Insulin receptor tyrosine kinase substrate activates EGFR/ERK signalling pathway and promotes cell proliferation of hepatocellular carcinoma
Insulin receptor tyrosine kinase substrate activates EGFR/ERK signalling pathway and promotes cell proliferation of hepatocellular carcinoma
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胰岛素受体酪氨酸激酶底物激活EGFR/ERK信号通路促进肝细胞癌细胞增殖
DOI：
10.1016/j.canlet.2013.05.019
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发表时间：
2013-08-28
期刊：
影响因子：
9.7
通讯作者：
Han, Ze-Guang
中科院分区：
文献类型：
--
作者：
Wang, Yu-Ping;Huang, Li-Yu;Han, Ze-Guang
胰岛素受体酪氨酸激酶底物(IRTKS)与肌动蛋白重塑和膜突起密切相关，但其在包括肝细胞癌在内的恶性肿瘤发病机制中的作用尚不清楚。在这项研究中，我们发现IRTKS在肝细胞癌样本中频繁上调，其表达水平与肿瘤大小显著相关。IRTKS在人肝癌细胞系中的增强表达显著促进其体外增殖和集落形成，并促进其体内移植瘤的形成，而IRTKS的下调则产生相反的作用。溴脱氧尿嘧啶核苷(BrdU)掺入分析和碘化丙啶染色结果表明，IRTKS可促进细胞周期进入S期。值得注意的是，IRTKS可以与表皮生长因子受体(EGFR)相互作用，导致细胞外信号调节激酶(ERK)的磷酸化。相反，抑制ERK的激活可以减弱IRTKS过表达对细胞增殖的影响。综上所述，这些数据表明IRTKS通过增强EGFR-ERK信号通路促进肝癌细胞的增殖。(C)2013爱思唯尔爱尔兰有限公司。保留所有权利。
Insulin receptor tyrosine kinase substrate (IRTKS) is closely associated with actin remodelling and membrane protrusion, but its role in the pathogenesis of malignant tumours, including hepatocellular carcinoma (HCC), is still unknown. In this study, we showed that IRTKS was frequently upregulated in HCC samples, and its expression level was significantly associated with tumour size. Enforced expression of IRTKS in human HCC cell lines significantly promoted their proliferation and colony formation in vitro, and their capacity to develop tumour xenografts in vivo, whereas knockdown of IRTKS resulted in the opposite effects. Furthermore, the bromodeoxyuridine (BrdU) incorporation analyses and propidium iodide staining indicated that IRTKS can promote the entry into S phase of cell cycle progression. Significantly, IRTKS can interact with epidermal growth factor receptor (EGFR), results in the phosphorylation of extracellular signal-regulated kinase (ERK). By contrast, inhibition of ERK activation can attenuate the effects of IRTKS overexpression on cellular proliferation. Taken together, these data demonstrate that IRTKS promotes the proliferation of HCC cells by enhancing EGFR-ERK signalling pathway. (C) 2013 Elsevier Ireland Ltd. All rights reserved.