LncRNA NEAT1 promotes docetaxel resistance in prostate cancer by regulating ACSL4 via sponging miR-34a-5p and miR-204-5p
LncRNA NEAT1 promotes docetaxel resistance in prostate cancer by regulating ACSL4 via sponging miR-34a-5p and miR-204-5p
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LncRNA NEAT1 通过海绵 miR-34a-5p 和 miR-204-5p 调节 ACSL4 促进前列腺癌中的多西他赛耐药
DOI：
10.1016/j.cellsig.2019.109422
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发表时间：
2020-01-01
影响因子：
4.8
通讯作者：
Ma, Baojie
中科院分区：
文献类型：
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作者：
Jiang, Xingkang;Guo, Shanqi;Ma, Baojie
多西紫杉醇耐药仍然是转移性前列腺癌(PCa)临床治疗的主要问题之一。以前的研究发现，在多西他赛耐药的前列腺癌细胞系中，lncRNAs的表达存在差异，但其可能的机制尚不清楚。在本研究中，我们发现NEAT1在多西紫杉醇耐药的PCa临床样本和相关细胞系中高水平表达。当NEAT1基因被敲除后，多西紫杉醇耐药的PCa细胞在体内外的增殖和侵袭能力均被下调。我们进一步的研究解释了NEAT1通过竞争性地“海绵”miR-34a-5p和miR-204-5p在PCa中发挥致癌作用。抑制miR-34a-5p或miR-204-5p的表达可模拟NEAT1的多西紫杉醇耐药活性，而异位表达miR-34a-5p或miR-204-5p可减弱NEAT1在PCa细胞中的抗药功能。此外，我们还发现ACSL4是miR-34a-5p和miR-204-5p的靶标，并且ACSL4也被miR-34a-5p和miR-204-5p抑制。此外，抑制miR-34a-5p或/和miR-204-5p可显著抑制NEAT1过表达时ACSL4的表达。MiR-34a-5p和miR-204a-5p联合表达协同抑制ASCL4的表达，表明miR-34a-5p和miR-204a-5p协同抑制ACSL4的表达。创新性地，我们得出结论，NEAT1通过在PCa细胞中海绵miR-34a-5p和miR-204-5p而增加ACSL4，从而促进了多西紫杉醇的耐药性。
Docetaxel resistance remains one of the main problems in clinical treatment of metastatic prostate cancer (PCa). Previous studies identified differently expressed lncRNAs in docetaxel-resistant PCa cell lines, while the potential mechanisms were still unknown. In the present study, we found NEAT1 was expressed at high levels in docetaxel-resistant PCa clinical samples and related cell lines. When knockdown NEAT1, cell proliferation and invasion in docetaxel-resistant PCa cells in vitro and in vivo were downregulated. Our further researches explained that NEAT1 exerts oncogenic function in PCa by competitively 'sponging' both miR-34a-5p and miR-204-5p. Inhibition of miR-34a-5p or miR-204-5p expression mimics the docetaxel-resistant activity of NEAT1, whereas ectopic expression of miR-34a-5p or miR-204-5p attenuates the anti-drug function of NEAT1 in PCa cells. Besides, we also found ACSL4 is a target of both miR-34a-5p and miR-204-5p, and ACSL4 was also inhibited by miR-34a-5p and miR-204-5p. Moreover, suppression of miR-34a-5p or/and miR-204-5p greatly restrained the expression of ACSL4 upon NEAT1 overexpression. Joint expression of miR-34a-5p and miR-204a-5p synergistically decreased the expression of ASCL4, indicating miR-34a-5p and miR-204a-5p collaboratively inhibit the expression of ACSL4. Innovatively, we concluded that NEAT1 contributes to the docetaxel resistance by increasing ACSL4 via sponging miR-34a-5p and miR-204-5p in PCa cells.