miR-21与消化系统肿瘤

microRNA（miRNA）是一类内源性非编码蛋白短链RNA,参与细胞增殖、分化、凋亡等多种重要活动的调控。近来研究发现miRNA具有癌基因或抑癌基因样作用,参与多种恶性肿瘤的演进,是肿瘤发生、发展过程中的重要分子,其中miR-21最受关注。miR-21在消化系统肿瘤如食管癌、胃癌、肝癌、胆管癌、胰腺癌、结直肠癌等的细胞或组织中表达上调,发挥着类似于癌基因的作用。miR-21通过对靶基因的调控,增强了肿瘤细胞的增殖、浸润及转移能力,并与消化系统肿瘤患者的无复发时间与总生存时间密切相关。目前体外研究证实,miR-21抑制物能够提高恶性肿瘤细胞对化疗药物的敏感性,使化疗药物的杀伤肿瘤效果更加明显,而miR-21类似物,可抵消一部分化疗药物的疗效,从而提示抑制miR-21的表达或阻碍miR-21与靶基因的相互作用在消化系统肿瘤的治疗中具有广阔的应用前景。本文就miR-21在消化系统肿瘤的调控机制、增殖与凋亡、侵袭、耐药与转移中的作用,及其临床价值作一综述。      

微小RNA-30a:肿瘤治疗的潜在靶点

微小RNA(miRNA)是长约20~25个核苷酸的内源性非编码RNA,主要通过抑制mRNA翻译和诱导mRNA降解而调节靶基因的表达,人类大约30%的基因受miRNAs调节。研究发现,大量miRNAs在肿瘤中表达失调,常常引起多种重要过程的紊乱,包括细胞增殖、侵袭与转移、凋亡以及耐药等。在肿瘤的发生过程中,不同的miRNA可能起着类似抑癌基因或者癌基因的作用,参与调节肿瘤细胞发生、发展等过程。miR-30a是miRNA的成员之一,通过调节靶基因的表达,参与调控肿瘤细胞增殖、转移和凋亡等过程。不同肿瘤血清中miR-30a的表达水平对肿瘤的早期诊断、治疗以及预后判断有着重要作用。此外,miR-30a的表达失调还与抗肿瘤药物耐药性的产生密切相关,推测其有望成为肿瘤治疗的一个潜在新靶标。本文就近年来miR-30a在肿瘤中作用的最新研究进展作一综述。     

miR-221和miR-222在肿瘤中的研究进展

 由于微小RNA(miRNA)在肿瘤中发挥重要调控作用及其自身特点,使其可能成为基因靶向治疗的有效工具。因此,人们致力于寻找调节关键癌基因或抑癌基因的miRNA。研究发现miR-221及miR-222在多种人类肿瘤中不仅表达异常,而且在不同类型的肿瘤中也发挥着不同的癌基因或抑癌基因样作用,通过调控miR-221和miR-222的表达可能成为肿瘤治疗的有效方法。     

microRNA-196a与肿瘤相关性的研究进展

microRNA-196a(miR-196a)作为miRNA家族中的成员之一,近年来受到了广泛关注。miR-196a不但在多种生物学过程中起重要的调控作用,同时还有研究表明在肿瘤的发生发展中miR-196a还发挥类似癌基因的功能。研究发现,miR-196a在肿瘤患者的血清、组织及细胞中呈高表达,而且能够促进肿瘤细胞增殖、侵袭及转移,抑制肿瘤细胞凋亡,增强肿瘤耐药性。本文结合国内外最新报道对miR-196a与肿瘤相关性研究进展做一综述。     

miR-21作用于PTEN与肿瘤耐药关系的研究进展

miRNA(microRNA)是一类非编码的微小RNA,其成熟体通过与靶mRNA 3' 端非编码区特异性结合,可在翻译和转录后水平调控靶基因的表达。有研究表明miRNA与细胞的发展、分化、凋亡和增殖有着密切的关系。miR-21(microRNA-21)作为miRNA的一个重要分子,在肿瘤的形成和耐药中发挥着重要作用。在众多耐药肿瘤细胞中,miR-21通过下调靶基因PTEN从而抑制肿瘤细胞的凋亡,增加肿瘤细胞的生长、转移和侵袭。本文就miR-21通过作于其靶基因PTEN与肿瘤耐药的关系作一综述。     

