GAB2 promotes cell proliferation by activating the ERK signaling pathway in hepatocellular carcinoma
GAB2 promotes cell proliferation by activating the ERK signaling pathway in hepatocellular carcinoma
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DOI：
10.1007/s13277-016-5019-9
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发表时间：
2016-09-01
期刊：
影响因子：
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通讯作者：
Chen, Xudong
中科院分区：
文献类型：
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作者：
Chen, Yuyan;Liu, Qingqing;Chen, Xudong
Grb 2相关结合蛋白2（GAB 2）是Gab支架衔接子家族的关键成员，在磷脂酰肌醇3激酶（PI 3 K）和细胞外信号调节激酶（ERK）信号通路中发挥重要作用，与细胞增殖、细胞转化和肿瘤进展密切相关。但其在肝细胞癌（HCC）中的作用尚不清楚。本研究旨在探讨GAB 2在肝癌中的表达及其潜在的临床和生物学意义。Western blot和免疫组化分析显示GAB 2在肝癌组织中表达明显上调。同时，通过进一步分析，GAB 2与组织学分级、肿瘤大小和增殖标记物Ki-67显著相关。Kaplan-Meier生存曲线还显示，GAB 2表达增加与HCC患者的不良预后直接相关，并可作为总生存期的独立预后指标。此外，血清饥饿-再喂养，RNA干扰，CCK-8，EDU，集落形成和流式细胞术分析都进行了研究GAB 2的肝癌细胞增殖的调节。结果表明，GAB 2在细胞进入S期时进行性积累。结果表明，小分子干扰RNA明显抑制细胞增殖。更有趣的是，我们发现GAB 2通过增强ERK信号促进细胞增殖，并且GAB 2诱导的细胞增殖通过抑制ERK活化而被抑制。最后，证实GAB 2能够赋予HCC细胞中的阿霉素抗性。综上所述，GAB 2可能通过增强ERK信号通路促进肝癌细胞增殖，为肝癌的治疗提供了一种新的思路。
Grb2-associated binding protein 2 (GAB2), a key member of the family of Gab scaffolding adaptors, is important in the phospoinositide3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) signaling pathways, and is closely associated with cell proliferation, cell transformation, and tumor progression. But its role in hepatocellular carcinoma (HCC) is still unknown. In this study, we investigated the expression of GAB2 and its potential clinical and biological significances in HCC. Western bolt and immunohistochemistrical analyses revealed that GAB2 was obviously upregulated in HCC tissues. Meanwhile, GAB2 was significantly associated with histological grade, tumor size, and the proliferation marker Ki-67 through our further analysis. The Kaplan-Meier survival curves also showed that increased GAB2 expression was directly correlated with poor prognosis in HCC patients and served as an independent prognostic marker of overall survival. Moreover, serum starvation-refeeding, RNA interference, CCK-8, EDU, colony formation, and flow-cytometry analyses were all performed with the purpose of investigating GAB2's regulation of HCC cell proliferation. Our results indicated that GAB2 progressively accumulated when cells entered into S phase. Consistently, cell proliferation was distinctly hindered by small interfering RNA. More interestingly, we discovered that GAB2 promoted cell proliferation by enhancing ERK signaling and GAB2-induced cell proliferation was inhibited by the inhibition of ERK activation. Finally, GAB2 was verified to be able to confer doxorubicin resistance in HCC cells. In summary, these data demonstrated that GAB2 might promote HCC cell proliferation by enhancing ERK signaling, and all above findings provided a potential therapeutic strategy for the treatment of HCC.