Journal Article

Upregulator of Cell Proliferation Predicts Poor Prognosis in Hepatocellular Carcinoma and Contributes to Hepatocarcinogenesis by Downregulating FOXO3a

Li, Jun, Yun, Jing-ping, Lai, Jia-ming, Yuan, Yun-fei, Lin, Bing-liang, Li, Mengfeng, Gao, Zhi-liang, Xie, Chan, Xie, Dong-ying, Song, Li-bing, Wu, Jue-heng

2012

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: 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