Myotubularin-related protein 7 inhibits insulin signaling in colorectal cancer

// Philip Weidner 1, * , Michaela Söhn 1, * , Tobias Gutting 1 , Teresa Friedrich 1 , Timo Gaiser 2 , Julia Magdeburg 3 , Peter Kienle 3 , Hermelindis Ruh 4 , Carsten Hopf 4 , Hans-Michael Behrens 5 , Christoph Röcken 5 , Tamar Hanoch 6 , Rony Seger 6 , Matthias P.A. Ebert 1 , Elke Burgermeister 1 1 Department of Medicine II, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, D-68167 Mannheim, Germany 2 Institute of Pathology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, D-68167 Mannheim, Germany 3 Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, D-68167 Mannheim, Germany 4 ABIMAS Research Center, Mannheim University of Applied Sciences, D-68163 Mannheim, Germany 5 Institute of Pathology, Christian Albrecht University, D-24105 Kiel, Germany 6 Department of Biological Regulation, Weizmann Institute of Science, I-7610001 Rehovot, Israel * These authors have contributed equally to this work Correspondence to: Elke Burgermeister, email: elke.burgermeister@medma.uni-heidelberg.de Keywords: colorectal cancer, insulin, MTMR7, phosphatase, myotubularin Received: January 13, 2016 Accepted: June 16, 2016 Published: July 07, 2016 ABSTRACT 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.