药物顺铂和长春瑞滨的药物敏感性基因,其生物学功能类型见
表1 顺铂和长春瑞滨的药物敏感性基因数量
Tab.1 Drug sensitivity genes of cisplatin and vinorelbine
通过CCC算法分析NCI 60细胞系与 Potti198样本中具有共同表达模式的基因,筛选出可能应用于预测NSCLC化疗药物敏感性的基因。化疗药物顺铂和长春瑞滨的药物敏感性基因数量见
将CCC算法分析结果取合集,在DAVID网站进行KEGG通路富集分析,将具有相似功能的基因放到一起,进一步解读基因的功能,作气泡图。
表2 CCC基因的生物学功能
Tab.2 Biological functions of CCC genes
NSCLC是一种异质性疾病,肿瘤异质性一直以来是影响抗肿瘤药物治疗敏感性的一个关键问题,筛选生物标志物能预测患者对化疗的敏感性,能够为临床提供更有效的个体化化疗方案。生物信息学中某些算法可以通过从细胞系中初步筛选出适用于临床精准化疗的肿瘤学生物标志物,如进一步运用临床样本进行模型构建、验证与优化,可为克服肿瘤异质性、提高抗肿瘤药物治疗敏感性提供精准治疗方案。近年来,生物信息学被广泛应用于癌症生物标志物的筛选。ZHU等[14]通过生物信息学中最大化
笔者在本研究采用生物信息学中CCC算法,预测NSCLC患者一线化疗NP方案(顺铂+长春瑞滨)的药物敏感性基因。研究中对5种统计方法得到的药物敏感性基因取合集,并通过KEGG通路富集分析,对筛选出的药物敏感性基因功能进行了分类阐释。顺铂能够与DNA分子交叉联结,影响DNA复制,高浓度时也能抑制RNA及蛋白质合成。富集分析后发现药物敏感性基因主要与蛋白聚糖和细菌侵袭通路有关。由性别、烟草史和组织学类型建立的Cox回归模型显示,肺癌组织中蛋白聚糖表达水平高的患者具有较高的生存风险[16]。细菌侵袭通路中PTK2是miR-16-5p 的靶标蛋白,miR-16-5p的过表达抑制了NSCLC细胞的增殖和侵袭[17]。上皮-间质转化(epithelial-mesenchymal transition,EMT)是癌细胞转移和化学耐药所必需的细胞过程,而CRK家族衔接子蛋白有望抵消EMT和化学抗性[18]。长春瑞滨为周期特异药物,抑制微管蛋白的聚合,并使分裂期微管崩解,导致细胞在有丝分裂过程中微管形成障碍。富集分析后发现其药物敏感性基因主要与癌症信号通路有关,可能与蛋白聚糖表达有关。研究显示表麻黄醇A通过抑制癌症信号通路中细胞迁移关键调节剂蛋白激酶B(Akt)的激活,进而抑制肺癌细胞的迁移[19]。SU等[20]研究发现通过直接介导FZD1下调,miR-135b抑制NSCLC的化学耐药性。黄芩素通过靶向RHOA / ROCK信号通路,抑制了NSCLC中血管生成拟态(VM)的形成,发挥抗癌作用[21]。
本研究通过生物信息学中CCC算法初步筛选出可能应用于NSCLC化疗的NP方案药物敏感性基因。但由于可以获得的公开数据集非常有限,目前得到的这些基因只能够作为NSCLC化疗中的候选药物敏感性基因,尚需通过更多的临床研究数据集或临床样本信息进行验证与优化。未来我们将密切关注TCGA、GEO等数据库中含有两种药物治疗信息的新公开数据集;同时,课题组拟开展相关临床研究,收集临床样本,基于上述初筛结果完善相关生物标记物检测并收集与分析患者信息(如人口学信息、预后等各种临床指标),以进一步构建、验证和优化NSCLC的NP方案精准化疗模型[22]。
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Platinum-based chemotherapy is commonly used to treat non-small cell lung cancer (NSCLC). However, its efficacy is limited and no molecular biomarkers that predict response are available. In this review, we summarize current knowledge concerning potential epigenetic predictive markers for platinum-based chemotherapy response in NSCLC. A systematic search of PubMed and ClinicalTrials.gov using keywords
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Purpose: No validated biomarkers that could identify the subset of patients with lung adenocarcinoma who might benefit from chemotherapy have yet been well established. This study aimed to explore potential biomarker model predictive of efficacy and survival outcomes after first-line pemetrexed plus platinum doublet based on metabolomics profiling.Experimental Design: In total, 354 consecutive eligible patients were assigned to receive first-line chemotherapy of pemetrexed in combination with either cisplatin or carboplatin. Prospectively collected serum samples before initial treatment were utilized to perform metabolomics profiling analyses under the application of LC/MS-MS. Binary logistic regression analysis was carried out to establish discrimination models.Results: There were 251 cases randomly sorted into discovery set, the rest of 103 cases into validation set. Seven metabolites including hypotaurine, uridine, dodecanoylcarnitine, choline, dimethylglycine, niacinamide, and l-palmitoylcarnitine were identified associated with chemo response. On the basis of the seven-metabolite panel, a discriminant model according to logistic regression values g(z) was established with the receiver operating characteristic curve (AUC) of 0.912 (Discovery set) and 0.909 (Validation set) in differentiating progressive disease (PD) groups from disease control (DC) groups. The median progression-free survival (PFS) after chemotherapy in patients with g(z) 0.155 (10.3 vs.4.5 months, P < 0.001).Conclusions: This study developed an effective and convenient discriminant model that can accurately predict the efficacy and survival outcomes of pemetrexed plus platinum doublet chemotherapy prior to treatment delivery. Clin Cancer Res; 24(9); 2100-9. (c)2018 AACR.
