title: Low expression of Mig-6 is associated with poor survival outcome in NSCLC and inhibits cell apoptosis via ERK-mediated upregulation of Bcl-2.
abstract: Mitogen-inducible gene-6 (Mig-6), an immediate early response gene, is a specific negative regulator of epidermal growth factor receptor (EGFR). Ablation of Mig-6 has been shown to induce tumor formation in various tissues, supporting the tumor suppressor function of Mig-6. However, little is known about the role of Mig-6 in non-small cell lung cancer (NSCLC) apoptosis, nor has the contribution of upregulated Mig-6 on biological behaviors of A549 and H157 cells previously been reported. The aim of the present study was to investigate the effects of exogenously transfected Mig-6 on proliferation, invasion and apoptosis of A549 and H157 cells and to identify novel underlying mechanisms of Mig-6-induced apoptosis. We used immunohistochemical staining to examine the expression of Mig-6 protein in NSCLC tissues. For evaluation of the prognostic value of Mig-6 expression to each clinicopathologic factor, Kaplan-Meier method and Cox's proportional hazards model were employed. Mig-6 low expression was correlated with a poor prognosis in patients with lung cancer. Patients with high expression of Mig-6 had a statistically significantly longer survival than those with low expression of Mig-6. Cox's regression analysis indicated that loss of Mig-6 expression was an independent, unfavorable prognostic factors. We utilized siRNA-targeting Mig-6 and Mig-6 overexpression plasmid to determine the effect of Mig-6 on lung cancer cells. Flow cytometry studies revealed Mig-6 overexpression promoted apoptosis in NSCLC cell lines. siRNA-mediated Mig-6 knockdown inhibited apoptosis of cancer cells, but this anti-apoptotic effect was abolished by inhibition of ERK. Upregulation of Mig-6 decreased the proliferation and invasive potential of transfected cells. Moreover, upregulation of Mig-6 inhibited proliferation and invasion of A549 and H157 cells. Collectively, our results showed that Mig-6 is a potential biomarker for evaluation of tumor prognosis of lung cancer. Mig-6 promotes apoptosis in lung cancer cells via the ERK pathway.
authors.affiliation: Department of Pathology, The First Affiliated Hospital of China Medical University and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Zixuan
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Lianyue
authors.initials: L
authors.lastname: Qu
authors.affiliation: Department of Radiology and Key Laboratory of Diagnostic Imaging and Interventional Radiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Hongshan
authors.initials: H
authors.lastname: Zhong
authors.affiliation: Department of Radiology and Key Laboratory of Diagnostic Imaging and Interventional Radiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.affiliation: Department of Pathology, The First Affiliated Hospital of China Medical University and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Xueshan
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Department of Pathology, The First Affiliated Hospital of China Medical University and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Enhua
authors.initials: E
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D011379:Prognosis; D016016:Proportional Hazards Models; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C484017:ERRFI1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins; D048049:Extracellular Signal-Regulated MAP Kinases