Epigenetic silencing of the endothelin-B receptor gene in non-small cell lung cancer
Epigenetic silencing of the endothelin-B receptor gene in non-small cell lung cancer
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DOI：
10.3892/ijo_00000171
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发表时间：
2009-02-01
影响因子：
5.2
通讯作者：
Liloglou, Triantafillos
中科院分区：
文献类型：
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作者：
Knight, Lucy J.;Burrage, Joseph;Liloglou, Triantafillos
内皮素-1在几种肿瘤类型中过表达。激活内皮素-A （ET(A)）受体可促进细胞生长、血管生成和侵袭，抑制细胞凋亡过程，而激活内皮素-B （ET(B)）受体可诱导细胞凋亡死亡，抑制肿瘤进展。ET(B)受体基因启动子的超甲基化和随后的沉默已在某些癌症类型中报道。由于内皮素通路是癌症药物治疗研究的主题，我们研究了ET(B)受体基因在非小细胞肺癌（NSCLC）中表观遗传失调的程度。我们对64例NSCLC配对肿瘤/正常手术标本进行了扫描，通过开发四种覆盖24个CpGs的焦磷酸测序检测ET(B)受体启动子的甲基化。ET(B)受体启动子在31例（48%）肿瘤样本中显著高甲基化，与正常组织相比，22/24 CpG位点的甲基化明显更高。与正常邻近肺组织相比，所有肺肿瘤中ET(B)受体mRNA水平均降低，表明该基因在肺癌发展中可能具有重要作用。此外，与未甲基化的肿瘤样本相比，ET(B)受体基因甲基化的肿瘤样本往往具有较低的受体mRNA水平，这表明ET(B)受体沉默的主要表观遗传作用。我们的研究结果表明，ET(B)受体表观遗传失调在肺癌发病机制中的重要作用，使该基因成为对调节内皮素轴的方案反应的有希望的候选生物标志物。
Endothelin-1 is overexpressed in several tumor types. Activation of the endothelin-A (ET(A)) receptor may promote cell growth, angiogenesis and invasion, and inhibits the apoptotic process, while activation of the endothelin-B (ET(B)) receptor may induce cell death by apoptosis and inhibit tumor progression. Hypermethylation and subsequent silencing of the ET(B) receptor gene promoter has been reported in some cancer types. As the endothelin pathway is Subject to research for pharmacological cancer treatment, we investigated the extent of epigenetic deregulation of the ET(B) receptor gene in non-small cell lung cancer (NSCLC). We scanned 64 NSCLC paired tumor/normal surgical specimens for the ET(B) receptor promoter for methylation by developing four pyrosequencing assays that covered 24 CpGs. The ET(B) receptor promoter was significantly hypermethylated in 31 (48%) of tumor samples, presenting considerably higher methylation in 22/24 CpG sites compared with the normal counterpart tissues. ET(B) receptor mRNA levels were reduced in all lung tumors compared with normal adjacent lung tissue, indicating the potentially important involvement of this gene in lung cancer development. Furthermore, tumor samples with ET(B) receptor gene methylation tended to have lower receptor mRNA levels compared with unmethylated tumor specimens, suggesting a primary epigenetic role in ET(B) receptor silencing. Our results point to a significant involvement of ET(B) receptor epigenetic deregulation in the pathogenesis of lung cancer making the gene a promising candidate biomarker for response to regimens modulating the endothelin axis.