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

Department of Biopharmaceutical Sciences, University of California-San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0446, USA.
Cancer Research (Impact Factor: 9.33). 02/2009; 69(1):253-61. DOI: 10.1158/0008-5472.CAN-08-2514
Source: PubMed


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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    • "A connection has also been made in liver cancer where cooperation between activated Met and constitutively active forms of b-catenin induced development of HCC in mice (Tward et al. 2007). While many of the proproliferative effects of b-catenin are mediated by expression of cyclin D1, Met and b-catenin cooperation in liver tumor development seems to be independent of cyclin D1 expression (Patil et al. 2009). Such cooperation between signaling pathways may also be important in human tumors as an association between phosphorylated Met and mutated b-catenin was observed in a subset of human HCC (Tward et al. 2007). "
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