title: Expression and inhibitory role of TIMP-3 in hepatocellular carcinoma.
abstract: As a member of the tissue inhibitor of metallo-proteinases (TIMP) family, it has been reported that TIMP-3 is involved in human cancer development. However, the function of TIMP-3 in hepatocellular carcinoma (HCC) development is unclear. We aimed to determine the biological role of TIMP-3 in HCC by evaluating the effects of its methylation status and expression on HCC cell function. TIMP-3 expression in HCC tissues was visibly analyzed by immunohistochemistry. Methylation of the TIMP-3 promoter was evaluated by methylation-specific PCR. Effects of TIMP-3 on HCC cell growth, apoptosis, migration, and invasion were examined by transfecting the TIMP-3-expressing plasmid, pCMV6. TIMP-3 was expressed in non-tumorous live tissue, but silenced or downregulated in 60% of HCC cases (P<0.05). Reduced protein expression of TIMP-3 was associated with reduced tumor differentiation (P=0.003) and increased metastatic activity (P=0.005) in HCC cell lines. Promoter methylation contributed to the TIMP-3 inactivation. Overexpression of TIMP-3 in HCC cell lines suppressed cell proliferation, induced apoptosis, and inhibited migration and invasion in vitro. TIMP-3 expression is suppressed by promoter methylation in HCC. This inhibitory protein acts as a functional tumor suppressor by inhibiting HCC cell proliferation, invasion, and migration and by inducing apoptosis and cell cycle arrest at the G2/M phase.
authors.affiliation: Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China.
authors.forename: Bo
authors.initials: B
authors.lastname: Shen
authors.affiliation: Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Gastroenterology, Guangzhou Red Cross Hospital, Ji'nan University, Guangzhou, Guangdong 510180, P.R. China.
authors.forename: Yuan-Ran
authors.initials: YR
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China.
authors.forename: Hui-Cong
authors.initials: HC
authors.lastname: Zheng
authors.affiliation: Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zeng
authors.affiliation: Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China.
authors.forename: Yu-Yuan
authors.initials: YY
authors.lastname: Li
authors.affiliation: Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China.
authors.forename: Aoxian
authors.initials: A
authors.lastname: Yin
authors.affiliation: Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510180, P.R. China.
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Nie
mesh_terms: D017209:Apoptosis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D025521:Tumor Suppressor Proteins