miR-96 induces cisplatin chemoresistance in non-small cell lung cancer cells by downregulating SAMD9.
miR-96 induces cisplatin chemoresistance in non-small cell lung cancer cells by downregulating SAMD9.
复制标题
DOI：
10.3892/ol.2015.4000
复制
发表时间：
2016-02
期刊：
影响因子：
2.9
通讯作者：
Li K
中科院分区：
文献类型：
--
作者：
Wu L;Pu X;Wang Q;Cao J;Xu F;Xu LI;Li K
顺铂作为单一药物或与其他药物联合治疗非小细胞肺癌（NSCLC）有效。以顺铂为基础的非小细胞肺癌化疗的一个临床挑战是对顺铂的内在和获得性化疗耐药。无菌α基序结构域（SAMD9）基因是一种抑制非小细胞肺癌肿瘤发生和进展的有效肿瘤抑制基因。microRNAs （miRNA）在肿瘤化疗耐药调控中发挥着重要作用。据我们所知，本研究首次探讨了miRNA/SAMD9信号在调节非小细胞肺癌顺铂化疗耐药中的作用。在预测结合SAMD9基因3 ' -非翻译区（UTR）的几个候选mirna中，miRNA-96 （miR-96）在NSCLC细胞中显示出对SAMD9 3 ' -UTR荧光素酶报告活性的显著靶向序列特异性抑制。此外，虽然NSCLC肿瘤样本中miR-96的表达水平明显高于邻近正常组织，但SAMD9的表达水平明显低于邻近正常组织。miR-96和SAMD9在人NSCLC H358和H23细胞系中过表达和敲低，并以顺铂半数最大抑制浓度（IC50）和顺铂治疗下细胞凋亡率作为顺铂化疗耐药指标。本研究结果发现，在NSCLC细胞中，过表达miR-96可显著降低SAMD9的表达和顺铂诱导的细胞凋亡，并增加顺铂的IC50，而过表达SAMD9可消除这种作用。相比之下，使用antagomir-96敲除NSCLC细胞中的miR-96可显著增加SAMD9的表达和顺铂诱导的细胞凋亡，降低顺铂IC50，而敲除SAMD9可完全逆转这一过程。综上所述，本研究表明miR-96在NSCLC中靶向并下调SAMD9，从而减少顺铂诱导的NSCLC细胞凋亡并诱导顺铂化疗耐药。本研究的发现为miR-96和SAMD9在癌症中的功能以及NSCLC化疗耐药的分子机制提供了新的见解。
Cisplatin is effective as a single agent or in combination with other drugs for the treatment of non-small cell lung cancer (NSCLC). A concerning clinical challenge with cisplatin-based NSCLC chemotherapy is the intrinsic and acquired chemoresistance to cisplatin. The sterile α motif domain-containing (SAMD9) gene has been reported as a potent tumor suppressor gene that inhibits tumorigenesis and progression of NSCLC. microRNAs (miRNA) have been revealed to play important roles in the regulation of cancer chemoresistance. To the best of our knowledge the present study explored the role of miRNA/SAMD9 signaling in regulating cisplatin chemoresistance in NSCLC for the first time. Out of the several candidate miRNAs predicted to bind the 3′-untranslated region (UTR) of the SAMD9 gene, miRNA-96 (miR-96) demonstrated significant target-sequence-specific inhibition of the SAMD9 3′-UTR luciferase reporter activity in NSCLC cells. In addition, while NSCLC tumor samples exhibited significantly higher expression levels of miR-96 compared with adjacent normal tissues, the expression levels of SAMD9 were significantly lower than those in adjacent normal tissues. miR-96 and SAMD9 were overexpressed and knocked down in the human NSCLC H358 and H23 cell lines and the half maximal inhibitory concentration (IC50) of cisplatin and cell apoptosis rate under cisplatin treatment were used as measures of cisplatin chemoresistance. The present results identified that overexpression of miR-96 in NSCLC cells markedly decreased SAMD9 expression and cisplatin-induced apoptosis, and increased the cisplatin IC50, which could be eliminated by overexpression of SAMD9. By contrast, knocking down miR-96 in NSCLC cells using antagomir-96 significantly increased SAMD9 expression and the cisplatin-induced apoptosis and decreased cisplatin IC50, which could be completely reversed by a knockdown of SAMD9. In conclusion, the current study demonstrates that miR-96 targets and downregulates SAMD9 in NSCLC, which decreases cisplatin-induced apoptosis and induces cisplatin chemoresistance in NSCLC cells. The findings of the present study add novel insights into the function of miR-96 and SAMD9 in cancer, as well as into the molecular mechanisms underlying NSCLC chemoresistance.