Occupational Exposure to Heavy Metal Initiate Carcinogenesis Though BRAF/KRAS Over Expression and DNA Methylation
Subject Areas : Journal of Chemical Health RisksAhmed Talaat Abd Elaziz 1 , Hanaa Mohamed Elzahed 2 , Shar Hassan Ahmed 3 , Wael Fathy 4
1 - Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University (MD)
2 - Forensic Medicine Department, Faculty of Medicine, Cairo University (MD)
3 - Lab Technology Department, Faculty of Applied Medical Science, Misr University For Science &Technology (MD)
4 - Tropical Medicine Department, Beni Suef University, Beni Suef, Egypt (MD)
Keywords: Colorectal cancer, Heavy metals, DNA methylation,
Abstract :
Colorectal carcinoma (CRC) is a leading cause of death especially in industries worker. The aim of this study is to identify the role of heavy elements exposure on CRC DNA methylation.The study was conducted on 25 CRC patients. Biopsies were taken by colonoscopy from malignant tissue and adjacent normal tissues for comparative assessment of BRAF/KRAS, methylated MLH1 and MGMT between the normal and malignant tissues by using real time PCR. In an attempt to identify wither heavy metal like Lead, Aluminum and Mn have a role in cancer development or not, we compared their levels in the serum of 25 CRC patients and 25 normal volunteers by using atomic absorption. The expressions of BRAF/KRAS, methylated MLH1 and MGMT were significantly higher in malignant tissues compared to normal tissues (p value<0.001). Additionally, the levels of lead and aluminum but not Mn were statistically significantly increased in CRC patients compared to normal controls (p value<0.001). Lead and Aluminum were positively correlated with all studied parameters. Heavy metals act as starting signals for carcinogenesis through DNA methylation.
1. Granados-Romero J.J., Valderrama-Treviño A.I., Contreras-Flores E.H., Barrera-Mera B., Enríquez M.H., Uriarte-Ruíz K., Ceballos-Villalva J.C., Estrada-Mata A.G., Rodríguez C.A., Arauz-Peña G. 2017. Colorectal cancer: a review. Int J Res Med Sci. 5(11), 4667-4676.
2. Bond C.E., Liu C., Kawamata F., McKeone D.M., Fernando W., Jamieson S., Pearson S.A., Kane A.,Woods S.L., Lannagan T.R.M., Somashekar R., Lee Y., Dumenil T., Hartel G., Spring K.J., Borowsky J., Fennell L., Bettington M., Lee J., Worthley D.L.,Leggett B.A., Whitehall V.L.J., 2018. Oncogenic BRAF mutation induces DNA methylation changes in a murine model for human serrated colorectal neoplasia. Epigenetics. 13(1), 40-48.
3. Ursem C., Atreya C.E., Van Loon K., 2018. Emerging treatment options for BRAF-mutant colorectal cancer. Gastrointest Cancer. 8, 13–23
4. Porru M., Pompili L., Caruso C., Biroccio A., Leonetti C., 2018. Targeting KRAS in metastatic colorectal cancer: current strategies and emerging opportunities. J Exp Clin Cancer Res. 37(1), 57-65.
5. Cox A.D., Fesik S.W., Kimmelman A.C., Luo J., Der C.J., 2014. Drugging the undruggable RAS: mission possible? Nat Rev Drug Discov. 13, 828–851.
6. Sanz-Garcia E., Argiles G., Elez E., Tabernero J. 2017. BRAF mutant colorectal cancer: prognosis, treatment, and new perspectives. Annals of Oncology. 28(11), 2648–2657
7. Kondo Y., Issa J.P., 2004. Epigenetic changes in colorectal cancer. Cancer Metastasis Rev. 23, 29–39.
8. Zhang L., Zeng J., Zeng Z., Wang F., Wang D., Chen C., Li C., An X., Xu R., Huang P., Ba Y., Li Y. 2016. MGMT in colorectal cancer: a promising component of personalized treatment. Tumour Biol. 37(8), 11443-56.
9. Morales M.E., Derbes R.S., Ade C.M., Ortego J.C., Stark J., Deininger P.L., Roy-Engel A.M., 2016. Heavy Metal Exposure Influences Double Strand Break DNA Repair Outcomes. PLoS ONE 11(3), e0151367.
10. Sohrabi M., Gholami A., Azar M.H., Yaghoobi M., Shahi M.M., Shirmardi S., Nikkhah M., Kohi Z., Salehpour D., Khoonsari M.R., Hemmasi G., Zamani F., Sohrabi M., Ajdarkosh H., 2018. Trace Element and Heavy Metal Levels in Colorectal Cancer: Comparison Between Cancerous and Non-cancerous Tissues. Biol Trace Elem Res. 183(1),1-8.
11. Emre O., Demir H., Dogan E., Esen R., Gur T., Demir C., Gonullu E., Turan N. Özbay M., 2013. Plasma Concentrations of Some Trace Element and Heavy Metals in Patients with Metastatic Colon Cancer Journal of Cancer Therapy, 4(6), 1085-1090.
