Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 28, 2015; 21(48): 13447-13456
Published online Dec 28, 2015. doi: 10.3748/wjg.v21.i48.13447
Hypoxia-inducible factor-1 modulates upregulation of mutT homolog-1 in colorectal cancer
Yuan Qiu, Hong Zheng, Li-Hua Sun, Ke Peng, Wei-Dong Xiao, Hua Yang
Yuan Qiu, Li-Hua Sun, Ke Peng, Wei-Dong Xiao, Hua Yang, Department of General Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
Hong Zheng, Institute of Immunology of PLA, Third Military Medical University, Chongqing 400037, China
Author contributions: Qiu Y and Zheng H contributed equally to this work; Yang H designed the study; Qiu Y and Zheng H contributed to tissue collection and review of patients’ histopathology; Qiu Y, Zheng H, Sun LH, and Peng K contributed to conduction of experiments and data analysis; Zheng H and Xiao WD provided vital reagents and analytical tools and revised the manuscript.
Supported by The National Natural Science Foundation of China, No. 81330013 and No. 81272078 to Yang H, No. 81270451 to Xiao WD; and the Program for Changjiang Scholars and Innovative Research Team in Universities, No. 13051 to Yang H.
Institutional review board statement: This study was approved by the Institutional Review Board of Third Military Medical University, Chongqing, China.
Institutional animal care and use committee statement: All animal use procedures were in strict accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Third Military Medical University Animal Care Committee.
Conflict-of-interest statement: The authors declared that there is no conflict of interest related to this study.
Data sharing statement: No additional unpublished data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Hua Yang, MD, PhD, Department of General Surgery, Xinqiao Hospital, Third Military Medical University, Xinqiaozhengjie, Chongqing 400037, China. hwbyang@qq.com
Telephone: +86-23-68755705 Fax: +86-23-68774005
Received: May 25, 2015
Peer-review started: May 27, 2015
First decision: August 26, 2015
Revised: September 12, 2015
Accepted: October 17, 2015
Article in press: October 20, 2015
Published online: December 28, 2015
Abstract

AIM: To investigate the roles and interactions of mutT homolog (MTH)-1 and hypoxia-inducible factor (HIF)-1α in human colorectal cancer (CRC).

METHODS: The expression and distribution of HIF-1α and MTH-1 proteins were detected in human CRC tissues by immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). SW480 and HT-29 cells were exposed to normoxia or hypoxia. Protein and mRNA levels of HIF-1α and MTH-1 were analyzed by western blotting and qRT-PCR, respectively. In order to determine the effect of HIF-1α on the expression of MTH-1 and the amount of 8-oxo-deoxyguanosine triphosphate (dGTP) in SW480 and HT-29 cells, HIF-1α was silenced with small interfering RNA (siRNA). Growth studies were conducted on cells with HIF-1α inhibition using a xenograft tumor model. Finally, MTH-1 protein was detected by western blotting in vivo.

RESULTS: High MTH-1 mRNA expression was detected in 64.2% of cases (54/84), and this was significantly correlated with tumor stage (P = 0.023) and size (P = 0.043). HIF-1α protein expression was correlated significantly with MTH-1 expression (R = 0.640; P < 0.01) in human CRC tissues. Hypoxic stress induced mRNA and protein expression of MTH-1 in SW480 and HT-29 cells. Inhibition of HIF-1α by siRNA decreased the expression of MTH-1 and led to the accumulation of 8-oxo-dGTP in SW480 and HT-29 cells. In the in vivo xenograft tumor model, expression of MTH-1 was decreased in the HIF-1α siRNA group, and the tumor volume was much smaller than that in the mock siRNA group.

CONCLUSION: MTH-1 expression in CRC cells was upregulated via HIF-1α in response to hypoxic stress, emphasizing the crucial role of HIF-1α-induced MTH-1 in tumor growth.

Keywords: Hypoxia-inducible factor-1α, Colorectal cancer, MutT homolog-1, 8-oxo-dGTP, Hypoxia

Core tip: Hypoxia is a common characteristic of solid tumors. However, the relationship between hypoxia-inducible factor (HIF)-1α and the human mutT homolog (MTH)-1 had not been clearly investigated. The present study revealed a new mechanism through which HIF-1α upregulates MTH-1 expression in colorectal cancer and provided evidence that hypoxia enhances the expression of MTH-1, likely by modulating HIF-1α protein level. These results emphasize the important role of HIF-1α-induced MTH-1 in tumor progression.