Suppression of SHIP2 contributes to tumorigenesis and proliferation of gastric cancer cells via activation of Akt
Suppression of SHIP2 contributes to tumorigenesis and proliferation of gastric cancer cells via activation of Akt
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抑制 SHIP2 通过激活 Akt 促进胃癌细胞的肿瘤发生和增殖
DOI：
10.1007/s00535-015-1101-0
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发表时间：
2016-03
影响因子：
6.3
通讯作者：
Zhang, Lin Jie
中科院分区：
文献类型：
--
作者：
Hu, Wang Lai;Zhang, Xu Dong;Xu, Jiegou;Zhang, Lin Jie
背景含Src同源2的肌醇5-磷酸酶2（SHIP 2）与糖尿病、关节硬化和癌症有关。然而，SHIP 2在人胃癌中的作用仍不清楚。MethodsSHIP 2在胃癌组织中的表达水平，一组胃癌细胞系，和正常胃上皮细胞通过免疫组化（IHC），Western blot和实时定量RT-PCR（qRT-PCR）进行了分析。分析过表达SHIP 2或共过表达SHIP 2和Akt的胃癌细胞以确定细胞增殖、集落形成、凋亡、细胞迁移和侵袭测定。通过锚定非依赖性生长测定对具有敲低的SHIP 2或共敲低的SHIP 2和Akt的正常胃上皮细胞进行处理。结果SHIP 2在胃癌组织中的表达普遍低于正常胃黏膜组织，SHIP 2的过表达在体外抑制胃癌细胞的增殖、诱导凋亡、抑制细胞的运动和侵袭，在体内抑制胃癌移植瘤的生长。而在正常胃上皮细胞中敲低SHIP 2促进锚定非依赖性生长。此外，SHIP 2的过表达使Akt失活，并上调p21、p27和促凋亡蛋白Bim。恢复Akt在胃癌细胞中的激活在很大程度上阻断了SHIP 2对PI 3 K/Akt信号的抑制作用，并逆转了SHIP 2对肿瘤发生和增殖的抑制作用。结论这项研究首次表明，SHIP 2在胃癌中经常下调，SHIP 2表达减少通过激活PI 3 K/Akt信号促进胃癌的发生和增殖。
BackgroundThe Src homology 2-containing inositol 5-phosphatase 2 (SHIP2) is implicated in diabetes, arthrosclerosis, and cancer. However, the role of SHIP2 in human gastric cancer remains unclear.MethodsThe expression levels of SHIP2 in gastric cancer tissues, a panel of gastric cancer cell lines, and normal gastric epithelial cells were analyzed by immunohistochemistry (IHC), Western blot, and real-time quantitative RT-PCR (qRT-PCR). Gastric cancer cells with either overexpressed SHIP2 or co-overexpressed SHIP2 and Akt were analyzed to determine cell proliferation, colony formation, apoptosis, cell migration, and invasion assays. Normal gastric epithelial cells with knockdown SHIP2 or co-knockdown SHIP2 and Akt were subjected by anchorage-independent growth assays. The effect of SHIP2 on tumor growth in vivo was detected by xenograft tumorigenesis assays.ResultsSHIP2 was commonly downregulated in gastric cancer compared with normal gastric mucosa, and overexpression of SHIP2 inhibited cell proliferation, induced apoptosis, suppressed cell motility and invasion in gastric cancer cells in vitro, and retarded the growth of xenograft gastric tumors in vivo, while knockdown of SHIP2 in normal gastric epithelial cells promoted anchorage-independent growth. Moreover, overexpression of SHIP2 inactivated Akt, and upregulated p21, p27, and the pro-apoptotic protein Bim. Restoring Akt activation in gastric cancer cells largely blocked the inhibition of PI3K/Akt signaling by SHIP2 and reversed the inhibitory effect of SHIP2 on tumorigenesis and proliferation.ConclusionsThis study demonstrates, for the first time, that SHIP2 is frequently downregulated in gastric cancer, and reduced SHIP2 expression promotes tumorigenesis and proliferation of gastric cancer via activation of the PI3K/Akt signaling.
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影响因子：
64.8
作者：
Colaluca, Ivan N.;Tosoni, Daniela;Di Fiore, Pier Paolo
通讯作者：
Di Fiore, Pier Paolo
影响因子：
11.2
作者：
Carracedo A;Alimonti A;Pandolfi PP
通讯作者：
Pandolfi PP
影响因子：
4.8
作者：
Kisseleva, MV;Cao, L;Majerus, PW
通讯作者：
Majerus, PW
影响因子：
4.8
作者：
Raaijmakers, Judith H.;Deneubourg, Laurence;Bos, Johannes L.
通讯作者：
Bos, Johannes L.
影响因子：
20.3
作者：
Ong, Christopher J.;Ming-Lum, Andrew;Mui, Alice L. -F.
通讯作者：
Mui, Alice L. -F.