Correlations between transmembrane 4 L6 family member 5 (TM4SF5), CD151, and CD63 in liver fibrotic phenotypes and hepatic migration and invasive capacities

• Published in: PloS one 2014-07, Vol.9 (7), p.e102817
• Main Authors: Kang, Minkyung, Ryu, Jihye, Lee, Doohyung, Lee, Mi-Sook, Kim, Hye-Jin, Nam, Seo Hee, Song, Haeng Eun, Choi, Jungeun, Lee, Gyu-Ho, Kim, Tai Young, Lee, Hansoo, Kim, Sang Jick, Ye, Sang-Kyu, Kim, Semi, Lee, Jung Weon
• Format: Article
• Language: English
• Subjects: Antigens; Biology and Life Sciences; Carbon tetrachloride; Carcinogenesis - metabolism; Carcinogenesis - pathology; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; CD63 antigen; Cell Line; Cell Line, Tumor; Cell migration; Cell Movement - physiology; Cell surface; Correlation; Extracellular matrix; Extracellular Matrix - metabolism; Extracellular Matrix - pathology; Fibrosis; Genetic aspects; Genetic engineering; Hepatocellular carcinoma; Hepatocytes; Hepatocytes - metabolism; Hepatocytes - pathology; Humans; Interdisciplinary aspects; Internalization; Invasiveness; Kinases; Liver; Liver - metabolism; Liver - pathology; Liver cancer; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Liver diseases; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Malignancy; Medicine and Health Sciences; Melanoma; Membrane proteins; Membrane Proteins - metabolism; Membranes; Metastasis; Motility; Neoplasm Invasiveness - pathology; Pharmaceutical sciences; Pharmacy; Phenotype; Proteins; Signal transduction; Tetraspanin 24 - metabolism; Tetraspanin 30 - metabolism; Tetraspanins - metabolism; Therapeutic applications; Tissues; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; Transforming growth factors; Tumorigenesis
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0102817

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.