Li Zixuan, Qu Lianyue, Zhong Hongshan, Xu Ke, Qiu Xueshan, Wang Enhua
Department of Pathology, The First Affiliated Hospital of China Medical University and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning 110001, P.R. China.
Department of Pharmacy, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
Oncol Rep. 2014 Apr;31(4):1707-14. doi: 10.3892/or.2014.3050. Epub 2014 Feb 24.
Mitogen-inducible gene-6 (Mig-6), an immediate early response gene, is a specific negative regulator of epidermal growth factor receptor (EGFR). Ablation of Mig-6 has been shown to induce tumor formation in various tissues, supporting the tumor suppressor function of Mig-6. However, little is known about the role of Mig-6 in non-small cell lung cancer (NSCLC) apoptosis, nor has the contribution of upregulated Mig-6 on biological behaviors of A549 and H157 cells previously been reported. The aim of the present study was to investigate the effects of exogenously transfected Mig-6 on proliferation, invasion and apoptosis of A549 and H157 cells and to identify novel underlying mechanisms of Mig-6-induced apoptosis. We used immunohistochemical staining to examine the expression of Mig-6 protein in NSCLC tissues. For evaluation of the prognostic value of Mig-6 expression to each clinicopathologic factor, Kaplan-Meier method and Cox's proportional hazards model were employed. Mig-6 low expression was correlated with a poor prognosis in patients with lung cancer. Patients with high expression of Mig-6 had a statistically significantly longer survival than those with low expression of Mig-6. Cox's regression analysis indicated that loss of Mig-6 expression was an independent, unfavorable prognostic factors. We utilized siRNA-targeting Mig-6 and Mig-6 overexpression plasmid to determine the effect of Mig-6 on lung cancer cells. Flow cytometry studies revealed Mig-6 overexpression promoted apoptosis in NSCLC cell lines. siRNA-mediated Mig-6 knockdown inhibited apoptosis of cancer cells, but this anti-apoptotic effect was abolished by inhibition of ERK. Upregulation of Mig-6 decreased the proliferation and invasive potential of transfected cells. Moreover, upregulation of Mig-6 inhibited proliferation and invasion of A549 and H157 cells. Collectively, our results showed that Mig-6 is a potential biomarker for evaluation of tumor prognosis of lung cancer. Mig-6 promotes apoptosis in lung cancer cells via the ERK pathway.
丝裂原诱导基因6（Mig-6）是一种即刻早期反应基因，是表皮生长因子受体（EGFR）的特异性负调节因子。已表明Mig-6的缺失会在各种组织中诱导肿瘤形成，这支持了Mig-6的肿瘤抑制功能。然而，关于Mig-6在非小细胞肺癌（NSCLC）细胞凋亡中的作用知之甚少，之前也没有报道过Mig-6上调对A549和H157细胞生物学行为的影响。本研究的目的是探讨外源性转染Mig-6对A549和H157细胞增殖、侵袭和凋亡的影响，并确定Mig-6诱导凋亡的新潜在机制。我们采用免疫组织化学染色检测NSCLC组织中Mig-6蛋白的表达。为了评估Mig-6表达对各临床病理因素的预后价值，采用了Kaplan-Meier法和Cox比例风险模型。Mig-6低表达与肺癌患者预后不良相关。Mig-6高表达的患者生存期在统计学上显著长于Mig-6低表达的患者。Cox回归分析表明Mig-6表达缺失是一个独立的、不利的预后因素。我们利用靶向Mig-6的小干扰RNA（siRNA）和Mig-6过表达质粒来确定Mig-6对肺癌细胞的影响。流式细胞术研究显示Mig-6过表达促进NSCLC细胞系凋亡。siRNA介导的Mig-6敲低抑制癌细胞凋亡，但这种抗凋亡作用被ERK抑制所消除。Mig-6上调降低了转染细胞的增殖和侵袭潜能。此外，Mig-6上调抑制了A549和H157细胞的增殖和侵袭。总体而言，我们的结果表明Mig-6是评估肺癌肿瘤预后的潜在生物标志物。Mig-6通过ERK途径促进肺癌细胞凋亡。
