NR2F1-AS1 Promotes Pancreatic Ductal Adenocarcinoma Progression Through Competing Endogenous RNA Regulatory Network Constructed by Sponging miRNA-146a-5p/miRNA-877-5p.

Dong Luo,Xiao Yu,Zhiqiang Li,Yunfei Liu,Hongwei Zhu

doi:10.3389/fcell.2021.736980

Abstract

The role of NR2F1-AS1 in pancreatic ductal adenocarcinoma (PDAC) remains unknown. Therefore, we aimed to investigate the biological mechanism of NR2F1-AS1 in PDAC. The expression of NR2F1-AS1 was measured by using microarray data and real-time PCR. The effects of NR2F1-AS1 knockdown on proliferation, cell cycle progression, invasion in vitro and tumorigenesis in vivo were investigated. The mechanism of competitive endogenous RNAs was determined from bioinformatics analyses and validated by a dual-luciferase reporter gene assay. Potential target mRNAs from TargetScan 7.2 were selected for subsequent bioinformatics analysis. Key target mRNAs were further identified by screening hub genes and coexpressed protein-coding genes (CEGs) of NR2F1-AS1. NR2F1-AS1 was highly expressed in PDAC, and the overexpression of NR2F1-AS1 was associated with overall survival and disease-free survival. The knockdown of NR2F1-AS1 impaired PDAC cell proliferation, migration, invasion and tumorigenesis. NR2F1-AS1 competitively sponged miR-146a-5p and miR-877-5p, and low expression of the two miRNAs was associated with a poor prognosis. An integrative expression and survival analysis of the hub genes and CEGs demonstrated that the NR2F1-AS1–miR-146a-5p/miR-877-5p–GALNT10/ZNF532/SLC39A1/PGK1/LCO3A1/NRP2/LPCAT2/PSMA4 and CLTC ceRNA networks were linked to the prognosis of PDAC. In conclusion, NR2F1-AS1 overexpression was significantly associated with poor prognosis. NR2F1-AS1 functions as an endogenous RNA to construct a novel ceRNA network by competitively binding to miR-146a-5p/miR-877-5p, which may contribute to PDAC pathogenesis and could represent a promising diagnostic biomarker or potential novel therapeutic target in PDAC.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) remains a highly fatal disease with a 5-year survival rate of 10% (Siegel et al, 2021)
We found that NR2F1-AS1 was overexpressed in pancreatic ductal adenocarcinoma (PDAC) based on a bioinformatics analysis of publicly available datasets (e.g., Gene Expression Omnibus, GEO)
We downloaded a total of 4711 long non-coding RNAs (lncRNAs) (Supplementary Table 2), with valid names obtained from the HGNC database of human gene names when this work was initiated, they were analyzed by gene expression profiling interactive analysis (GEPIA)

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) remains a highly fatal disease with a 5-year survival rate of 10% (Siegel et al, 2021). PDAC accounts for almost as many deaths (466,000) as cases (496,000) because of its poor prognosis, and it is the seventh leading cause of cancer death in both sexes in 2020 (Sung et al, 2021) and projected to become the second leading cause of cancer-related death by 2030 (Rahib et al, 2014). Pancreatic ductal adenocarcinoma is characterized by late diagnosis, metastasis and acquired resistance to chemotherapeutic agents in the clinic (Zheng et al, 2015; Sakamoto et al, 2020). Only10–20% of PDAC patients are diagnosed with localized surgically resectable disease (Strobel et al, 2019). The prognosis for PDAC is still poor despite diagnostic progress and new chemotherapeutic regimens. Research on the genetic alterations and underlying molecular mechanism of PDAC is still urgently required to find new treatment strategies

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