| Summary: | 博士 === 高雄醫學大學 === 醫學研究所博士班 === 96 === Her-2/neu ( known as c-erbB2) belongs to epidermal growth factor receptor gene family. After Her-2/neu is activated, it will induce cell proliferation. Overexpression of Her-2/neu promotes cell over-proliferation and enhances metastatic potential. Overexpression or gene amplification of HER-2/neu has been reported frequently in many types of human cancer, including breast, ovary, lung, stomach and colon cancer. Overexpression or gene amplification of HER-2/neu enhances tumor cell proliferation, metastatic potential and tumor angiogenesis.
Her-2/neu is a pro-oncongene and may regulate expression of many target genes through different signaling pathways after activation. Her-2/neu regulates various biological functions of cells, such as cell cycle progression, proliferation, metastasis and angiogenesis via activation of these molecular effectors. In this study, I identify two target genes for Her-2/neu and study the mechanism of gene regulation and biological function.
In part I, i identified the mechanism of Her-2/neu-induced repression of RECK gene. My study has shown that ERKs, a major downstream target of Her-2/neu signaling pathway, phosphorylated Thr453 and Thr739 of Sp1 protein to enhance its DNA binding activity and induced recruitment of HDAC1 which repressed transcription of RECK gene. The reduction of RECK increases enzyme activity and release of MMPs to promote tumor cell invasion.
In part Ⅱ, my data have shown that Her-2/neu promoted TCF-4/β-catenin complex to bind to the TCF-4 binding site of Jab1 promoter via PI3K/AKT signaling pathway. Her-2/neu induced Jab1 expression and subsequently led to the translocation of p27 from nucleus to cytoplasm where p27 was degraded through 26S proteasome pathway. The mislocation or degradation of p27 attenuated its ability to inhibit cell cycle progression and suppress cell proliferation. Conversely, knockdown of Jab1 by using siRNA increased p27 protein level which inhibited cell proliferation. In immunohistochemical study, we demonstrated that Jab1 is overexpressed in 53 (80.3%) of a series of 66 human breast tumor tissues and its expression is significantly correlated with HER-2/neu overexpression (p=0.0318). In addition, our study showed that HER-2/neu-overexpressing MDA-MB-453 human breast cancer cells exhibited higher expression of Jab1 than that of MCF-7 breast cancer cells and Jab1 is a downstream target for HER-2/neu in human breast cancer cells.
Taken together, RECK and Jab1 are key mediators of
HER-2/neu-induced tumorigenesis.
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