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      Deregulated Expression of SRC, LYN and CKB Kinases by DNA Methylation and Its Potential Role in Gastric Cancer Invasiveness and Metastasis

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          Kinases are downstream modulators and effectors of several cellular signaling cascades and play key roles in the development of neoplastic disease. In this study, we aimed to evaluate SRC, LYN and CKB protein and mRNA expression, as well as their promoter methylation, in gastric cancer. We found elevated expression of SRC and LYN kinase mRNA and protein but decreased levels of CKB kinase, alterations that may have a role in the invasiveness and metastasis of gastric tumors. Expression of the three studied kinases was also associated with MYC oncogene expression, a possible biomarker for gastric cancer. To understand the mechanisms that regulate the expression of these genes, we evaluated the DNA promoter methylation of the three kinases. We found that reduced SRC and LYN methylation and increased CKB methylation was associated with gastric cancer. The reduced SRC and LYN methylation was associated with increased levels of mRNA and protein expression, suggesting that DNA methylation is involved in regulating the expression of these kinases. Conversely, reduced CKB methylation was observed in samples with reduced mRNA and protein expression, suggesting CKB expression was found to be only partly regulated by DNA methylation. Additionally, we found that alterations in the DNA methylation pattern of the three studied kinases were also associated with the gastric cancer onset, advanced gastric cancer, deeper tumor invasion and the presence of metastasis. Therefore, SRC, LYN and CKB expression or DNA methylation could be useful markers for predicting tumor progression and targeting in anti-cancer strategies.

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          Most cited references 71

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                Author and article information

                [1 ]Centro de Ciências Biológicas e da Saúde, Universidade Federal de Campina Grande, Campina Grande, PB, Brazil
                [2 ]Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brazil
                [3 ]Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
                [4 ]Laboratorio de Oncogenética Molecular, Hospital Universitario La Paz, Madrid, Madrid, Spain
                [5 ]Departmento de Biomedicina, Universidade Federal do Piauí, Parnaíba, PI, Brazil
                [6 ]Laboratório de Testes de Ácidos Nucleicos, Fundação Centro de Hemoterapia e Hematologia do Pará, Belém, PA, Brazil
                [7 ]Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil
                [8 ]Departamento de Patologia Oral, Faculdade de Odontologia, Universidade Federal do Ceará, Fortaleza, CE, Brasil
                [9 ]Núcleo de Pesquisa em Oncologia, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, PA, Brazil
                [10 ]Centro de Tecnologia Agropecuária, Instituto Socioambiental e dos Recursos Hídricos, Universidade Federal Rural da Amazônia, Belém, PA, Brazil
                University of Florida, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MFL JAR MCS RRB. Performed the experiments: AAM MFL GRP LML APNNA BNB. Analyzed the data: AAM MFL JAR RRB. Contributed reagents/materials/analysis tools: JAR LML RCM PPA BNB MCS RRB. Wrote the paper: AAM MFL MCS RRB. Contributed with sample collection: AAM RCM PPA.

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                13 October 2015
                : 10
                : 10

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                Figures: 7, Tables: 4, Pages: 23
                This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; grants #471072/2012-5 and 402283/2013-9; fellowship to MCS and RRB), Fundação de Amparo à Pesquisa do Pará (FAPESPA; grant #ICAAF 123/2014 to RRB) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; grant #2009/07145-9; fellowship to MFL) as grants and fellowship awards. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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