title: Myotubularin-related protein 7 inhibits insulin signaling in colorectal cancer.
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.
authors.affiliation: Department of Medicine II, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, D-68167 Mannheim, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Weidner
authors.affiliation: Department of Medicine II, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, D-68167 Mannheim, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Söhn
authors.affiliation: Department of Medicine II, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, D-68167 Mannheim, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Gutting
authors.affiliation: Department of Medicine II, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, D-68167 Mannheim, Germany.
authors.forename: Teresa
authors.initials: T
authors.lastname: Friedrich
authors.affiliation: Institute of Pathology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, D-68167 Mannheim, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Gaiser
authors.affiliation: Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, D-68167 Mannheim, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Magdeburg
authors.affiliation: Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, D-68167 Mannheim, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kienle
authors.affiliation: ABIMAS Research Center, Mannheim University of Applied Sciences, D-68163 Mannheim, Germany.
authors.forename: Hermelindis
authors.initials: H
authors.lastname: Ruh
authors.affiliation: ABIMAS Research Center, Mannheim University of Applied Sciences, D-68163 Mannheim, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Hopf
authors.affiliation: Institute of Pathology, Christian Albrecht University, D-24105 Kiel, Germany.
authors.forename: Hans-Michael
authors.initials: HM
authors.lastname: Behrens
authors.affiliation: Institute of Pathology, Christian Albrecht University, D-24105 Kiel, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Röcken
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, I-7610001 Rehovot, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Hanoch
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, I-7610001 Rehovot, Israel.
authors.forename: Rony
authors.initials: R
authors.lastname: Seger
authors.affiliation: Department of Medicine II, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, D-68167 Mannheim, Germany.
authors.forename: Matthias P A
authors.initials: MP
authors.lastname: Ebert
authors.affiliation: Department of Medicine II, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, D-68167 Mannheim, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Burgermeister
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D018392:Genomic Imprinting; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D046888:Tissue Array Analysis; D014018:Tissue Distribution
chemical_list: C035170:IGF2 protein, human; D007328:Insulin; D007335:Insulin-Like Growth Factor II; C000625961:MTMR7 protein, human; C478104:Mtmr7 protein, mouse; D054558:Protein Tyrosine Phosphatases, Non-Receptor
keywords: MTMR7; colorectal cancer; insulin; myotubularin; phosphatase