MicroRNA-222-3p associated with Helicobacter pylori targets HIPK2 to promote cell proliferation, invasion, and inhibits apoptosis in gastric cancer
MicroRNA-222-3p associated with Helicobacter pylori targets HIPK2 to promote cell proliferation, invasion, and inhibits apoptosis in gastric cancer
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DOI：
10.1002/jcb.26542
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发表时间：
2018-07-01
影响因子：
4
通讯作者：
Jia, Yujie
中科院分区：
文献类型：
--
作者：
Tan, Xiaoyan;Tang, Haiying;Jia, Yujie
胃癌是世界范围内恶性肿瘤死亡的第二大原因，且多在晚期才被诊断出来。MicroRNA-222- 3 p（miR-222- 3 p）在包括胃癌在内的多种恶性肿瘤中异常上调，但其在胃癌中的作用和潜在的分子机制仍不清楚。幽门螺杆菌（H. pylori）感染是胃癌发生的一个诱因，越来越多的证据表明H. pylori影响microRNA表达。本研究将胃癌组织标本分为H. pylori阳性组（+）和阴性组（-）。QRT-PCR显示miR-222- 3 p在H. pylori（+）组与H. pylori（-）组，荧光素酶报告基因检测将同源域相互作用蛋白激酶2（HIPK 2）鉴定为胃癌中miR-222- 3 p的新靶点。免疫组化显示H. pylori（+）组与H. pylori（-）。功能实验表明，miR-222- 3 p过表达促进胃癌细胞的增殖和侵袭，抑制胃癌细胞的凋亡，而miR-222- 3 p敲低则表现出相反的作用。此外，HIPK 2敲低诱导的效果与miR-222- 3 p过表达在SGC 7901细胞中相似。裸鼠实验进一步表明，HIPK 2过表达信号减弱了miR-222- 3 p过表达对细胞增殖的增强作用，表明miR-222- 3 p对胃癌进展的作用至少部分依赖于HIPK 2。综上所述，我们的研究结果表明miR-222- 3 p/HIPK 2信号通路调控胃癌细胞的增殖、凋亡和侵袭，为H.幽门。
Gastric cancer ranks as the second leading cause of malignancy-related death worldwide, and always diagnosed at advanced stage. MicroRNA-222-3p (miR-222-3p) is aberrantly upregulated in various malignant tumors including gastric cancer, but its role and underlying molecular mechanisms in gastric cancer remain largely unknown. Helicobacter pylori (H. pylori) infection acts as a trigger in the development of gastric cancer, and increasing evidence suggests that H. pylori affects microRNA expression. In this study, gastric cancer tissue samples were divided into H. pylori positive group (+) and negative group (-). QRT-PCR showed that miR-222-3p was significantly upregulated in H. pylori (+) group compared with H. pylori (-) group, and luciferase reporter assays identified homeodomain-interacting protein kinase 2 (HIPK2) as a novel target of miR-222-3p in gastric cancer. Immunohistochemistry revealed that HIPK2 levels were decreased in H. pylori (+) group compared with H. pylori (-). After that, functional experiments indicated that miR-222-3p overexpression promoted the proliferation and invasion, while inhibiting apoptosis of SGC7901 gastric cancer cells, but miR-222-3p knockdown exhibited the opposite effects. Also, HIPK2 knockdown induced similar effects as miR-222-3p overexpression in SGC7901 cells. Nude mouse experiments further suggested that HIPK2 overexpression signally attenuated the enhancing effect of miR-222-3p overexpression on cell proliferation, indicating that the effect of miR-222-3p on gastric cancer progression depends on HIPK2, at least in part. Overall, our results demonstrated that miR-222-3p/HIPK2 signal pathway regulated gastric cancer cell proliferation, apoptosis, and invasion, provided a novel therapeutic target for the treatment of gastric cancer infected by H. pylori.