Fu Yunfeng, Li Chengyuan, Luo Yanwei, Li Lian, Liu Jing, Gui Rong
The Third Xiangya Hospital of Central South University, Changsha, China.
Front Pharmacol. 2018 Feb 13;9:82. doi: 10.3389/fphar.2018.00082. eCollection 2018.
Long non-coding RNA (lncRNA) myocardial infarction associated transcript (MIAT) was recently identified as oncogene in several cancers. However, the role of MIAT on acquired resistance in lung cancer and the underlying mechanisms remain unclear. Here, we showed that the expression of MIAT in lung cancer tissues was upregulated compared with adjacent tissues. LncRNA MIAT expression was associated with tumor size, lymph node metastasis, distant metastasis and TNM stage. Univariate analysis and multivariate analysis revealed that the lncRNA MIAT to be an independent factor for predicating the prognosis of lung cancer patients. Low lncRNA MIAT have longer overall survival time and progression-free survival time than patients with high lncRNA MIAT expression. Moreover, the knockdown of MIAT significantly sensitized PC9 and gefitinib-resistant PC9 cells to gefitinib and , and increased the expression of miR-34a and inactivated PI3K/Akt signaling. MIAT interacted with miR-34a and epigenetically controlled the miR-34a expression by hyper-methylating its promotor. Taken together, our findings demonstrated that knockdown of MIAT by siRNA enhances lung cancer cells to gefitinib through the PI3K/Akt signaling pathway by epigenetically regulating miR-34a. Thus, MIAT may be a useful prognostic marker and therapeutic target for lung cancer patients.
长链非编码RNA（lncRNA）心肌梗死相关转录本（MIAT）最近在几种癌症中被鉴定为癌基因。然而，MIAT在肺癌获得性耐药中的作用及其潜在机制仍不清楚。在此，我们发现肺癌组织中MIAT的表达与相邻组织相比上调。lncRNA MIAT的表达与肿瘤大小、淋巴结转移、远处转移和TNM分期相关。单因素分析和多因素分析显示，lncRNA MIAT是预测肺癌患者预后的独立因素。与lncRNA MIAT高表达的患者相比，lncRNA MIAT低表达的患者总生存时间和无进展生存时间更长。此外，敲低MIAT可使PC9和吉非替尼耐药的PC9细胞对吉非替尼显著敏感，并增加miR-34a的表达并使PI3K/Akt信号失活。MIAT与miR-34a相互作用，并通过使其启动子超甲基化在表观遗传上控制miR-34a的表达。综上所述，我们的研究结果表明，通过小干扰RNA敲低MIAT可通过表观遗传调控miR-34a，通过PI3K/Akt信号通路增强肺癌细胞对吉非替尼的敏感性。因此，MIAT可能是肺癌患者有用的预后标志物和治疗靶点。
