Imaging, Diagnosis, Prognosis CD24 Is a Novel Predictor for Poor Prognosis of Hepatocellular Carcinoma after Surgery

Purpose: To investigate the role of CD24 in tumor invasion and prognostic significance in hepatocellular carcinoma (HCC). Experimental Design: CD24 expression was measured in stepwise metastatic HCC cell lines, tumor, peritumoral tissues, and normal liver tissues by quantitative real-time PCR and Western blot. The role of CD24 in HCC was investigated by CD24 depletion using small interfering RNA. Tumor tissue microarrays of 314 HCC patients who underwent resection between 1997 and 2000 were used to detect expression of CD24, β-catenin, and proliferating cell nuclear antigen. Prognostic significance was assessed using Kaplan-Meier survival estimates and log-rank tests. Results: CD24 was overexpressed in the highly metastatic HCC cell line and in tumor tissues of patients with recurrent HCC. Depletion of CD24 caused a notable decrease in cell proliferation, migration, and invasiveness in vitro. Univariate and multivariate analyses revealed that CD24 was a significant predictor for overall survival and relapse-free survival. CD24 expression was correlated with poor prognosis independent of α-fetoprotein, tumor-node-metastasis stage, and Edmondson stage. High CD24 expression was significantly associated with cytoplasmic and nuclear accumulation of β-catenin (P = 0.023), high tumor proliferative status (P = 0.018), and diffused intrahepatic recurrence and distant metastasis (P = 0.026). Adjuvant transcatheter arterial chemoembolization after surgery reduced the rate of early recurrence (≤1 year) in CD24 HCC patients (P = 0.024) but had no significant effect in CD24 patients (P = 0.284). Conclusions: Overexpression of CD24 in HCC was associated with high invasiveness and metastatic potential, high tumor proliferation status, and activation of the Wnt/ β-catenin pathway. CD24 may be a novel predictor for poor prognosis of HCC patients after surgery. (Clin Cancer Res 2009;15(17):5518–27) Hepatocellular carcinoma (HCC) is one of the most prevalent tumor types, and both incidence and mortality rates of HCC have increased in recent years (1). Surgery, which includes liver resection and transplantation, remains the most effective treatment for HCC, but the high rate of recurrence or metastasis after surgery (50-70% at 5 years) hinders further improvements in HCC survival (2). Cancer classification using biomarkers can identify patients with a high risk of recurrence or metastases who may be difficult to identify using traditional clinicopathologic indexes (3). Availability of reliable biomarkers for HCC would help clinicians select therapeutic strategies for individual patients and provide personalized therapy according to the predicted risk of recurrence (4). CD24 is a small, heavily glycosylated, mucin-like cell surface protein that is expressed in a wide variety of human malignancies, including B-cell lymphoma (5), renal cell carcinoma (6), Authors' Affiliations: Liver Cancer Institute, Zhong Shan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, Chinese Ministry of Education; National Laboratory for Oncogenes and Related Genes, WHOCollaborating Center for Research on Cancer, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine; Experimental Research Center, Zhongshan Hospital, Fudan University; Institute of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China Received 1/21/09; revised 4/30/09; accepted 6/8/09; published OnlineFirst 8/25/09. Grant support: National Key Sci-Tech Special Project of Infectious Diseases grant 2008ZX10002-022, National Natural Science Foundation of China grants 30500594 and 30873039, and Shanghai Science and Technology Development Funds grants 06QA14012, 07SP07003, and 07JC14010. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). X.-R. Yang, Y. Xu, and B. Yu contributed equally to this work. Requests for reprints: Jia Fan, Liver Cancer Institute, Zhong Shan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, Chinese Ministry of Education, 136 Yi Xue Yuan Road, Shanghai 200032, People's Republic of China. Phone: 86-21-64037181; Fax: 86-21-64037181; E-mail: jiafan99@ yahoo.com. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-0151 5518 Clin Cancer Res 2009;15(17) September 1, 2009 www.aacrjournals.org Published Online First on August 25, 2009 as 10.1158/1078-0432.CCR-09-0151 Research. on June 8, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst August 25, 2009; DOI: 10.1158/1078-0432.CCR-09-0151