miR-21与肿瘤

MicroRNA（miRNA）是一类具有调控功能的小分子非编码RNA,主要参与基因转录后水平的调控,对生物体的生长、发育、衰老和死亡等生命过程都有着重要的作用。近年来,大量研究结果表明,许多miRNA可作为原癌基因或者抑癌基因,在肿瘤的发生和发展中扮演着重要的角色,其中miR-21最受人重视。大量实验证明在多种肿瘤细胞中,miR-21的表达均出现显著异常,揭示miR-21作为一个致癌miRNA,在多种肿瘤的发生和发展中起着重要的作用。本文综述了miR-21在肿瘤细胞中调控的靶基因及其功能,以及miR-21自身的表达调控机制研究进展,这将为miR-21在肿瘤的诊断、治疗和预后判断中的应用提供重要资料。     

上皮性卵巢癌中microRNA的研究进展

非编码短序列RNA(microRNA,miRNA)是一类长度约为21～22个核苷酸的短序列、非编码、具有调控作用的单链RNA分子,可以在转录水平后调控mRNA的表达.作为一个重要的基因调节因子,miRNA在肿瘤中发挥癌基因或抑癌基因样作用,与肿瘤癌细胞的增殖、凋亡、转移、耐药等机制密切相关.卵巢癌是严重威胁女性健康的常见恶性肿瘤之一,在女性肿瘤中病死率居第5位,因病灶隐匿,不易早期发现,故发现时多为晚期,5年生存率低.随着miRNA在肿瘤中的深入研究,miRNA在卵巢癌中存在差异表达,其与卵巢癌的作用日渐明朗,有望成为新一代敏感的肿瘤标志物,并通过对其靶基因的研究,最终达到早期诊断及提高卵巢癌治疗效果的目的.     

miR-19与肿瘤

 miR-17~92基因簇编码6种成熟的miRNA,包括miR-17、miR-20a、miR-18a、miR-19a、miR-19b和miR-92a-1,是一类典型的致癌多作用子miRNA。miR-19（包括miR-19a和miR-19b）是其中最重要的致癌miRNA,在淋巴瘤、白血病、肺癌、乳腺癌、多发性骨髓瘤等肿瘤中均表达上调,成为研究的热点之一。miR-19可通过抑制靶基因如PTEN、PP2A、Bim、SOCS1等促进肿瘤的增殖、侵袭和转移,与PI3K-AKT-mTOR信号转导通路关系密切,在肿瘤的发生发展中起着非常重要的作用。     

miR-181b在恶性肿瘤中的研究进展

miRNA是一种存在于真核生物中的内源性非编码短链RNA,具有极其复杂的调控机制,可对肿瘤的发生发展起到广泛调节的作用,即可作为致瘤因子,亦可作为抑瘤因子。随着对miRNA研究的不断深入,miR-181b在恶性肿瘤中的表达已成为医学领域关注的热点问题。研究表明,miR-181b存在多个靶点,每个靶基因又参与调控多种细胞功能,从而在恶性肿瘤的增殖、凋亡、侵袭、转移及耐药等过程中起到错综复杂的作用。而且它还对肿瘤的早期诊断有预测作用。本文就miR-181b在恶性肿瘤中的研究进展作一综述。     

