Weidner Philip, Söhn Michaela, Gutting Tobias, Friedrich Teresa, Gaiser Timo, Magdeburg Julia, Kienle Peter, Ruh Hermelindis, Hopf Carsten, Behrens Hans-Michael, Röcken Christoph, Hanoch Tamar, Seger Rony, Ebert Matthias P A, Burgermeister Elke
Department of Medicine II, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, D-68167 Mannheim, Germany.
Institute of Pathology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, D-68167 Mannheim, Germany.
Oncotarget. 2016 Aug 2;7(31):50490-50506. doi: 10.18632/oncotarget.10466.
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.
磷酸肌醇（PIP）磷酸酶，如肌管素（MTMs），可抑制生长因子受体信号传导。然而，肌管素相关蛋白7（MTMR7）在癌症中的功能尚不清楚。我们发现，在1786例结直肠癌（CRC）患者中，MTMR7蛋白水平随着肿瘤分级（G）、大小（T）和分期（UICC）的增加而降低。基质中MTMR7的存在与预后不良相关，而肿瘤中MTMR7的表达并不能预测患者的生存情况。胰岛素降低了人CRC细胞系中MTMR7蛋白水平，患有2型糖尿病（T2DM）或胰岛素样生长因子2（IGF2）印记缺失（LOI）的CRC患者MTMR7缺失风险增加。机制上，MTMR7降低了PIPs水平，并抑制了人CRC细胞系中胰岛素介导的AKT-ERK1/2信号传导和增殖。MTMR7在生长因子信号传导与癌症之间建立了新的联系，因此可能构成人CRC的潜在标志物或药物靶点。
