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Enhanced RASGEF1A Expression Is Involved in the Growth and Migration of Intrahepatic Cholangiocarcinoma

Authors' Affiliations: ¹ Laboratory of Molecular Medicine and ² Promotion of Genome-Based Medicine Project, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan and ³ Department of Gastroenterological Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

Requests for reprints: Yoichi Furukawa, Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Phone: 81-3-5449-5373; Fax: 81-3-5449-5124; E-mail: furukawa{at}ims.u-tokyo.ac.jp.

Purpose and Experimental Design: To identify novel molecular targets for the treatment of intrahepatic cholangiocarcinoma (ICC), the second most common type of primary hepatobiliary cancer, we earlier analyzed genome-wide expression profiles of genes in 25 ICCs. Among the genes whose expression levels were commonly elevated in the tumors, we identified a novel gene termed RASGEF1A that encodes a putative Ras guanine nucleotide exchange factor domain-containing protein.

Results: We showed in this article that RASGEF1A protein has a guanine nucleotide exchange activity to K-RAS, H-RAS, and N-RAS proteins in vitro. Consistently, exogenous RASGEF1A expression increased the activity of Ras. In addition, suppression of RASGEF1A by small interfering RNA retarded the growth of cholangiocarcinoma cells. Interestingly, COS7 cells expressing exogenous RASGEF1A showed enhanced cellular motility in Transwell and wound-healing assays.

Conclusions: These data suggest that elevated expression of RASGEF1A may play an essential role for proliferation and progression of ICC. Our data indicate that RASGEF1A may be a promising therapeutic target for the majority of ICCs.

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