Sang Yun Ha1, So-Young Yeo2, Keun-Woo Lee2, Seok-Hyung Kim3,4. 1. Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Republic of Korea. 2. Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea. 3. Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 135-710, Republic of Korea. platoshkim@daum.net. 4. Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea. platoshkim@daum.net.
Abstract
PURPOSE: Chromosome 11q13.2, which contains genes cyclin D1 (CCND1), fibroblast growth factor 19 (FGF19), and Oral Cancer Overexpressed 1 (ORAOV1), is the most highly amplified peak in hepatocellular carcinoma (HCC). CCND1 and FGF19 have been already suggested as therapeutic targets of HCC, but the role of ORAOV1 in carcinogenesis of HCCs has not been reported. METHODS: This retrospective study investigated ORAOV1 expression using immunohistochemistry performed on tissue microarray blocks obtained from 259 HCC patients with curative resection, between 2000 and 2006. We assessed the prognostic significance of ORAOV1 expression by Kaplan-Meier method with log-rank test and Cox proportional hazards model. Also, we performed invasion, migration, apoptosis, and cell cycle assays in HCC cell lines, and evaluated the tumorigenicity of HCC xenografts in nude mice, after knockdown of ORAOV1. RESULTS: High expression of ORAOV1 protein was observed in 80% of HCC tissues. The ORAOV1 high expression group showed shorter recurrence free survival (RFS) (p < 0.001) and shorter disease-specific survival (DSS) than the low expression group. It was an independent prognostic factor for predicting early recurrence [Odds ratio 2.74 (95% confidence interval (CI) 1.27-5.93), p = 0.01] as well as short RFS [hazard ratio 2.23 (95% CI 1.40-3.54), p = 0.001] and DSS [hazard ratio 2.30 (95% CI 1.27-4.17), p = 0.006]. Knockdown of ORAOV1 induced significant decreases in migration, invasion, and tumorigenicity of HCC cells in in-vitro model, and inhibited the growth of HCC xenografts in nude mice. CONCLUSION: We demonstrated unfavorable prognostic effect of ORAOV1 expression with supporting experimental data in HCC. ORAOV1 may be used as a biomarker for predicting HCC prognosis and is a potential candidate for targeted therapy.
PURPOSE: Chromosome 11q13.2, which contains genes cyclin D1 (CCND1), fibroblast growth factor 19 (FGF19), and Oral Cancer Overexpressed 1 (ORAOV1), is the most highly amplified peak in hepatocellular carcinoma (HCC). CCND1 and FGF19 have been already suggested as therapeutic targets of HCC, but the role of ORAOV1 in carcinogenesis of HCCs has not been reported. METHODS: This retrospective study investigated ORAOV1 expression using immunohistochemistry performed on tissue microarray blocks obtained from 259 HCC patients with curative resection, between 2000 and 2006. We assessed the prognostic significance of ORAOV1 expression by Kaplan-Meier method with log-rank test and Cox proportional hazards model. Also, we performed invasion, migration, apoptosis, and cell cycle assays in HCC cell lines, and evaluated the tumorigenicity of HCC xenografts in nude mice, after knockdown of ORAOV1. RESULTS: High expression of ORAOV1 protein was observed in 80% of HCC tissues. The ORAOV1 high expression group showed shorter recurrence free survival (RFS) (p < 0.001) and shorter disease-specific survival (DSS) than the low expression group. It was an independent prognostic factor for predicting early recurrence [Odds ratio 2.74 (95% confidence interval (CI) 1.27-5.93), p = 0.01] as well as short RFS [hazard ratio 2.23 (95% CI 1.40-3.54), p = 0.001] and DSS [hazard ratio 2.30 (95% CI 1.27-4.17), p = 0.006]. Knockdown of ORAOV1 induced significant decreases in migration, invasion, and tumorigenicity of HCC cells in in-vitro model, and inhibited the growth of HCC xenografts in nude mice. CONCLUSION: We demonstrated unfavorable prognostic effect of ORAOV1 expression with supporting experimental data in HCC. ORAOV1 may be used as a biomarker for predicting HCC prognosis and is a potential candidate for targeted therapy.
Authors: Yujin Hoshida; Augusto Villanueva; Masahiro Kobayashi; Judit Peix; Derek Y Chiang; Amy Camargo; Supriya Gupta; Jamie Moore; Matthew J Wrobel; Jim Lerner; Michael Reich; Jennifer A Chan; Jonathan N Glickman; Kenji Ikeda; Masaji Hashimoto; Goro Watanabe; Maria G Daidone; Sasan Roayaie; Myron Schwartz; Swan Thung; Helga B Salvesen; Stacey Gabriel; Vincenzo Mazzaferro; Jordi Bruix; Scott L Friedman; Hiromitsu Kumada; Josep M Llovet; Todd R Golub Journal: N Engl J Med Date: 2008-10-15 Impact factor: 91.245