MiR-181b regulates cisplatin chemosensitivity and metastasis by targeting TGFβR1/Smad signaling pathway in NSCLC.
MiR-181b regulates cisplatin chemosensitivity and metastasis by targeting TGFβR1/Smad signaling pathway in NSCLC.
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MiR-181b 通过靶向 NSCLC 中的 TGFβR1/Smad 信号通路调节顺铂化疗敏感性和转移
DOI：
10.1038/srep17618
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发表时间：
2015-12-01
影响因子：
4.6
通讯作者：
Zhao Y
中科院分区：
文献类型：
--
作者：
Wang X;Chen X;Meng Q;Jing H;Lu H;Yang Y;Cai L;Zhao Y
MicroRNAs(MiRNAs)被认为是重要的转录后调节因子，参与细胞的各种生物学和病理过程，但其在化疗敏感性和转移中的潜在机制尚未完全阐明。本研究的目的是探讨miR-181b在非小细胞肺癌化疗敏感性和转移中的作用机制。我们发现在A549/DDP细胞中miR-181b的表达水平低于A549细胞。功能分析表明，miR-181b过表达抑制了NSCLC细胞的增殖，增强了对DDP的化疗敏感性，降低了细胞的迁移和转移能力。随后，转化生长因子βR1被确定为miR-181b的一个新的功能靶点。转化生长因子βR1基因敲除与异位表达miR-181b的作用相似，而过度表达转化生长因子βR1可挽救miR-181b介导的非小细胞肺癌细胞的生长、化疗敏感性和转移功能。此外，miR-181b还可使转化生长因子βR1/Smad信号通路失活。我们还观察到，miR-181b表达降低和转化生长因子βR1表达增加与非小细胞肺癌患者对顺铂的化疗敏感性和肿瘤转移显著相关。因此，miR-181b作为肿瘤抑制因子，通过靶向转化生长因子βR1/Smad信号通路，在非小细胞肺癌增殖、化疗敏感性和转移中发挥重要作用。
MicroRNAs (miRNAs) have been identified as important post-transcriptional regulators involved in various biological and pathological processes of cells, but their underlying mechanisms in chemosensitivity and metastasis have not been fully elucidated. The objective of this study was to identify miR-181b and its mechanism in the chemosensitivity and metastasis of NSCLC. We found that miR-181b expression levels were lower in A549/DDP cells compared with A549 cells. Functional assays showed that the overexpression of miR-181b inhibited proliferation, enhanced chemosensitivity to DDP, attenuated migration and metastatic ability in NSCLC cell linesin vitroandin vivo. TGFβR1 was subsequently identified as a novel functional target of miR-181b. TGFβR1 knockdown revealed similar effects as that of ectopic miR-181b expression, whereas overexpression of TGFβR1 rescued the function of miR-181b-mediated growth, chemosensitivity and metastasis in NSCLC cells. In addition, miR-181b could inactivate the TGFβR1/Smad signaling pathway. We also observed that decreased miR-181b expression and increased TGFβR1 expression were significantly associated with chemosensitivity to DDP and tumor metastasis in NSCLC patients. Consequently, miR-181b functions as a tumor suppressor and has an important role in proliferation, chemosensitivity to DDP and metastasis of NSCLC by targeting TGFβR1/Smad signaling pathway.