Myotubularin-related protein 7 inhibits insulin signaling in colorectal cancer
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Philip Weidner1,*, Michaela Söhn1,*, Tobias Gutting1, Teresa Friedrich1, Timo Gaiser2, Julia Magdeburg3, Peter Kienle3, Hermelindis Ruh4, Carsten Hopf4, Hans-Michael Behrens5, Christoph Röcken5, Tamar Hanoch6, Rony Seger6, Matthias P.A. Ebert1, Elke Burgermeister1
1Department of Medicine II, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, D-68167 Mannheim, Germany
2Institute of Pathology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, D-68167 Mannheim, Germany
3Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, D-68167 Mannheim, Germany
4ABIMAS Research Center, Mannheim University of Applied Sciences, D-68163 Mannheim, Germany
5Institute of Pathology, Christian Albrecht University, D-24105 Kiel, Germany
6Department of Biological Regulation, Weizmann Institute of Science, I-7610001 Rehovot, Israel
*These authors have contributed equally to this work
Elke Burgermeister, email: firstname.lastname@example.org
Keywords: colorectal cancer, insulin, MTMR7, phosphatase, myotubularin
Received: January 13, 2016 Accepted: June 16, 2016 Published: July 07, 2016
Phosphoinositide (PIP) phosphatases such as myotubularins (MTMs) inhibit growth factor receptor signaling. However, the function of myotubularin-related protein 7 (MTMR7) in cancer is unknown. We show that MTMR7 protein was down-regulated with increasing tumor grade (G), size (T) and stage (UICC) in patients with colorectal cancer (CRC) (n=1786). The presence of MTMR7 in the stroma correlated with poor prognosis, whereas MTMR7 expression in the tumor was not predictive for patients’ survival. Insulin reduced MTMR7 protein levels in human CRC cell lines, and CRC patients with type 2 diabetes mellitus (T2DM) or loss of imprinting (LOI) of insulin-like growth factor 2 (IGF2) had an increased risk for MTMR7 loss. Mechanistically, MTMR7 lowered PIPs and inhibited insulin-mediated AKT-ERK1/2 signaling and proliferation in human CRC cell lines. MTMR7 provides a novel link between growth factor signaling and cancer, and may thus constitute a potential marker or drug target for human CRC.
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