TIMM50 promotes tumor progression via ERK signaling and predicts poor prognosis of non-small cell lung cancer patients
TIMM50 promotes tumor progression via ERK signaling and predicts poor prognosis of non-small cell lung cancer patients
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TIMM50通过ERK信号促进肿瘤进展并预测非小细胞肺癌患者的不良预后
DOI：
10.1002/mc.22969
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发表时间：
2019-05-01
影响因子：
4.6
通讯作者：
Miao, Yuan
中科院分区：
文献类型：
--
作者：
Zhang, Xiupeng;Han, Shuai;Miao, Yuan
线粒体内膜转位酶50（TIMM50，也称为TIM50）在线粒体膜运输中起着至关重要的作用。现有文献表明，TIMM50在乳腺癌中可能作为一种致癌蛋白发挥作用。然而，其分子机制，尤其是在人类非小细胞肺癌（NSCLC）中，至今仍不确定。在本研究中，通过免疫组织化学方法，我们发现TIMM50的表达与较大的肿瘤尺寸（P = 0.049）、晚期TNM分期（P = 0.001）、区域淋巴结转移阳性（P = 0.007）以及较差的总体生存率（P = 0.001）显著相关。增殖和侵袭实验表明，TIMM50显著促进了NSCLC细胞的增殖和侵袭能力。随后的蛋白质印迹结果显示，TIMM50增强了细胞周期蛋白D1和Snail的表达，并抑制了E - 钙黏蛋白的表达。此外，TIMM50促进了磷酸化ERK和P90RSK的表达。加入ERK抑制剂可抵消由TIMM50过表达诱导的细胞周期蛋白D1和Snail的上调表达以及E - 钙黏蛋白表达的下调。总之，我们的数据表明，TIMM50通过增强其下游ERK/P90RSK信号通路的磷酸化促进了NSCLC的肿瘤增殖和侵袭。我们推测TIMM50可能是NSCLC患者的一个有用的预后标志物。
TIMM50 (Translocase of the inner mitochondrial membrane 50), also called TIM50, plays an essential role in mitochondrial membrane transportation. The existing literature suggests that TIMM50 may perform as an oncogenetic protein in breast cancer. However, the molecular mechanism, especially in human non-small cell lung cancer (NSCLC), is uncertain to date. In the present study, using immunohistochemistry, we found that TIMM50 expression significantly correlated with larger tumor size (P = 0.049), advanced TNM stage (P = 0.001), positive regional lymph node metastasis (P = 0.007), and poor overall survival (P = 0.001). Proliferation and invasion assay showed that TIMM50 dramatically promoted the ability of proliferation and invasion of NSCLC cells. Subsequent Western blotting results revealed that TIMM50 enhanced the expression of Cyclin D1 and Snail, and inhibited the expression of E-cadherin. Moreover, TIMM50 facilitated the expression of phosphorylated ERK and P90RSK. Incorporation of ERK inhibitor counteracted the upregulating expression of CyclinD1, and Snail, and downregulating expression of E-cadherin expression induced by TIMM50 overexpression. In conclusion, our data indicated that TIMM50 facilitated tumor proliferation and invasion of NSCLC through enhancing phosphorylation of its downstream ERK/P90RSK signaling pathway. We speculated that TIMM50 might be a useful prognosis marker of NSCLC patients.