The noncoding function of NELFA mRNA promotes the development of oesophageal squamous cell carcinoma by regulating the Rad17‐RFC2‐5 complex
The noncoding function of NELFA mRNA promotes the development of oesophageal squamous cell carcinoma by regulating the Rad17‐RFC2‐5 complex
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DOI：
10.1002/1878-0261.12619
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发表时间：
2019-12
影响因子：
6.6
通讯作者：
Jiancheng Xu;Guangchao Wang;Wei Gong;Shichao Guo;Dan Li;Q. Zhan
中科院分区：
文献类型：
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作者：
Jiancheng Xu;Guangchao Wang;Wei Gong;Shichao Guo;Dan Li;Q. Zhan
近年来，研究发现RNA与蛋白质相互作用在食管鳞状细胞癌（ESCC）的发生、发展中起重要作用。在这项研究中，我们发现NELFA mRNA通过一种新的非编码模式在细胞核中与Rad 17相互作用，并且USF 2的异常表达有助于Rad 17和NELFA的上调。随后的实验表明，NELFA mRNA的缺失显着降低ESCC的增殖和集落形成在体外。此外，NELFA mRNA敲低抑制DNA损伤修复并促进细胞凋亡。机制研究表明，NELFA mRNA调节Rad 17和RFC 2 - 5之间的相互作用，这对CHK 1，CHK 2和BRCA 1的磷酸化有重要影响。ESCC患者中NELFA mRNA表达持续升高，与总生存率降低密切相关。总之，我们的研究结果证实了NELFA mRNA的非编码功能在ESCC肿瘤发生中的关键作用，并表明NELFA mRNA可以被视为ESCC患者的治疗靶点和独立的预后指标。
Recently, RNAs interacting with proteins have been implicated in playing an important role in the occurrence and progression of oesophageal squamous cell carcinoma (ESCC). In this study, we found that NELFA mRNA interacts with Rad17 through a novel noncoding mode in the nucleus and that the aberrant expression of USF2 contributed to the upregulation of Rad17 and NELFA. Subsequent experiments demonstrated that the deletion of NELFA mRNA significantly decreased ESCC proliferation and colony formation in vitro. Moreover, NELFA mRNA knockdown inhibited DNA damage repair and promoted apoptosis. Mechanistic studies indicated that NELFA mRNA regulated the interaction between Rad17 and RFC2‐5, which had a major impact on the phosphorylation of CHK1, CHK2 and BRCA1. NELFA mRNA expression was consistently elevated in ESCC patients and closely related to decreased overall survival. Taken together, our results confirmed the critical role of the noncoding function of NELFA mRNA in ESCC tumorigenesis and indicated that NELFA mRNA can be regarded as a therapeutic target and an independent prognostic indicator in ESCC patients.