癌基因微小RNA在肿瘤中的作用

在恶性肿瘤中起作用的微小RNA(miRNA)被称为癌基因微小RNA(oncomiRs).在人类恶性肿瘤miRNA表达谱中发现了许多诊断和预后因子.oncomiRs在多种肿瘤的发生、演进中的作用及其作用于靶mRNA的机制和功能效应研究已取得了一些初步成果.     

A novel SOCS5/miR-18/miR-25 axis promotes tumorigenesis in liver cancer

The role of miRNAs with tumor suppressive activity in liver cancer has been well studied. However, little is known about potential oncomiRs in HCC. In our study, we conducted a systematic evaluation of candidate oncomiRs and found that upregulation of miR-18a and miR-25 in HCC was associated with poor patient survival and promoted proliferation in HCC cell lines. These two miRNAs belong to the polycistronic paralogous miR-17-92 and miR-25-106b clusters respectively. Although the members of both clusters are often upregulated in HCC, the contribution of individual miRNAs in these clusters to HCC tumorigenesis is not fully understood. We validated SOCS5 as a bona fide target of both miRNAs, and established, for the first time, the tumor suppressive role of SOCS5 in liver cancer. We further investigated the mechanism by which SOCS5 contributes to tumorigenesis, demonstrated that this SOCS5/miR-18a/miR-25 axis regulates the tumor suppressor TSC1 and downstream mTOR signaling, and highlighted the potential therapeutic use of miR-18a and miR-25 inhibition in restoring SOCS5 levels in HCC.     

MicroRNA-221 and microRNA-222 regulate gastric carcinoma cell proliferation and radioresistance by targeting PTEN

Background  

MicroRNAs (miRNAs) can function as either oncogenes or tumor suppressor genes via regulation of cell proliferation and/or apoptosis. MiR-221 and miR-222 were discovered to induce cell growth and cell cycle progression via direct targeting of p27 and p57 in various human malignancies. However, the roles of miR-221 and miR-222 have not been reported in human gastric cancer. In this study, we examined the impact of miR-221 and miR-222 on human gastric cancer cells, and identified target genes for miR-221 and miR-222 that might mediate their biology.     

miRNA-34a is associated with docetaxel resistance in human breast cancer cells

Docetaxel is a chemotherapy drug to treat breast cancer, however as with many chemotherapeutic drugs resistance to docetaxel occurs in 50% of patients, and the underlying molecular mechanisms of drug resistance are not fully understood. Gene regulation through microRNAs (miRNA) has been shown to play an important role in cancer drug resistance. By directly targeting mRNA, miRNAs are able to inhibit genes that are necessary for signalling pathways or drug induced apoptosis rendering cells drug resistant. This study investigated the role of differential miRNA expression in two in vitro breast cancer cell line models (MCF-7, MDA-MB-231) of acquired docetaxel resistance. MiRNA microarray analysis identified 299 and 226 miRNAs altered in MCF-7 and MDA-MB-231 docetaxel-resistant cells, respectively. Docetaxel resistance was associated with increased expression of miR-34a and miR-141 and decreased expression of miR-7, miR-16, miR-30a, miR-125a-5p, miR-126. Computational target prediction revealed eight candidate genes targeted by these miRNAs. Quantitative PCR and western analysis confirmed decreased expression of two genes, BCL-2 and CCND1, in docetaxel-resistant cells, which are both targeted by miR-34a. Modulation of miR-34a expression was correlated with BCL-2 and cyclin D1 protein expression changes and a direct interaction of miR-34a with BCL-2 was shown by luciferase assay. Inhibition of miR-34a enhanced response to docetaxel in MCF-7 docetaxel-resistant cells, whereas overexpression of miR-34a conferred resistance in MCF-7 docetaxel-sensitive cells. This study is the first to show differences in miRNA expression, in particular, increased expression of miR-34a in an acquired model of docetaxel resistance in breast cancer. This serves as a mechanism of acquired docetaxel resistance in these cells, possibly through direct interactions with BCL-2 and CCND1, therefore presenting a potential therapeutic target for the treatment of docetaxel-resistant breast cancer.     

