Hypoxia-induced long noncoding RNA NR2F1-AS1 maintains pancreatic cancer proliferation, migration, and invasion by activating the NR2F1/AKT/mTOR axis

Zhiwei He,Chengyi Sun,Shiyu Chen,Yanqing Liu,Kun Cai,Changhao Zhu,Feiqing Wang,Dijie Zheng,Chao Yu,Lin Li

doi:10.1038/s41419-022-04669-0

Abstract

Accumulating evidence has demonstrated the essential role of long noncoding RNAs (lncRNAs) in various types of human cancer, including pancreatic cancer (PC). However, the functions and regulatory mechanisms of nuclear receptor subfamily 2 group F member 1 antisense RNA 1 (NR2F1-AS1) that are responsible for its role in the malignant progression of PC cells remains to be investigated. In this study, the biological effects of NR2F1-AS1 and NR2F1 in PC were investigated by in vitro and in vivo experiments. The mechanisms of NR2F1-AS1 were monitored by bioinformatic predictive analysis and confirmatory experiments. Our results indicated that NR2F1-AS1 was overexpressed and positively correlated with poor survival in PC. Depletion of NR2F1-AS1 restrained PC cell proliferation, migration, invasion, and suppressed xenograft tumor growth and metastasis in vitro and in vivo. Mechanistic experiments suggested that NR2F1-AS1 positively regulated the neighboring NR2F1 gene, which subsequently activated AKT/mTOR signaling, resulting in the upregulation of hypoxia-inducible factor-1α (HIF-1α). Further investigations elucidated that NR2F1-AS1 expression was transcriptionally regulated by HIF-1α under hypoxia. These findings demonstrated that hypoxia-induced NR2F1-AS1 expression directly increased NR2F1 levels to promote PC cell proliferation, migration, and invasion by activating AKT/mTOR signaling. Together, these findings suggest that NR2F1-AS1 could be a prospective therapeutic target for PC.

Highlights

Pancreatic cancer (PC) is among the most fatal malignancies, ranking among the top ten causes of all cancer-associated mortality, with early local infiltration and distant metastasis being the predominant reasons for death [1]
NR2F1-AS1 expression is enhanced in PC tissue and cell lines According to The Cancer Genome Atlas (TCGA) data accessed via the GEPIA website, we identified NR2F1-AS1 to have markedly higher expression in pancreatic adenocarcinoma (PAAD) samples (Fig. 1A)
On the basis of the clinicopathologic characteristics of PC patients, we found that high NR2F1-AS1 expression was associated with large tumor size and perineural invasion (Supplementary Table S4)

Summary

INTRODUCTION

Pancreatic cancer (PC) is among the most fatal malignancies, ranking among the top ten causes of all cancer-associated mortality, with early local infiltration and distant metastasis being the predominant reasons for death [1]. LncRNA metastasis- RNA-FISH was performed using the RiboTM lncRNA FISH Probe Mix (Red) associated protein 2 transcriptional regulator (MTA2TR) is elevated and facilitates PC progression through a mechanism that is related to the reciprocal regulation of HIF-1α [13]. Another recent study revealed that NR2F1-AS1 was increased under hypoxia and contributed to hypoxia-triggered glycolysis and migration via regulating the miR-140/HK2 pathway in hepatocellular carcinoma (HCC) [14]. Firefly and Renilla luciferase activities were measured using the dual-luciferase reporter system kit (Beyotime, Shanghai, China) on a microplate reader according to the manufacturer’s suggestions and protocols. A P value < 0.05 was used to indicate significant differences (*P < 0.05, **P < 0.01, and ***P < 0.001)

RESULTS

DISCUSSION

ETHICS STATEMENT