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Suppression of SHIP2 contributes to tumorigenesis and proliferation of gastric cancer cells via activation of Akt

  • Original Article—Alimentary Tract
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Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 81301738), Anhui Provincial Natural Science Foundation (No. 1408085QH150), Anhui Medical University Training Program of National Outstanding Youth Foundation (No. GJYQ-1402), Research Fund of Anhui Medical University (No. XJ201328), and National Undergraduate Training Programs for Innovation and Entrepreneurship-China (No. 201410366023). We thank David B. Alexander for manuscript review and English checking.

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Authors and Affiliations

  1. Department of Immunology, Anhui Medical University, Hefei, 230032, Anhui, China

    Yan Ye, Yan Mei Ge, Miao Miao Xiao, Li Mei Guo, Qun Li, Wang Lai Hu, Jiegou Xu & Lin Jie Zhang

  2. Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China

    Ji Qing Hao & Jie Da

  3. School of Medicine and Public Health, The University of Newcastle, Newcastle, NSW, 2308, Australia

    Xu Dong Zhang

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  1. Yan Ye
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Correspondence to Jiegou Xu or Lin Jie Zhang.

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Electronic supplementary material

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535_2015_1101_MOESM1_ESM.pdf

This information includes: Table S1 Relationship between SHIP2 expression and clinicopathologic characteristics of GC; Fig. S1 The intracellular localization of SHIP2 in normal gastric mucosa tissues was detected by immunohistochemistry analysis; Fig S2 Expression of SHIP2 in intestinal metaplasia of stomach was detected by immunohistochemistry analysis; and Fig.S3 Migration of MGC-803.SHIP2 cells and their corresponding counterparts was measured by wound-healing assays. (PDF 465 kb)

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Ye, Y., Ge, Y.M., Xiao, M.M. et al. Suppression of SHIP2 contributes to tumorigenesis and proliferation of gastric cancer cells via activation of Akt. J Gastroenterol 51, 230–240 (2016). https://doi.org/10.1007/s00535-015-1101-0

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  • DOI: https://doi.org/10.1007/s00535-015-1101-0

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