Circular RNA CEP128 promotes bladder cancer progression by regulating Mir-145-5p/Myd88 via MAPK signaling pathway

The present experiment was designed for exploring the regulatory mechanism of circ-CEP128/miR-145-5p/MYD88 axis in bladder cancer. MiRNAs and circRNAs expression data were derived from Gene Expression Omnibus database with bladder tumor tissues and paracarcinoma tissue samples. Differentially expressed genes in tumor were analyzed via R software. Interaction network of differently expressed miRNAs and differently expressed mRNA was established by means of Cytoscape software. CircCEP128 and miR-145-5p expression levels were determined using qRT-PCR. The expression of MAPK signaling-related proteins MYD88, p38, ERK and JNK was examined by western blot. The relationship between circCEP128 and miR-145-5p was validated using RNA immunoprecipitation. The level of cell propagation and migration was determined by CCK8 and wound healing assay, 5-bromo-2′-deoxyuridine assay and migration assay. Cell apoptosis rate and cell cycle were detected via flow cytometry. Tumor xenograft assay was implemented to investigate the function of circCEP128 in vivo. CircCEP128 and MYD88 were overexpressed in bladder cancer based on microarray analysis and miR-145-5p was a potential targeting factor in bladder cancer. CircCEP128 targeted miR-145-5p and miR-145-5p targeted MYD88. Expression of miR-145-5p was decreased in cancer samples. Knockdown of circCEP128 induced the inhibition of cell viability and mobility and cell cycle arrest. Overexpression of miR-145-5p or knockdown of circCEP128 promoted MAKP signaling pathway and related proteins expression. In addition, knockdown of circCEP128 suppressed the growth of bladder cancer tumor tissues in vivo. Overexpression of circCEP128 promoted bladder cancer progression through modulating miR-145-5p and MYD88 via MAKP signaling pathway.     

MiR-219-5p对人脑成胶质细胞瘤恶性表型的影响

目的:探讨miR-219-5p对人脑成胶质细胞瘤(glioblastoma,GBM)的恶性表型——增殖、凋亡和侵袭的影响,初步寻找与miR-219-5p发挥抑癌作用有关的靶点基因.方法:在60例GBM组织中分析miR-219-5p表达水平及mRNA表达谱,筛选与miR-219-5p表达量呈负相关的mRNA;选取前50个相关性最大的mRNA,用基因功能分析软件DAVID从中筛选出与GBM恶性进展相关的2组mRNA;最后用4个在线靶点预测网站从这2组中预测miR-219-5p的潜在靶点.采用MTT法、流式细胞术和Transwell实验初步验证miR-219-5p对GBM细胞增殖、凋亡和侵袭的影响.结果:60例GBM组织中筛出14个与增殖和凋亡相关的基因和5个与侵袭相关的基因(P＜0.001);在这19个候选基因中预测到4个基因(TWIST1、MYO1B、WEE1和SPRED2)是miR-219-5p的潜在靶点.实验初步证明,miR-219-5p能够抑制GBM细胞的增殖和侵袭以及促进细胞凋亡(P＜0.05).结论:MiR-219-5p可能通过作用于多个靶点对GBM的恶性表型起到抑制作用.     

miR-485-5p在恶性肿瘤中的研究进展

MicroRNAs(miRNAs)是一类长度约22个核苷酸的非编码RNA,在基因表达调控中,参与多种重要的生理和病理过程。miRNAs能够特异性结合靶基因序列,抑制基因的转录或翻译,从而抑制基因在转录或转录后水平上的表达。miRNAs作为肿瘤抑制因子或促进因子在癌症发生发展中经常失调。最近的研究发现miR-485-5p在多种癌症中表达下调,并调控肿瘤细胞生长、增殖、侵袭和迁移。miR-485-5p在肿瘤诊断、治疗及预后相关方面可作为具有潜在价值的肿瘤标志物,并有望成为临床肿瘤靶向治疗的新的治疗靶点。本文围绕miR-485-5p在肝癌、胃癌、乳腺癌及其他恶性肿瘤中的研究进展展开综述并对其未来应用和发展进行展望。     

