title: Correlations between transmembrane 4 L6 family member 5 (TM4SF5), CD151, and CD63 in liver fibrotic phenotypes and hepatic migration and invasive capacities.
abstract: Transmembrane 4 L6 family member 5 (TM4SF5) is overexpressed during CCl4-mediated murine liver fibrosis and in human hepatocellular carcinomas. The tetraspanins form tetraspanin-enriched microdomains (TEMs) consisting of large membrane protein complexes on the cell surface. Thus, TM4SF5 may be involved in the signal coordination that controls liver malignancy. We investigated the relationship between TM4SF5-positive TEMs with liver fibrosis and tumorigenesis, using normal Chang hepatocytes that lack TM4SF5 expression and chronically TGFβ1-treated Chang cells that express TM4SF5. TM4SF5 expression is positively correlated with tumorigenic CD151 expression, but is negatively correlated with tumor-suppressive CD63 expression in mouse fibrotic and human hepatic carcinoma tissues, indicating cooperative roles of the tetraspanins in liver malignancies. Although CD151 did not control the expression of TM4SF5, TM4SF5 appeared to control the expression levels of CD151 and CD63. TM4SF5 interacted with CD151, and caused the internalization of CD63 from the cell surface into late lysosomal membranes, presumably leading to terminating the tumor-suppressive functions of CD63. TM4SF5 could overcome the tumorigenic effects of CD151, especially cell migration and extracellular matrix (ECM)-degradation. Taken together, TM4SF5 appears to play a role in liver malignancy by controlling the levels of tetraspanins on the cell surface, and could provide a promising therapeutic target for the treatment of liver malignancies.
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea; Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Medicinal Bioconvergence Research Center, Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul, Republic of Korea.
authors.forename: Minkyung
authors.initials: M
authors.lastname: Kang
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Medicinal Bioconvergence Research Center, Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul, Republic of Korea.
authors.forename: Jihye
authors.initials: J
authors.lastname: Ryu
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Medicinal Bioconvergence Research Center, Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul, Republic of Korea.
authors.forename: Doohyung
authors.initials: D
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Medicinal Bioconvergence Research Center, Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul, Republic of Korea.
authors.forename: Mi-Sook
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Medicinal Bioconvergence Research Center, Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul, Republic of Korea.
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul, Republic of Korea.
authors.forename: Seo Hee
authors.initials: SH
authors.lastname: Nam
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Medicinal Bioconvergence Research Center, Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul, Republic of Korea.
authors.forename: Haeng Eun
authors.initials: HE
authors.lastname: Song
authors.affiliation: Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul, Republic of Korea.
authors.forename: Jungeun
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Medicinal Bioconvergence Research Center, Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul, Republic of Korea.
authors.forename: Gyu-Ho
authors.initials: GH
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Medicinal Bioconvergence Research Center, Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul, Republic of Korea.
authors.forename: Tai Young
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Kangwon National University, Chunchon, Kangwon-do, Republic of Korea.
authors.forename: Hansoo
authors.initials: H
authors.lastname: Lee
authors.affiliation: Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, Republic of Korea.
authors.forename: Sang Jick
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Sang-Kyu
authors.initials: SK
authors.lastname: Ye
authors.affiliation: Department of Biological Sciences, Kangwon National University, Chunchon, Kangwon-do, Republic of Korea.
authors.forename: Semi
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Medicinal Bioconvergence Research Center, Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul, Republic of Korea; Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul, Republic of Korea.
authors.forename: Jung Weon
authors.initials: JW
authors.lastname: Lee
mesh_terms: D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology*; D010641:Phenotype; D060185:Tetraspanin 24 / Q000378:metabolism*; D060149:Tetraspanin 30 / Q000378:metabolism*; D059470:Tetraspanins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: C554715:CD151 protein, human; C554586:CD63 protein, human; D008565:Membrane Proteins; C508960:TGFB1 protein, human; C111029:TM4SF5 protein, human; D060185:Tetraspanin 24; D060149:Tetraspanin 30; D059470:Tetraspanins; D053773:Transforming Growth Factor beta1