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Background: Platinum resistance is a major limitation in the treatment of advanced non-small cell lung cancer (NSCLC). We previously demonstrated that low tissue platinum concentration in NSCLC specimens was significantly associated with reduced tumor response. Furthermore, low expression of the copper transporter CTR1, a transporter of platinum uptake was associated with poor clinical outcome following platinum-based therapy in NSCLC patients. We investigated the relationship between tissue platinum concentrations and CTR1 expression in NSCLC specimens.
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Methods: We identified paraffin-embedded NSCLC tissue blocks of known tissue platinum concentrations from 30 patients who underwent neoadjuvant platinum-based chemotherapy at MD Anderson Cancer Center. Expression of CTR1 in tumors and normal adjacent lung specimens was determined by immunohistochemistry with adequate controls. Results: Tissue platinum concentration significantly correlated with tumor response in 30 patients who received neoadjuvant platinum-based chemotherapy (P < 0.001). CTR1 was differentially expressed in NSCLC tumors. A subset of patients with undetectable CTR1 expression in their tumors had reduced platinum concentrations (P = 0.058) and tumor response (P = 0.016) compared to those with any level of CTR1 expression. We also observed that African Americans had significantly reduced CTR1 expression scores (P = 0.001), tissue platinum concentrations (P = 0.009) and tumor shrinkage (P = 0.016) compared to Caucasians. Conclusions: To our best knowledge this is the first study investigating the function of CTR1 in clinical specimens. CTR1 expression may be necessary for therapeutic efficacy of platinum drugs, consistent with previous preclinical studies. A prospective clinical trial is necessary to develop CTR1 into a potential biomarker for platinum drugs. (C) 2014 Elsevier Ireland Ltd. |
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Prognostic factors for patients with non-small cell lung cancer (NSCLC) who have been treated with neoadjuvant therapy have not been fully assessed. The purpose of this study was to analyze prognostic biomarkers in NSCLC after treatment with neoadjuvant therapy, with special reference to the immunophenotypes of both the cancer cells and stromal cells. A total of 52 patients with NSCLC who were treated with neoadjuvant therapy followed by complete resection were included. We examined the expressions of nine markers in the cancer cells and stromal cells. The 5-year disease-free survival rate of patients with high aldehyde dehydrogenase 1 (ALDH1) expression levels in their cancer cells was significantly lower than those with a low ALDH1 level (47.3% vs. 21.5%, respectively; P = 0.023). The other molecules expressed in cancer cells did not exhibit any prognostic value. In NSCLC without neoadjuvant therapy (case control, n = 104), expression of ALDH1 in cancer cells was not correlated with prognosis (P = 0.507). A multivariate analysis identified ALDH1 expression in cancer cells as significantly independent prognostic factors for disease-free survival (P = 0.045). The current study indicated that the immunophenotypes of ALDH1 in cancer cells could have prognostic value for patients with NSCLC who are treated with neoadjuvant therapy.
