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Abstract：
Previous investigations have reported that microRNA-126 (miR-126) and its host gene, epidermal growth factor-like domain-containing protein 7 (EGFL7) are involved in lung cancer progression, suggesting EGFL7 and miR-126 play a joint role in lung cancer development. In this study, we analyzed the methylation-associated regulation of EGFL7 and miR-126 in non-small cell lung cancer (NSCLC) and further investigated the association between EGFL7/miR-126 polymorphisms and NSCLC susceptibility in the Han Chinese population. Based on our data, relative to those in adjacent normal tissue, both EGFL7 expression and miR-126 expression were decreased significantly in lung cancer tissue (P = 3x10-4 and P < 1x10-4), and the expression of EGFL7 mRNA and miR-126 was significantly correlated in both NSCLC tissue n = 46, r = 0.43, P = 0.003 and adjacent normal tissue n = 46, r = 0.37, P = 0.011. Differential methylation analysis indicated that methylation levels of multiple CG loci in EGFL7 were significantly higher in the lung cancer samples than in the normal samples (P < 0.01). Moreover, EGFL7 mRNA and miR-126 were significantly upregulated after treatment with the DNA demethylating agent 5-aza-2\'-deoxycytidine (5-Aza-CdR) in lung cancer cell lines. In addition, the A allele of rs2297538 was significantly associated with a decreased NSCLC risk (OR = 0.68, 95% CI: 0.52~0.88), and the expression of EGFL7 and miR-126 was significantly lower in rs2297538 homozygous G/G tumor tissue than in A/G+A/A tumor tissue (P = 0.01 and P = 0.002). Our findings suggest that the expression of EGFL7 and miR-126 in NSCLC can be concomitantly downregulated through methylation and the EGFL7/miR-126 polymorphism rs2297538 is correlated with NSCLC risk. Together, these results provide new insights into the pathogenesis of NSCLC.
摘要：
先前的研究报道了microRNA-126(miR-126)及其宿主基因,表皮生长因子样结构域含蛋白7（EGFL7）参与肺癌的进展，提示EGFL7和miR-126在肺癌发生发展中发挥联合作用。在这项研究中,我们分析了EGFL7和miR-126在非小细胞肺癌(NSCLC)中的甲基化相关调控,并进一步研究了EGFL7/miR-126多态性与中国汉族人群NSCLC易感性之间的关联.根据我们的数据,相对于邻近的正常组织，肺癌组织中EGFL7表达和miR-126表达均显著降低(P=3x10-4,P<1x10-4),EGFL7mRNA和miR-126的表达在NSCLC组织中n=46，r=0.43，P=0.003，癌旁正常组织n=46，r=0.37，P=0.011。差异甲基化分析表明，肺癌样本中EGFL7中多个CG位点的甲基化水平明显高于正常样本（P<0.01）。此外，在肺癌细胞系中，用DNA去甲基化剂5-氮杂-2'-脱氧胞苷（5-Aza-CdR）处理后，EGFL7mRNA和miR-126显着上调。此外,rs2297538的A等位基因与NSCLC风险降低显著相关(OR=0.68,95%CI:0.52~0.88),rs2297538纯合G/G肿瘤组织中EGFL7和miR-126的表达显著低于A/G+A/A肿瘤组织(P=0.01和P=0.002)。我们的研究结果表明，EGFL7和miR-126在NSCLC中的表达可以通过甲基化同时下调，EGFL7/miR-126多态性rs2297538与NSCLC风险相关。一起,这些结果为NSCLC的发病机制提供了新的见解。
