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

Abstract

Activation of c-Met signaling and B-catenin mutations are frequent genetic events observed in liver cancer development. Recently, we demonstrated that activated B-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 B-catenin. To determine the importance of CCND1 as a mediator of c-Met-and B-catenin-induced hepatocarcinogenesis, we investigated the genetic interactions between CCND1, B-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 B-catenin/c-Met. In addition, when activated B-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 B-catenin during HCC pathogenesis, although other molecules may be required to fully propagate B-catenin signaling. Moreover, our data suggest that CCND1 expression is not essential for liver tumor development induced by c-Met and Bcatenin. [Cancer Res 2009;69(1):253-61]

Inhibition of insulin‐like growth factor 1 receptor enhances the efficacy of sorafenib in inhibiting hepatocellular carcinoma cell growth and survival

“…Co‐activation of MET and β‐catenin often occurs in HCC 22. Codelivery of both MET and CAT (ΔN90‐β‐catenin, exon 3 deleted), but neither MET nor CAT alone, into mouse livers using the sleeping beauty transposon system efficiently induces HCC within several weeks 22, 23, 24. Therefore, this model (referred to here as MET/CAT) is useful for studying the functions of genes in hepatocarcinogenesis because of its clinical relevance and efficiency of HCC induction.…”

“…For the c‐met (MET)/constitutively active β‐catenin (CAT)‐driven HCC model,19, 22, 23, 24 55 μg of total plasmids, encoding the sleeping beauty transposase (HSB2) and transposons with oncogenes MET/CAT and gaussia luciferase (Gluc) (22.5 μg pT3‐EF1a‐c‐MET [human], 22.5 μg pT3‐EF1a‐DN90‐β‐catenin [human], 5 μg pT3‐Gluc1, and 5 μg HSB2) were injected hydrodynamically into age‐ and sex‐matched mice. Six weeks after MET/CAT injection, mice were treated with vehicle (30% captisol), ceritinib (25 mg/kg), sorafenib (25 mg/kg), or a combination of ceritinib and sorafenib by oral gavage daily for 4 weeks prior to being sacrificed.…”

Prognostic significance of c-Met, β-catenin and FAK in patients with hepatocellular carcinoma following surgery

“…Activation of c-Met signaling and β-catenin mutations are frequent genetic occurrences observed in liver cancer initiation (9)(10)(11). Previous studies have reported that c-Met and β-catenin are coactivated in HCC, and possess a possible correlation with hepatic carcinogenesis (12,13).…”

“…Following the review of previous studies on FAK, c-Met and β-catenin oncoproteins, their correlation with HCC has been identified in a variety of studies (12,13,(18)(19)(20)(21)(22). However, the intercorrelation among them requires further investigation.…”

Putative Association of ITGB1 Haplotype with the Clearance of HBV Infection

“…Each step in the development of HCC appears to be linked to separate genetic and epigenetic aberrations. These changes are associated with alterations in the expression or formation of an oncogene or a tumor suppressor gene (Patil et al, 2009). In addition, several previous studies have also reported associations between genetic polymorphisms and the risk of HCC and/or HBV clearance, e.g., histone deacetylase-10 (HDAC10 ) and secreted phosphoprotein-1 (SPP1) polymorphisms, and interleukin-10 (IL10) haplotypes were also shown to be associated with HBV clearance and/or HCC development (Lin et al, 2005;Park et al, 2007;Shin et al, 2003;Shin et al, 2007).…”