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BACKGROUND: Taxane-based chemotherapy is widely used in lung cancer. ABCB1 have a role in the prediction of treatment response and toxicity of chemotherapy in solid tumors. In this retrospective study, we investigated ABCB1 polymorphism on response and toxicity in taxane-based chemotherapy in lung cancer patients. METHODS: A total of 122 lung cancer patients who received taxane-based chemotherapy were included in this study. Fluorescence in situ hybridization (FISH) was used for ABCB1 polymorphism detection. Turbidimetric inhibition immunoassay was used for pharmacokinetic analysis. Statistical analysis was performed using SPSS 20.0. RESULTS: The frequency of the ABCB1 2677 site TT/TG/GG genotype was 32.8%, 43.4% and 23.8%, respectively and the frequency of the 3435 sites the TT/TC/CC genotype was 13.9%, 44.3% and 41.8%, respectively. The occurrence of neurotoxicity was higher in patients who had ABCB1 3435 site mutation (TT 88.2%, TC 22.2%, CC 21.6% P = 0.004). There was no significant difference between ABCB1 genotypes with regard to other chemotherapy-induced toxicity. For non-small cell lung cancer (NSCLC) patients, those harboring ABCB1 2677 and 3435 site wild-type patients had longer median progression-free survival (PFS) in the paclitaxel subgroup (3435 site: TT 3.87 vs. TC 9.50 vs. CC 14.13 months; P < 0.001; 2677 site: TT 4.37 vs. TG 9.73 vs. GG 12.1 months; P = 0.013). The area under the concentration-time curve (AUC) of 20 patients treated with docetaxel increased for ABCB1 mutation subgroups. CONCLUSION: ABCB1 mutation is associated with higher neurotoxicity of taxane-based chemotherapy. It also predicts shorter PFS for NSCLC in paclitaxel-based treatment.
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Important advancements in the treatment of non-small cell lung cancer (NSCLC) have been achieved over the past two decades, increasing our understanding of the disease biology and mechanisms of tumour progression, and advancing early detection and multimodal care. The use of small molecule tyrosine kinase inhibitors and immunotherapy has led to unprecedented survival benefits in selected patients. However, the overall cure and survival rates for NSCLC remain low, particularly in metastatic disease. Therefore, continued research into new drugs and combination therapies is required to expand the clinical benefit to a broader patient population and to improve outcomes in NSCLC.
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PURPOSE: To evaluate the efficacy of pemetrexed plus cisplatin versus vinorelbine plus cisplatin as postoperative adjuvant chemotherapy in patients with pathologic stage II-IIIA nonsquamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We performed a randomized, open-label, phase III study at 50 institutions within 7 clinical study groups in Japan. Patients with completely resected pathologic stage II-IIIA (TNM 7th edition) nonsquamous NSCLC were randomly assigned to receive either pemetrexed (500 mg/m(2), day 1) plus cisplatin (75 mg/m(2), day 1) or vinorelbine (25 mg/m(2), days 1 and 8) plus cisplatin (80 mg/m(2), day 1) with stratification by sex, age, pathologic stage, EGFR mutation, and institution. These treatments were planned to be given every 3 weeks for 4 cycles. The primary end point was recurrence-free survival in the modified intent-to-treat population, excluding ineligible patients. RESULT: Between March 2012 and August 2016, 804 patients were enrolled (402 assigned to vinorelbine plus cisplatin and 402 assigned to pemetrexed plus cisplatin). Of 784 eligible patients, 410 (52%) had stage IIIA disease and 192 (24%) had EGFR-sensitive mutations. At a median follow-up of 45.2 months, median recurrence-free survival was 37.3 months for vinorelbine plus cisplatin and 38.9 months for pemetrexed plus cisplatin, with a hazard ratio of 0.98 (95% CI, 0.81 to 1.20; 1-sided P = .474). Grade 3-4 toxicities reported more frequently for vinorelbine plus cisplatin than for pemetrexed plus cisplatin were febrile neutropenia (11.6% v 0.3%, respectively), neutropenia (81.1% v 22.7%, respectively), and anemia (9.3% v 2.8%, respectively). One treatment-related death occurred in each arm. CONCLUSION: Although this study failed to show the superiority of pemetrexed plus cisplatin for patients with resected nonsquamous NSCLC, this regimen showed a better tolerability as adjuvant chemotherapy.
