Aberrant DNA methylation is a common form of epigenetic alterations and it has been proved to be closely related to many cancers, while its role in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) is not clear. This study focuses on the role of DNA methyltransferase 1 (DNMT1) in EGFR-mutated NSCLC pathogenesis. First, the expression of DNMT1 was up-regulated, while the expressions of human mutL homolog 1(hMLH1) and human mutS homolog 2 (hMSH2) were down-regulated in EGFR-mutated NSCLC patients and cell line HCC827. The results of the correlation analysis showed that DNMT1 expression was inversely correlated with the expressions of hMLH1 and hMSH2. Then, we found that DNMT1 enhanced the promoter methylation levels of hMLH1 and hMSH2, thus suppressing their expressions. DNMT1 knockdown inhibited the proliferation of HCC827 cells, while both hMLH1 knockdown and hMSH2 knockdown could eliminate its inhibitory effect on cell proliferation. In xenograft mouse models, lentiviral vector-sh-DNMT1 could significantly reduce tumor volumes, confirmed that DNMT1 inhibited tumor cell proliferation in vivo. In conclusion, DNMT1 suppressed the expressions of hMLH1 and hMSH2 via elevating their promoter methylation, thus promoting cell proliferation in EGFR-mutated NSCLC.

中文翻译：

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DNMT1通过甲基化hMLH1和hMSH2启动子在EGFR突变的非小细胞肺癌中促进细胞增殖。

异常的DNA甲基化是表观遗传学改变的一种常见形式，它已被证明与许多癌症密切相关，而其在表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）中的作用尚不清楚。这项研究集中于DNA甲基转移酶1（DNMT1）在EGFR突变的NSCLC发病机理中的作用。首先，在EGFR突变的NSCLC患者和细胞系HCC827中，DNMT1的表达被上调，而人mutL同系物1（hMLH1）和人mutS同系物2（hMSH2）的表达被下调。相关分析的结果表明，DNMT1表达与hMLH1和hMSH2的表达呈反相关。然后，我们发现DNMT1增强了hMLH1和hMSH2的启动子甲基化水平，从而抑制了它们的表达。DNMT1抑制可抑制HCC827细胞的增殖，而hMLH1抑制和hMSH2抑制均可消除其对细胞增殖的抑制作用。在异种移植小鼠模型中，慢病毒载体-sh-DNMT1可以显着减少肿瘤体积，证实DNMT1抑制了肿瘤细胞的增殖体内。总之，DNMT1通过提高启动子甲基化抑制hMLH1和hMSH2的表达，从而促进EGFR突变的NSCLC细胞的增殖。