Immunohistochemical Evaluation of Klotho and DNA Methyltransferase 3a in Oral Squamous Cell Carcinomas

Overview

Journal Med Mol Morphol

Publisher Springer

Specialties Cell Biology
Molecular Biology
Pathology

Date 2017 Mar 18

PMID 28303350

Citations 10

Authors

Bhoj Raj Adhikari

Osamu Uehara

Hirofumi Matsuoka

Rie Takai

Fumiya Harada

Masafumi Utsunomiya

Takatoshi Chujo

Tetsuro Morikawa

Mamata Shakya

Koki Yoshida

Jun Sato

Toshiya Arakawa

Michiko Nishimura

Hiroki Nagayasu

Itsuo Chiba

Yoshihiro Abiko

Affiliations

Soon will be listed here.

Abstract

Carcinoma follows a course of multiple changes that are affected by several important factors, with epigenetic silencing of the promoter gene being one of them. A series of studies have suggested that epigenetic changes in the anti-aging gene Klotho may be one of the emerging areas of concern in the study of carcinogenesis. We hypothesized that epigenetic silencing of Klotho due to hypermethylation of DNMT3a may be one of the causes of carcinoma in the oral and maxillofacial region. In this study, we analyzed the immunohistochemical expressions of Klotho and DNMT3a in tissues obtained from oral dysplasia and oral squamous cell carcinoma. Our results showed increased immune expression of DNMT3a, and decreased expression of Klotho in cells of the cancer tissues when compared with those in the dysplasia and healthy control samples. Chi-square tests complemented by adjusted residual analysis revealed significantly higher number of Klotho-positive and DNMT3a-negative cases in healthy controls, Klotho-negative and DNMT3a-negative cases in ODL, and Klotho-negative and DNMT3a-positive cases in OSCC when compared with the other types among the three groups (X = 46.66, p < 0.001). Thus, downregulation of Klotho may be associated with the overexpression of DNMT3a in cancer tissues.

Citing Articles

Correlation of DNA methylation of DNMT3A and TET2 with oral squamous cell carcinoma.

Li X, Li Z, Gao Q, Peng Y, Yu Y, Hu T Discov Oncol. 2024; 15(1):15.

PMID: 38246976 PMC: 10800327. DOI: 10.1007/s12672-024-00866-9.

Enhanced Transcriptional Signature and Expression of Histone-Modifying Enzymes in Salivary Gland Tumors.

Manou M, Loupis T, Vrachnos D, Katsoulas N, Theocharis S, Kanakoglou D Cells. 2023; 12(20).

PMID: 37887281 PMC: 10604940. DOI: 10.3390/cells12202437.

Epigenetic Regulations of Perineural Invasion in Head and Neck Squamous Cell Carcinoma.

Hurnik P, Chyra Z, Sevcikova T, Stembirek J, Smesny Trtkova K, Gaykalova D Front Genet. 2022; 13:848557.

PMID: 35571032 PMC: 9091179. DOI: 10.3389/fgene.2022.848557.

Expression of DNMTs and H3K9ac in Ameloblastoma and Ameloblastic Carcinoma.

Amaral-Silva G, Melo de Lima Morais T, Wagner V, Martins M, Fregnani E, Soares F Front Oral Health. 2022; 2:751162.

PMID: 35048062 PMC: 8757744. DOI: 10.3389/froh.2021.751162.

Role of Fibroblast Growth Factor 23 (FGF23) and αKlotho in Cancer.

Ewendt F, Feger M, Foller M Front Cell Dev Biol. 2021; 8:601006.

PMID: 33520985 PMC: 7841205. DOI: 10.3389/fcell.2020.601006.

References

Chen B, Wang X, Zhao W, Wu J . Klotho inhibits growth and promotes apoptosis in human lung cancer cell line A549. J Exp Clin Cancer Res. 2010; 29:99. PMC: 2912837. DOI: 10.1186/1756-9966-29-99. View

Williams M, Chakravarti N, Kies M, Maruya S, Myers J, Haviland J . Implications of methylation patterns of cancer genes in salivary gland tumors. Clin Cancer Res. 2006; 12(24):7353-8. DOI: 10.1158/1078-0432.CCR-06-1272. View

Daniel F, Rivero E, Modolo F, Lopes T, Salum F . Immunohistochemical expression of DNA methyltransferases 1, 3a and 3b in oral leukoplakias and squamous cell carcinomas. Arch Oral Biol. 2010; 55(12):1024-30. DOI: 10.1016/j.archoralbio.2010.08.009. View

