Oncogenic role of the frizzled-7/beta-catenin pathway in hepatocellular carcinoma.
Oncogenic role of the frizzled-7/beta-catenin pathway in hepatocellular carcinoma.
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发表时间：
2005
影响因子：
25.7
通讯作者：
P. Merle;Miran Kim;M. Herrmann;Anand Gupte;L. Lefrançois;Sophia Califano;C. Trépo;Shinji Tanaka;L. Vitvitski;S. M. de la Monte;J. Wands
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作者：
P. Merle;Miran Kim;M. Herrmann;Anand Gupte;L. Lefrançois;Sophia Califano;C. Trépo;Shinji Tanaka;L. Vitvitski;S. M. de la Monte;J. Wands
背景/目的肝癌发生的分子机制在很大程度上仍然未知。先前的研究表明，Wnt/ β -catenin通路的激活在肝细胞转化过程中很重要，但卷曲受体（FZD）在这一过程中的作用尚未明确。本研究利用转基因肝癌小鼠模型研究FZD对该通路的激活作用。方法采用单（c-myc, SV40-Tag）转基因品系，建立双[胰岛素受体底物-1 (IRS-1/c-myc)]和乙肝蛋白（X/c-myc）]转基因品系，均发生HCC。采用实时RT-PCR和Western blot检测9个FZD的表达。在发育不良组织和肿瘤中评估了β -连环蛋白的磷酸化和细胞积累。我们研究了显性阴性（DN） FZD7对SV40来源的HCC细胞系中TCF转录活性的影响。结果FZD7在HCC中mRNA和蛋白水平高度过表达，并发生在非典型增生中。FZD7的上调与β -连环蛋白磷酸化的降低有关，并导致HCC肿瘤中的核积累。异位表达DN FZD7结构可降低肿瘤细胞中TCF的转录活性。结论：这些观察结果表明，FZD7受体的上调与典型Wnt/ β -连环蛋白通路的激活相关，是HCC中常见的分子事件。
BACKGROUND/AIMS The molecular mechanisms of hepatocarcinogenesis remain largely unknown. Previous studies suggest that activation of the Wnt/beta-catenin pathway is important during hepatocyte transformation but the role of Frizzled receptor (FZD) in this process has not been defined. Here we investigate activation of this pathway by FZD using transgenic hepatocellular carcinoma (HCC) murine models. METHODS We employed single (c-myc, SV40-Tag) and established double [insulin receptor substrate-1 (IRS-1/c-myc) and hepatitis Bx protein (X/c-myc)] transgenic lines and all developed HCC. Expression of 9 FZD was measured by real time RT-PCR and Western blot analysis. Phosphorylation and cellular accumulation of beta-catenin were assessed in both dysplastic tissue and tumors. We investigated the effect of a dominant negative (DN) FZD7 on TCF transcriptional activity in a SV40 derived HCC cell line. RESULTS FZD7 was highly overexpressed at the mRNA and protein level(s) in HCC and occurred in dysplasia. Upregulation of FZD7 was associated with reduced phosphorylation of beta-catenin and led to nuclear accumulation in HCC tumors. Ectopic expression of a DN FZD7 construct decreased TCF transcriptional activity in tumor cells. CONCLUSIONS These observations suggest that upregulation of FZD7 receptors in association with activation of the canonical Wnt/beta-catenin pathway is a common molecular event in HCC.