Oncotarget

Research Papers:

Myotubularin-related protein 7 inhibits insulin signaling in colorectal cancer

Philip Weidner, Michaela Söhn, Tobias Gutting, Teresa Friedrich, Timo Gaiser, Julia Magdeburg, Peter Kienle, Hermelindis Ruh, Carsten Hopf, Hans-Michael Behrens, Christoph Röcken, Tamar Hanoch, Rony Seger, Matthias P.A. Ebert and Elke Burgermeister _

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Oncotarget. 2016; 7:50490-50506. https://doi.org/10.18632/oncotarget.10466

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Abstract

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

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.


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