Tang X, Wang Y, Fan Z, Ji G, Wang M, Lin J . Klotho: a tumor suppressor and modulator of the Wnt/β-catenin pathway in human hepatocellular carcinoma. Lab Invest. 2015; 96(2):197-205. PMC: 4731258. DOI: 10.1038/labinvest.2015.86. View

Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T . Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997; 390(6655):45-51. DOI: 10.1038/36285. View

Okano M, BELL D, Haber D, Li E . DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999; 99(3):247-57. DOI: 10.1016/s0092-8674(00)81656-6. View

De Marzo A, Marchi V, Yang E, Veeraswamy R, Lin X, Nelson W . Abnormal regulation of DNA methyltransferase expression during colorectal carcinogenesis. Cancer Res. 1999; 59(16):3855-60. View

Peng D, Kanai Y, Sawada M, Ushijima S, Hiraoka N, Kosuge T . Increased DNA methyltransferase 1 (DNMT1) protein expression in precancerous conditions and ductal carcinomas of the pancreas. Cancer Sci. 2005; 96(7):403-8. PMC: 11159105. DOI: 10.1111/j.1349-7006.2005.00071.x. View

Lin R, Hsu H, Chang J, Chen C, Chen J, Wang Y . Alteration of DNA methyltransferases contributes to 5'CpG methylation and poor prognosis in lung cancer. Lung Cancer. 2006; 55(2):205-13. DOI: 10.1016/j.lungcan.2006.10.022. View

10.

Nakayama S, Sasaki A, Mese H, Alcalde R, Tsuji T, Matsumura T . The E-cadherin gene is silenced by CpG methylation in human oral squamous cell carcinomas. Int J Cancer. 2001; 93(5):667-73. DOI: 10.1002/ijc.1386. View

11.

Schuebel K, Chen W, Cope L, Glockner S, Suzuki H, Yi J . Comparing the DNA hypermethylome with gene mutations in human colorectal cancer. PLoS Genet. 2007; 3(9):1709-23. PMC: 1988850. DOI: 10.1371/journal.pgen.0030157. View

12.

Choi M, Shim Y, Hwa J, Lee S, Ro J, Kim J . Expression of DNA methyltransferases in multistep hepatocarcinogenesis. Hum Pathol. 2003; 34(1):11-7. DOI: 10.1053/hupa.2003.5. View

13.

Robertson K . DNA methylation, methyltransferases, and cancer. Oncogene. 2001; 20(24):3139-55. DOI: 10.1038/sj.onc.1204341. View

14.

Chedin F, Lieber M, Hsieh C . The DNA methyltransferase-like protein DNMT3L stimulates de novo methylation by Dnmt3a. Proc Natl Acad Sci U S A. 2002; 99(26):16916-21. PMC: 139244. DOI: 10.1073/pnas.262443999. View

15.

Tang X, Fan Z, Wang Y, Ji G, Wang M, Lin J . Expression of klotho and β-catenin in esophageal squamous cell carcinoma, and their clinicopathological and prognostic significance. Dis Esophagus. 2014; 29(3):207-14. DOI: 10.1111/dote.12289. View

16.

Chen Q, Lipkina G, Song Q, Kramer R . Promoter methylation regulates cadherin switching in squamous cell carcinoma. Biochem Biophys Res Commun. 2004; 315(4):850-6. DOI: 10.1016/j.bbrc.2004.01.143. View

17.

Kademani D . Oral cancer. Mayo Clin Proc. 2007; 82(7):878-87. DOI: 10.4065/82.7.878. View

18.

Sun L, Hui A, Kanai Y, Sakamoto M, Hirohashi S . Increased DNA methyltransferase expression is associated with an early stage of human hepatocarcinogenesis. Jpn J Cancer Res. 1998; 88(12):1165-70. PMC: 5921336. DOI: 10.1111/j.1349-7006.1997.tb00345.x. View

19.

Hermann A, Gowher H, Jeltsch A . Biochemistry and biology of mammalian DNA methyltransferases. Cell Mol Life Sci. 2004; 61(19-20):2571-87. DOI: 10.1007/s00018-004-4201-1. View

20.

Hasegawa M, Nelson H, Peters E, Ringstrom E, Posner M, Kelsey K . Patterns of gene promoter methylation in squamous cell cancer of the head and neck. Oncogene. 2002; 21(27):4231-6. DOI: 10.1038/sj.onc.1205528. View