Cytochrome b5 reductase 2 is a novel candidate tumor suppressor gene frequently inactivated by promoter hypermethylation in human nasopharyngeal carcinoma
Tóm tắt
Cytochrome b5 reductase 2 (CYB5R2), a member of the flavoprotein pyridine nucleotide cytochrome reductase family, is associated with a number of physiological reactions. However, its role in cancer, especially nasopharyngeal carcinoma (NPC), has not been addressed. Here, we investigate the transcript levels and promoter methylation status of CYB5R2 in NPC derived cell lines and tumor biopsies and experimentally address its role as a tumor suppressor gene. We find that CYB5R2 transcript levels are decreased in NPC cell lines and tumor biopsies. Promoter hypermethylation of CYB5R2 was detected in all six tested NPC cell lines and in 84 % of primary NPC tumor biopsies but not in normal nasopharyngeal epithelium. Clinically, CYB5R2 methylation was associated with lymph node metastasis in NPC patients (P < 0.05). The endogenous expression of CYB5R2 could be restored in vitro by the methyltransferase inhibitor 5-aza-2′-deoxycytidine in NPC cell lines. Ectopic expression of CYB5R2 had an inhibitory effect on proliferation, clonogenicity and migration of NPC cells. Moreover, in vivo tests in nude mice indicated that ectopic expression of CYB5R2 reduces the tumorigenicity of CYB5R2-negative NPC cells. Collectively, these findings suggest that CYB5R2 may be a functional tumor suppressor gene, frequently inactivated by hypermethylation of its promoter in NPC. We report here the first instance of epigenetic downregulation in NPC tumor biopsies of a key enzyme, CYB5R2, which is responsible for the detoxification of environmental carcinogens. We propose the possibility of utilizing CYB5R2 promoter methylation as a diagnostic biomarker of NPC in the future.
Tài liệu tham khảo
Tao Q, Chan AT. Nasopharyngeal carcinoma: molecular pathogenesis and therapeutic developments. Expert Rev Mol Med. 2007;9:1–24.
Jia WH, Huang QH, Liao J, Ye W, Shugart YY, Liu Q, et al. Trends in incidence and mortality of nasopharyngeal carcinoma over a 20–25 year period (1978/1983–2002) in Sihui and Cangwu counties in Southern China. BMC Cancer. 2006;6:178.
Chang ET, Adami HO. The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev. 2006;15:1765–77.
Lin TM, Chang HJ, Chen CJ, Cheng YJ, Yang CS, Tu SM, et al. Risk factors for nasopharyngeal carcinoma. Anticancer Res. 1986;6:791–6.
Yu MC, Yuan JM. Epidemiology of nasopharyngeal carcinoma. Semin Cancer Biol. 2002;12:421–9.
Lo KW, To KF, Huang DP. Focus on nasopharyngeal carcinoma. Cancer Cell. 2004;5:423–8.
Xu FH, Xiong D, Xu YF, Cao SM, Xue WQ, Qin HD, et al. An epidemiological and molecular study of the relationship between smoking, risk of nasopharyngeal carcinoma, and Epstein–Barr virus activation. J Natl Cancer Inst. 2012;104:1396–410.
Yu MC, Ho JH, Lai SH, Henderson BE. Cantonese-style salted fish as a cause of nasopharyngeal carcinoma: report of a case–control study in Hong Kong. Cancer Res. 1986;46:956–61.
Croom E. Metabolism of xenobiotics of human environments. Prog in Mole Biol Transl Sci. 2012;112:31–88.
Nazar-Stewart V, Vaughan TL, Burt RD, Chen C, Berwick M, Swanson GM. Glutathione S-transferase M1 and susceptibility to nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev. 1999;8:547–51.
Tiwawech D, Srivatanakul P, Karalak A, Ishida T. Glutathione S-transferase M1 gene polymorphism in Thai nasopharyngeal carcinoma. Asian Pac J Cancer Prev : APJCP. 2005;6:270–5.
Jiang Y, Li N, Dong P, Zhang N, Sun Y, Han M, et al. Polymorphisms in GSTM1, GSTTI and GSTP1 and nasopharyngeal cancer in the east of China: a case–control study. Asian Pac J Cancer Prev : APJCP. 2011;12:3097–100.