miR-199a-3p在乳腺癌中的表达及其作用

背景与目的：多种微小RNA(microRNA,miRNA)在乳腺癌中异常表达,在乳腺癌的发生、发展中起重要作用。miRNA可能是治疗乳腺癌的新靶点。该研究旨在探讨miR-199a-3p在乳腺癌中的表达水平,及其对乳腺癌癌细胞增殖和凋亡的影响。方法：运用实时定量聚合酶链式反应(quantitative real-time polymerase chain reaction,QRT-PCR)检测乳腺癌患者癌组织、癌旁正常组织、人乳腺癌细胞和人乳腺细胞中miRNA-199a-3p的表达水平,miR-199a-3p mimic(或inhibitor)转染乳腺癌细胞MDA-MB-231过表达(或沉默)miR-199a-3p的表达后,通过MTT法检测细胞增殖能力,Hoechst染色法和caspase-3活力测试检测细胞凋亡情况。结果：相对癌旁正常组织和人正常乳腺细胞,miR-199a-3p在乳腺癌患者癌组织和人乳腺癌细胞中表达下调。在MDA-MB-231中转染miR-199a-3p mimic过表达miR-199a-3p可抑制细胞增殖,促进其凋亡;在MDA-MB-231中转染miR-199a-3p inhibitor沉默miR-199a-3p可促进细胞增殖,抑制其凋亡。结论：miR-199a-3p在乳腺癌中表达下调,并通过调节乳腺癌细胞增殖和凋亡发挥抑癌作用。     

miR-199a通过下调ITGA3抑制卵巢癌细胞的增殖、迁移与侵袭

目的:探讨miR-199a对卵巢癌细胞增殖、迁移与侵袭的作用及机制。方法:采用qRT-PCR和Western blot分别检测卵巢癌组织和细胞中miR-199a和整合素α3（integrin alpha 3，ITGA3）的表达。将miR-199a mimic转染入CAR3细胞后，双荧光素酶报告基因实验、Western blot检测miR-199a对ITGA3的调控作用；MTT和Transwell实验研究了miR-199a和ITGA3对CAR3细胞增殖、迁移与侵袭的作用。结果:卵巢癌组织和细胞中miR-199a表达降低（P＜0.01），ITGA3表达增加（P＜0.01）。双荧光素酶报告基因实验结果显示miR-199a与ITGA3 3'-UTR有结合作用。Western blot结果证实miR-199a可抑制ITGA3表达（P＜0.01）。miR-199a过表达抑制CAR3细胞增殖、迁移与侵袭（P＜0.01）；而过表达ITGA3能逆转miR-199a过表达的作用（P＜0.01）。结论:miR-199a抑制卵巢癌细胞增殖、迁移与侵袭的作用可能与其通过下调靶基因ITGA3表达相关。     

miR-199-3p通过对FGF2的调控抑制肝癌细胞MHCC97H的增殖、迁移作用及机制

目的:探讨miR-199-3p通过靶向调控抑制靶基因FGF2从而抑制肝癌MHCC97H细胞的增殖和迁移及机制。方法:qRT-PCR检测癌旁正常组织及肝癌肿瘤组织中miR-199-3p的表达水平;Transwell细胞侵袭实验检测肝癌细胞株Huh7、MHCC-97L、SMMC7721、HepG2和MHCC97H株其侵袭能力;qRT-PCR检测miR-199-3p在5株肝癌细胞系中的表达量;通过生物信息软件预测靶基因FGF2 mRNA 3' UTR的碱基存在miR-199-3p可能互补结合的位点并用荧光报告基因法及WB进行验证;通过qRT-PCR、免疫组化及Western blot检测FGF2在肝癌肿瘤组织和癌旁正常组织及各类肝癌细胞株表达的影响;Transwell、划痕、CCK8及流式细胞法检测miR-199-3p与FGF2对肝癌MHCC97H细胞增殖、侵袭、迁移及周期S期聚集能力的调控;采用MHCC97H细胞构建肝癌肿瘤异种移植小鼠模型进行肿瘤观测及免疫组化实验验证miR-199-3p对肝癌的调控作用。结果:miR-199-3p的表达水平与肝癌细胞侵袭转移能力相关;miR-199-3p能够通过抑制FGF2的mRNA翻译,抑制FGF2蛋白水平表达;FGF2与肝癌细胞侵袭转移能力相关;miR-199-3p可以负调控FGF2抑制肝癌MHCC97H细胞的生物行为;miR-199-3p 可抑制肝癌细胞中阳性信号,细胞增殖水平显著降低。结论:miR-199-3p通过抑制FGF2抑制肝癌细胞MHCC97H的增殖和迁移。     

