miR-17-5p downregulation contributes to paclitaxel resistance of lung cancer cells through altering beclin1 expression.
miR-17-5p downregulation contributes to paclitaxel resistance of lung cancer cells through altering beclin1 expression.
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DOI：
10.1371/journal.pone.0095716
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Chakrabarti G
中科院分区：
文献类型：
--
作者：
Chatterjee A;Chattopadhyay D;Chakrabarti G
非小细胞肺癌（NSCLC）是全世界癌症相关死亡的最主要原因之一。长期以来，基于紫杉醇的联合疗法一直被用作侵袭性NSCLC的标准治疗。但紫杉醇耐药已成为非小细胞肺癌治疗中的一个主要临床问题，自噬是其重要机制之一。在本研究中，我们使用microRNA（miRNA）阵列筛选紫杉醇敏感的肺癌细胞A549及其紫杉醇耐药细胞变异体（A549-T24）之间差异表达的miRNA。我们鉴定了与紫杉醇敏感的亲本细胞相比，miR-17- 5 p是紫杉醇耐药肺癌细胞中最显著下调的miRNA之一。我们发现miR-17- 5 p的过表达使紫杉醇耐药肺癌细胞对紫杉醇敏感，从而诱导细胞凋亡。此外，本研究还发现miR-17- 5 p可直接与自噬调节因子beclin 1基因的3′-UTR结合。miR-17- 5 p在紫杉醇耐药肺癌细胞中的过表达降低了beclin 1的表达，并使细胞自噬一致性下降。在另一种紫杉醇耐药的肺腺鳞癌细胞（H596-TxR）中也观察到类似的结果。我们的研究结果表明，肺癌紫杉醇耐药与miR-17- 5 p表达下调有关，miR-17- 5 p表达下调可能导致BECN 1表达上调。
Non- small- cell lung cancer (NSCLC) is one of the most leading causes of cancer-related deaths worldwide. Paclitaxel based combination therapies have long been used as a standard treatment in aggressive NSCLCs. But paclitaxel resistance has emerged as a major clinical problem in combating non-small-cell lung cancer and autophagy is one of the important mechanisms involved in this phenomenon. In this study, we used microRNA (miRNA) arrays to screen differentially expressed miRNAs between paclitaxel sensitive lung cancer cells A549 and its paclitaxel-resistant cell variant (A549-T24). We identified miR-17-5p was one of most significantly downregulated miRNAs in paclitaxel-resistant lung cancer cells compared to paclitaxel sensitive parental cells. We found that overexpression of miR-17-5p sensitized paclitaxel resistant lung cancer cells to paclitaxel induced apoptotic cell death. Moreover, in this report we demonstrated that miR-17-5p directly binds to the 3′-UTR of beclin 1 gene, one of the most important autophagy modulator. Overexpression of miR-17-5p into paclitaxel resistant lung cancer cells reduced beclin1 expression and a concordant decease in cellular autophagy. We also observed similar results in another paclitaxel resistant lung adenosquamous carcinoma cells (H596-TxR). Our results indicated that paclitaxel resistance of lung cancer is associated with downregulation of miR-17-5p expression which might cause upregulation of BECN1 expression.
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