Decrease of Inosine Triphosphatase Gene Expression in Human Gastric Adenocarcinoma Tumors

Authors
F. Soleimani
A. H. Ahmadi
M. Behmanesh
B. Mohammad Soltani
M. Behmanesh
Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University Tehran, Iran
Abstract
Objective: A pure nucleotide pool is essential for correct DNA replication in addition to the prevention of mutagenesis and abnormalities in a living cell. Inosine triphosphatase (ITPase) is a critical enzyme for the removal of deaminated rough purine nucleotides such as inosine from the nucleotide pool. It has been shown that abnormal function and expression of the ITPA gene is followed by an increased substitution mutation rate in the genome. This study compares the ITPA gene expression level between human adenocarcinoma tumors and their normal marginal tissues.
Method: We examined ITPA gene expression in 24 pairs of gastric adenocarcinoma tumors and their normal adjacent tissues by quantitative real-time PCR.
Result: There was reduced ITPA gene expression in tumor tissues compared with the adjacent normal tissues. The decline in ITPA gene expression was more significant in the higher grade samples.
Conclusion: ITPA is involved in omitting deaminated purines from the nucleotide pool. Therefore its abnormal function increases the frequency of mutations and causes higher genomic instability. Our data suggest that lower expression of ITPA can be considered a risk factor for the development and progression of gastric cancer.

Keywords

[1]     Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144(5): 646-74.
[2]     Menezes MR, Waisertreiger IS, Lopez-Bertoni H, Luo X, Pavlov YI. Pivotal role of inosine triphosphate pyrophosphatase in maintaining genome stability and the prevention of apoptosis in human cells. PLoS One 2012; 7(2): e32313.
[3]     Galperin MY, Moroz OV, Wilson KS, Murzin AG. House cleaning, a part of good housekeeping. Mol Microbiol 2006; 59(1): 5-19.
[4]     Friedberg EC, McDaniel LD, Schultz RA. The role of endogenous and exogenous DNA damage and mutagenesis. Curr Opin Genet Dev 2004; 14(1): 5-10.
[5]     Bradshaw JS, Kuzminov A. RdgB acts to avoid chromosome fragmentation in Escherichia coli. Mol Microbiol 2003; 48(6): 1711-25.
[6]     Burgis NE, Brucker JJ, Cunningham RP. Repair system for noncanonical purines in Escherichia coli. J Bacteriol 2003; 185(10): 3101-10.
[7]     Sumi S, Marinaki AM, Arenas M, Fairbanks L, Shobowale-Bakre M, Rees DC, Thein SL, Ansari A, Sanderson J, De Abreu RA, Simmonds HA, Duley JA. Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency. Hum Genet 2002; 111(4-5): 360-7.
[8]     Lin S, McLennan AG, Ying K, Wang Z, Gu S, Jin H, Wu C, Liu W, Yuan Y, Tang R, Xie Y, Mao Y. Cloning, expression, and characterization of a human inosine triphosphate pyrophosphatase encoded by the itpa gene. J Biol Chem 2001; 276(22): 18695-701.
[9]     Behmanesh M, Sakumi K, Abolhassani N, Toyokuni S, Oka S, Ohnishi YN, Tsuchimoto D, Nakabeppu Y. ITPase-deficient mice show growth retardation and die before weaning. Cell Death Differ 2009; 16(10): 1315-22.
[10] Abolhassani N, Iyama T, Tsuchimoto D, Sakumi K, Ohno M, Behmanesh M, Nakabeppu Y. NUDT16 and ITPA play a dual protective role in maintaining chromosome stability and cell growth by eliminating dIDP/IDP and dITP/ITP from nucleotide pools in mammals. Nucleic Acids Res 2010; 38(9): 2891-903.
[11] Hasannia B, Behmanesh M, Akbari M. Comparison expression of inosine triphosphate pyrophosphatase in CML and healthy individuals. Modares Journal of Medical Sciences: Pathobiology 2008; 11(1): 45-55. (Persian)
[12] Danai Y, Behmanesh M, Sadeghizadeh M. expression evaluation of inosine triphosphate pyrophosphorylase in K562. Modares Journal of Medical Sciences: Pathobiology 2007; 10(2): 1-10. (Persian)
[13] Kelley JR, Duggan JM. Gastric cancer epidemiology and risk factors. J Clin Epidemiol 2003; 56(1): 1-9.
[14] Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol 2006; 12(3): 354-62.
[15] Sadjadi A, Nouraie M, Mohagheghi MA, Mousavi-Jarrahi A, Malekezadeh R, Parkin DM. Cancer occurrence in Iran in 2002, an international perspective. Asian Pac J Cancer Prev 2005; 6(3): 359-63.
[16] Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61(2): 69-90.
[17] Uppal DS, Powell SM. Genetics/genomics/ proteomics of gastric adenocarcinoma. Gastroenterol Clin North Am 2013; 42(2): 241-60.
[18] Waisertreiger IS, Menezes MR, Randazzo J, Pavlov YI. Elevated Levels of DNA Strand Breaks Induced by a Base Analog in the Human Cell Line with the P32T ITPA Variant. J Nucleic Acids 2010; 2010.
[19] Xiong H, Xin HW, Wu XC, Li Q, Xiong L, Yu AR. Association between inosine triphosphate pyrophosphohydrolase deficiency and azathioprine-related adverse drug reactions in the Chinese kidney transplant recipients. Fundam Clin Pharmacol 2010; 24(3): 393-400.
[20] Kamiya H. Mutagenic potentials of damaged nucleic acids produced by reactive oxygen/nitrogen species: approaches using synthetic oligonucleotides and nucleotides: survey and summary. Nucleic Acids Res 2003; 31(2): 517-31.
[21] Simone PD, Pavlov YI, Borgstahl GE. ITPA (inosine triphosphate pyrophosphatase): from surveillance of nucleotide pools to human disease and pharmacogenetics. Mutat Res 2013; 753(2): 131-46.
[22] Caldecott KW. Single-strand break repair and genetic disease. Nat Rev Genet 2008; 9(8): 619-31.
[23] Kuzminov A. Single-strand interruptions in replicating chromosomes cause double-strand breaks. Proc Natl Acad Sci U S A 2001; 98(15): 8241-6.
[24] Shrivastav M, De Haro LP, Nickoloff JA. Regulation of DNA double-strand break repair pathway choice. Cell Res 2008; 18(1): 134-47.
Pathobiology Reserach
Volume 18, Issue 2
June 2015
Pages 97-105