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BACKGROUND: Clinical trials have indicated a benefit of adjuvant chemotherapy for patients with stage IB, II, or IIIA--but not stage IA--non-small-cell lung cancer (NSCLC). This classification scheme is probably an imprecise predictor of the prognosis of an individual patient. Indeed, approximately 25 percent of patients with stage IA disease have a recurrence after surgery, suggesting the need to identify patients in this subgroup for more effective therapy. METHODS: We identified gene-expression profiles that predicted the risk of recurrence in a cohort of 89 patients with early-stage NSCLC (the lung metagene model). We evaluated the predictor in two independent groups of 25 patients from the American College of Surgeons Oncology Group (ACOSOG) Z0030 study and 84 patients from the Cancer and Leukemia Group B (CALGB) 9761 study. RESULTS: The lung metagene model predicted recurrence for individual patients significantly better than did clinical prognostic factors and was consistent across all early stages of NSCLC. Applied to the cohorts from the ACOSOG Z0030 trial and the CALGB 9761 trial, the lung metagene model had an overall predictive accuracy of 72 percent and 79 percent, respectively. The predictor also identified a subgroup of patients with stage IA disease who were at high risk for recurrence and who might be best treated by adjuvant chemotherapy. CONCLUSIONS: The lung metagene model provides a potential mechanism to refine the estimation of a patient's risk of disease recurrence and, in principle, to alter decisions regarding the use of adjuvant chemotherapy in early-stage NSCLC.
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A new reproducibility index is developed and studied. This index is the correlation between the two readings that fall on the 45 degree line through the origin. It is simple to use and possesses desirable properties. The statistical properties of this estimate can be satisfactorily evaluated using an inverse hyperbolic tangent transformation. A Monte Carlo experiment with 5,000 runs was performed to confirm the estimate's validity. An application using actual data is given.
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Lin's concordance correlation coefficient (CCC) is a very popular scaled index of agreement used in applied statistics. To obtain a confidence interval (CI) for the estimate of CCC, jackknifing was proposed and shown to perform well in simulation as well as in applications. However, a theoretical proof of the validity of the jackknife CI for the CCC has not been presented yet. In this note, we establish a sufficient condition for using the jackknife method to construct the CI for the CCC. Copyright (c) 2013 John Wiley & Sons, Ltd.
DOI:10.1002/sim.5931
URL
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PURPOSE: The JBR.10 trial demonstrated benefit from adjuvant cisplatin/vinorelbine (ACT) in early-stage non-small-cell lung cancer (NSCLC). We hypothesized that expression profiling may identify stage-independent subgroups who might benefit from ACT. PATIENTS AND METHODS: Gene expression profiling was conducted on mRNA from 133 frozen JBR.10 tumor samples (62 observation [OBS], 71 ACT). The minimum gene set that was selected for the greatest separation of good and poor prognosis patient subgroups in OBS patients was identified. The prognostic value of this gene signature was tested in four independent published microarray data sets and by quantitative reverse-transcriptase polymerase chain reaction (RT-qPCR). RESULTS: A 15-gene signature separated OBS patients into high-risk and low-risk subgroups with significantly different survival (hazard ratio [HR], 15.02; 95% CI, 5.12 to 44.04; P < .001; stage I HR, 13.31; P < .001; stage II HR, 13.47; P < .001). The prognostic effect was verified in the same 62 OBS patients where gene expression was assessed by qPCR. Furthermore, it was validated consistently in four separate microarray data sets (total 356 stage IB to II patients without adjuvant treatment) and additional JBR.10 OBS patients by qPCR (n = 19). The signature was also predictive of improved survival after ACT in JBR.10 high-risk patients (HR, 0.33; 95% CI, 0.17 to 0.63; P = .0005), but not in low-risk patients (HR, 3.67; 95% CI, 1.22 to 11.06; P = .0133; interaction P < .001). Significant interaction between risk groups and ACT was verified by qPCR. CONCLUSION: This 15-gene expression signature is an independent prognostic marker in early-stage, completely resected NSCLC, and to our knowledge, is the first signature that has demonstrated the potential to select patients with stage IB to II NSCLC most likely to benefit from adjuvant chemotherapy with cisplatin/vinorelbine.
