miRNA-100 Inhibits Human Bladder Urothelial Carcinogenesis by Directly Targeting mTOR
miRNA-100 Inhibits Human Bladder Urothelial Carcinogenesis by Directly Targeting mTOR
复制标题
miRNA-100 通过直接靶向 mTOR 抑制人膀胱尿路上皮癌变
DOI：
10.1158/1535-7163.mct-12-0273
复制
发表时间：
2013-02-01
影响因子：
5.7
通讯作者：
Sun, Yinghao
中科院分区：
文献类型：
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作者：
Xu, Chuanliang;Zeng, Qinsong;Sun, Yinghao
mirna作为肿瘤抑制因子或致癌基因参与了癌症的发生和发展。本研究利用20个GeneChip miRNA阵列对10对膀胱癌组织进行了miRNA谱分析，并在膀胱癌及其邻近非癌组织中发现了10个差异表达的miRNA。通过实时荧光定量PCR （qRT-PCR）在67对膀胱癌组织和10株人膀胱癌细胞系的扩大队列中进行验证，发现miR-100在癌组织中下调最为显著。在体外实验中，miR-100在膀胱癌细胞中的表达异位恢复可抑制细胞增殖和运动，诱导细胞周期阻滞，并在体内皮下和膀胱内通道中抑制肿瘤发生。生物信息学分析表明mTOR基因是miR-100的直接靶点。sirna介导的mTOR敲低在膀胱癌细胞系中表型化了miR-100的作用。此外，以原发性膀胱癌细胞系为基础建立的癌转移裸鼠模型表明，miR-100/mTOR调节细胞运动，与肿瘤转移有关。mTOR和p70S6K（下游信使）在远处转移灶（如肝和肾转移）中的表达水平均高于原发肿瘤。综上所述，miR-100可能在膀胱癌中起肿瘤抑制作用，将这种成熟的miRNA重新引入肿瘤组织可能是一种通过降低靶基因表达的治疗策略。巨蟹座；12 (2);207 - 19所示。AACR©2012。
miRNAs are involved in cancer development and progression, acting as tumor suppressors or oncogenes. In this study, miRNA profiling was conducted on 10 paired bladder cancer tissues using 20 GeneChip miRNA Array, and 10 differentially expressed miRNAs were identified in bladder cancer and adjacent noncancerous tissues of any disease stage/grade. After being validated on expanded cohort of 67 paired bladder cancer tissues and 10 human bladder cancer cell lines by quantitative real-time PCR (qRT-PCR), it was found that miR-100 was downregulated most significantly in cancer tissues. Ectopic restoration of miR-100 expression in bladder cancer cells suppressed cell proliferation and motility, induced cell-cycle arrest in vitro, and inhibited tumorigenesis in vivo both in subcutaneous and in intravesical passage. Bioinformatic analysis showed that the mTOR gene was a direct target of miR-100. siRNA-mediated mTOR knockdown phenocopied the effect of miR-100 in bladder cancer cell lines. In addition, the cancerous metastatic nude mouse model established on the basis of primary bladder cancer cell lines suggested that miR-100/mTOR regulated cell motility and was associated with tumor metastasis. Both mTOR and p70S6K (downstream messenger) presented higher expression levels in distant metastatic foci such as in liver and kidney metastases than in primary tumor. Taken together, miR-100 may act as a tumor suppressor in bladder cancer, and reintroduction of this mature miRNA into tumor tissue may prove to be a therapeutic strategy by reducing the expression of target genes. Mol Cancer Ther; 12(2); 207–19. ©2012 AACR.