ABSTRACT

Gastric cancer (GC) is one of the leading types of fatal cancer worldwide. Epigenetic manipulation of cancer cells is a useful tool to better understand gene expression regulatory mechanisms and contributes to the discovery of novel biomarkers. Our research group recently reported a list of 83 genes that are potentially modulated by DNA methylation in GC cell lines. Herein, we further explored the regulation of one of these genes, LRRC37A2, in clinical samples. LRRC37A2 expression was evaluated by RT-qPCR, and DNA methylation was studied using next-generation bisulphite sequencing in 36 GC and paired adjacent nonneoplastic tissue samples. We showed that both reduced LRRC37A2 mRNA levels and increased LRRC37A2 exon methylation were associated with undifferentiated and poorly differentiated tumours. Moreover, LRRC37A2 gene expression and methylation levels were inversely correlated at the +45 exon CpG site. We suggest that DNA hypermethylation may contribute to reducing LRRC37A2 expression in undifferentiated and poorly differentiated GC. Therefore, our results show how some genes may be useful to stratify patients who are more likely to benefit from epigenetic therapy.Abbreviations: AR: androgen receptor; 5-AZAdC: 5-aza-2'-deoxycytidine; B2M: beta-2-microglobulin; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GC: gastric cancer; GLM: general linear model; LRRC37A2: leucine-rich repeat containing 37 member A2; SD: standard deviation; TFII-I: general transcription factor II-I; TSS: transcription start site; XBP1: X-box binding protein 1

摘要

胃癌（GC）是全球主要的致命癌症类型之一。癌细胞的表观遗传操作是更好地了解基因表达调控机制的有用工具，并有助于发现新的生物标志物。我们的研究小组最近报告了 83 个基因的列表，这些基因可能受到 GC 细胞系中 DNA 甲基化的调节。在这里，我们进一步探索了临床样本中这些基因之一LRRC37A2的调控。通过 RT-qPCR 评估LRRC37A2表达，并使用下一代亚硫酸氢盐测序在 36 GC 和配对的相邻非肿瘤组织样本中研究 DNA 甲基化。我们发现LRRC37A2 mRNA 水平降低和LRRC37A2增加外显子甲基化与未分化和低分化肿瘤有关。此外，LRRC37A2基因表达和甲基化水平在 +45 外显子 CpG 位点呈负相关。我们认为 DNA 高甲基化可能有助于降低未分化和低分化 GC 中的LRRC37A2表达。因此，我们的结果显示了一些基因如何有助于对更有可能从表观遗传治疗中受益的患者进行分层。缩写： AR：雄激素受体；5-AZAdC：5-aza-2'-脱氧胞苷；B2M：β-2-微球蛋白；GAPDH：甘油醛-3-磷酸脱氢酶；GC：胃癌；GLM：一般线性模型；LRRC37A2：富含亮氨酸的重复序列，包含 37 个成员 A2；SD：标准差；TFII-I：通用转录因子 II-I；TSS：转录起始位点；XBP1：X-box 结合蛋白 1