MiR-548an, Transcriptionally Downregulated by HIF1 alpha/HDAC1, Suppresses Tumorigenesis of Pancreatic Cancer by Targeting Vimentin Expression
MiR-548an, Transcriptionally Downregulated by HIF1 alpha/HDAC1, Suppresses Tumorigenesis of Pancreatic Cancer by Targeting Vimentin Expression
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MiR-548an 受 HIF1 α/HDAC1 转录下调，通过靶向波形蛋白表达抑制胰腺癌的肿瘤发生
DOI：
10.1158/1535-7163.mct-15-0877
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发表时间：
2016
影响因子：
5.7
通讯作者：
Zhao Gang
中科院分区：
文献类型：
--
作者：
Zhu Shuai;He Chi;Deng Shijiang;Li Xiang;Cui Shipeng;Zeng Zhu;Liu Mingliang;Zhao Shufeng;Chen Jingyuan;Jin Yan;Chen Hengyu;Deng Shichang;Liu Yang;Wang Chunyou;Zhao Gang
低氧微环境通过调节一种称为“低氧mirna”的mirna亚群的表达，促进了许多癌症的肿瘤发生。然而，这些失调的mirna在胰腺癌缺氧微环境中的功能和机制仍不清楚。本研究表明，miR-548an在胰腺癌组织中显著下调，并与肿瘤大小增大、TNM分期晚期、远处转移和预后不良相关。此外，过表达miR-548an可显著抑制体外和体内胰腺癌细胞的增殖和侵袭。我们进一步发现缺氧诱导因子-1α (HIF-1α)在缺氧时诱导胰腺癌细胞中miR-548an的下调。我们的co-IP和ChIP分析显示HIF-1α和组蛋白去乙酰化酶1 （HDAC1）形成复合物并结合miR-548an启动子上的缺氧反应元件（HRE）。此外，用曲古抑素A抑制HDAC1可拮抗缺氧对miR-548的抑制。我们的双荧光素酶测定证实miR-548an直接结合到vimentin mRNA的3 '非翻译区。vimentin的下调可抑制胰腺癌细胞在体外和体内的增殖和侵袭。此外，vimentin与mir -548a在胰腺癌样本中的表达呈负相关。总之，我们的研究结果表明，HIF-1α-HDAC1复合体在缺氧时转录抑制mir -548a的表达，导致波形蛋白上调，促进胰腺肿瘤的发生。巨蟹座；15 (9);2209 - 19所示。AACR©2016。
Hypoxic microenvironments contribute to the tumorigenesis of numerous cancers by regulating the expression of a subset of miRNAs called “hypoxiamiRs.” However, the function and mechanism of these deregulated miRNAs in hypoxic microenvironments within pancreatic cancers remain undefined. This study demonstrates that miR-548an is significantly downregulated in pancreatic cancer tissues and correlates with increased tumor size, advanced TNM stage, distant metastasis, and poor prognosis. Moreover, the overexpression of miR-548an significantly inhibited the proliferation and invasion of pancreatic cancer cellsin vitroandin vivo. We further revealed that hypoxia-induced factor-1α (HIF-1α) induces the downregulation of miR-548an in pancreatic cancer cells during hypoxia. Our co-IP and ChIP assays revealed that HIF-1α and histone deacetylase 1 (HDAC1) form a complex and bind to the hypoxia response elements (HRE) on the miR-548an promoter. In addition, inhibition of HDAC1 with trichostatin A antagonizes the suppression of miR-548 by hypoxia. Our dual luciferase assay validated that miR-548an directly binds to the 3′ untranslated region of vimentin mRNA. The downregulation of vimentin suppresses the proliferation and invasion of pancreatic cancer cellsin vitroandin vivo. In addition, vimentin was inversely correlated with miR-548an expression in pancreatic cancer samples. In conclusion, our findings suggest that the HIF-1α–HDAC1 complex transcriptionally inhibits miR-548an expression during hypoxia, resulting in the upregulation of vimentin that facilitates the pancreatic tumorigenesis.Mol Cancer Ther; 15(9); 2209–19. ©2016 AACR.