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pRb2/p130, Vascular Endothelial Growth Factor, p27^(KIP1), and Proliferating Cell Nuclear Antigen Expression in Hepatocellular Carcinoma

Their Clinical Significance

¹ Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania; ² Dipartimento di Scienze Odontostomatologiche e Maxillofacciali, Università di Napoli "Federico II," Italy; ³ Department of Human Pathology and Oncology, University of Siena, Italy; ⁴ Drexel University, College of Medicine, Department of Pathology and Laboratory Medicine, Philadelphia, Pennsylvania; ⁵ Istituto di Istologia ed Embriologia, Università di Bologna, Italy; ⁶ Dipartimento di Scienze Chirurgiche, ⁷ Istituto di Cardiologia, Dipartimento di Medicina Cardiovascolare; ⁸ Istituto di Anatomia Patologica, and ⁹ Istituto di Medicina Interna e Geriatria, Università Cattolica del Sacro Cuore, Roma, Italy

Hepatocarcinoma (HCC) is the fifth most common cancer, with more than one million fatalities occurring annually worldwide. Multiple risk factors are associated with HCC disease etiology, the highest incidence being in patients with chronic hepatitis B virus and hepatitis C virus, although other factors such as genetic makeup and environmental exposure are involved. Multiple genetic alterations including the activation of oncogenes and inactivation of tumor suppressor genes are required for malignancy in human cancers and are correlated with increased stages of carcinogenesis and further tumor progression. In this study of 21 HCC patients, we analyzed pRb2/p130, vascular endothelial growth factor (VEGF), p27^(KIP1), and proliferating cell nuclear antigen as potential HCC molecular biomarkers. In our sample set, we found that p27^(KIP1) was absent. Univariate survival analysis showed that proliferating cell nuclear antigen expression (diffuse staining >50% of positive cells in tumor) was confirmed as a significant HCC prognostic biomarker for determining patient survival agreeing with previous studies (P = 0.0126, log-rank test). Lower pRb2/p130 expression was associated to a borderline P value of inverse correlation with tumor malignancy and to a positive correlation with respect to the time from HCC diagnosis (Spearman coefficient = 0.568; P < 0.05). Conversely, higher VEGF expression was associated with a poor survival (P = 0.0257, log-rank test). We demonstrate for the first time that pRb2/p130 is inversely correlated with VEGF expression and tumor aggressiveness (P < 0.05) in p27^(KIP1)-negative HCC patients. pRb2/p130 and VEGF expression are independent from tumor staging, suggesting their possible role as independent prognostic molecular biomarkers in HCC. Furthermore, we have evidence that VEGF together with pRb2/p130 may act as new HCC biomarkers in a p27^(KIP1)-independent manner. Additional studies with larger numbers of patient data would allow the use of multivariable techniques and would be able to further identify patients with poorer survival.

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