생명과학회지 (Journal of Life Science)

  • 제20권5호
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  • Pages.703-709
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  • 2010
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  • 1225-9918(pISSN)
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  • 2287-3406(eISSN)
한국생명과학회 (Korean Society of Life Science)
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UGT2B17 유전자의 deletion polymorphism과 폐암과의 연관성

Deletion Polymorphism of UGT2B17 and Its Relation to Lung Cancer

  • 이세라 (동아대학교 자연과학대학 생명과학과) ;
  • 안명현 (동아대학교 자연과학대학 생명과학과) ;
  • 설소영 (동아대학교 자연과학대학 생명과학과) ;
  • 이지선 (동아대학교 자연과학대학 생명과학과) ;
  • 정정남 (동아대학교 자연과학대학 생명과학과) ;
  • 임선희 (동아대학교 자연과학대학 생명과학과)
  • Lee, Se-Ra (Department of Biological Science, Dong-A University) ;
  • Ahn, Myoung-Hyun (Department of Biological Science, Dong-A University) ;
  • Seol, So-Young (Department of Biological Science, Dong-A University) ;
  • Lee, Ji-Sun (Department of Biological Science, Dong-A University) ;
  • Chung, Chung-Nam (Department of Biological Science, Dong-A University) ;
  • Leem, Sun-Hee (Department of Biological Science, Dong-A University)
  • 투고 : 2010.01.20
  • 심사 : 2010.03.16
  • 발행 : 2010.05.31
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초록

Glucuronidation은 NNAL [4-(methylnitrosamno)-1-(3-pyridyl)-1-butanol]의 주요 pathway이며, UGT2B의 family인 UGT2B17 (UGT, uridine diphospho-glucuronosyltransferase) 유전자는 발암원의 glucuronidation에 관여 한다. UGT2B17 결손은 NNAL의 감소 수준과 특정 암에 있어 위험도를 증가시킨다. UGT2B17 유전자의 copy 수는 사람에서 개인별로 0~2로 다양하다. 본 연구에서는 UGT2B17 결손이 폐암의 위험도와 연관성을 가지는 가를 알아보기 위해 한국인인 271명의 대조군과 176명의 폐암환자의 샘플로 PCR 방법으로 CNV를 조사하였다. 그 결과, 현재까지 보고된 백인과 흑인에 비해 한국인에서 결실 대립형질이 현저히 높게 나타났다. 백인에서 유전자 두 개 모두가 결실된 0 copy 수가 약 10%를 나타낸 것에 비해, 본 연구의 한국인에서는 0 copy 수가 약 74%를 나타내었다. 더욱이 양 쪽 결실이 여성그룹에서 전반적으로 남성그룹에 비해 높게 나타났다. 그러나 UGT2B17 유전자가 CNV와 폐암과의 연관성은 찾을 수 없었다. 이러한 결과는 UGT2B17 유전자의 결실이 폐암의 감수성과는 연관되어 있지 않으나, UGT2B17 CNV 다형성이 인종간의 진화적 분석의 유용한 마커로 사용이 가능할 것으로 사료된다.

Glucuronidation is a major pathway for NNAL [4-(methylnitrosamno)-1-(3-pyridyl)-1-butanol] and UGT2B17 (UGT, uridine diphospho-glucuronosyltransferase) is from the UGT2B family that glucuronidates carcinogens. UGT2B17 deletion was associated with decreased levels of NNAL and with increased risk of some cancers. The UGT2B17 gene varies in copy number from zero to two per individual in humans. To examine whether UGT2B17 gene deletion is associated with the risk of lung cancer, we investigated copy number variants (CNV) in 271 cancer-free controls and 176 cases of lung cancer in Koreans by a PCR-based method. The frequency of the UGT2B17 deleted alleles was much higher than in other Caucasian and African-American groups which have already been reported. While only up to 10% of Caucasians have zero copies of the gene, up to 74% of Koreans in this study showed that both copies of the gene were deleted. Furthermore, the overall frequency of this dual deletion in female groups was higher than in male groups. However, there was no association between CNV in UGT2B17 and lung cancer. This result suggested that the UGT2B17 deletion allele was not associated with the susceptibility of lung cancers in the Korean group. However, this UGT2B17 CNV polymorphism may be a useful marker for evolutionary analysis among races.

