The noncoding function of NELFA mRNA promotes the development of oesophageal squamous cell carcinoma by regulating the Rad17-RFC2-5 complex

Jiancheng Xu; Guangchao Wang; Wei Gong; Shichao Guo; Dan Li; Qimin Zhan

doi:10.1002/1878-0261.12619

The noncoding function of NELFA mRNA promotes the development of oesophageal squamous cell carcinoma by regulating the Rad17-RFC2-5 complex

Mol Oncol. 2020 Mar;14(3):611-624. doi: 10.1002/1878-0261.12619. Epub 2020 Jan 28.

Authors

Jiancheng Xu¹, Guangchao Wang¹, Wei Gong¹, Shichao Guo¹, Dan Li¹, Qimin Zhan^{1

2}

Affiliations

¹ State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
² Laboratory of Molecular Oncology, Peking University Cancer Hospital and Institute, Beijing, China.

Abstract

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.

Keywords: ESCC; NELFA mRNA; RFC2-5; Rad17; USF2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Apoptosis / genetics*
BRCA1 Protein / metabolism
Cell Cycle Proteins / metabolism*
Cell Line, Tumor
Cell Nucleus / metabolism
Cell Proliferation / genetics*
Checkpoint Kinase 1 / metabolism
Checkpoint Kinase 2 / metabolism
Chromatin Immunoprecipitation
DNA Repair / genetics
Esophageal Neoplasms / genetics
Esophageal Neoplasms / metabolism*
Esophageal Neoplasms / mortality
Esophageal Squamous Cell Carcinoma / genetics
Esophageal Squamous Cell Carcinoma / metabolism*
Esophageal Squamous Cell Carcinoma / mortality
Female
Gene Expression Regulation, Neoplastic / genetics
Gene Knockdown Techniques
Humans
Male
Phosphorylation
Prognosis
RNA, Small Interfering
Replication Protein C / metabolism*
Transcriptional Elongation Factors / genetics
Transcriptional Elongation Factors / metabolism*
Up-Regulation
Upstream Stimulatory Factors / genetics
Upstream Stimulatory Factors / metabolism

Substances

BRCA1 Protein
BRCA1 protein, human
Cell Cycle Proteins
NELFA protein, human
RFC2 protein, human
RNA, Small Interfering
Rad17 protein, human
Transcriptional Elongation Factors
USF2 protein, human
Upstream Stimulatory Factors
Checkpoint Kinase 2
CHEK1 protein, human
CHEK2 protein, human
Checkpoint Kinase 1
Replication Protein C