MicroRNA-29c mediates initiation of gastric carcinogenesis by directly targeting ITGB1.
MicroRNA-29c mediates initiation of gastric carcinogenesis by directly targeting ITGB1.
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DOI：
10.1136/gutjnl-2013-306640
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发表时间：
2015-02
期刊：
影响因子：
24.5
通讯作者：
Yang HK
中科院分区：
文献类型：
--
作者：
Han TS;Hur K;Xu G;Choi B;Okugawa Y;Toiyama Y;Oshima H;Oshima M;Lee HJ;Kim VN;Chang AN;Goel A;Yang HK
胃癌（GC）由于临床挑战的异质性而难以治愈，并且这种疾病的分子机制复杂且尚未完全了解。越来越多的证据表明microRNAs（miRNAs）在胃癌中起着重要作用，但具体的miRNAs在胃癌中的作用尚不清楚。我们进行了基于下一代测序（NGS）的全转录组分析，以发现GC特异性miRNA，然后对结果进行功能验证。在GC和相邻正常粘膜（NM）的匹配对中产生基于NGS的miRNA谱。在274例胃组织中进行了miR-29 c表达的定量RT-PCR验证，其中包括2组匹配的GC和NM标本。在细胞系以及K19-C2mE和K19-Wnt 1/C2mE转基因小鼠中进行miR-29 c及其基因靶标的功能验证。NGS分析显示了四个GC特异性miRNA。胃癌组织中miR-29 c的表达显著低于癌旁正常组织（P<0.001）。miR-29 c模拟物在GC细胞系中的异位表达导致增殖、粘附、侵袭和迁移减少。高miR-29 c表达抑制裸鼠异种移植瘤生长。在细胞系和转基因小鼠中鉴定了miR-29 c与其新发现的靶点ITGB 1之间的直接相互作用。在GC的转基因小鼠模型中，miR-29 c表达在野生型-增生-发育不良级联中表现出逐步降低。miR-29 c通过直接靶向ITGB 1在GC中充当肿瘤抑制剂。miR-29 c表达缺失是胃癌发生的早期事件，可作为胃癌患者诊断和治疗的生物标志物。
Gastric cancer (GC) remains difficult to cure due to heterogeneity in a clinical challenge and the molecular mechanisms underlying this disease are complex and not completely understood. Accumulating evidence suggests that microRNAs (miRNAs) play an important role in GC, but the role of specific-miRNAs involved in this disease remains elusive. We performed next generation sequencing (NGS) based whole-transcriptome profiling to discover GC-specific miRNAs, followed by functional validation of results. NGS-based miRNA profiles were generated in matched pairs of GCs and adjacent normal mucosa (NM). Quantitative RT-PCR validation of miR-29c expression was performed in 274 gastric tissues, which included 2 cohorts of matched GC and NM specimens. Functional validation of miR-29c and its gene targets was undertaken in cell lines, as well as K19-C2mE and K19-Wnt1/C2mE transgenic mice. NGS analysis revealed four GC-specific miRNAs. Among these, miR-29c expression was significantly decreased in GC vs. NM tissues (P<0.001). Ectopic expression of miR-29c mimics in GC cell lines resulted in reduced proliferation, adhesion, invasion, and migration. High miR-29c expression suppressed xenograft tumor growth in nude mice. Direct interaction between miR-29c and its newly discovered target, ITGB1, was identified in cell lines and transgenic mice. MiR-29c expression demonstrated a step-wise decrease in wild type-hyperplasia-dysplasia cascade, in transgenic mice models of GC. MiR-29c acts as a tumor suppressor in GC by directly targeting ITGB1. Loss of miR-29c expression is an early event in the initiation of gastric carcinogenesis, and may serve as a diagnostic and therapeutic biomarker for patients with GC.
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影响因子：
24.5
作者：
Hur K;Cejas P;Feliu J;Moreno-Rubio J;Burgos E;Boland CR;Goel A
通讯作者：
Goel A
miR-29c在胃癌中被下调，并通过靶向RCC2来调节细胞增殖。
影响因子：
37.3
作者：
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通讯作者：
Moriyama M
影响因子：
4.4
作者：
Li SC;Liao YL;Ho MR;Tsai KW;Lai CH;Lin WC
通讯作者：
Lin WC
影响因子：
11.2
作者：
Kim YH;Liang H;Liu X;Lee JS;Cho JY;Cheong JH;Kim H;Li M;Downey TJ;Dyer MD;Sun Y;Sun J;Beasley EM;Chung HC;Noh SH;Weinstein JN;Liu CG;Powis G
通讯作者：
Powis G
影响因子：
24.5
作者：
Hur K;Toiyama Y;Takahashi M;Balaguer F;Nagasaka T;Koike J;Hemmi H;Koi M;Boland CR;Goel A
通讯作者：
Goel A