키워드

참고문헌

  1. Bao, B. Y., B. F. Chuang, Q. Wang, O. Sartor, S. P. Balk, M. Brown, P. W. Kantoff, and G. S. Lee. 2008. Androgen receptor mediates the expression of UDP-glucuronosyltransferase 2 B15 and B17 genes. Prostate 68, 839-848. https://doi.org/10.1002/pros.20749
  2. Beaulieu, M., E. Levesque, D. W. Hum, and A. Belanger. 1996. Isolation and characterization of a novel cDNA encoding a human UDP-glucuronosyltransferase active on C19 steroids. J. Biol. Chem. 271, 22855-22862. https://doi.org/10.1074/jbc.271.37.22855
  3. Chakravarti, A. and A. Lynn. 2004. Meiotic mapping in human. In: Birren B., E. D. Green, S. Klapholz, R. M. Myers, Roskams (eds.), Genome analysis: A laboratory manual. Cold Spring Harber Laboratory Press, CSH, NewYork. Vol 4.
  4. Chen, G., R. W. Dellinger, D. Sun, T. E. Spratt, and P. Lazarus. 2008. Glucuronidation of tobacco-specific nitrosamines by UGT2B10. Drug Metab. Dispos. 36, 824-830. https://doi.org/10.1124/dmd.107.019406
  5. Chouinard, S., O. Barbier, and A. Bélanger. 2007. UDP-glucuronosyltransferase 2B15 (UGT2B15) and UGT2B17 enzymes are major determinants of the androgenresponse in prostate cancer LNCaP cells. J. Biol. Chem. 282, 33466-33474. https://doi.org/10.1074/jbc.M703370200
  6. Gallagher, C. J., F. F. Kadlubar, J. E. Muscat, C. B. Ambrosone, N. P. Lang, and P. Lazarus. 2007. The UGT2B17 gene deletion polymorphism and risk of prostate cancer. A case-control study in Caucasians. Cancer Detect Prev. 31, 310-315. https://doi.org/10.1016/j.cdp.2007.07.005
  7. Gallagher, C. J., J. E. Muscat, A. N. Hicks, Y. Zheng, A. M. Dyer, G. A. Chase, J. Richie, and P. Lazarus. 2007. The UDP-glucuronosyltransferase 2B17 gene deletion polymorphism: sex-specific association with urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol glucuronidation phenotype and risk for lung cancer. Cancer Epidemiol Biomarkers Prev. 16, 823-828. https://doi.org/10.1158/1055-9965.EPI-06-0823
  8. Guillemette, C. 2003. Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Pharmacogenomics J. 3, 136-158. https://doi.org/10.1038/sj.tpj.6500171
  9. Hecht, S. S., S. G. Carmella, I. Stepanov, J. Jensen, A. Anderson, and D. K. Hatsukami. 2008. Metabolism of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone to its biomarker total NNAL insmokeless tobacco users. Cancer Epidemiol Biomarkers Prev. 17, 732-735. https://doi.org/10.1158/1055-9965.EPI-07-2843
  10. Hirsch, F. R., M. V. Garcia, F. Cappuzzo, and et al. 2007. Combination of EGFR gene copy number and protein expression predicts outcome for advanced non-small-cell lung cancer patients treated with gefitinib. Ann. Oncol. 18, 752-760.
  11. Jakobsson, J., L. Ekstrom, N. Inotsume, M. Garle, M. Lorentzon, C. Ohlsson, H. K. Roh, K. Carlström, and A. Rane. 2006. Large differences in testosterone excretion in Korean and Swedish men are strongly associated with a UDP-glucuronosyl transferase 2B17 polymorphism. J. Clin. Endocrinol Metab. 91, 687-693. https://doi.org/10.1210/jc.2005-1643
  12. Jemal, A., K. C. Chu, and R. E. Tarone. 2001. Recent trends in lung cancer mortality in the United States. J. Natl. Cancer Inst. 93, 277-283. https://doi.org/10.1093/jnci/93.4.277
  13. Kim, Y. C., Y. S. Kwon, I. J. Oh, K. S. Kim, S. Y. Kim, J. S. Ryu, H. K. Yum, S. J. Yong, K. H. Lee, C. G. Lee, S. Y. Lee, S. Y. Lee, M. H. Jung, E. T. Jeong, and K. H. In. 2007. National survey of lung cancer in Korea, 2005. J. Lung Cancer 6, 67-73. https://doi.org/10.6058/jlc.2007.6.2.67
  14. Lazarus, P., Y. Zheng, E. A. Runkle, J. E. Muscat, and D. Wiener. 2005. Genotype-phenotype correlation between the polymorphic UGT2B17 gene deletion and NNAL glucuronidation activities in human liver microsomes. Pharmacogenet Genomics 15, 769-778. https://doi.org/10.1097/01.fpc.0000175596.52443.ef