MicroRNA signatures in human ovarian cancer

Epithelial ovarian cancer (EOC) is the sixth most common cancer in women worldwide and, despite advances in detection and therapies, it still represents the most lethal gynecologic malignancy in the industrialized countries. Unfortunately, still relatively little is known about the molecular events that lead to the development of this highly aggressive disease. The relatively recent discovery of microRNAs (miRNA), a class of small noncoding RNAs targeting multiple mRNAs and triggering translation repression and/or RNA degradation, has revealed the existence of a new level of gene expression regulation. Multiple studies involving various types of human cancers proved that miRNAs have a causal role in tumorigenesis. Here we show that, in comparison to normal ovary, miRNAs are aberrantly expressed in human ovarian cancer. The overall miRNA expression could clearly separate normal versus cancer tissues. The most significantly overexpressed miRNAs were miR-200a, miR-141, miR-200c, and miR-200b, whereas miR-199a, miR-140, miR-145, and miR-125b1 were among the most down-modulated miRNAs. We could also identify miRNAs whose expression was correlated with specific ovarian cancer biopathologic features, such as histotype, lymphovascular and organ invasion, and involvement of ovarian surface. Moreover, the levels of miR-21, miR-203, and miR-205, up-modulated in ovarian carcinomas compared with normal tissues, were significantly increased after 5-aza-2'-deoxycytidine demethylating treatment of OVCAR3 cells, suggesting that the DNA hypomethylation could be the mechanism responsible for their overexpression. Our results indicate that miRNAs might play a role in the pathogenesis of human EOC and identify altered miRNA gene methylation as a possible epigenetic mechanism involved in their aberrant expression.     

miR-199b在肿瘤中研究的新进展

MicroRNA是一类内源性非编码小RNA,它通过部分或完全互补与mRNA结合引起mRNA降解或翻译抑制从而导致靶基因表达受抑。研究发现miR-199b表达水平的异常与多种疾病有关,尤其是在肿瘤的发生、发展、转移、侵袭等过程中具有重要意义。miR-199b在一些肿瘤中很可能成为诊断肿瘤的标志物,而且还可能为治疗肿瘤提供新靶点。本文主要对miR-199b在各种肿瘤中的作用及其机制加以阐述。     

miR-19a Promotes Cell Growth and Tumorigenesis throughTargeting SOCS1 in Gastric Cancer

Accumulating evidence has shown that microRNAs are involved in cancer development and progression.However, it remains unknown about the potential role of miR-19a in the pathogenesis of gastric cancer. Here, wereport that suppressor of cytokine signaling 1 (SOCS1) is a novel target of miR-19a in gastric cancer cells andthat miR-19a expression is inversely correlated with SOCS1 expression in gastric cancer cells and a subset ofgastric cancer tissues. Ectopic expression of miR-19a dramatically promoted proliferation and tumorigenicity ofgastric cancer cells both in vitro and in vivo. Moreover, we showed that silencing of SOCS1 promoted cell growthand colony formation resembling that of miR-19a overexpression, whereas re-introduction of SOCS1 (withoutthe 3’-UTR) attenuated the pro-tumorigenic functions. Taken together, our findings suggest that the SOCS1gene is a direct target of miR-19a, which functions as an oncogenic miRNA in gastric cancer by repressing theexpression of tumor suppressor SOCS1.     

Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer

Axl is a receptor that induces proliferation, migration and invasion in cancer. In this study, we show that specific microRNAs (miRNAs) target the 3'-UTR of Axl. Luciferase-reporter assays with wild-type and deleted miR-34 and miR-199a/b seed sequences of Axl 3'-UTR confirmed the specificity of targeting. An inverse correlation between Axl protein and miR-34a expression in a panel of non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and breast cancer (BRC) cell lines was observed, while miR-199a/b expression was completely suppressed. Pre-miR transfection inhibited in vitro migration and invasion and, in vivo, reduced the number of distant lung- or liver-metastases in a chorion-allantoic-membrane (CAM) assay. Moreover, methylation-specific PCR on bisulfite-converted DNA obtained from the cell lines showed that the miR-34a promoter methylation status was inversely correlated with its expression, and that miR-199a/b promoter regions were methylated in all cells tested. In a panel of NSCLC tissues (n=44), miR-34a and miR-199a/b were found to be downregulated and significantly co-expressed. A lower expression of all three miRs was significantly associated with squamous histotypes, and, in a preliminary series, NSCLC patients with miR-34a upregulation showed a positive association towards a longer survival. These results indicate that Axl receptor expression can be regulated by miR-34a and miR-199a/b, which are suppressed by promoter methylation in solid cancer cells.     

miR-199a-3p inhibits hepatocyte growth factor/c-Met signaling in renal cancer carcinoma

MicroRNAs (miRNAs) are a class of small non-coding RNAs that bind protein-coding mRNAs and negatively regulate protein expression by translation repression or mRNA cleavage. Accumulating evidence suggests that miRNAs are involved in cancer development and progression, acting as either tumor suppressors or oncogenes. It has been shown that miR-199a-3p was significantly down-regulated in several types of cancers. However, its role and relevance in renal cell carcinoma (RCC) are still largely unknown. Here, we show that miR-199a-3p is significantly down-regulated in human RCC primary tumors and cell lines compared to their non-tumor counterparts. Moreover, the down-regulation of miR-199a-3p is correlated with the histological grade and TNM (tumor–lymph node–metastasis) stage of RCC. Reintroducing miR-199a-3p in RCC cell lines 769-P and Caki-1 inhibited cell proliferation and caused G1 phase arrest. We found that c-Met was up-regulated in RCC cell lines and its expression could be repressed by miR-199a-3p. Moreover, c-Met was up-regulated in RCC primary tumors and reversely correlated with miR-199a-3p expression in the same paired RCC tissues. Reintroducing miR-199a-3p inhibited c-Met expression and led to attenuated activation of c-Met downstream signaling pathways including STAT3, mTOR and ERK1/2. We found that the concentrations of serum hepatocyte growth factor (HGF), the ligand of c-Met receptor, were significantly elevated in RCC patients compared to healthy persons. In addition, HGF treatment could promote proliferation of RCC cells, and the increased cell proliferation was abrogated by miR-199a-3p. Our findings indicated that miR-199a-3p target HGF/c-Met signaling pathway which is crucial for RCC development and suggest that miR-199a-3p may serve as a potential target miRNA for RCC therapy.     

The hypoxia-related microRNA miR-199a-3p displays tumor suppressor functions in ovarian carcinoma

During the dissemination of ovarian cancer cells, the cells float in the peritoneal cavity without access to a vascular supply and so are exposed to hypoxic conditions, which may cause the ovarian cancer cells to acquire a more aggressive and malignant phenotype. In this study, we screened microRNAs (miRNAs) to identify those that displayed altered expression patterns under hypoxic conditions and then analyzed their functional roles in ovarian cancer progression. miRNA PCR arrays performed on cells from 2 ovarian cancer cell lines (CaOV3 and RMUG-S) revealed miR-199a-3p as one of the miRNAs that are downregulated under hypoxia. In silico analyses indicated that MET is one of the target genes for miR-199a-3p; subsequently, miR-199a-3p expression was found to be inversely correlated with c-Met expression in ovarian cancer. Transfection of precursor miR-199a-3p into ovarian cancer cells reduced c-Met expression and inhibited the phosphorylation of c-Met, extracellular signal-regulated kinase, and AKT; in addition, proliferation, adhesion, and invasiveness were inhibited. Moreover, overexpression of miR-199a-3p in cancer cells significantly suppressed peritoneal dissemination in a xenograft model. In summary, the hypoxia-related microRNA miR-199a-3p drastically inhibits ovarian cancer progression through the downregulation of c-Met expression. Therefore, miR-199a-3p is a potential target for treating ovarian cancer dissemination.