Robe of Cyclin D1 as a Mediator of c-Met- and beta-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: 9.28). 02/2009; 69(1):253-61. DOI: 10.1158/0008-5472.CAN-08-2514
Source: PubMed

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.

Download full-text


Available from: Chuanrui xu, Jun 28, 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: This paper presents the application of a mobile 3φ medium voltage sub-cycle transfer switch (MVSTS). This application is a 15 kV class switch rated at a continuous current of 600 A. The function of a sub-cycle switch is to maintain AC electrical power to a critical load by switching between 2 independent sources within 4 ms. This switching time is sufficiently fast to preserve the operation of even the most sensitive customer equipment loads during distribution system disturbances such as voltage sags or swells. The mobile unit will allow a quick installation to a customer's facility for temporary reliability assurance in a preferred/alternate or split-bus arrangement. This application also gives a customer the flexibility of trying the MVSTS before committing to a permanent installation
    Energy Conversion Engineering Conference, 1996. IECEC 96. Proceedings of the 31st Intersociety; 09/1996
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Wnt/beta-catenin signaling pathway and cell cycle play the key roles during the genesis and development of hepatocellular carcinoma (HCC). The cytoplasmic protein beta-catenin is a multifunctional protein and a central molecule in the Wnt signaling pathway. Cell cycle is regulated by a a series of regulatory factors. Current researches indicated that expression of cyclin D1 and c-myc decreased after silencing beta-catenin gene in HCC, but it is unclear if other cyclins are affected. To determine the relation, small interference RNA(siRNA) against beta-catenin was transfected into HCC cell line HepG(2), and cell cycle and cyclin A and cyclin E protein expression were detected. We demonstrated that cell cycle was arrested in G(0)/G(1) at 72 h after the transfection and with the time passing, the cell cycle began to transfer from G(0)/G(1) to G(2)/M through S and had a trend to revert at 96 h. In addition, beta-catenin protein expression was decreased at both 72 and 96 h, although the level was slightly higher at 96 h than that at 72 h. However, cyclin A and cyclin E protein expression increased at 72 h and decreased at 96 h. These findings suggest that silencing beta-catenin gene may induce the changes of cell cycle and cyclin A and cyclin E expression. Wnt/beta-catenin signaling pathway probably takes part in the genesis and development of HCC through regulating cell cycle and the expression of cyclin A and cyclin E.
    Cell cycle (Georgetown, Tex.) 06/2009; 8(10):1567-70. · 5.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The hepatocyte growth factor (HGF)-mesenchymal-epithelial transition factor (MET) pathway has a key role in carcinogenesis; it is implicated in proliferation, inhibition of apoptosis, angiogenesis, migration, invasiveness, and metastasis. All of these molecular events are driven through membrane and intracellular coplayers and several downstream effector proteins. MET has been shown to cross react with epithelial growth factor receptor (EGFR) proteins and possibly substitutes their activity, thus conferring resistance to EGFR-targeting drugs. Therefore, identification of MET inhibitors might lead to new treatments for MET-triggered neoplasia and improve the sensitivity of molecularly targeted antineoplastic compounds that are currently in use. In this Review, we outline current data regarding the HGF-MET pathway during carcinogenesis and the strategies for therapeutic targeting of this pathway. We also discuss the rationale and future perspectives of the combinatorial blockade of HGF-MET and EGFR signalling cascades in cancer treatment.
    The Lancet Oncology 08/2009; 10(7):709-17. DOI:10.1016/S1470-2045(09)70137-8 · 24.73 Impact Factor