title: Hypoxia-inducible factor-1 modulates upregulation of mutT homolog-1 in colorectal cancer.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: 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.
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.affiliation: 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.
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Sun
authors.affiliation: 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.
authors.forename: Ke
authors.initials: K
authors.lastname: Peng
authors.affiliation: 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.
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Xiao
authors.affiliation: 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.
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
mesh_terms: D015687:Cell Hypoxia; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D003848:Deoxyguanine Nucleotides / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D064593:Heterografts; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D047368:Tumor Burden; D059016:Tumor Microenvironment
chemical_list: D003848:Deoxyguanine Nucleotides; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C078206:8-oxodeoxyguanosine triphosphate; D010744:Phosphoric Monoester Hydrolases; C078207:8-oxodGTPase; D045643:DNA Repair Enzymes
keywords: 8-oxo-dGTP; Colorectal cancer; Hypoxia; Hypoxia-inducible factor-1α; MutT homolog-1