Wei Ting, Zhu Weiliang, Fang Shun, Zeng Xiangpin, Huang Jie, Yang Jie, Zhang Jian, Guo Linlang
Department of Oncology, Zhujiang Hospital, Southern Medical University Guangzhou, China.
Department of Pathology, Zhujiang Hospital, Southern Medical University Guangzhou, China.
Am J Cancer Res. 2017 Mar 1;7(3):628-646. eCollection 2017.
miR-495 serves as an oncogenic miRNA or a tumor suppressor in different types of cancer. However, its role in the drug resistance of small cell lung cancer (SCLC) remains unidentified. In this study, we investigated whether miR-495 regulates the chemoresistance of SCLC through the epithelial-mesenchymal transition (EMT) via Epithelial and endothelial tyrosine kinase (Etk/BMX) using two drug-resistant cell lines. Loss- and gain-of-function experiments showed miR-495 regulated cell proliferation, tumor growth and drug resistance. miR-495 suppression or Etk/BMX elevation in SCLC specimens was correlated with poor pathologic stage and survival time. Etk/BMX was one of the directly targeted genes of miR-495. Ectopic expression of Etk/BMX obviously rescued the miR-495 elevation elevation-induced inhibition of drug resistance. Etk/BMX over-expression led to higher levels of EMT mesenchymal factors (Zeb-2, Twist, Vim) and lower levels of the epithelial molecule β-catenin, while suppression of Etk/BMX showed the opposite trend. Knockdown of Zeb-2 and Twist inhibited the chemoresistance of cells. Our study revealed that miR-495 promoted the chemoresistance of SCLC through the epithelial-mesenchymal transition via Etk/BMX. miR-495 re-expression or Etk/BMX depletion is a promising strategy for interfering with chemoresistance in SCLC.
在不同类型的癌症中，miR-495既可以作为致癌性微小RNA，也可以作为肿瘤抑制因子。然而，其在小细胞肺癌（SCLC）耐药性方面的作用仍不明确。在本研究中，我们使用两种耐药细胞系，研究了miR-495是否通过上皮-间质转化（EMT）经由上皮和内皮酪氨酸激酶（Etk/BMX）来调节SCLC的化疗耐药性。功能缺失和功能获得实验表明，miR-495可调节细胞增殖、肿瘤生长和耐药性。SCLC标本中miR-495的抑制或Etk/BMX的升高与病理分期差和生存时间相关。Etk/BMX是miR-495的直接靶基因之一。Etk/BMX的异位表达明显挽救了miR-495升高诱导的耐药性抑制。Etk/BMX过表达导致更高水平的EMT间质因子（Zeb-2、Twist、波形蛋白）和更低水平的上皮分子β-连环蛋白，而抑制Etk/BMX则呈现相反的趋势。敲低Zeb-2和Twist可抑制细胞的化疗耐药性。我们的研究表明，miR-495通过Etk/BMX经由上皮-间质转化促进了SCLC的化疗耐药性。miR-495的重新表达或Etk/BMX的缺失是干扰SCLC化疗耐药性的一种有前景的策略。
