Potential role of HIF-1-responsive microRNA210/HIF3 axis on gemcitabine resistance in cholangiocarcinoma cells

Runglawan Silakit; Yingpinyapat Kitirat; Suyanee Thongchot; Watcharin Loilome; Anchalee Techasen; Piti Ungarreevittaya; Narong Khuntikeo; Puangrat Yongvanit; Ji Hye Yang; Nam Hee Kim; Jong In Yook; Nisana Namwat

doi:10.1371/journal.pone.0199827

Potential role of HIF-1-responsive microRNA210/HIF3 axis on gemcitabine resistance in cholangiocarcinoma cells

PLoS One. 2018 Jun 28;13(6):e0199827. doi: 10.1371/journal.pone.0199827. eCollection 2018.

Authors

Runglawan Silakit^{1

2}, Yingpinyapat Kitirat^{1

2}, Suyanee Thongchot^{1

2}, Watcharin Loilome^{1

2}, Anchalee Techasen^{2

3}, Piti Ungarreevittaya^{2

4}, Narong Khuntikeo^{2

5}, Puangrat Yongvanit², Ji Hye Yang⁶, Nam Hee Kim⁶, Jong In Yook⁶, Nisana Namwat^{1

2}

Affiliations

¹ Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
² Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand.
³ Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand.
⁴ Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
⁵ Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
⁶ Department of Oral Pathology, Oral Cancer Research Institute, College of Dentistry, Yonsei University, Seoul, Korea.

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

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis Regulatory Proteins
Basic Helix-Loop-Helix Transcription Factors / metabolism*
Bile Duct Neoplasms / metabolism*
Bile Duct Neoplasms / pathology
Cell Line, Tumor
Cholangiocarcinoma / metabolism*
Cholangiocarcinoma / pathology
Cobalt / pharmacology
Drug Resistance, Neoplasm*
Female
Gene Expression Regulation, Neoplastic*
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Male
MicroRNAs / biosynthesis*
Neoplasm Proteins / metabolism*
RNA, Neoplasm / biosynthesis*
Repressor Proteins
Signal Transduction*
Tumor Hypoxia*

Substances

Apoptosis Regulatory Proteins
Basic Helix-Loop-Helix Transcription Factors
HIF1A protein, human
HIF3A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
MIRN210 microRNA, human
MicroRNAs
Neoplasm Proteins
RNA, Neoplasm
Repressor Proteins
Cobalt
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.