Different splicing isoforms of ERCC1 affect the expression of its overlapping genes CD3EAP and PPP1R13L, and indicate a potential application in non-small cell lung cancer treatment
Different splicing isoforms of ERCC1 affect the expression of its overlapping genes CD3EAP and PPP1R13L, and indicate a potential application in non-small cell lung cancer treatment
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ERCC1的不同剪接异构体影响其重叠基因CD3EAP和PPP1R13L的表达，并表明其在非小细胞肺癌治疗中的潜在应用。
DOI：
10.3892/ijo.2018.4347
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发表时间：
2018-06-01
影响因子：
5.2
通讯作者：
Lu, Xiaobo
中科院分区：
文献类型：
--
作者：
Zhang, Guopei;Xue, Ping;Lu, Xiaobo
许多基因以复杂的重叠和交错的模式排列，这种排列可能有助于基因表达的调节。既往研究发现，染色体19q13. 3中包含重叠基因切除修复交叉互补组1 （ERCC1）、CD3e分子相关蛋白（CD3EAP）和蛋白磷酸酶1调控亚基13样（PPP1R13L）的区域与非小细胞肺癌（NSCLC）的风险和预后相关。本研究证实了这些重叠基因之间存在共表达模式的假设。通过对非小细胞肺癌组织样本进行定量聚合酶链反应（qPCR）分析，验证了肿瘤基因组图谱的生物信息学证据。此外，通过微阵列分析、qPCR和cDNA末端3′快速扩增（3′race）评估顺铂诱导的DNA损伤细胞模型，验证和量化共表达的选择性剪接异构体在NSCLC组织以及癌症A549和正常16HBE细胞中的表达水平。CD3EAP外显子1的表达与PPP1R13L外显子1显著相关，而CD3EAP外显子3的表达与ERCC1外显子11在正常和非小细胞肺癌组织中显著相关。结果发现，ERCC1、CD3EAP和PPP1R13L的短转录本在A549细胞中共表达，全长转录本在16HBE细胞中共表达。此外，基于重叠基因的位置关联，描述了一种新的转录调控模式。重叠基因ERCC1、CD3EAP和PPP1R13L所在区域可能参与了上下游基因的连接，而ERCC1的不同剪接异构体会影响其重叠基因的表达，提示其在非小细胞肺癌顺铂耐药治疗中的潜在应用。
Numerous genes are arranged in complex overlapping and interlaced patterns, and such arrangements potentially contribute to the regulation of gene expression. Previous studies have demonstrated that a region in chromosome 19q13.2-3 encompassing the overlapping genes excision repair cross-complementation group 1 (ERCC1), CD3e molecule associated protein (CD3EAP) and protein phosphatase 1 regulatory subunit 13 like (PPP1R13L) was found to be associated with the risk and prognosis of non-small cell lung cancer (NSCLC). The present study confirmed the hypothesis that there are co-expression patterns among these overlapping genes. The suggestive bioinformatic evidence of The Cancer Genome Atlas was verified by quantitative polymerase chain reaction (qPCR) analysis of NSCLC tissue samples. In addition, a cisplatin-induced DNA damage cell model was assessed by microarray analysis, qPCR and 3' rapid amplification of cDNA ends (3'RACE) to verify and quantify the expression levels of co-expressed alternative splicing isoforms in the NSCLC tissues, as well as in cancer A549 and normal 16HBE cells. The expression of CD3EAP exon 1 was demonstrated to be significantly associated with PPP1R13L exon 1, while CD3EAP exon 3 was significantly associated with ERCC1 exon 11 in normal and NSCLC tissues. It was observed that short transcripts of ERCC1, CD3EAP and PPP1R13L are co-expressed in A549 cells and full-length transcripts are co-expressed in 16HBE cells. Furthermore, a novel transcriptional regulation pattern was described based on the positional associations of overlapping genes. The region encompassing the overlapping genes ERCC1, CD3EAP and PPP1R13L may be involved in linking the upstream and downstream genes, while the different splicing isoforms of ERCC1 affect the expression of its overlapping genes, suggesting potential application in cisplatin resistance in NSCLC treatment.