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Role of Cyclin D1 as a Mediator of c-Met– and β-Catenin–Induced Hepatocarcinogenesis

Departments of ¹ Biopharmaceutical Sciences, ² Liver Center, and ³ Pathology, University of California, San Francisco, California; ⁴ Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, North Carolina; and ⁵ Center for Stem Cell Research and Application, Union Hospital of Huazhong University of Science and Technology, Wuhan, People's Republic of China

Requests for reprints: Xin Chen, Department of Biopharmaceutical Sciences, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0446. Phone: 415-502-6526; Fax: 415-502-4322; E-mail: xin.chen{at}ucsf.edu.

Key Words: HCC • Cyclin D1 • Wnt pathway • β-catenin • c-Met

Activation of c-Met signaling and β-catenin mutations are frequent genetic events observed in liver cancer development. Recently, we demonstrated that activated β-catenin can cooperate with c-Met to induce liver cancer formation in a mouse model. Cyclin D1 (CCND1) is an important cell cycle regulator that is considered to be a downstream target of β-catenin. To determine the importance of CCND1 as a mediator of c-Met– and β-catenin–induced hepatocarcinogenesis, we investigated the genetic interactions between CCND1, β-catenin, and c-Met in liver cancer development using mouse models. We coexpressed CCND1 with c-Met in mice and found CCND1 to cooperate with c-Met to promote liver cancer formation. Tumors induced by CCND1/c-Met had a longer latency period, formed at a lower frequency, and seemed to be more benign compared with those induced by β-catenin/c-Met. In addition, when activated β-catenin and c-Met were coinjected into CCND1-null mice, liver tumors developed despite the absence of CCND1. Intriguingly, we observed a moderate accelerated tumor growth and increased tumor malignancy in these CCND1-null mice. Molecular analysis showed an up-regulation of cyclin D2 (CCND2) expression in CCND1-null tumor samples, indicating that CCND2 may replace CCND1 in hepatic tumorigenesis. Together, our results suggest that CCND1 functions as a mediator of β-catenin during HCC pathogenesis, although other molecules may be required to fully propagate β-catenin signaling. Moreover, our data suggest that CCND1 expression is not essential for liver tumor development induced by c-Met and β-catenin. [Cancer Res 2009;69(1):253–61]