title: Targeting EMP3 suppresses proliferation and invasion of hepatocellular carcinoma cells through inactivation of PI3K/Akt pathway.
abstract: Epithelial membrane protein-3 (EMP3), a typical member of the epithelial membrane protein (EMP) family, is epigenetically silenced in some cancer types, and has been proposed to be a tumor suppressor gene. However, its effects on tumor suppression are controversial and its roles in development and malignancy of hepatocellular carcinoma (HCC) remain unclear. In the present study, we found that EMP3 was highly expressed in the tumorous tissues comparing to the matched normal tissues, and negatively correlated with differentiated degree of HCC patients. Knockdown of EMP3 significantly reduced cell proliferation, arrested cell cycle at G1 phase, and inhibited the motility and invasiveness in accordance with the decreased expression and activity of urokinase plasminogen activator (uPA) and matrix metalloproteinase 9 (MMP-9) in HCC cells. The in vivo tumor growth of HCC was effectively suppressed by knockdown of EMP3 in a xenograft mouse model. The EMP3 knockdown-reduced cell proliferation and invasion were attenuated by inhibition of phosphatidylinositol 3-kinase (PI3K) or knockdown of Akt, and rescued by overexpression of Akt in HCC cells. Clinical positive correlations of EMP3 with p85 regulatory subunit of PI3K, p-Akt, uPA, as well as MMP-9 were observed in the tissue sections from HCC patients. Here, we elucidated the tumor progressive effects of EMP3 through PI3K/Akt pathway and uPA/MMP-9 cascade in HCC cells. The findings provided a new insight into EMP3, which might be a potential molecular target for diagnosis and treatment of HCC.
authors.affiliation: Department of Biochemistry, School of Medicine, Chung Shan Medical University, Taichung, Taiwan.|Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Yi-Hsien
authors.initials: YH
authors.lastname: Hsieh
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Shu-Ching
authors.initials: SC
authors.lastname: Hsieh
authors.affiliation: Graduate Institute of Medical Sciences, Chang Jung Christian University, Tainan, Taiwan.|Division of Pediatric Surgery, Department of Surgery, Children's Hospital of China Medical University, Taichung, Taiwan.
authors.forename: Chien-Hsing
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Shun-Fa
authors.initials: SF
authors.lastname: Yang
authors.affiliation: Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Chun-Wen
authors.initials: CW
authors.lastname: Cheng
authors.affiliation: Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Meng-Ju
authors.initials: MJ
authors.lastname: Tang
authors.affiliation: Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Chia-Liang
authors.initials: CL
authors.lastname: Lin
authors.affiliation: Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Chu-Liang
authors.initials: CL
authors.lastname: Lin
authors.affiliation: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, Taiwan.|Department of Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Ruey-Hwang
authors.initials: RH
authors.lastname: Chou
mesh_terms: D000368:Aged; D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D046888:Tissue Array Analysis
chemical_list: C485157:EMP3 protein, human; D008562:Membrane Glycoproteins; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt
keywords: epithelial membrane protein-3; hepatocellular carcinoma; invasion; migration; proliferation