  15. Mackenzie, P. I., I. S. Owens, B. Burchell, K. W. Bock, A. Bairoch, A. Bélanger, S. Fournel-Gigleux, M. Green, D. W. Hum, T. Iyanagi, D. Lancet, P. Louisot, J.Magdalou, J. R. Chowdhury, J. K. Ritter, H. Schachter, T. R. Tephly, K. F. Tipton, and D. W. Nebert. 1997. The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence. Pharmacogenetics 7, 255-269. https://doi.org/10.1097/00008571-199708000-00001
  16. Mackenzie, P. I., K. W. Bock, B. Burchell, C. Guillemette,S. Ikushiro, T. Iyanagi, J. O. Miners, I. S. Owens, andD. W. Nebert. 2005. Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily. Pharmacogenet Genomics 15, 677-85. https://doi.org/10.1097/01.fpc.0000173483.13689.56
  17. Menard, V., O. Eap, M. Harvey, C. Guillemette, and E. Levesque. 2009. Copy-number variations (CNVs) of the human sex steroid metabolizing genes UGT2B17 and UGT2B28 and their associations with a UGT2B15 functionalpolymorphism. Hum. Mutat. 30, 1310-1319. https://doi.org/10.1002/humu.21054
  18. Park, J., L. Chen, L. Ratnashinge, T. A. Sellers, J. P. Tanner, J. H. Lee, N. Dossett, N. Lang, F. F. Kadlubar, C. B. Ambrosone, B. Zachariah, R. V. Heysek, S. Patterson, and J. Pow-Sang. 2006. Deletion Polymorphism of UDP-Glucuronosyltransferase 2B17 and Risk of Prostate Cancer in African American and Caucasian Men. Cancer Epidermiol Biomarkers Prev. 15, 1473-1478. https://doi.org/10.1158/1055-9965.EPI-06-0141
  19. Toschi, L. and F. Cappuzzo. 2007. Understanding the new genetics of responsiveness to epidermal growth factor receptor tyrosine kinase inhibitors. Oncologist 12, 211-220. https://doi.org/10.1634/theoncologist.12-2-211
  20. Tukey, R. H. and C. P. Strassburg. 2000. Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu Rev. Pharmacol. Toxicol. 40, 581-616. https://doi.org/10.1146/annurev.pharmtox.40.1.581
  21. Turgeon, D., J. S. Carrier, E. Levesque, B. G. Beatty, A. Belanger, and D. W. Hum. 2000. Isolation and characterization of the human UGT2B15 gene, localized within a cluster of UGT2B genes and pseudogenes on chromosome 4. J. Mol. Biol. 295, 489-504. https://doi.org/10.1006/jmbi.1999.3374
  22. Wilson, W., F. Pardo-Manuel de Villena, B. D. Lyn-Cook, P. K. Chatterjee, T. A. Bell, D. A. Detwiler, R. C. Gilmore, I. C. Valladeras, C. C. Wright, D. W. Threadgill, and D. J. Grant. 2004. Characterization of a common deletionpolymorphism of the UGT2B17 gene linked to UGT2B15. Genomics 84, 707-714. https://doi.org/10.1016/j.ygeno.2004.06.011
  23. Xue, Y., D. Sun, A. Daly, F. Yang, X. Zhou, M. Zhao,N. Huang, T. Zerjal, C. Lee, N. P. Carter, M. E. Hurles,and C. Tyler-Smith. 2008. Adaptive evolution of UGT2B17 copy-number variation. Am. J. Hum. Genet. 83, 337-346. https://doi.org/10.1016/j.ajhg.2008.08.004
  24. Yang, T. L., X. D. Chen, Y. Guo, S. F. Lei, J. T. Wang, Q. Zhou, F. Pan, Y. Chen, Z. X. Zhang, S. S. Dong, X. H. Xu, H. Yan, X. Liu, C. Qiu, X. Z. Zhu, T. Chen, M. Li, H. Zhang, L. Zhang, B. M. Drees, J. J. Hamilton, C. J. Papasian, R. R. Recker, X. P. Song, J. Cheng, and H. W. Deng. 2008. Genome-wide copy-number-variation study identified a susceptibility gene, UGT2B17, for osteoporosis. Am. J. Hum. Genet. 83, 663-674. https://doi.org/10.1016/j.ajhg.2008.10.006
  25. Yoon, Y. H., S. Y. Seol, J. H. Heo, C. N. Chung, I. H. Park, and S. H. Leem. 2008. Analysis of VNTRs in the solute carrier family 6, member 18 (SLC6A18) and lack of association with hypertension. DNA and Cell Biology 27, 559-567. https://doi.org/10.1089/dna.2008.0755
  26. Zheng, Z., J. L. Fang, and P. Lazarus. 2002. Glucuronidation: an important mechanism for detoxification of benzo[a]pyrene metabolites in aerodigestive tract tissues. Drug Metab. Dispos. 30, 397-403. https://doi.org/10.1124/dmd.30.4.397

피인용 문헌

  1. Influence of polymorphisms of UDP-glycosyltransferases (UGT) 2B family genes UGT2B15, UGT2B17 and UGT2B28 on the development of prostate cancer in Korean men vol.38, pp.2, 2016, https://doi.org/10.1007/s13258-015-0379-x