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BACKGROUND: The malignancy-risk gene signature is composed of numerous proliferative genes and has been applied to predict breast cancer risk. We hypothesized that the malignancy-risk gene signature has prognostic and predictive value for early-stage non-small cell lung cancer (NSCLC) patients. METHODS: The ability of the malignancy-risk gene signature to predict overall survival (OS) of early-stage NSCLC patients was tested using a large NSCLC microarray dataset from the Director's Challenge Consortium (n = 442) and two independent NSCLC microarray datasets (n = 117 and 133, for the GSE13213 and GSE14814 datasets, respectively). An overall malignancy-risk score was generated by principal component analysis to determine the prognostic and predictive value of the signature. An interaction model was used to investigate a statistically significant interaction between adjuvant chemotherapy (ACT) and the gene signature. All statistical tests were two-sided. RESULTS: The malignancy-risk gene signature was statistically significantly associated with OS (P < .001) of NSCLC patients. Validation with the two independent datasets demonstrated that the malignancy-risk score had prognostic and predictive values: Of patients who did not receive ACT, those with a low malignancy-risk score had increased OS compared with a high malignancy-risk score (P = .007 and .01 for the GSE13212 and GSE14814 datasets, respectively), indicating a prognostic value; and in the GSE14814 dataset, patients receiving ACT survived longer in the high malignancy-risk score group (P = .03), and a statistically significant interaction between ACT and the signature was observed (P = .02). CONCLUSIONS: The malignancy-risk gene signature was associated with OS and was a prognostic and predictive indicator. The malignancy-risk gene signature could be useful to improve prediction of OS and to identify those NSCLC patients who will benefit from ACT.
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Matrix proteoglycans (PGs) have shown promise as biomarker in malignancies. We employed agarose gel eletrophoresis, quantitative real- time reverse transcription-polymerase chain reaction and immunohistochemistry to evaluate the content of sulfated glicosaminoglycans (chondroitin sulfate and heparan sulfate) and expression of PG (biglycan, glypican, perlecan, syndecan e versican) in patient-matched normal and tumor tissues obtained from resected specimens of lung cancer. A significant increase of heparan sulfate (HS) and chondroitin sulfate (CS) concentrations was found in tumor tissue samples when compared to normal lung tissue samples. HS was also significantly increased in adenocarcinomas compared to squamous cell carcinomas. PG gene expression, with exception of syndecan, were significantly decreased in tumor tissue compared to normal lung, coinciding with significant decrease of PG protein levels in tumor cells and stroma compared to normal lung tissue (Kappa coefficient 0.41, 0.42 and 0,28, respectively). Women patients (p = 0.02), non smokers (p = 0.05), T stage (p = 0.009), N stage (p = 0.03) and adenocarcinoma (p = 0.05) were associated with improved overall survival (OS). Patients presenting tumors with low concentration of sulfated GAG and high PGs levels presented better OS compared to patients with high concentration of sulfated GAG and low expression of PGs. Cox regression model controlled by gender, tobacco history and histological type, showed that patients with high perlecan and versican expression in tumor presented respectively high probability of life (beta risk 11.64; 1.27 to 15.90) and low risk of death (beta risk 0.11; 0.02-0.51). The combined approach suggest matrix (PGs) as biomarkers in lung cancer.
