Abstract
Abnormal hypermethylation of CpG islands not only associated with tumor suppressor genes can lead to repression of gene expression, but also contribute to escape of the tumor from immune surveillance and contribute significantly to tumorigenesis. In the present study, we studied the hypermethylation of low molecular-weight protein (LMP) gene and its regulation on protein expression in biopsies from resected tissues from Kazak’s esophageal squamous cell carcinoma (ESCC) patients and their neighboring normal tissues. LMP2 and LMP7 genes promoter region methylation sequences were maped in esophageal cancer cell line Eca109 by bisulfite-sequencing PCR and quantitative detection of methylated DNA from 30 pairs of Kazak’s ESCC and adjacent normal tissues by MassARRAY (Sequenom, San Diego, CA, USA) and LMP2 and LMP7 protein expression were analyzed with immunohistochemistry. In Eca109, we identified 6 CG sites methylated from all of 22 CpG sites of LMP7 gene. However, no methylation was found for LMP2. The analysis of the data resulted from the quantitative analysis of single CpG site methylation by Sequenom MassARRAY platform, has shown that the methylation level between two groups CpG sites (CpG_5, CpG_9, CpG_20, CpG_21 and CpG_20) from CpG_1, CpG_2, CpG_3, CpG_4, CpG_5, CpG_6, CpG_7, CpG_8, CpG_9, CpG_10.11, CpG_12.13.14, CpG_15.16.17.18, CpG_19, CpG_20, CpG_21 and CpG_22 significant differences between ESCC and neighboring normal tissues. The analysis of methylation level of whole target CpG fragment indicated that the methylation level of LMP7 was significant higher in ESCC (0.0517 ± 0.0357) than in neighboring normal tissues (0.0380 ± 0.0214, P < 0.05). there was a tendency of decreasing the LMP7 proteins expression as the increasing the methylation level of LMP7 gene promoter regions (F = 7.69, P = 0.041). The LMP7 gene promoter methylation and protein downregulation were correlated at high extent in Kazakh’s ESCC patients, and may explain the epigenetic regulation on gene expression.
Similar content being viewed by others
References
Sarah BU, David EF (2008) Esophageal cancer: epidemiology, pathogenesis and prevention. Nat Clin Pract Gastroenterol Hepatol 5:517–526
Lambert R, Hainaut P (2007) The multidisciplinary management of gastrointestinal cancer. Epidemiology of oesophagogastric cancer. Best Pract Res Clin Gastroenterol 21:921–945
Jemal A, Siegel R, Xu JQ et al (2010) Cancer statistics, 2010. CA Cancer J Clin 60:277–300
Zhang Y (1988) The distribution of esophageal cancer in Xinjiang. Xinjiang Yixueyuan Xuebao 11:139–144
Zheng S, Vuitton L, Sheyhidin I et al (2010) Northwestern China: a place to learn more on oesophageal cancer. Part one: behaviour and environmental risk factors. Eur J Gastroenterol Hepatol 22:917–925
Yang CS (1980) Research on esophageal cancer in China: a review. Cancer Res 40:2633–2644
Morgan GP (1995) Epidemiology of esophageal cancer. J R Soc Med 88:119
Hasim A, Hong MA, Sheyhidin I, Zhang L, Abudula A (2011) Association of defective HLA-I expression with antigen processing machinery and their association with clinicopathological characteristics in Kazak patients with esophageal cancer. Chin Med J 124(3):341–346
Knutson KL, Disis ML (2005) Tumor antigen-specific T helper cells in cancer immunity and immunotherapy. Cancer Immunol Immunother 54:721–728
Meissner M, Reichert TE, Kunkel M, Gooding W, Whiteside TL, Ferrone S, Seliger B (2005) Defects in the human leukocyte antigen class I antigen-processing machinery in head and neck squamous cell carcinoma: association with clinical outcome. Clin Cancer Res 11(7):2552–2560
Shen YQ, Zhang JQ, Xia M, Miao FQ, Shan XN, Xie W (2007) Low-molecular-weight protein (LMP)2/LMP7 abnormality underlies the downregulation of human leukocyte antigen class I antigen in a hepatocellular carcinoma cell line. J Gastroenterol Hepatol 22(7):1155–1161
Cathro HP, Smolkin ME, Theodorescu D et al (2010) Relationship between HLA class I antigen processing machinery component expression and the clinico- pathologic characteristics of bladder carcinomas. Cancer Immunol Immunother 59:465–472
Liu Q, Hao C, Su P, Shi J (2009) Down-regulation of HLA class I antigen-processing machinery components in esophageal squamous cell carcinomas: association with disease progression. Scand J Gastroenterol 44(8):960–969
Nie Y, Liao J, Zhao X, Song Y, Yang GY, Wang LD, Yang CS (2002) Detection of multiple gene hypermethylation in the development of esophageal squamous cell carcinoma. Carcinogenesis 23(10):1713–1720
Ingrid C, Cristina B, Eleonora M, Silvia B, Fabio F, Ester F, Stefano F, Vitalba D, Maria AZ, Fulvio M et al (2011) Renal cell carcinoma primary cultures maintain genomic and phenotypic profile of parental tumor tissues. BMC Cancer 2011(11):244
Hasim A, Tuerxun H, Kuerban G, MA J, Abudla A (2012) Relationship and significance between HPV infection in Uyghur women cervical lesions and LMP gene promoter methylation. Chin J Microbiol Immunol 3:213–216
Tomasi TB, Magner WJ, Khan AN (2006) Epigenetic regulation of immune escape genes in cancer. Cancer Immunol Immunother 10:1159–1184
Manning J, Indrova M, Lubyova B, Pribylova H, Bieblova J, Hejnar J, Simova J, Jandlova T, Bubenik J, Reinis M (2008) Induction of MHC class I molecule cell surface expression and epigenetic activation of antigen-processing machinery components in a murine model for human papilloma virus 16-associated tumours. Immunology 123:218–227
Khan AN, Gregorie CJ, Tomasi TB (2008) Histone deacetylase inhibitors induce TAP, LMP, tapasin genes and MHC class I antigen presentation by melanoma cells. Cancer Immunol Immunother 57:647–654
Author information
Authors and Affiliations
Corresponding author
Additional information
Feng Zheng and Ayshamgul Hasim contributed equally to this study.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Zheng, F., Hasim, A., Anwer, J. et al. LMP gene promoter hypermethylation is a mechanism for its down regulation in Kazak’s esophageal squamous cell carcinomas. Mol Biol Rep 40, 2069–2075 (2013). https://doi.org/10.1007/s11033-012-2138-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-012-2138-2