RhoC is a major target of microRNA-93-5P in epithelial ovarian carcinoma tumorigenesis and progression.
RhoC is a major target of microRNA-93-5P in epithelial ovarian carcinoma tumorigenesis and progression.
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RhoC 是 microRNA-93-5P 在上皮性卵巢癌肿瘤发生和进展中的主要靶标
DOI：
10.1186/s12943-015-0304-6
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发表时间：
2015-02-04
期刊：
影响因子：
37.3
通讯作者：
Zhao Y
中科院分区：
文献类型：
--
作者：
Chen X;Chen S;Xiu YL;Sun KX;Zong ZH;Zhao Y
越来越多的证据表明，microRNA调节各种生物学过程，包括细胞分化、细胞增殖、细胞凋亡、耐药性和脂肪代谢。研究表明，miR-93在癌症中的靶组尚未完全确定。此外，miR-93在上皮性卵巢癌（EOC）中的作用仍然很大程度上未知。对正常卵巢组织、良性肿瘤、交界性肿瘤、原发性卵巢癌和转移性网膜中的MIR-93 mRNA表达进行定量。将miR-93- 5 P转染卵巢癌细胞株OVCAR 3、SKOV 3/DDP和HO 8910-PM，检测细胞表型和相关分子的表达。采用双荧光素酶报告基因分析和异种移植小鼠模型检测miR-93及其靶基因RHOC（Ras homolog gene family member C）。MIR-93 mRNA在卵巢癌和交界性肿瘤中的表达明显低于正常卵巢组织（p < 0.05），在转移性大网膜中的表达明显低于相对原发性卵巢癌（p < 0.05）。miR-93 mRNA的表达与卵巢癌的分化程度（良、差、中）、国际妇产科联盟分期（FIGO I/II期、III/IV期）呈负相关（p < 0.05），且在粘液腺癌中的表达高于其他类型（p < 0.05）。miR-93- 5 P过表达降低增殖（p < 0.05）;促进G1或S期阻滞和凋亡（p <0.05）;抑制迁移和侵袭（p < 0.05）;并降低RhoC、P70 S6激酶、Bcl-xL、基质金属蛋白酶9（MMP 9）mRNA或蛋白表达;相反，它诱导P53和切割PARP表达（p < 0.05）。双荧光素酶报告基因检测表明，miR-93通过与RhoC的3′端非翻译区结合而直接靶向RhoC。MiR-93- 5 P转染还在异种移植小鼠模型中体内抑制肿瘤发展和RhoC表达（通过免疫组织化学测定）（p < 0.05）。这是首次证明miR-93- 5 P可以通过靶向RhoC抑制EOC肿瘤发生和进展。这些发现表明miR-93- 5 P是卵巢细胞增殖的潜在抑制剂。miR-93- 5 P介导的RhoC下调参与抑制EOC侵袭性，可能为深入了解癌症侵袭性的分子机制提供更多信息。
An increasing amount of evidence has revealed that microRNAs regulate various biological processes, including cell differentiation, cell proliferation, apoptosis, drug resistance, and fat metabolism. Studies have shown that miR-93’s targetome in cancer has not been fully defined. Moreover, the role of miR-93 in epithelial ovarian carcinoma (EOC) remains largely unknown. MIR-93 mRNA expression in normal ovarian tissue, benign tumors, borderline tumors, primary ovarian carcinomas, and metastatic omentum was quantified. The ovarian carcinoma cell lines OVCAR3, SKOV3/DDP, and HO8910-PM were transfected with miR-93-5P, after which cell phenotype and expression of relevant molecules were assayed. Dual-luciferase reporter assay and a xenograft mouse model were used to examine miR-93 and its target gene RHOC (Ras homolog gene family member C). MIR-93 mRNA expression was significantly lower in ovarian carcinomas and borderline tumors than in normal ovarian tissues (p < 0.05), and was lower in metastatic omentum than in relative primary ovarian carcinomas (p < 0.05). MIR-93 mRNA expression was also negatively associated with differentiation (well vs. poor and moderate) and International Federation of Gynecology and Obstetrics staging (FIGO stage I/II vs. stage III/IV) in ovarian carcinoma (p < 0.05), besides, miR-93 was higher expressed in mucinous adenocarcinoma than the other types (p < 0.05). MiR-93-5P overexpression reduced proliferation (p < 0.05); promoted G1 or S arrest and apoptosis (p < 0.05); suppressed migration and invasion (p < 0.05); and reduced RhoC, P70S6 kinase, Bcl-xL, matrix metalloproteinase 9 (MMP9) mRNA or protein expression; conversely, it induced P53 and cleaved PARP expression (p < 0.05). Dual-luciferase reporter assay indicated that miR-93 directly targeted RhoC by binding its 3′ untranslated region. MiR-93-5P transfection also suppressed tumor development and RhoC expression (determined by immunohistochemistry) in vivo in the xenograft mouse model (p < 0.05). This is the first demonstration that miR-93-5P may inhibit EOC tumorigenesis and progression by targeting RhoC. These findings indicate that miR-93-5P is a potential suppressor of ovarian cellular proliferation. The involvement of miR-93-5P–mediated RhoC downregulation in inhibiting EOC aggressiveness may provide extended insight into the molecular mechanisms underlying cancer aggressiveness.
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影响因子：
3.7
作者：
Sanchez-Diaz PC;Hsiao TH;Chang JC;Yue D;Tan MC;Chen HI;Tomlinson GE;Huang Y;Chen Y;Hung JY
通讯作者：
Hung JY
影响因子：
11.5
作者：
Nam, Eun Ji;Yoon, Heejei;Kim, Sunghoon
通讯作者：
Kim, Sunghoon
影响因子：
4.8
作者：
Long, Jianyin;Wang, Yin;Danesh, Farhad R.
通讯作者：
Danesh, Farhad R.
DOI：
10.1158/1541-7786.mcr-08-0512
发表时间：
2009-11
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Islam M;Lin G;Brenner JC;Pan Q;Merajver SD;Hou Y;Kumar P;Teknos TN
通讯作者：
Teknos TN
影响因子：
7.3
作者：
Farazi, Thalia A.;Spitzer, Jessica I.;Morozov, Pavel;Tuschl, Thomas
通讯作者：
Tuschl, Thomas