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OBJECTIVE: Long noncoding RNAs (lncRNAs) are important regulators involved in a variety of cancer development. However, the role of Linc00210 in non-small cell lung cancer (NSCLC) remains unknown. This study aims to investigate the clinical value of Linc00210 in NSCLC patients and the biological functions of Linc00210 in NSCLC. PATIENTS AND METHODS: Gene expression in NSCLC tissues and cell lines was detected using qRT-PCR or Western blot. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and colony formation assays were conducted to evaluate the effect of Linc00210 on NSCLC cell proliferation. Transwell assay and annexin V-Fluorescein 5-isothiocyanate (FITC)/Propidium Iodide (PI) were done to analyze the effect of Linc00210 on cancer cell invasion and apoptosis, respectively. Luciferase reporter assay and RIP assay were performed to determine the target of Linc00210 and miR-16-5p. Besides, these assays were used to determine reciprocally inhibition of each other-controlled NSCLC cell behaviors. In vivo tumorigenesis experiments were applied to exhibit subcutaneous tumor growth. RESULTS: Linc0021 was highly expressed in NSCLC tissues and cell lines. Knockdown of Linc00210 inhibited cancer cell proliferation and invasion, and increased cell apoptosis, and regulated the expression of Cyclin A1, proliferating cell nuclear antigen (PCNA), E-cadherin, N-cadherin, Bax, and Bcl-2 in NSCLC cells. Further data showed Linc00210 bound to and directly modulated the miR-16-5p levels. Impressively, overexpression of miR-16-5p suppressed NSCLC cell proliferation and invasion, but increased cell apoptosis, and these behaviors could be overturned by overexpression of Linc00210 in vitro and in vivo. Finally, Linc00210 and miR-16-5p cooperatively controlled expression of protein tyrosine kinase 2 (PTK2), a miR-16-5p target. CONCLUSIONS: Linc00210/miR-16-5p/PTK2 signaling suggests a promising novel strategy for anti-NSCLC therapy.
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| [18] |
Epithelial-mesenchymal transition (EMT) is a cell plasticity process required for metastasis and chemoresistance of carcinoma cells. We report a crucial role of the signal adaptor proteins CRK and CRKL in promoting EMT and tumor aggressiveness, as well as resistance against chemotherapy in colorectal and pancreatic carcinoma. Genetic loss of either CRKL or CRK partially counteracted EMT in three independent cancer cell lines. Strikingly, complete loss of the CRK family shifted cells strongly toward the epithelial phenotype. Cells exhibited greatly increased E-cadherin and grew as large, densely packed clusters, completely lacked invasiveness and the ability to undergo EMT induced by cytokines or genetic activation of SRC. Furthermore, CRK family-deficiency significantly reduced cell survival, proliferation and chemoresistance, as well as ERK1/2 phosphorylation and c-MYC protein levels. In accordance, MYC-target gene expression was identified as novel hallmark process positively regulated by CRK family proteins. Mechanistically, CRK proteins were identified as pivotal amplifiers of SRC/FAK signaling at focal adhesions, mediated through a novel positive feedback loop depending on RAP1. Expression of the CRK family and the EMT regulator ZEB1 was significantly correlated in samples from colorectal cancer patients, especially in invasive regions. Further, high expression of CRK family genes was significantly associated with reduced survival in locally advanced colorectal cancer, as well as in pan-cancer datasets from the TCGA project. Thus, CRK family adaptor proteins are promising therapeutic targets to counteract EMT, chemoresistance, metastasis formation and minimal residual disease. As proof of concept, CRK family-mediated oncogenic signaling was successfully inhibited by a peptide-based inhibitor.
