Lipid phosphatase SHIP2 functions as oncogene in colorectal cancer by regulating PKB activation
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Elmer Hoekstra1, Asha M. Das2, Marcella Willemsen1, Marloes Swets3, Peter J.K. Kuppen3, Christien J. van der Woude1, Marco J. Bruno1, Jigisha P. Shah4, Timo L.M. ten Hagen2, John D. Chisholm4, William G. Kerr5, Maikel P. Peppelenbosch1, Gwenny M. Fuhler1
1Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
2Department of Surgery, Section Surgical Oncology, Laboratory Experimental Surgical Oncology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
3Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
4Department of Chemistry, Syracuse University, Syracuse, New York, United States of America
5Department of Microbiology and Immunology, State University of New York (SUNY) Upstate Medical University, Syracuse, New York, United States of America
Gwenny M. Fuhler, email: email@example.com
Keywords: colorectal cancer, SHIP2, phosphatases, migration, small molecule inhibitor
Received: April 29, 2016 Accepted: September 19, 2016 Published: September 28, 2016
Colorectal cancer (CRC) is the second most common cause of cancer-related death, encouraging the search for novel therapeutic targets affecting tumor cell proliferation and migration. These cellular processes are under tight control of two opposing groups of enzymes; kinases and phosphatases. Aberrant activity of kinases is observed in many forms of cancer and as phosphatases counteract such “oncogenic” kinases, it is generally assumed that phosphatases function as tumor suppressors. However, emerging evidence suggests that the lipid phosphatase SH2-domain-containing 5 inositol phosphatase (SHIP2), encoded by the INPPL1 gene, may act as an oncogene. Just like the well-known tumor suppressor gene Phosphatase and Tensin Homolog (PTEN) it hydrolyses phosphatidylinositol (3,4,5) triphosphate (PI(3,4,5)P3). However, unlike PTEN, the reaction product is PI(3,4)P2, which is required for full activation of the downstream protein kinase B (PKB/Akt), suggesting that SHIP2, in contrast to PTEN, could have a tumor initiating role through PKB activation. In this work, we investigated the role of SHIP2 in colorectal cancer. We found that SHIP2 and INPPL1 expression is increased in colorectal cancer tissue in comparison to adjacent normal tissue, and this is correlated with decreased patient survival. Moreover, SHIP2 is more active in colorectal cancer tissue, suggesting that SHIP2 can induce oncogenesis in colonic epithelial cells. Furthermore, in vitro experiments performed on colorectal cancer cell lines shows an oncogenic role for SHIP2, by enhancing chemoresistance, cell migration, and cell invasion. Together, these data indicate that SHIP2 expression contributes to the malignant potential of colorectal cancer, providing a possible target in the fight against this devastating disease.
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