miR-21 plays a pivotal role in gastric cancer pathogenesis and progression
miR-21 plays a pivotal role in gastric cancer pathogenesis and progression
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miR-21在胃癌发病机制和进展中发挥着关键作用
DOI：
10.1038/labinvest.2008.94
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发表时间：
2008-12-01
影响因子：
5
通讯作者：
Lu, Hong
中科院分区：
文献类型：
--
作者：
Zhang, Zhiyu;Li, Zejuan;Lu, Hong
胃癌每年在全世界造成近100万人死亡。尽管幽门螺杆菌感染是约80%或更多胃癌的主要危险因素，但幽门螺杆菌感染导致胃癌发生的分子途径尚不清楚。最近越来越多的证据表明，microRNAs （miRNAs）可能调节多种生物过程，并可能在肿瘤发生中起重要作用。miR-21在各种肿瘤中经常被观察到异常过表达。通过TaqMan实时荧光定量PCR，我们证实miR-21在人胃癌组织和细胞系中显著过表达。值得注意的是，miR-21在幽门螺杆菌感染的胃粘膜中也显著过表达，这意味着胃癌中miR-21的过表达可能部分与幽门螺杆菌感染有关。更重要的是，我们发现，在人胃癌细胞系AGS细胞中，强迫表达miR-21可显著增强细胞增殖和侵袭，而抑制剂敲低miR-21可显著降低细胞增殖，显著增加细胞凋亡。此外，我们证明miR-21的敲低可显著降低AGS细胞的侵袭和迁移。最后，我们发现胃癌中已知的肿瘤抑制因子RECK是miR-21的真正靶点。综上所述，miR-21可能通过调节RECK在胃癌的发生和发展中发挥重要作用。我们的研究结果提示了一种潜在的调控途径，即幽门螺杆菌感染上调miR-21的表达，进而下调RECK的表达，从而导致胃癌的发生。
Gastric cancer causes nearly one million deaths worldwide per year. Although Helicobacter pylori infection is the main risk factor, in about 80% or more of gastric cancers, the molecular pathway underlying H. pylori infection leading to the development of gastric cancers remains unclear. Recently accumulating evidence suggests that microRNAs (miRNAs) may regulate diverse biological processes and may be important in tumorigenesis. miR-21 has been frequently observed to be aberrantly overexpressed in various tumors. Using TaqMan quantitative real-time PCR, we confirmed that miR-21 was significantly overexpressed in human gastric cancer tissues and cell lines. Remarkably, miR-21 was also significantly overexpressed in H. pylori-infected gastric mucosa, implying that overexpression of miR-21 in gastric cancer may be due in part to H. pylori infection. More importantly, we showed that forced expression of miR-21 significantly enhanced cell proliferation and invasion in AGS cells, a human gastric cancer cell line, whereas knockdown of miR-21 by inhibitor caused a significant reduction in cell proliferation and a significant increase in apoptosis. Furthermore, we demonstrated that knockdown of miR-21 significantly decreased cell invasion and migration of AGS cells. Finally, we showed that RECK, a known tumor suppressor in gastric cancer, is a bona fide target of miR-21. Taken together, miR-21 may be important in the initiation and progression of gastric cancers as an oncomiR, likely through regulating RECK. Our findings suggest a potential regulatory pathway in which H. pylori infection upregulates expression of miR-21, which in turn downregulates RECK, and then leads to the development of gastric cancer.