Deregulated Expression of SRC, LYN and CKB Kinases by DNA Methylation and Its Potential Role in Gastric Cancer Invasiveness and Metastasis.
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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DOI：
10.1371/journal.pone.0140492
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Burbano RR
中科院分区：
文献类型：
--
作者：
Mello AA;Leal MF;Rey JA;Pinto GR;Lamarão LM;Montenegro RC;Alves AP;Assumpção PP;Borges Bdo N;Smith MC;Burbano RR
激酶是几种细胞信号级联的下游调节剂和效应物，并且在肿瘤疾病的发展中起关键作用。本研究旨在探讨胃癌组织中SRC、林恩和CKB蛋白和mRNA的表达及其启动子甲基化。我们发现SRC和林恩激酶mRNA和蛋白表达升高，而CKB激酶水平降低，这些改变可能在胃肿瘤的侵袭和转移中起作用。三种研究激酶的表达也与MYC癌基因表达相关，MYC癌基因表达是胃癌的可能生物标志物。为了了解调节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。我们发现SRC和林恩甲基化降低以及CKB甲基化升高与胃癌相关。SRC和林恩甲基化的降低与mRNA和蛋白质表达水平的增加相关，表明DNA甲基化参与调节这些激酶的表达。相反，在mRNA和蛋白质表达降低的样品中观察到CKB甲基化降低，表明发现CKB表达仅部分受DNA甲基化调节。此外，我们还发现，这三种研究激酶的DNA甲基化模式的改变也与胃癌的发病、进展期胃癌、更深的肿瘤浸润和转移的存在相关。因此，SRC、林恩和CKB表达或DNA甲基化可能是预测肿瘤进展和在抗癌策略中靶向的有用标志物。
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.