MicroRNA-424 inhibits Akt3/E2F3 axis and tumor growth in hepatocellular carcinoma

By comparing the expression profiles of miRNAs in different subtypes of HCC, we identified miR-424 as a HCC related miRNA. We found that the expression of miR-424 was significantly decreased in HCC tissues and six liver cancer cell lines. Significantly, its expression levels were correlated with tumor size, multiple nodules, vein invasion, TNM stage and overall survival of HCC. We showed that up-regulated miR-424 suppressed HCC cell proliferation in vivo and in vitro. Multi-pathway reporter arrays suggested that miR-424 suppressed the pRb-E2F pathway. Consistently, Akt3 and E2F3 were identified as the targets of miR-424 as evidenced by that ectopic miR-424 expression suppressed Akt3 and E2F3 expressions. Silencing Akt3 and E2F3 by siRNA pheno-copied the effect of ectopic miR-424 on HCC growth. Whereas, overexpression of Akt3 and E2F3 attenuated the effect of miR-424 on HCC growth. Together, our data demonstrated a tumor suppressor role for miR-424 in HCC development and progression with therapeutic implications. The strong correlation of miR-424 expression with HCC patient survival suggests that miR-424 could be a valuable biomarker for HCC prognosis.     

MicroRNA-126 inhibits invasion in bladder cancer via regulation of ADAM9

Background:

The miRNA deregulation is commonly observed in human malignancies, where they act as tumour suppressors or oncogenes. Despite the association of several miRNAs with bladder cancer, little is known about the miRNAs that contribute to bladder cancer progression from non-muscle invasive (NMI) to muscle-invasive (MI) disease.

Methods:

We first profiled the expression of miRNAs and mRNAs in a cohort of urothelial carcinomas and further characterised the role of miR-126 in invasion, as it emerged as the most downregulated miRNA between MI and NMI tumours.

Results:

We found that restoration of miR-126 levels attenuated the invasive potential of bladder cancer cells. Mechanistically, we identified the role of miR-126 in invasion through its ability to target ADAM9. Notably, a significant inverse correlation between miR-126 and ADAM9 expression was observed, where ADAM9 was upregulated in MI bladder cancer cells. While knockdown of ADAM9 attenuated the invasiveness of cells with low miR-126 levels, experimental upregulation of ADAM9 recapitulated the invasive phenotype. Furthermore, ADAM9 expression assessed by immunohistochemistry significantly correlated with poor prognosis in patients with urothelial carcinoma.

Conclusions:

In this study we describe the role of miR-126 in bladder cancer progression, identifying miR-126 and ADAM9 as potential clinical biomarkers of disease aggressiveness.     

MiR-25 regulates apoptosis by targeting Bim in human ovarian cancer

MicroRNAs (miRNAs) are emerging as a class of small regulatory RNAs whose alterations are implicated in the initiation and progression of human cancers. Our study showed that miR-25 was highly expressed both in clinical ovarian cancer samples and cell lines. Down-regulation of miR-25 in ovarian cancer cells induced apoptosis whereas overexpression of miR-25 enhanced cell proliferation. The effects of miR-25 abrogation were partly mediated by the intrinsic apoptosis pathway. Many pro-apoptotic proteins such as Bim, Bax and caspase-3 were up-regulated after transfection. Furthermore, luciferase assays demonstrated that Bim was the direct target of miR-25. Introducing Bim cDNA without 3'UTR abrogated miR-25-induced cell survival. Finally, there was an inverse relationship between Bim and miR-25 expression in ovarian cancer tissues. Taken together, these data indicate that miR-25 directly regulates apoptosis by targeting Bim in ovarian cancer and that miR-25 could be a potential therapeutic target for ovarian cancer intervention.