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Silencing of LncRNA C1RL-AS1 Suppresses the Malignant Phenotype in Gastric Cancer Cells via the AKT/β-Catenin/c-Myc Pathway

ABSTRACT: Purpose: Numerous studies have shown that lncRNAs play vital roles in the development and progression of cancer. However, investigations of lncRNAs in gastric cancer are limited and need to be further pursued. Materials and Methods: According to RNA-seq results of gastric cancer (GC) tissues, we identified a novel lncRNA, C1RL-AS1. qRT-PCR was used to detect the expression level of C1RL-AS1 in paired GC and normal tissues. Nuclear/cytoplasmic fractionation was applied to evaluate the distribution of C1RL-AS1 in GC cells. For functional evaluation, CCK-8, colony formation, transwell, and apoptosis assays were used to determine the oncogenic role of C1RL-AS1. Results: C1RL-AS1 was upregulated in GC tissues, and high expression levels of C1RL-AS1 were associated with poor prognosis. Further in vitro functional assays revealed that silencing C1RL-AS1 attenuated the proliferation rate and migration ability and enhanced the apoptotic rate and the senescence of GC cells. The subsequent underlying mechanistic investigation revealed that Wnt/β-catenin was involved in C1RL-AS1-mediated signaling. Rescue experiments suggested that C1RL-AS1 probably promoted the malignant phenotype via the AKT/β-catenin pathway by downregulating c-Myc. Conclusions: C1RL-AS1 probably exerts its biological function by mediating the AKT/β-catenin/c-Myc pathway, indicating a novel therapeutic target in GC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE192468 | GEO | 2021/12/27

REPOSITORIES: GEO

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Project description:Background: Helicobacter pylori (HP) infection may initiate and promote progression of gastric carcinogenesis. ONECUT2 shows promise for tumor diagnosis, prognosis, and treatment. This study explored ONECUT2's role and specific mechanism underlying HP infection-associated gastric carcinogenesis to suggest a basis for targeting ONECUT2 as a therapeutic strategy for gastric cancer (GC). Methods: Public data, single-cell RNA sequencing, spatial transcriptome analysis, RNA sequencing, GC tissue specimens, and clinical survival data were analyzed. Human GC organoids, HP infection, 3D sphere-forming, and extreme-dilution nude mouse models were constructed. Western blotting, qPCR, immunohistochemical staining, dual-luciferase reporter assays, phosphokinase microarray, and immunofluorescence were used. Results: Multidimensional data supported an association between ONECUT2, HP infection, and GC pathogenesis. HP infection upregulated ONECUT2 transcriptional activity via NFκB. In vitro and in vivo experiments demonstrated that ONECUT2 increases stemness in GC cells. ONECUT2 was also shown to inhibit PPP2R4 transcription, resulting in reduced PP2A activity, which in turn increased AKT/β-catenin phosphorylation. AKT/β-catenin phosphorylation facilitates β-catenin translocation to the nucleus, initiating transcription of downstream stemness-associated genes in GC cell. HP infection could upregulate the phosphorylation of AKT and β-catenin triggered by ONECUT2 downregulation via induction of ONECUT2. Clinical survival analysis indicated that high ONECUT2 expression might be an indicator of poor prognosis in GC. Conclusion: This study highlights a critical role played by ONECUT2 in promoting HP infection-associated GC by enhancing cell stemness through the PPP2R4/AKT/β-catenin signaling pathway. These findings suggest promising therapeutic strategies and potential therapeutic targets for GC treatment. Keywords: Helicobacter pylori; gastric cancer; prognosis; tumor stemness; ONECUT2

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Silencing of LncRNA C1RL-AS1 Suppresses the Malignant Phenotype in Gastric Cancer Cells via the AKT/β-Catenin/c-Myc Pathway

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