MiR-548an, Transcriptionally Downregulated by HIF1α/HDAC1, Suppresses Tumorigenesis of Pancreatic Cancer by Targeting Vimentin Expression.

Abstract

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 cells in vitro and in 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 cells in vitro and in 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.

• Authors: Shuai Zhu, Chi He, Shijiang Deng, Xiang Li, Shipeng Cui, Zhu Zeng, Mingliang Liu, Shufeng Zhao, Jingyuan Chen, Yan Jin, Hengyu Chen, Shichang Deng, Yang Liu, Chunyou Wang, Gang Zhao
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 15 Issue 9 Pg. 2209-19 (09 2016) ISSN: 1538-8514 [Electronic] United States
• PMID: 27353169 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• MIRN548 microRNA, human
• MicroRNAs
• Vimentin
• HDAC1 protein, human
• Histone Deacetylase 1

Topics

• Animals
• Cell Hypoxia
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival
• Cell Transformation, Neoplastic (genetics)
• Disease Models, Animal
• Down-Regulation
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Histone Deacetylase 1 (metabolism)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Male
• Mice
• MicroRNAs (genetics)
• Pancreatic Neoplasms (genetics, metabolism, pathology, therapy)
• RNA Interference
• Transcription, Genetic
• Vimentin (genetics)
• Xenograft Model Antitumor Assays