Dong Zuoliang, Ren Li, Lin Li, Li Jiang, Huang Yiwen, Li Jinhong
Department of Clinical Laboratory, Tianjin Medical University General Hospital, Heping District, Tianjin 300052, P.R. China.
Department of Clinical Laboratory, Key Laboratory of Cancer Prevention and Therapy, Tianjin Lung Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, Hexi 300060, P.R. China.
Mol Med Rep. 2015 Jan;11(1):682-90. doi: 10.3892/mmr.2014.2662. Epub 2014 Oct 15.
Lung cancer is a predominant cause of cancer-related mortality and numerous lung cancer patients succumb to the disease due to drug resistance. A number of microRNAs (miRNAs) are upregulated in cancer and are involved in tumorigenesis, functioning as oncogenes. Several functional studies have shown that miR-21 is important in carcinogenesis; however, none of these studies has investigated multidrug resistance (MDR) reversal in human lung cancer cells. In the present study, the effect of miR-21 on MDR reversal was analyzed in A549/DDP lung cancer cells. The data demonstrated the following after miR-21 silencing: Proliferation of the tumor cells was inhibited, cell apoptosis and oxidative damage were increased, the cell cycle was blocked at the G0/G1 phase, expression levels of P-glycoprotein were reduced, accumulation of Rhodamine 123 was increased, and the MDR-related genes encoding MDR1, MPR, glutathione S-transferase-π, B-cell lymphoma 2, cyclin-dependent kinase 1, cystathione and glutathione were downregulated. Further mechanistic analysis revealed that miR-21 silencing reduced AKT phosphorylation and transcriptional activation of E2F-1 and Twist. In conclusion, this study demonstrated that miR-21 silencing reversed lung cancer cell MDR by modulation of MDR-related gene expression and inhibition of the AKT signaling pathway, suggesting that miR-21 may be a potential therapeutic candidate in patients with MDR lung cancer.
肺癌是癌症相关死亡的主要原因，许多肺癌患者因耐药性而死于该疾病。一些微小RNA（miRNA）在癌症中上调，并参与肿瘤发生，发挥癌基因的作用。多项功能研究表明，miR-21在致癌过程中很重要；然而，这些研究均未调查人肺癌细胞中的多药耐药（MDR）逆转情况。在本研究中，分析了miR-21对A549/DDP肺癌细胞中MDR逆转的影响。miR-21沉默后的数据表明：肿瘤细胞增殖受到抑制，细胞凋亡和氧化损伤增加，细胞周期阻滞在G0/G1期，P-糖蛋白表达水平降低，罗丹明123蓄积增加，编码MDR1、MPR、谷胱甘肽S-转移酶-π、B细胞淋巴瘤2、细胞周期蛋白依赖性激酶1、胱硫醚和谷胱甘肽的MDR相关基因下调。进一步的机制分析表明，miR-21沉默降低了AKT磷酸化以及E2F-1和Twist的转录激活。总之，本研究表明，miR-21沉默通过调节MDR相关基因表达和抑制AKT信号通路逆转肺癌细胞MDR，提示miR-21可能是MDR肺癌患者的潜在治疗靶点。
