title: Deregulated Expression of SRC, LYN and CKB Kinases by DNA Methylation and Its Potential Role in Gastric Cancer Invasiveness and Metastasis.
abstract: 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.
authors.affiliation: Centro de Ciências Biológicas e da Saúde, Universidade Federal de Campina Grande, Campina Grande, PB, Brazil.
authors.forename: Adriano Azevedo
authors.initials: AA
authors.lastname: Mello
authors.affiliation: Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brazil; Departamento de Ortopedia e Traumatologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
authors.forename: Mariana Ferreira
authors.initials: MF
authors.lastname: Leal
authors.affiliation: Laboratorio de Oncogenética Molecular, Hospital Universitario La Paz, Madrid, Madrid, Spain.
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Rey
authors.affiliation: Departmento de Biomedicina, Universidade Federal do Piauí, Parnaíba, PI, Brazil.
authors.forename: Giovanny Rebouças
authors.initials: GR
authors.lastname: Pinto
authors.affiliation: Laboratório de Testes de Ácidos Nucleicos, Fundação Centro de Hemoterapia e Hematologia do Pará, Belém, PA, Brazil; Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil.
authors.forename: Leticia Martins
authors.initials: LM
authors.lastname: Lamarão
authors.affiliation: Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil.
authors.forename: Raquel Carvalho
authors.initials: RC
authors.lastname: Montenegro
authors.affiliation: Departamento de Patologia Oral, Faculdade de Odontologia, Universidade Federal do Ceará, Fortaleza, CE, Brasil.
authors.forename: Ana Paula Negreiros Nunes
authors.initials: AP
authors.lastname: Alves
authors.affiliation: Núcleo de Pesquisa em Oncologia, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, PA, Brazil.
authors.forename: Paulo Pimentel
authors.initials: PP
authors.lastname: Assumpção
authors.affiliation: Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil; Centro de Tecnologia Agropecuária, Instituto Socioambiental e dos Recursos Hídricos, Universidade Federal Rural da Amazônia, Belém, PA, Brazil.
authors.forename: Barbara do Nascimento
authors.initials: Bdo N
authors.lastname: Borges
authors.affiliation: Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
authors.forename: Marília Cardoso
authors.initials: MC
authors.lastname: Smith
authors.affiliation: Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil; Núcleo de Pesquisa em Oncologia, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, PA, Brazil.
authors.forename: Rommel Rodriguez
authors.initials: RR
authors.lastname: Burbano
mesh_terms: D003402:Creatine Kinase / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013274:Stomach Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D019061:src-Family Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D003402:Creatine Kinase