Abstract
MicroRNA-210 (miR-210) is a robust target for hypoxia-inducible factor, and its overexpression has been detected in a variety of solid tumors. However, the role of miR-210 in the development, progression and response to therapy in cholangiocarcinoma (CCA) remains undefined. We report here that high miR-210 expression was significantly correlated with the shorter survival of CCA patients. Overexpression of miR-210 inhibited CCA cell proliferation at the G2/M phase and reduced the gemcitabine sensitivity in CCA cells under CoCl2-induced pseudohypoxia. Concomitantly, inhibition of endogenous miR-210 activity using miRNA sponges increased cell proliferation under CoCl2-induced pseudohypoxia, resulting in an increase in gemcitabine sensitivity in CCA cells. We showed that HIF-3α, a negative controller of HIF-1α, was a target of miR-210 constituting a feed-forward hypoxic regulatory loop. Our data suggest an important role of miR-210 in sustaining HIF-1α activity via the suppression of HIF-3α, regulating cell growth and chemotherapeutic drug resistance in CCA.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis Regulatory Proteins
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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Bile Duct Neoplasms / metabolism*
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Bile Duct Neoplasms / pathology
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Cell Line, Tumor
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Cholangiocarcinoma / metabolism*
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Cholangiocarcinoma / pathology
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Cobalt / pharmacology
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Drug Resistance, Neoplasm*
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Female
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Gene Expression Regulation, Neoplastic*
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Male
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MicroRNAs / biosynthesis*
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Neoplasm Proteins / metabolism*
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RNA, Neoplasm / biosynthesis*
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Repressor Proteins
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Signal Transduction*
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Tumor Hypoxia*
Substances
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Apoptosis Regulatory Proteins
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Basic Helix-Loop-Helix Transcription Factors
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HIF1A protein, human
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HIF3A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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MIRN210 microRNA, human
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MicroRNAs
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Neoplasm Proteins
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RNA, Neoplasm
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Repressor Proteins
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Cobalt
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cobaltous chloride
Grants and funding
This study was supported by the Thailand Research Fund through Khon Kaen University and the Royal Golden Jubilee Ph.D. Program (Grant No. PHD/0185/2552) to RS and NN and a grant from Cholangiocarcinoma Screening and Care Program (CASCAP07), Khon Kaen University Thailand to NN. This work was also supported by grants from the National Research Foundation of Korea (NRF-2014R1A2A1A05004670) funded by the Korea government (MSIP) to JIY, a grant from the National Research Foundation of Korea (NRF-2014R1A6A3A04055110) funded by the Korea government (MOE) to JIY. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.