Suppressing the CDC37 cochaperone in hepatocellular carcinoma cells inhibits cell cycle progression and cell growth.

The molecular cochaperone CDC37 regulates the activities of multiple protein kinases, and is an attractive broad-spectrum target in many types of cancers in which it is over-expressed. This study investigates the antitumour effects of inhibiting CDC37 in human hepatocellular carcinoma (HCC). A total of 91 patients were enrolled for CDC37 mRNA detection by using quantitative real-time PCR. Cell proliferation, gene expression changes and tumourigenicity were determined by targeting CDC37 using RNA interference in human hepatoma cell lines. We confirmed the significant over-expression of CDC37 transcript and protein in HBV-associated HCC patients. Using a CDC37-specific small oligo-siRNA, we silenced CDC37 expression in HepG2 and Huh7 hepatoma cell lines, and observed inhibition of in vitro cell proliferation, cell cycle arrest at the G1 phase, and enhanced apoptosis. Specifically, we found concomitant down-regulation of Cyclin D1, CDK4, and pRB (S807/811 and S795) upon CDC37 suppression, which could mediate the arrest of cell cycle progression at the G1 phase. Gene expression profiling further identified several genes involved in cell proliferation, cell cycle progression, and apoptosis that are regulated by CDC37 suppression. Huh7 cells with stable knockdown of CDC37 showed decreased in vitro colony formation ability, and significantly slowed xenograft growth in vivo. On the basis of the observed antitumour effects of inhibiting CDC37 expression, we propose that CDC37 is a promising therapeutic target in HCC. Its ability to regulate multiple pathways makes it potentially valuable in treating the heterogeneous subtypes of this malignancy.

Wang Z ，Wei W ，Sun CK ，Chua MS ，So S ... -  《-》

Mybl2 expression is under genetic control and contributes to determine a hepatocellular carcinoma susceptible phenotype.

MYBL2 is implicated in human malignancies and over expressed in hepatocellular carcinoma (HCC). We investigated Mybl2 role in the acquisition of susceptibility to HCC and tumor progression. MYBL2 mRNA and protein levels were evaluated by quantitative RT-PCR and immunoblotting, respectively. MYBL2 expression in HCC cell lines was controlled through MYBL2 cDNA or anti-MYBL2 siRNA transfection. Gene expression profile of cells transfected with MYBL2 was analyzed by microarray. Low induction of Mybl2 and its target Clusterin mRNAs, in low-grade dysplastic nodules (DN), progressively increased in fast growing high-grade DN and HCC of F344 rats, susceptible to hepatocarcinogenesis, whereas no/lower increases occurred in slow growing lesions of resistant BN rats. Highest Mybl2 protein activation, prevalently nuclear, occurred in F344 than BN lesions. Highest Mybl2, Clusterin, Cdc2, and Cyclin B1 expression occurred in fast progressing DN and HCC of E2f1 transgenics, compared to c-Myc transgenics, and anti-Mybl2 siRNA had highest anti-proliferative and apoptogenic effects in cell lines from HCC of E2f1 transgenics. MYBL2 transfected HepG2 and Huh7 cells exhibited increased cell proliferation and G1-S and G2-M cell cycle phases. The opposite occurred when MYBL2 was silenced by specific siRNA. MYBL2 transfection in Huh7 cells led to upregulation of genes involved in signal transduction, cell proliferation, cell motility, and downregulation of oncosuppressor and apoptogenic genes. mybl2 expression and activation are under genetic control. Mybl2 upregulation induces fast growth and progression of premalignant and malignant liver, through cell cycle deregulation and activation of genes and pathways related to tumor progression.

Frau M ，Ladu S ，Calvisi DF ，Simile MM ，Bonelli P ，Daino L ，Tomasi ML ，Seddaiu MA ，Feo F ，Pascale RM ... -  《-》

Vitamins K2, K3 and K5 exert in vivo antitumor effects on hepatocellular carcinoma by regulating the expression of G1 phase-related cell cycle molecules.

Kuriyama S ，Hitomi M ，Yoshiji H ，Nonomura T ，Tsujimoto T ，Mitoro A ，Akahane T ，Ogawa M ，Nakai S ，Deguchi A ，Masaki T ，Uchida N ... -  《INTERNATIONAL JOURNAL OF ONCOLOGY》

Overexpression of SYF2 correlates with enhanced cell growth and poor prognosis in human hepatocellular carcinoma.

Zhang S ，Shi W ，Chen Y ，Xu Z ，Zhu J ，Zhang T ，Huang W ，Ni R ，Lu C ，Zhang X ... -  《-》

Notch1 is a potential therapeutic target for the treatment of human hepatitis B virus X protein-associated hepatocellular carcinoma.

Sun Q ，Wang R ，Wang Y ，Luo J ，Wang P ，Cheng B ... -  《-》