DLK1基因在非小细胞肺癌中异常表达及其调控机制

Up-regulation of DLK1 in non-small cell lung cancer and the relevant molecular mechanism

目的 探讨DLK1基因在非小细胞肺癌患者肿瘤组织中的表达情况及其调控机制。方法 采用免疫组化检测DLK1蛋白在204例非小细胞肺癌组织中的表达，分析DLK1蛋白表达与患者临床特征的关系。采用亚硫酸氢盐测序法检测18例非小细胞肺癌肿瘤组织中DLK1基因启动子区CpG岛的DNA甲基化状态，结合相应组织中DLK1蛋白的表达情况，配对分析DNA甲基化状态与DLK1蛋白表达水平的关系。 结果 在102例肺鳞癌及癌旁支气管上皮组织中，DLK1呈阳性表达分别72例和37例，差异有统计学意义（P＝0.001）；在102例肺腺癌及癌旁肺泡组织中，DLK1呈阳性表达分别77例和7例，差异有统计学意义（P〈0.001）。DLK1蛋白的表达水平与患者的组织类型、临床分期和肿瘤大小均有关（均P〈0.05），DLK1蛋白的表达水平与基因启动子区CpG岛甲基化程度呈负相关关系（P〈0.05）。 结论 在非小细胞肺癌组织中DLK1蛋白异常高表达，而DLK1基因启动子区的低甲基化是导致其异常高表达的调控机制之一。

Objective To explore the expression of delta-like 1 homolog （DLK1） gene in non-small cell lung cancer （NSCLC） and its regulatory mechanism. Methods The expression levels of DLK1 protein in 204 NSCLC tissues were examined by immunohistochemical （IHC） staining, and the correlation between DLKlexpression and elinieopathologieal features was analyzed. Bisulfate sequencing PCR （BSP） of DNA samples from the tumor tissues of 18 NSCLC patients was performed to evaluate the DNA methylation status of CpG island in the DLK1 promoter region, and also compared with the corresponding IHC staining of DLK1 protein in the same samples. Results Among the 102 squamous cell carcinoma （ SCC ） tissue specimens and their adjacent normal bronchial epithelia, DLK1 was up-regulated in 72 and 37 samples, respectively （P = 0.001）, and among 102 adenocarcinomas （ADC） tissues and their adjacent alveolar tissues, DLK1 was up- regulated in 77 and 7 samples, respectively （ P 〈 0. 001 ）. In addition, overexpression of DLK1 was significantly associated with histological type, clinical stage and tumor size of NSCLC （P〈0.05 for all）. The expression of DLKlprotein was inversely correlated with its promoter methylation （P〈0.05）. Conclusion DLK1 expression is up-regulated in NSCLCs, which may be due, at least in part, to the DNA hypomethylation in the promoter region of theDLK1 gene.