Demethylation-Induced Overexpression of Shc3 Drives c-Raf-Independent Activation of MEK/ERK in HCC
Demethylation-Induced Overexpression of Shc3 Drives c-Raf-Independent Activation of MEK/ERK in HCC
复制标题
HCC 中去甲基化诱导的 Shc3 过度表达驱动 MEK/ERK 的 c-Raf 独立激活
DOI：
10.1158/0008-5472.can-17-2432
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发表时间：
2018-05-01
期刊：
影响因子：
11.2
通讯作者：
Zhang, Ning
中科院分区：
文献类型：
--
作者：
Liu, Yun;Zhang, Xinran;Zhang, Ning
侵袭和肝内转移是肝细胞癌（HCC）预后不良的主要因素。在这项研究中，我们发现，增加Src同源物和胶原同源物3（Shc 3）在恶性肝癌细胞系的表达与肝癌的侵袭和转移。与邻近正常组织相比，Shc 3（N-Shc）在33个HCC患者样品的肿瘤中显著上调。对52例HCC患者样本的进一步分析表明，Shc 3表达与微血管浸润、癌症分期和不良预后相关。Shc 3与主要穹窿蛋白相互作用，导致MEK 1/2和ERK 1/2独立于Shc 1和c-Raf的激活;这种相互作用因此诱导上皮-间质转化并促进HCC细胞增殖和转移。观察到的Shc 3水平的增加是由于其上游启动子的去甲基化，这允许c-Jun结合。反过来，Shc 3的表达促进了c-Jun磷酸化的正反馈回路。使用肿瘤异种移植小鼠模型的转移分析进一步证实了Shc 3在体内的作用。综上所述，我们的研究结果表明，Shc 3在肝癌进展中的重要性，并确定Shc 3作为一种新的生物标志物和潜在的治疗靶点在HCC.Significance：Shc 3的异位表达与MVP/MEK/ERK形成复合物，以加强ERK激活，并在肝癌索拉非尼耐药中起重要作用。(C)2018年AACR。
Invasion and intrahepatic metastasis are major factors of poor prognosis in patients with hepatocellular carcinoma(HCC). In this study, we show that increased Src homolog and collagen homolog 3 (Shc3) expression in malignant HCC cell lines associate with HCC invasion and metastasis. Shc3 (N-Shc) was significantly upregulated in tumors of 33 HCC patient samples as compared with adjacent normal tissues. Further analysis of 52 HCC patient samples showed that Shc3 expression correlated with microvascular invasion, cancer staging, and poor prognosis. Shc3 interacted with major vault protein, resulting in activation of MEK1/2 and ERK1/2 independently of Shc1 and c-Raf; this interaction consequently induced epithelial-mesenchymal transition and promoted HCC cell proliferation and metastasis. The observed increase in Shc3 levels was due to demethylation of its upstream promoter, which allowed c-Jun binding. In turn, Shc3 expression promoted c-Jun phosphorylation in a positive feedback loop. Analysis of metastasis using a tumor xenograft mouse model further confirmed the role of Shc3 in vivo. Taken together, our results indicate the importance of Shc3 in HCC progression and identify Shc3 as a novel biomarker and potential therapeutic target in HCC.Significance: Ectopic expression of Shc3 forms a complex with MVP/MEK/ERK to potentiate ERK activation and plays an important role in sorafinib resistance in HCC. (C) 2018 AACR.