Ye Yan, Ge Yan Mei, Xiao Miao Miao, Guo Li Mei, Li Qun, Hao Ji Qing, Da Jie, Hu Wang Lai, Zhang Xu Dong, Xu Jiegou, Zhang Lin Jie
Department of Immunology, Anhui Medical University, Hefei, 230032, Anhui, China.
Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
J Gastroenterol. 2016 Mar;51(3):230-40. doi: 10.1007/s00535-015-1101-0. Epub 2015 Jul 23.
The 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.
The 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.
SHIP2 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.
This 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.
含Src同源2结构域的肌醇5-磷酸酶2（SHIP2）与糖尿病、动脉粥样硬化和癌症有关。然而，SHIP2在人类胃癌中的作用仍不清楚。
通过免疫组织化学（IHC）、蛋白质印迹法和实时定量逆转录聚合酶链反应（qRT-PCR）分析SHIP2在胃癌组织、一组胃癌细胞系和正常胃上皮细胞中的表达水平。对SHIP2过表达或SHIP2与Akt共过表达的胃癌细胞进行分析，以确定细胞增殖、集落形成、凋亡、细胞迁移和侵袭试验。对SHIP2敲低或SHIP2与Akt共敲低的正常胃上皮细胞进行非锚定依赖性生长试验。通过异种移植瘤形成试验检测SHIP2对体内肿瘤生长的影响。
与正常胃黏膜相比，SHIP2在胃癌中普遍下调，SHIP2过表达抑制胃癌细胞的增殖，诱导凋亡，抑制细胞运动和侵袭，并在体内延缓异种移植胃肿瘤的生长，而在正常胃上皮细胞中敲低SHIP2则促进非锚定依赖性生长。此外，SHIP2过表达使Akt失活，并上调p21、p27和促凋亡蛋白Bim。在胃癌细胞中恢复Akt激活在很大程度上阻断了SHIP2对PI3K/Akt信号通路的抑制，并逆转了SHIP2对肿瘤发生和增殖的抑制作用。
本研究首次证明SHIP2在胃癌中经常下调，SHIP2表达降低通过激活PI3K/Akt信号通路促进胃癌的发生和增殖。
