Role of cyclin D1 as a mediator of c-Met- and beta-catenin-induced hepatocarcinogenesis.
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.
Patil
Mohini A
MA
Department of Biopharmaceutical Sciences, University of California-San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0446, USA.
Lee
Susie A
SA
Macias
Everardo
E
Lam
Ernest T
ET
Xu
Chuanrui
C
Jones
Kirk D
KD
Ho
Coral
C
Rodriguez-Puebla
Marcelo
M
Chen
Xin
X
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000235:genetics; D056742:Cyclin D2; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis / Q000235:genetics*; D014162:Transfection; D015854:Up-Regulation; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics*
C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D016213:Cyclins; D051176:beta Catenin; D019938:Cyclin D1; D019859:Proto-Oncogene Proteins c-met