GSTM5 在肺腺癌中的异常表达与 DNA 高甲基化和不良预后相关。
Aberrant expression of GSTM5 in lung adenocarcinoma is associated with DNA hypermethylation and poor prognosis.
机构信息
Department of Biochemistry, Inspection Institute, Harbin Medical University-Daqing, Daqing, China.
School of Biomedical Sciences and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.
出版信息
BMC Cancer. 2022 Jun 21;22(1):685. doi: 10.1186/s12885-022-09711-0.
BACKGROUND
Glutathione-S transferases (GSTs) comprise a series of critical enzymes involved in detoxification of endogenous or xenobiotic compounds. Among several GSTs, Glutathione S-transferases mu (GSTM) has been implicated in a number of cancer types. However, the prognostic value and potential functions of the GSTM family genes have not been investigated in lung adenocarcinoma (LUAD).
METHODS
We examined the expression of GSTM5 in LUAD and identified associations among GSTM5 expression, clinicopathological features, survival data from the Cancer Genome Atlas (TCGA). The correlation between GSTM5 DNA methylation and its expression was analyzed using the MEXPRESS tool and UCSC Xena browser. The methylation status of GSTM5 in the promoter region in lung cancer cells was measured by methylation-specific PCR (MSP). After 5-aza-2'-deoxycytidine treatment of lung cancer cells, expression of GSTM5, cell proliferation and migration were assessed by RT-PCR, CCK-8 and transwell assays, respectively.
RESULTS
The results showed that GSTM5 was abnormally down-regulated in LUAD patients' tissues, and patients with low GSTM5 expression level had significantly shorter OS. Cox regression analyses revealed that GSTM5 was associated with overall survival (OS) of LUAD patients, which expression was an independent prognostic indicator in terms of OS (hazard ratio: 0.848; 95% CI: 0.762-0.945; P = 0.003). In addition, we found the promoter region of GSTM5 was hypermethylated in the tumor tissue compared with adjacent normal tissues, and the average methylation level of GSTM5 were moderately correlated with its expression. Moreover, methylation-specific PCR also showed that the GSTM5 gene promoter was hypermethylated in lung cancer cells, and treatment with 5-Aza-CdR can restore the gene expression and inhibit cell proliferation and migration. Finally, Gene Set Enrichment Analysis (GSEA) revealed that low GSTM5 expression was significantly related to DNA repair pathways.
CONCLUSION
Our data demonstrate that low GSTM5 expression and its high DNA methylation status may act as a novel putative molecular target gene for LUAD.
背景
谷胱甘肽 S-转移酶（GSTs）是一系列参与内源性或外源性化合物解毒的关键酶。在几种 GSTs 中，谷胱甘肽 S-转移酶 mu（GSTM）已被牵连到多种癌症类型中。然而，GSTM 家族基因的预后价值和潜在功能尚未在肺腺癌（LUAD）中进行研究。
方法
我们检测了 LUAD 中 GSTM5 的表达，并确定了 GSTM5 表达与临床病理特征、癌症基因组图谱（TCGA）生存数据之间的关联。使用 MEXPRESS 工具和 UCSC Xena 浏览器分析 GSTM5DNA 甲基化与其表达之间的相关性。通过甲基化特异性 PCR（MSP）测量肺癌细胞中 GSTM5 启动子区域的甲基化状态。在肺癌细胞中用 5-氮杂-2'-脱氧胞苷处理后，通过 RT-PCR、CCK-8 和 Transwell 测定分别评估 GSTM5 的表达、细胞增殖和迁移。
结果
结果表明，GSTM5 在 LUAD 患者组织中异常下调，低 GSTM5 表达水平的患者 OS 明显缩短。Cox 回归分析显示，GSTM5 与 LUAD 患者的总生存期（OS）相关，其表达是 OS 的独立预后指标（风险比：0.848；95%CI：0.762-0.945；P=0.003）。此外，我们发现 GSTM5 的启动子区域在肿瘤组织中比相邻正常组织中过度甲基化，GSTM5 的平均甲基化水平与其表达中度相关。此外，甲基化特异性 PCR 还表明肺癌细胞中 GSTM5 基因启动子过度甲基化，用 5-Aza-CdR 处理可恢复基因表达并抑制细胞增殖和迁移。最后，基因集富集分析（GSEA）显示低 GSTM5 表达与 DNA 修复途径显著相关。
结论
我们的数据表明，低 GSTM5 表达及其高 DNA 甲基化状态可能是 LUAD 的一个新的潜在分子靶基因。
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