RETRACTED: NR2F1-AS1/miR-190a/PHLDB2 Induces the Epithelial–Mesenchymal Transformation Process in Gastric Cancer by Promoting Phosphorylation of AKT3

Abstract

The median survival time of patients with advanced gastric cancer (GC) who received radiotherapy and chemotherapy was <1 year. Epithelial–mesenchymal transformation (EMT) gives GC cells the ability to invade, which is an essential biological mechanism in the progression of GC. The long non-coding RNA (lncRNA)-based competitive endogenous RNA (ceRNA) system has been shown to play a key role in the GC-related EMT process. Although the AKT pathway is essential for EMT in GC, the relationship between AKT3 subtypes and EMT in GC is unclear. Here, we evaluated the underlying mechanism of ceRNA involving NR2F1-AS1/miR-190a/PHLDB2 in inducing EMT by promoting the expression and phosphorylation of AKT3. The results of bioinformatics analysis showed that the expression of NR2F1-AS1/miR-190a/PHLDB2 in GC was positively associated with the pathological features, staging, poor prognosis, and EMT process. We performed cell transfection, qRT-PCR, western blot, cell viability assay, TUNEL assay, Transwell assay, cell morphology observation, and double luciferase assay to confirm the regulation of NR2F1-AS1/miR-190a/PHLDB2 and its effect on EMT transformation. Finally, GSEA and GO/KEGG enrichment analysis identified that PI3K/AKT pathway was positively correlated to NR2F1-AS1/miR-190a/PHLDB2 expression. AKT3 knockout cells were co-transfected with PHLDB2-OE, and the findings revealed that AKT3 expression and phosphorylation were essential for the PHLDB2-mediated EMT process. Thus, our results showed that NR2F1-AS1/miR-190a/PHLDB2 promoted the phosphorylation of AKT3 to induce EMT in GC cells. This study provides a comprehensive understanding of the underlying mechanism involved in the EMT process as well as the identification of new EMT markers.

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“…Finally, annealing and extension at 95°C for 15 seconds, 60°C for 60 seconds and 95°C for 15 seconds. Glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) was regarded as an internal reference, and the relative level was analyzed using the 2 −ΔΔCT method [ 23 ]. The primers used in this study are listed in Table 1 .…”

“…The transwell assay was conducted in accordance with a previous study [ 23 ]. Transwell chambers (Millipore, USA) were inserted into each well of a 24-well plate, where 5 × 10 4 cells were placed in the upper layer of the chamber, and 600 μL of medium containing 10% FBS was added to the bottom.…”

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

“…Based on KEGG pathway analysis, we found that both NR2F1-AS1 and NR2F1 were significantly related to the PI3K/AKT pathway, which controls key cellular processes such as metabolism, growth, invasion, and the survival, expansion, and spread of cancer cells [ 29 ]. Previous studies have demonstrated that lncRNA NR2F1-AS1 can influence breast and gastric cancer progression by activating insulin-like growth factor-1 (IGF-1)/IGF-1R/ERK [ 20 ], MAP3K2 [ 30 ], and AKT3 [ 31 ], which crosstalk with AKT. We also verified that NR2F1-AS1 promoted AKT/mTOR signaling, indicating that NR2F1-AS1 is a critical gene for the growth and metastasis of PC.…”

Epithelial-mesenchymal transition-related long noncoding RNAs in gastric carcinoma

“…Depletion of CXCR1 up-regulates E-cadherin in GC cells ( Wang J. et al, 2016 ). Nuclear receptor subfamily two group F member 1-antisense RNA 1 (NR2F1-AS1)/miR-190a/Pleckstrin Homology Like Domain Family Member 2 (PHLDB2), a ceRNA, can facilitate the EMT process of GC cells, and PHLDB2 can enhance the expression and phosphorylation of AKT3 to promote the EMT process of GC cells ( Lv et al, 2021 ). LINC00689/miR-526b-3p/A disintegrin and metalloproteinase domain 9 (ADAM9) participates in many biological processes, including myogenesis, fertilization, cell migration, inflammatory response, proliferation, and cell-cell interactions ( Yin et al, 2020 ).…”