title: Down-regulation of CMTM8 induces epithelial-to-mesenchymal transition-like changes via c-MET/extracellular signal-regulated kinase (ERK) signaling.
abstract: The acquisition of an invasive phenotype is a critical turning point for malignant tumor cells. CMTM8, a potential tumor suppressor, is frequently down-regulated in solid tumors, and its overexpression induces tumor cell apoptosis. Here, we identify a new role for CMTM8 in regulating tumor cell migration. Reducing CMTM8 expression in HepG2 hepatocellular carcinoma cells results in the acquisition of epithelial-to-mesenchymal transition (EMT) features, including a morphological change from organized epithelial sheets to scattered fibroblast-like shapes, reduction of the epithelial marker E-cadherin, and an increased invasive and migratory ability. These phenotypic changes are mediated in large part by the ERK-MAPK pathway, as the MEK inhibitor U0126 and shRNA-mediated knockdown of ERK2 significantly reversed these phenotypes. Hepatocyte growth factor binding to the c-MET receptor is known to induce EMT in HepG2 cells. We found that CMTM8 knockdown in HepG2 cells induced c-MET signaling and ERK activation. Inhibition of c-MET signaling with the small molecule inhibitor SU11274 or c-MET RNAi blocked the EMT-like changes following CMTM8 knockdown. CMTM8 overexpression in HepG2 cells inhibited hepatocyte growth factor-induced EMT-like morphological changes and cell motility. Down-regulation of CMTM8 also promoted an EMT-like change in MCF-10A cells, indicating a broader role for CMTM8 in regulating cellular transformation.
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Key Laboratory of Medical Immunology, Ministry of Health, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Zhang
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Mendoza
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Pei
authors.forename: Didem
authors.initials: D
authors.lastname: Ilter
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Mahoney
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Zhang
authors.forename: Dalong
authors.initials: D
authors.lastname: Ma
authors.forename: John
authors.initials: J
authors.lastname: Blenis
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
mesh_terms: D002465:Cell Movement; D048430:Cell Shape; D018925:Chemokines / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System; D062792:MARVEL Domain-Containing Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference
chemical_list: C507076:CMTM8 protein, human; D018925:Chemokines; D062792:MARVEL Domain-Containing Proteins; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D016283:Proto-Oncogene Proteins p21(ras)