Role of cyclin D1 as a mediator of c-Met- and beta-catenin-induced hepatocarcinogenesis.

Abstract

Activation of c-Met signaling and beta-catenin mutations are frequent genetic events observed in liver cancer development. Recently, we demonstrated that activated beta-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 beta-catenin. To determine the importance of CCND1 as a mediator of c-Met- and beta-catenin-induced hepatocarcinogenesis, we investigated the genetic interactions between CCND1, beta-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 beta-catenin/c-Met. In addition, when activated beta-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 beta-catenin during HCC pathogenesis, although other molecules may be required to fully propagate beta-catenin signaling. Moreover, our data suggest that CCND1 expression is not essential for liver tumor development induced by c-Met and beta-catenin.

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Authors

Mohini A Patil, Susie A Lee, Everardo Macias, Ernest T Lam, Chuanrui Xu, Kirk D Jones, Coral Ho, Marcelo Rodriguez-Puebla, Xin Chen

Department of Biopharmaceutical Sciences, University of California-San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0446, USA.

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Journal Cancer Research

Volume 69

Issue 1

Pages 253-61

Publication Date 1 January 2009

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Publication metadata is provided by PubMed®, a database of the U.S. National Library of Medicine. Information for this publication was last updated on 2 August 2014.

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