title: pRb2/p130, vascular endothelial growth factor, p27(KIP1), and proliferating cell nuclear antigen expression in hepatocellular carcinoma: their clinical significance.
abstract: 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.
authors.affiliation: Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania 19122, USA. claudio@temple.edu
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Claudio
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Russo
authors.forename: Christine A C Y
authors.initials: CA
authors.lastname: Kumar
authors.forename: Corrado
authors.initials: C
authors.lastname: Minimo
authors.forename: Antonio
authors.initials: A
authors.lastname: Farina
authors.forename: Steve
authors.initials: S
authors.lastname: Tutton
authors.forename: Gennaro
authors.initials: G
authors.lastname: Nuzzo
authors.forename: Felice
authors.initials: F
authors.lastname: Giuliante
authors.forename: Giulia
authors.initials: G
authors.lastname: Angeloni
authors.forename: Vellone
authors.initials: V
authors.lastname: Maria
authors.forename: Fabio Maria
authors.initials: FM
authors.lastname: Vecchio
authors.forename: Cristiana Di
authors.initials: CD
authors.lastname: Campli
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000502:physiology*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis / Q000502:physiology*; D011506:Proteins / Q000378:metabolism / Q000502:physiology*; D050717:Retinoblastoma-Like Protein p130; D013997:Time Factors; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000502:physiology*
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D018809:Proliferating Cell Nuclear Antigen; D011506:Proteins; C493837:RBL2 protein, human; D050717:Retinoblastoma-Like Protein p130; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27