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Identification of ROBO1 as a Novel Hepatocellular Carcinoma Antigen and a Potential Therapeutic and Diagnostic Target

Authors' Affiliations: ¹ Genome Science Division and ² Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, the University of Tokyo; ³ Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, the University of Tokyo; ⁴ Perseus Proteomics, Inc., Tokyo, Japan; and ⁵ Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan; ⁶ Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kanagawa, Japan; and ⁷ Department of Pathology and ⁸ Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan

Requests for reprints: Hiroyuki Aburatani, Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan. Phone: 81-3-5452-5352; Fax: 81-3-5452-5355; E-mail: haburata-tky{at}umin.ac.jp.

Purpose: Hepatocellular carcinoma is the most common primary malignancy of the liver and accounts for as many as one million deaths annually worldwide. The present study was done to identify new transmembrane molecules for antibody therapy in hepatocellular carcinoma.

Experimental Design: Gene expression profiles of pooled total RNA from three tissues each of moderately differentiated and poorly differentiated hepatocellular carcinoma were compared with those of normal liver, noncancerous liver tissue in hepatocellular carcinoma patients, 30 normal tissue samples, and five fetal tissue samples. Target genes up-regulated specifically in hepatocellular carcinoma were validated by immunohistochemical analysis and complement-dependent cytotoxicity assay using monoclonal antibodies generated against target molecules.

Results: The human homologue of the Drosophila Roundabout gene, axon guidance receptor homologue 1, ROBO1/DUTT1, a member of the immunoglobulin superfamily, was highly expressed in hepatocellular carcinoma, whereas it showed only a limited distribution in normal tissues. On immunohistochemical analysis using a newly generated anti-ROBO1 monoclonal antibody, positive signals were observed in 83 of 98 cases of hepatocellular carcinoma (84.7%). The mAb B2318C induced complement-dependent cytotoxicity in ROBO1-expressing cell lines and in the liver cancer cell line PLC/PRF/5. Strikingly, the ectodomain of ROBO1 was detected not only in the culture medium of liver cancer cell lines (PLC/PRF/5, HepG2, etc.) but also in sera from hepatocellular carcinoma patients (6 of 11).

Conclusions: This is the first report that ROBO1 is overexpressed in hepatocellular carcinoma and shed into serum in humans. These observations suggest that ROBO1 is a potential new serologic marker for hepatocellular carcinoma and may represent a new therapeutic target.

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