ERCC6L, a DNA helicase, is involved in cell proliferation and associated with survival and progress in breast and kidney cancers.
ERCC6L, a DNA helicase, is involved in cell proliferation and associated with survival and progress in breast and kidney cancers.
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ERCC6L 是一种 DNA 解旋酶，参与细胞增殖并与乳腺癌和肾癌的生存和进展相关
DOI：
10.18632/oncotarget.14998
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发表时间：
2017-06-27
期刊：
影响因子：
--
通讯作者：
Kong QP
中科院分区：
文献类型：
--
作者：
Pu SY;Yu Q;Wu H;Jiang JJ;Chen XQ;He YH;Kong QP
通过分析来自癌症基因组图谱（TCGA）的4987个癌症转录组，我们确定了切除修复交叉互补组6样（ERCC 6L），一种新发现的DNA解旋酶，在12种实体癌中高度表达。然而，其在肿瘤发生中的作用和机制在很大程度上是未知的。在本研究中，我们发现通过小内环RNA（siRNA）或短发夹RNA（shRNA）沉默ERCC 6L显著抑制乳腺癌细胞（MCF-7，MDA-MB-231）和肾癌细胞（786-0）的增殖。ERCC 6L基因沉默可使细胞周期阻滞于G 0/G1期，但不影响细胞凋亡。然后，我们在ERCC 6L沉默后进行RNA测序（RNA-seq）分析，并确定RAB 31在转录和翻译水平上均显著下调。ERCC 6L基因沉默还抑制了其下游蛋白磷酸化MAPK和CDK 2的表达。裸鼠移植瘤实验表明，ERCC 6L基因沉默后，从移植瘤第7天开始，肿瘤生长受到显著抑制。此外，研究发现，ERCC 6L的高表达与乳腺癌和肾癌的临床生存率显著相关。结论：ERCC 6L可能通过RAB 31-MAPK-CDK 2途径促进细胞周期，从而刺激肿瘤细胞增殖，有望成为肿瘤预后的生物标志物和肿瘤治疗的靶点。
By analyzing 4987 cancer transcriptomes from The Cancer Genome Atlas (TCGA), we identified that excision repair cross-complementation group 6 like (ERCC6L), a newly discovered DNA helicase, is highly expressed in 12 solid cancers. However, its role and mechanism in tumorigenesis are largely unknown. In this study, we found that ERCC6L silencing by small interring RNA (siRNA) or short hairpin RNA (shRNA) significantly inhibited the proliferation of breast (MCF-7, MDA-MB-231) and kidney cancer cells (786-0). Furthermore, ERCC6L silencing induced cell cycle arrest at G0/G1 phase without affecting apoptosis. We then performed RNA sequencing (RNA-seq) analysis after ERCC6L silencing and identified that RAB31 was markedly downregulated at both the transcriptional and translational levels. Its downstream protein, phosphorylated MAPK and CDK2 were also inhibited by ERCC6L silencing. The xenograft experiment showed that silencing of ERCC6L strikingly inhibited tumor growth from the 7th day after xenograft in nude mice. In addition, higher ERCC6L expression was found to be significantly associated with worse clinical survival in breast and kidney cancers. In conclusion, our results suggest that ERCC6L may stimulates cancer cell proliferation by promoting cell cycle through a way of RAB31-MAPK-CDK2, and it could be a potential biomarker for cancer prognosis and target for cancer treatment.
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