Mello Adriano Azevedo, Leal Mariana Ferreira, Rey Juan Antonio, Pinto Giovanny Rebouças, Lamarão Leticia Martins, Montenegro Raquel Carvalho, Alves Ana Paula Negreiros Nunes, Assumpção Paulo Pimentel, Borges Barbara do Nascimento, Smith Marília Cardoso, Burbano Rommel Rodriguez
Centro de Ciências Biológicas e da Saúde, Universidade Federal de Campina Grande, Campina Grande, PB, Brazil.
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.
PLoS One. 2015 Oct 13;10(10):e0140492. doi: 10.1371/journal.pone.0140492. eCollection 2015.
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.
激酶是多种细胞信号级联反应的下游调节因子和效应器，在肿瘤性疾病的发生发展中起关键作用。在本研究中，我们旨在评估胃癌中SRC、LYN和CKB蛋白及mRNA表达，以及它们的启动子甲基化情况。我们发现SRC和LYN激酶的mRNA及蛋白表达升高，但CKB激酶水平降低，这些改变可能在胃肿瘤的侵袭和转移中发挥作用。所研究的三种激酶的表达也与MYC癌基因表达相关，MYC可能是胃癌的生物标志物。为了解调控这些基因表达的机制，我们评估了这三种激酶的DNA启动子甲基化情况。我们发现SRC和LYN甲基化降低以及CKB甲基化增加与胃癌相关。SRC和LYN甲基化降低与mRNA和蛋白表达水平升高相关，表明DNA甲基化参与调控这些激酶的表达。相反，在mRNA和蛋白表达降低的样本中观察到CKB甲基化降低，提示CKB表达仅部分受DNA甲基化调控。此外，我们发现所研究的三种激酶的DNA甲基化模式改变也与胃癌的发生、进展期胃癌、肿瘤浸润深度及转移的存在相关。因此，SRC、LYN和CKB的表达或DNA甲基化可能是预测肿瘤进展及抗癌策略靶向治疗的有用标志物。