Hildesheim A, Anderson LM, Chen CJ, Cheng YJ, Brinton LA, Daly AK, et al. Cyp2e1 genetic polymorphisms and risk of nasopharyngeal carcinoma in Taiwan. J Natl Cancer Inst. 1997;89:1207–12.
Lung HL, Cheung AK, Ko JM, Cheng Y, Stanbridge EJ, Lung ML. Deciphering the molecular genetic basis of npc through functional approaches. Semin Cancer Biol. 2012;22:87–95.
Lo KW, Chung GT, To KF. Deciphering the molecular genetic basis of NPS through molecular, cytogenetic, and epigenetic approaches. Semin Cancer Biol. 2012;22:79–86.
Kurian JR, Chin NA, Longlais BJ, Hayes KL, Trepanier LA. Reductive detoxification of arylhydroxylamine carcinogens by human NADH cytochrome b5 reductase and cytochrome b5. Chem Res Toxicol. 2006;19:1366–73.
Sofos E, Pescosolido MF, Quintos JB, Abuelo D, Gunn S, Hovanes K et5 al. A novel familial 11p15.4 microduplication associated with intellectual disability, dysmorphic features, and obesity with involvement of the ZNF214 gene. Am J Med Genet A. 2012;158A:50–8.
Zhang Z, Sun D, Van do N, Tang A, Hu L, Huang G. Inactivation of RASSF2A by promoter methylation correlates with lymph node metastasis in nasopharyngeal carcinoma. Int J Cancer. 2007;120:32–8.
Olek A, Oswald J, Walter J. A modified and improved method for bisulphite based cytosine methylation analysis. Nucleic Acids Res. 1996;24:5064–6.
Raab-Traub N. Novel mechanisms of EBV-induced oncogenesis. Curr Opin Virol. 2012;2:453–8.
Poirier S, Ohshima H, de-The G, Hubert A, Bourgade MC, Bartsch H. Volatile nitrosamine levels in common foods from Tunisia, South China and Greenland, high-risk areas for nasopharyngeal carcinoma (NPC). Int J Cancer. 1987;39:293–6.
Vaughan TL, Stewart PA, Teschke K, Lynch CF, Swanson GM, Lyon JL, et al. Occupational exposure to formaldehyde and wood dust and nasopharyngeal carcinoma. Occup Environ Med. 2000;57:376–84.
Armstrong RW, Imrey PB, Lye MS, Armstrong MJ, Yu MC, Sani S. Nasopharyngeal carcinoma in Malaysian Chinese: occupational exposures to particles, formaldehyde and heat. Int J Epidemiol. 2000;29:991–8.
Yang XR, Diehl S, Pfeiffer R, Chen CJ, Hsu WL, Dosemeci M, et al. Chinese, American Genetic Epidemiology of NPCST: Evaluation of risk factors for nasopharyngeal carcinoma in high-risk nasopharyngeal carcinoma families in taiwan. Cancer Epidemiol Biomarkers Prev. 2005;14:900–5.
Xue WQ, Qin HD, Ruan HL, Shugart YY, Jia WH. Quantitative association of tobacco smoking with the risk of nasopharyngeal carcinoma: a comprehensive meta-analysis of studies conducted between 1979 and 2011. Am J Epidemiol. 2013;178:325–38.
Hecht SS. Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst. 1999;91:1194–210.
Hecht SS. Tobacco smoke carcinogens and breast cancer. Environ and Mole Mutagen. 2002;39:119–26.
Turashvili G, Bouchal J, Baumforth K, Wei W, Dziechciarkova M, Ehrmann J, et al. Novel markers for differentiation of lobular and ductal invasive breast carcinomas by laser microdissection and microarray analysis. BMC Cancer. 2007;7:55.
Lotem J, Sachs L. Epigenetics and the plasticity of differentiation in normal and cancer stem cells. Oncogene. 2006;25:7663–72.
Wei WI, Sham JS. Nasopharyngeal carcinoma. Lancet. 2005;365:2041–54.