PDIA6 modulates apoptosis and autophagy of non-small cell lung cancer cells via the MAP4K1/JNK signaling pathway
PDIA6 modulates apoptosis and autophagy of non-small cell lung cancer cells via the MAP4K1/JNK signaling pathway
复制标题
PDIA6通过MAP4K1/JNK信号通路调节非小细胞肺癌细胞的凋亡和自噬
DOI：
10.1016/j.ebiom.2019.03.045
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发表时间：
2019-04-01
期刊：
影响因子：
11.1
通讯作者：
Shao, Shujuan
中科院分区：
文献类型：
--
作者：
Bai, Yuxin;Liu, Xuefeng;Shao, Shujuan
背景：非小细胞肺癌(NSCLC)是最常见的肺癌类型，预后差。我们先前发现蛋白二硫键异构酶家族6(PDIA6)在肺鳞状细胞癌(LSCC)中上调。本研究旨在阐明PDIA6在非小细胞肺癌中的临床意义、生物学功能和分子机制。方法：应用TCGA数据库、Western blotting和免疫组织化学方法检测PDIA6在NSCLC中的表达。分析PDIA6的表达与临床病理及生存特征的关系。在体外和体内，采用功能得失策略研究了PDIA6在调控NSCLC细胞生长、凋亡和自噬中的作用。结果：PDIA6在非小细胞肺癌组织中表达上调，与癌旁正常组织相比，PDIA6高表达与预后不良相关。PDIA6基因敲除抑制了NSCLC细胞的增殖，增加了顺铂诱导的内源性细胞凋亡，而PDIA6过表达则有相反的作用。此外，PDIA6调节顺铂诱导的自噬，这有助于PDIA6介导的NSCLC细胞凋亡。机制上，PDIA6降低了JNK和c-jun的磷酸化水平。此外，PDIA6与MAP4K1相互作用并抑制其磷酸化，最终抑制JNK/c-Jun信号通路。解释：PDIA6在NSCLC中高表达，并通过MAP4K1/JNK/c-Jun信号通路抑制顺铂诱导的NSCLC细胞凋亡和自噬，提示PDIA6可能作为NSCLC患者的生物标志物和治疗靶点。(C)2019年提交人。爱思唯尔出版公司(Elsevier B.V.)
Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer with a poor prognosis. We previously found that protein disulfide isomerase family 6 (PDIA6) is upregulated in lung squamous cell carcinoma (LSCC). This study aimed to elucidate the clinical relevance, biological functions, and molecular mechanisms of PDIA6 in NSCLC.Methods: The expression of PDIA6 in NSCLC was assessed using the TCGA database, western blotting, and immunohistochemistry. Correlations of PDIA6 expression with clinicopathological and survival features were evaluated. The functions of PDIA6 in regulating NSCLC cell growth, apoptosis, and autophagy were investigated using gain-and loss-of-function strategies in vitro or in vivo. The underlying molecular mechanisms of PDIA6 function were examined by human phospho-kinase array and co-immunoprecipitation.Findings: PDIA6 expression was upregulated in NSCLC compared with adjacent normal tissues, and the higher PDIA6 expression was correlated with poor prognosis. PDIA6 knockdown decreased NSCLC cell proliferation and increased cisplatin-induced intrinsic apoptosis, while PDIA6 overexpression had the opposite effects. In addition, PDIA6 regulated cisplatin-induced autophagy, and this contributed to PDIA6-mediated apoptosis in NSCLC cells. Mechanistically, PDIA6 reduced the phosphorylation levels of JNK and c-Jun. Moreover, PDIA6 interacted with MAP4K1 and inhibited its phosphorylation, ultimately inhibiting the JNK/c-Jun signaling pathway.Interpretation: PDIA6 is overexpressed in NSCLC and inhibits cisplatin-induced NSCLC cell apoptosis and autophagy via the MAP4K1/JNK/c-Jun signaling pathway, suggesting that PDIA6 may serve as a biomarker and therapeutic target for NSCLC patients. (C) 2019 The Authors. Published by Elsevier B.V.