title: Cyclin-dependent kinase-associated protein phosphatase is overexpressed             in alcohol-related hepatocellular carcinoma and influences xenograft tumor growth.
abstract: The cyclin-dependent kinase (Cdk)-associated protein phosphatase (KAP) is             a dual-specificity phosphatase that dephosphorylates Cdk2 and inhibits cell cycle             progression. The overexpression of KAP has been found in breast, prostate and             renal cell carcinomas. However, the role of KAP in hepatocellular carcinoma (HCC)             remains unclear. Therefore, the aim of this study was to investigate the expression             of KAP in HCC and elucidate its role in tumorigenesis. HCC tissues from 117 patients             undergoing surgical resection were collected for western blot analysis and immuno-histochemichal             analysis to establish clinical correlation. The antisense-mediated inhibition             of KAP expression was performed in Huh-7 cell lines for tumorigenicity and growth             regulation experiments. Clinicopathological analysis indicated that KAP was overexpressed             in HCC tissue from alcoholic patients (P<0.001). It was significantly overexpressed             in patients with a tumor number of <3 (P=0.0271), suggesting the potential             role of KAP in tumorigenesis during early‑stage alcohol-related HCC. Additionally,             the antisense-mediated inhibition of KAP in Huh-7 HCC cells interfered with cell             cycle progression, decreased cell proliferation, reduced the colony‑forming ability             of the cells and increased apoptosis. Tumorigenicity experiments showed that the             KAP knockdown in Huh-7 cells generated smaller tumors in nude mice compared with             the mock controls (P=0.018). In the cells in which KAP had been knocked down,             the physical inter-action between KAP and Cdk2 significantly increased, despite             the reduced expression levels of KAP. The phosphorylation of cell proliferation             and apoptosis-associated proteins, including phosphatase and tensin homolog (PTEN),             glycogen synthase kinase (GSK), p44/42 and Akt, was decreased. Therefore, it can             be concluded that KAP is overexpressed in alcohol-related HCC. The antisense-mediated             knockdown of KAP in Huh-7 cells decreased cell proliferation, reduced the colony‑forming             ability of the cells, interfered with cell cycle progression and suppressed xenograft             tumor formation, partly through enhanced KAP and Cdk2 interaction.
authors.affiliation: Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC.
authors.forename: Wey-Ran
authors.initials: WR
authors.lastname: Lin
authors.forename: Ming-Wei
authors.initials: MW
authors.lastname: Lai
authors.forename: Chau-Ting
authors.initials: CT
authors.lastname: Yeh
mesh_terms: D000328:Adult; D000368:Aged; D000428:Alcohol Drinking / Q000009:adverse effects*; D000437:Alcoholism / Q000150:complications / Q000201:enzymology; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics / Q000378:metabolism*; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D011485:Protein Binding
chemical_list: D050756:Cyclin-Dependent Kinase Inhibitor Proteins; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; C084429:CDKN3 protein, human; D054637:Dual-Specificity Phosphatases