Correlation between Promoter Hypermethylation and Expression Profiles of P15INK4b and P16INK4a Genes on Development of Pterygium Disease

Document Type : Original Article


1 Department of Biology, University of Sistan and Baluchestan, Zahedan, Iran

2 Department of Ophthalmology, Al-Zahra Eye Hospital, Zahedan University of Medical Sciences, Zahedan, Iran


< p>Background: It is not thoroughly clear that what is the exact etiology of pterygium. Recently, it has been illustrated that pterygium is a benign and destructive condition. The aim of this study was to examine the correlation between promoter hypermethylation of P15INK4band P16INK4a genes on progress of pterygium. Materials and methods: We extracted DNA from 81 primary pterygium and 75 normal conjunctiva tissues. Methylation specific polymerase chain reaction (MSP) technique was used to analyze of promoter hypermethylation of P15INK4b and P16INK4a genes. The expression levels ofthesegenes were also assessed in mRNA from 23 pterygium and 18 normal conjunctiva tissue samples using real-time quantitative reverse transcriptase PCR.  Results: The frequency of methylation for P15INK4b was 97.5% and 72% among cases and controls respectively. P16INK4 gene methylation at promoter was 69.1% and 33.3% for pterygium and normal conjunctiva tissue respectively. A statistically significant relationship was found for methylation of P15INK4b and P16INK4a genes between cases and controls (p


Agarwal, A., et al. (2012). Role of epigenetic alterations in the pathogenesis of Barrett’s esophagus and esophageal adenocarcinoma. International Journal of Clinical and Experimental Pathology, 5(5): 382.
Balci, M., et al. (2011). Investigation of oxidative stress in pterygium tissue. Molecular Vision, 17: 443.
Chen, P. L., et al. (2006). Hypermethylation of the p16 gene promoter in pterygia and its association with the expression of DNA methyltransferase 3b. Mol Vis, 12(141): l-1416.
Chui, J., et al. (2011). Ophthalmic pterygium: a stem cell disorder with premalignant features. The American Journal of Pathology, 178(2): 817-827.
Detorakis, E. T., & Spandidos, D. A.  (2009). Pathogenetic mechanisms and treatment options for ophthalmic pterygium: trends and perspectives. International Journal of Molecular Medicine, 23(4): 439-447.
Džunić, B., et al. (2010). Analysis of pathohistological characteristics of pterygium. Bosnian journal of Basic Medical Sciences, 10(4): 307.
E., M. (2008). Epigenetics in Cancer. N Engl J Med. 2008 Mar 13, doi: 10.1056/NEJMra072067, 358(11):1148-59.
Ellis, L., et al. (2009). Epigenetics in cancer: targeting chromatin modifications. Molecular Cancer Therapeutics, 8(6): 1409-1420.
Esteller, M. (2002). CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene, 21(35): 5427-5440.
Henley, S. A. & Dick, F. A.  (2012). The retinoblastoma family of proteins and their regulatory functions in the mammalian cell division cycle. Cell Division, 7(1): 10.
Ho, E., et al. (2011). Dietary factors and epigenetic regulation for prostate cancer prevention. Advances in Nutrition,  2(6): 497-510.
Holdt, L. M., & Teupser, D. (2012). Recent studies of the human chromosome 9p21 locus, which is associated with atherosclerosis in human populations. Arteriosclerosis, Thrombosis, and Vascular Biology, 32(2): 196-206.
Huang, Q., et al. (1999). Mutations of several tumor suppressor genes in primary retinoblastoma. Zhonghua zhong liu za zhi [Chinese Journal of Oncology], 21(1): 10-12.
Iraji, R., et al. (2018). Expression and promoter-hyper methylation analysis of MGMT gene in patients with pterygium.
Jha, A., et al. (2010). Reversal of hypermethylation and reactivation of the RARbeta2 gene by natural compounds in cervical cancer cell lines. Folia Biol (Praha), 56(5): 195-200.
Jha, A. K., et al. (2011). Epigenetics and its role in ageing and cancer. J Med Med Sci, 2(3): 696-713.
Jha, A. K., et al. (2012). p16INK4a and p15INK4b gene promoter methylation in cervical cancer patients. Oncology letters, 3(6): 1331-1335.
Jones, P. A., & Baylin, S. B.  (2002). The fundamental role of epigenetic events in cancer. Nature Reviews Genetics, 3(6): 415-428.
Kim, J., et al. (2009). Epigenetic mechanisms in mammals. Cellular and Molecular Life Sciences, 66(4): 596.
Kordi-Tamandani, D. M., et al. (2012). Analysis of p15 ink4b and p16 ink4a gene methylation in patients with oral squamous cell carcinoma. Biochemical Genetics, 50(5-6): 448-453.
Kordi-Tamandani, D. M., et al. (2010). Promoter hypermethylation and expression profile of MGMT and CDH1 genes in oral cavity cancer. Archives of Oral Biology, 55(10): 809-814.
Mascolo, M., et al. (2012). Epigenetic disregulation in oral cancer. International Journal of Molecular Sciences, 13(2): 2331-2353.
Muntean, A. G. and Hess, J. L.  (2009). Epigenetic dysregu- lation in cancer. The American Journal of Pathology, 175(4): 1353-1361.
Osman, W., et al. (2012). A genome-wide association study in the Japanese population confirms 9p21 and 14q23 as susceptibility loci for primary open angle glaucoma. Human Molecular Genetics, 21(12): 2836-2842.
Sharma, S., et al. (2010). Epigenetics in cancer. Carcinogenesis, 31(1): 27-36.
Tabish, A. M., et al. (2012). Epigenetic factors in cancer risk: effect of chemical carcinogens on global DNA methylation pattern in human TK6 cells. PloS One, 7(4).
Tan, D. T., et al. (2000). Apoptosis and apoptosis related gene expression in normal conjunctiva and pterygium. British Journal of Ophthalmology, 84(2): 212-216.
Tradjutrisno, N. (2016). Pterygium: degeneration, exube- rant wound healing or benign neoplasm?. Universa Medicina, 28(3): 179-187.
Tradjutrisno, N. (September-December, 2009). Pterygium: degeneration, exuberant wound healing or benign neoplasm?. Universa Medicina, 28(3): 179-187.
Vermeulen, K., et al. (2003). The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell proliferation, 36(3): 131-149.
Young, C. H., et al. (2010). E-cadherin promoter hyperme- thylation may contribute to protein inactivation in pterygia. Molecular Vision, 16: 1047.
Yuen, P. W. and Wong, S. (2004). The study of p16 and p15 gene methylation in head and neck squamous cell carcinoma and their quantitative evaluation in plasma by real-time PCR, AACR.
Zhuang, J., et al. (2012). Methylation of p15INK4b and expression of ANRIL on chromosome 9p21 are associated with coronary artery disease. PloS One, 7(10).
Volume 2, Issue 1
January 2021
Pages 25-30
  • Receive Date: 04 September 2019
  • Revise Date: 01 November 2020
  • Accept Date: 10 November 2020
  • First Publish Date: 01 January 2021