[本文引用:1]
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| [19] |
BACKGROUND/AIM: Epithelial to mesenchymal transition (EMT) is a cellular process that facilitates cancer metastasis. Therefore, therapeutic approaches that target EMT have garnered increasing attention. The present study aimed to examine the in vitro effects of ephemeranthol A on cell death, migration, and EMT of lung cancer cells. MATERIALS AND METHODS: Ephemeranthol A was isolated from Dendrobium infundibulum. Non-small cell lung cancer cells H460 were treated with ephemeranthol A and apoptosis was evaluated by Hoechst 33342 staining. Anoikis resistance was determined by soft agar assay. Wound healing assay was performed to test the migration. The regulatory proteins of apoptosis and cell motility were determined by western blot. RESULTS: Treatment with ephemeranthol A resulted in a concentration-dependent cell apoptosis. At non-toxic concentrations, the compound could inhibit anchorage-independent growth of the cancer cells, as indicated by the decreased colony size and number. Ephemeranthol A also exhibited an inhibitory effect on migration. We further found that ephemeranthol A exerts its antimetastatic effects via inhibition of EMT, as indicated by the markedly decrease of N-cadherin, vimentin, and Slug. Furthermore, the compound suppressed the activation of focal adhesion kinase (FAK) and protein kinase B (Akt) proteins, which are key regulators of cell migration. As for the anticancer activity, ephemeranthol A induced apoptosis by decreasing Bcl-2 followed by the activation of caspase 3 and caspase 9. CONCLUSION: The pro-apoptotic and anti-migratory effects of ephemeranthol A on human lung cancer cells support its use for the development of novel anticancer therapies.
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| [20] |
BACKGROUND: Non-small cell lung cancer (NSCLC) chemoresistance usually limits the clinical efficacy of chemotherapeutic approaches. However, few reports have revealed the regulation of miR-135b and Frizzled-1 (FZD1) involved in NSCLC chemoresistance. METHODS: To identify the mechanism of miR-135b and FZD1 in NSCLC chemoresistance and to observe their biological functions, we detected the expression levels of miR-135b and FZD1 by conducting quantitative real-time polymerase chain reaction (RT-qPCR) and modified the expressions of miR-135b and FZD1 by transiently transfecting cells with miR-135b mimics or FZD1-siRNA. The 3'-untranslated region (3'-UTR) of FZD1 combined with miR-135b was verified through dual-luciferase reporter assay. RESULTS: Compared with that in A549 parental cell lines, the miR-135b expression in drug-resistant lung cancer cell lines (A549/DDP) was decreased and their FZD1 expression was increased. The increased miR-135b expression and silenced FZD1 expression enhanced the sensitivity of resistant cells to cisplatin treatment. The high expression of miR-135b in A549/DDP cells remarkably decreased the mRNA levels of FZD1. FZD1 was further identified as the functional downstream target of miR-135b by directly targeting the 3'-UTR of FZD1. CONCLUSION: The amplification of miR-135b suppressed NSCLC chemoresistance by directly mediating the FZD1 downregulation.
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| [21] |
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| [22] |
ER-negative breast cancer includes most aggressive subtypes of breast cancer such as triple negative (TN) breast cancer. Excluded from hormonal and targeted therapies effectively used for other subtypes of breast cancer, standard chemotherapy is one of the primary treatment options for these patients. However, as ER- patients have shown highly heterogeneous responses to different chemotherapies, it has been difficult to select most beneficial chemotherapy treatments for them. In this study, we have simultaneously developed single drug biomarker models for four standard chemotherapy agents: paclitaxel (T), 5-fluorouracil (F), doxorubicin (A) and cyclophosphamide (C) to predict responses and survival of ER- breast cancer patients treated with combination chemotherapies. We then flexibly combined these individual drug biomarkers for predicting patient outcomes of two independent cohorts of ER- breast cancer patients who were treated with different drug combinations of neoadjuvant chemotherapy. These individual and combined drug biomarker models significantly predicted chemotherapy response for 197 ER- patients in the Hatzis cohort (AUC = 0.637, P = 0.002) and 69 ER- patients in the Hess cohort (AUC = 0.635, P = 0.056). The prediction was also significant for the TN subgroup of both cohorts (AUC = 0.60, 0.72, P = 0.043, 0.009). In survival analysis, our predicted responder patients showed significantly improved survival with a >17 months longer median PFS than the predicted non-responder patients for both ER- and TN subgroups (log-rank test P-value = 0.018 and 0.044). This flexible prediction capability based on single drug biomarkers may allow us to even select new drug combinations most beneficial to individual patients with ER- breast cancer.
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