Upregulator of cell proliferation predicts poor prognosis in hepatocellular carcinoma and contributes to hepatocarcinogenesis by downregulating FOXO3a

• Published in: PloS one Vol. 7; no. 7; p. e40607
• Main Authors: Xie, Chan, Song, Li-bing, Wu, Jue-heng, Li, Jun, Yun, Jing-ping, Lai, Jia-ming, Xie, Dong-ying, Lin, Bing-liang, Yuan, Yun-fei, Li, Mengfeng, Gao, Zhi-liang
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16.07.2012; Public Library of Science (PLoS)
• Subjects: AKT protein; Analysis; Animals; Bioindicators; Biology; Biomarkers; Biotechnology; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell cycle; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - pathology; Correlation analysis; Cyclin D1; Cyclin D1 - metabolism; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclin-dependent kinase inhibitor p27; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Cyclin-Dependent Kinases - metabolism; Development and progression; Down-Regulation - drug effects; Ectopic expression; Forkhead Box Protein O3; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; FOXO3 protein; Gene Expression Regulation, Neoplastic - drug effects; Gene Knockdown Techniques; Gene Silencing - drug effects; Health aspects; Hepatocellular carcinoma; Hepatocytes; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Kinases; Liver; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Male; Medical prognosis; Medicine; Mice; Mice, SCID; Neoplasm Proteins - metabolism; Paraffin; Phase transitions; Prognosis; Protein Kinase Inhibitors - pharmacology; Regulators; Rodents; Subgroups; Tissues; Transcription; Transcription, Genetic - drug effects; Tumorigenesis; Up-Regulation - drug effects; Western blotting; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0040607

The goal of the present study was to investigate the potential correlation between the expression level of upregulator of cell proliferation (URGCP/URG4) and the prognosis of hepatocellular carcinoma (HCC), and to examine the biological function of URGCP/URG4 in the progression of HCC, to better understand its underlying molecular mechanism in hepatic tumorigenesis. URGCP/URG4 expression was analyzed in 15 HCC cell lines, in 278 archived paraffin-embedded HCC sections, and in 10 pairs of fresh HCC tumor and para-tumor non-cancerous tissues using immunohistochemistry (IHC) and Western blotting analysis (WB). The effect of URGCP/URG4 on cell proliferation and tumorigenesis was examined in vitro and in vivo. WB and luciferase reporter analyses were performed to identify the effects of URGCP/URG4-overexpression or -knockdown on expression of cell cycle regulators and transcriptional activity of FOXO3a. IHC results revealed an upregulation of URGCP/URG4 in all HCC cell lines and fresh HCC samples as compared with normal liver cells and para-tumor tissues, respectively. URGCP/URG4 was also expressed at a high level in 122 of the 278 (43.8%) archived HCC specimens. The expression level of URGCP/URG4 was significantly correlated with clinical staging and poor patient survival of HCC in the study cohort, and in various clinical subgroups. Strikingly, ectopic expression of URGCP/URG4 induced proliferation and anchorage-independent growth of HCC cells, while silencing of URGCP/URG4 had the opposite effect. Furthermore, URGCP/URG4 overexpression in HCC cells increased cellular entry into the G1/S transitional phase, associated with downregulation of p27(Kip1) and p21(Cip1) and upregulation of cyclin D1. These effects were accompanied by enhanced Akt activity and reduced FOXO3a transcriptional activity. URGCP/URG4 plays an important role in promoting proliferation and tumorigenesis of HCC and may represent a novel prognostic biomarker and therapeutic target for this disease.