title: Suppression of SHIP2 contributes to tumorigenesis and proliferation of gastric cancer cells via activation of Akt.
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.
authors.affiliation: Department of Immunology, Anhui Medical University, Hefei, 230032, Anhui, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Department of Immunology, Anhui Medical University, Hefei, 230032, Anhui, China.
authors.forename: Yan Mei
authors.initials: YM
authors.lastname: Ge
authors.affiliation: Department of Immunology, Anhui Medical University, Hefei, 230032, Anhui, China.
authors.forename: Miao Miao
authors.initials: MM
authors.lastname: Xiao
authors.affiliation: Department of Immunology, Anhui Medical University, Hefei, 230032, Anhui, China.
authors.forename: Li Mei
authors.initials: LM
authors.lastname: Guo
authors.affiliation: Department of Immunology, Anhui Medical University, Hefei, 230032, Anhui, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
authors.forename: Ji Qing
authors.initials: JQ
authors.lastname: Hao
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Da
authors.affiliation: Department of Immunology, Anhui Medical University, Hefei, 230032, Anhui, China.
authors.forename: Wang Lai
authors.initials: WL
authors.lastname: Hu
authors.affiliation: School of Medicine and Public Health, The University of Newcastle, Newcastle, NSW, 2308, Australia.
authors.forename: Xu Dong
authors.initials: XD
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Anhui Medical University, Hefei, 230032, Anhui, China. xujiegou@ahmu.edu.cn.
authors.forename: Jiegou
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Immunology, Anhui Medical University, Hefei, 230032, Anhui, China. zlj33@ahmu.edu.cn.
authors.forename: Lin Jie
authors.initials: LJ
authors.lastname: Zhang
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D005753:Gastric Mucosa / Q000166:cytology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
keywords: Akt; Gastric cancer; Proliferation; SHIP2; Tumorigenesis