ERCC6L that is up-regulated in high grade of renal cell carcinoma enhances cell viability in vitro and promotes tumor growth in vivo potentially through modulating MAPK signalling pathway
ERCC6L that is up-regulated in high grade of renal cell carcinoma enhances cell viability in vitro and promotes tumor growth in vivo potentially through modulating MAPK signalling pathway
复制标题
ERCC6L 在高级别肾细胞癌中上调，可通过调节 MAPK 信号通路增强体外细胞活力并潜在促进体内肿瘤生长
DOI：
10.1038/s41417-018-0064-8
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发表时间：
2019-09-01
影响因子：
6.4
通讯作者：
Zeng, Yu
中科院分区：
文献类型：
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作者：
Zhang, Gejun;Yu, Zi;Zeng, Yu
肾细胞癌（RCC）是全世界诊断最多的泌尿系统恶性肿瘤之一，通常与遗传和细胞过程的异常有关。在本研究中，通过分析癌症基因组图谱（TCGA）数据集，我们根据其在ccRCC组织中的表达量较正常肾组织增加以及其与癌症预后的可能相关性，筛选出ERCC6L作为与RCC发生潜在相关的候选基因。有证据表明ERCC6L是哺乳动物细胞有丝分裂不可或缺的组成部分，但未能揭示ERCC6L在肿瘤发生中的作用。通过使用RT-PCR，证实28个配对样本中的ERCC6L mRNA表达与正常对照相比在RCC组织中上调。此外，对包含150个ccRCC样本的组织微阵列（TMA）进行的免疫组织化学研究表明，ERCC6L的染色评分与癌症的Fuhrman分级呈正相关。接下来，当特定shRNA降低ERCC6L的表达时，786-O和Caki-1细胞中的细胞活力被显着抑制，同时细胞凋亡也相应被诱导。与此同时，在免疫缺陷小鼠中，转染了针对 ERCC6L 的 shRNA 的 RCC 细胞的生长速度明显慢于亲本细胞。这些结果一致表明 ERCC6L 可能在体外和体内调节 RCC 细胞活力中发挥作用。此外，敲除 786-O 细胞中 ERCC6L 表达后进行的基因表达微阵列分析和验证蛋白质印迹强调了 MAPK 信号通路参与 ERCC6L 对 RCC 细胞过程的调节。总之，本研究表明 ERCC6L 可能对 RCC 的发展具有促进作用。因此，显然需要进一步研究探索 ERCC6L 作为 RCC 新治疗靶点的潜在用途。
Renal cell carcinoma (RCC), which is one of the most diagnosed urological malignancies worldwide, is usually associated with abnormality in both genetic and cellular processes. In the present study, through analyzing The Cancer Genome Atlas (TCGA) dataset, we screened out ERCC6L as a candidate gene that is potentially related to the development of RCC based on its increased expression in ccRCC tissues compared with normal kidney tissues as well as its possible relevance to cancer prognosis. Evidence indicates that ERCC6L is an indispensable component of mammalian cell mitosis, while it fails to disclose the role of ERCC6L in tumorigenesis. By using RT-PCR, it was confirmed that the mRNA expression of ERCC6L was upregulated in RCC tissues as compared to normal controls in 28 pared samples. In addition, the immunohistochemistry study in a tissue microarray (TMA) containing 150 ccRCC samples showed that the staining score of ERCC6L was positively correlated with the Fuhrman grade of cancers. Next, when the expression of ERCC6L was lowered by specific shRNA, the cell viability was significantly inhibited in 786-O and Caki-1 cells, while the apoptosis was induced accordingly. At the same time, RCC cells those were transfected with shRNA targeting to ERCC6L grew significantly slower than parental cells in immunodeficient mice. These results consistently suggest that ERCC6L may play a role in regulating the cell viability of RCC both in vitro and in vivo. Further, gene expression microarray analysis followed by the validating western blot after knocking down ERCC6L expression in 786-O cells highlighted the involvement of MAPK signaling pathway in regulation of ERCC6L on cellular process of RCC. In conclusion, the present study suggests a likely promoting role of ERCC6L on the development of RCC. Thus, further study to explore the potential utility of ERCC6L as a novel therapeutic target of RCC is clearly needed.