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

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.

LncRNA NR2F1-AS1 inhibits the malignant properties of cervical cancer cells via targeting miR-642a-3p/NR2F1 axis

“…In addition, functional experiments demonstrated that NR2F1-AS1 upregulation repressed CC cell proliferation, migration, invasion, and EMT process. These findings demonstrated that NR2F1-AS1 acted as a tumor suppressor in CC, which is inconsistent with the general oncogenic role of NR2F1-AS1 in multiple other cancers, such as neuroblastoma34, gastric cancer35, and pancreatic cancer 36 .…”

Identification of a lncRNA based signature for pancreatic cancer survival to predict immune landscape and potential therapeutic drugs

“…Numerous studies have revealed that dysregulated lncRNA participates in processes of carcinogenesis and progression of pancreatic cancer. For instance, Liu has reported that lncRNA NR2F1-AS1 promotes proliferation and invasion of pancreatic cancer by regulating the neighboring NR2F1 gene and activating AKT/mTOR signaling pathway ( Liu et al, 2022 ). Huang has demonstrated that lncRNA LNC00842 prompts the malignancy of pancreatic cancer by preventing acetylate PGC-1α from deacetylation and remodeling the metabolic status of cancer cells ( Huang et al, 2021 ).…”

Long noncoding RNAs in pancreas cancer: from biomarkers to therapeutic targets

“…The active AKT/mTOR pathway promotes PC cell proliferation, migration, and invasion. Moreover, it was suggested that NR2F1-AS1 may be a potential prognostic biomarker and therapeutic target for PC [ 40 ].…”