12. Rinaldi L., Barabino G., Klein J.P., Bitounis D., Pourchez J., Forest V., Boudard D., Leclerc L., Sarry G., Roblin X., Cottier M., Phelip J.M., 2015. Metals distribution in colorectal biopsies: New insight on the elemental fingerprint of tumour tissue. Dig Liver Dis. 47(7), 602-7.
13. Jaishankar M., Tseten T., Anbalagan N., Mathew B.B., Beeregowda K.N., 2104. Toxicity, mechanism and health effects of some heavy metals. Interdiscip Toxicol. 7(2), 60-72.
14. Li H., Swiercz R., Englander E.W., 2009. Elevated metals compromise repair of oxidative DNA damage via the base excision repair pathway: implications of pathologic iron overload in the brain on integrity of neuronal DNA. J Neurochem. 110(6), 1774-83.
15. Susan E.S., Christine D.S., Denise C.H., Parker L.S., Peter M.G., 2017. Nickel induces transcriptional down-regulation of DNA repair pathways in tumorigenic and non-tumorigenic lung cells. Carcinogenesis. 38(6), 627–637
16. Li X., Wang Y., Zhang Z., Yao X., Ge J., Zhao Y., 2013. Correlation of MLH1 and MGMT methylation levels between peripheral blood leukocytes and colorectal tissue DNA samples in colorectal cancer patients. Oncol Lett. 6(5), 1370-1376.
17. Brocato J., Costa M., 2013. Basic mechanics of DNA methylation and the unique landscape of the DNA methylome in metal-induced carcinogenesis. Crit Rev Toxicol. 43(6), 493-514.
18. Sun H., Zhou X., Chen H., Li Q., Costa M., 2009. Modulation of histone methylation and MLH1 gene silencing by hexavalent chromium. Toxicol Appl Pharmacol. 15;237(3), 258-66.
19. Devóz P.P., Gomes W.R., De Araújo M.L., Ribeiro D.L., Pedron T., Greggi Antunes L.M., Batista B.L., Barbosa F. J., Barcelos G.R.M., 2017. Lead (Pb) exposure induces disturbances in epigenetic status in workers exposed to this metal. J Toxicol Environ Health. 80(19-21), 1098-1105.
20. Mahmut S.T., Murat A., Burcu S., Semra Y., Esra A., Guleray A., 2018. Aluminum-Induced Changes on DNA Damage, DNA Methylation and LTR Retrotransposon Polymorphism in Maize. Arabian Journal for Science and Engineering. 43(1), 123–131.
21. Peyssonnaux C., Eychene A., 2001. The Raf/MEK/ERK pathway: new concepts of activation. Biol Cell. 93, 53–62.
22. Tian S., Simon I., Moreno V., Roepman P., Tabernero J., Snel M., van't Veer L., Salazar R., Bernards R., Capella G.A., 2013. combined oncogenic pathway signature of BRAF, KRAS and PI3KCA mutation improves colorectal cancer classification and cetuximab treatment prediction. Gut. 62(4), 540-9.
23. Kumar K., Brim H., Giardiello F., Smoot D.T., Nouraie M., Lee E.L., Ashktorab H., 2009. Distinct BRAF (V600E) and KRAS mutations in high microsatellite instability sporadic colorectal cancer in African Americans. Clin Cancer Res. 15, 1155–1161.
24. Li X., Yao X., Wang Y., Hu F., Wang F., Jiang L., Liu Y., Wang D., Sun G., Zhao Y., 2013. MLH1 Promoter Methylation Frequency in Colorectal Cancer Patients and Related Clinicopathological and Molecular Features. PLoS One. 8(3), e59064.
25. Larki P., Gharib E., Yaghoob Taleghani M., Khorshidi F., Nazemalhosseini-Mojarad E., Asadzadeh Aghdaei H., 2017. Coexistence of KRAS and BRAF Mutations in Colorectal Cancer: A Case Report Supporting The Concept of Tumoral Heterogeneity. Cell J. 19(1), 113-117.
26. Renaud S., Romain B., Falcoz P.E., Olland A., Santelmo N., Brigand C., Rohr S., Guenot D., Massard G., 2015. KRAS and BRAF mutations are prognostic biomarkers in patients undergoing lung metastasectomy of colorectal cancer. Br J Cancer. 112(4), 720-8.
27. de Vogel S., Weijenberg M.P., Herman J.G., Wouters K.A., de Goeij A.F., van den Brandt P.A., de Bruïne A.P., van Engeland M., 2009. MGMT and MLH1 promoter methylation versus APC, KRAS and BRAF gene mutations in colorectal cancer: indications for distinct pathways and sequence of events. Ann Oncol. 20(7), 1216-22.
28. Sinha R., Hussain S., Mehrotra R., Kumar R.S., Kumar K., Pande P., Doval D.C., Basir S.F., Bharadwaj M., 2013. Kras gene mutation and RASSF1A, FHIT and MGMT gene promoter hypermethylation: indicators of tumor staging and metastasis in adenocarcinomatous sporadic colorectal cancer in Indian population. PLoS One. 8(4), e60142.