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LncRNA NR2F2-AS1 induces epithelial-mesenchymal transition of non-small cell lung cancer by modulating BVR/ATF-2 pathway via regulating miR-545-5p/c-Met axis

ABSTRACT: Non-small cell lung cancer (NSCLC) is one type of the most common cancers, which results in the major death worldwide. This study focuses on the understanding of the molecular mechanism of lncRNA NR2F2-AS1 and its regulation on epithelial-mesenchymal transition (EMT) in the development of NSCLC. Expressions of lncRNA NR2F2-AS1, miR-545-5p, c-Met, biliverdin reductase (BVR), ATF-2 and EMT-related markers in NSCLC tissues and cells were measured by western blotting and RT-qPCR assays. The impact of lncRNA NR2F2-AS1 and miR-545-5p on the cell proliferation, migration, invasion and EMT were analyzed by CCK-8, colony formation, wound healing and transwell assays. The interactions among lncRNA NR2F2-AS1, miR-545-5p and c-Met predicted by bioinformatic analysis were evaluated through dual luciferase reporter assay and fluorescence in situ hybridization (FISH). After generating tumor xenografts, immunohistochemistry was utilized to measure the expression of Ki-67 and EMT-related proteins in vivo. Our results showed that lncRNA NR2F2-AS1, c-Met, BVR and ATF-2 were overexpressed while miR-545-5p was silenced in NSCLC tissues and cells. Silencing of lncRNA NR2F2-AS1 or upregulating miR-545-5p significantly inhibited the cell proliferation, migration, invasion and EMT process. The EMT process could be inhibited by suppressing c-Met/BVR/ATF-2 axis. The tumor xenograft experiments demonstrated that the tumor growth and EMT process were significantly inhibited by silencing lncRNA NR2F2-AS1 or overexpression of miR-545-5p in vivo. LncRNA NR2F2-AS1 promoted the NSCLC development through suppressing miR-545-5p to activate EMT process through c-Met/BVR/ATF-2 axis. Our study indicated that lncRNA NR2F2-AS1 and miR-545-5p could be used as potential therapeutic targets to improve NSCLC treatment.

SUBMITTER: Liu C

PROVIDER: S-EPMC8569365 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundBreast cancer (BC) is a prevalent malignancy with complex etiology and varied clinical behavior. Long non-coding RNAs (lncRNAs) have emerged as key regulators in cancer progression, including BC. Among these, lncRNA TDRKH-AS1 has been implicated in several cancers, but its role in BC remains unclear.MethodsWe conducted a comprehensive investigation to elucidate the role of TDRKH-AS1 in BC. Clinical samples were collected from BC patients, and BC cell lines were cultured. Bioinformatics analysis using the starBase database was carried out to assess TDRKH-AS1 expression levels in BC tissue samples. Functional experiments, including knockdown, colony formation, CCK-8, Transwell, and wound-healing assays, were conducted to determine the role of TDRKH-AS1 in BC cell proliferation and invasion. Luciferase reporter and RIP assays were used to examine the interactions between TDRKH-AS1 and miR-134-5p. In addition, the downstream target gene of miR-134-5p, cAMP response element-binding protein 1 (CREB1), was identified and studied using various methods, including RT-qPCR, immunoprecipitation, and rescue experiments. In vivo experiments using mouse tumor xenograft models were conducted to examine the role of TDRKH-AS1 in BC tumorigenesis.ResultsTDRKH-AS1 was found to be significantly upregulated in BC tissues and cell lines. High TDRKH-AS1 expression correlated with advanced BC stages and worse patient outcomes. Knockdown of TDRKH-AS1 led to decreased BC cell proliferation and invasion. Mechanistically, TDRKH-AS1 acted as a sponge for miR-134-5p, thereby reducing the inhibitory effects of miR-134-5p on CREB1 expression. Overexpression of CREB1 partially rescued the effects of TDRKH-AS1 knockdown in BC cells. In vivo studies further confirmed the tumor-promoting role of TDRKH-AS1 in BC.ConclusionsOur study unveiled a novel regulatory axis involving TDRKH-AS1, miR-134-5p, and CREB1 in BC progression. TDRKH-AS1 functioned as an oncogenic lncRNA by promoting BC cell proliferation and invasion through modulation of the miR-134-5p/CREB1 axis. These findings highlighted TDRKH-AS1 as a potential diagnostic biomarker and therapeutic target for BC treatment.

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LncRNA NR2F2-AS1 induces epithelial-mesenchymal transition of non-small cell lung cancer by modulating BVR/ATF-2 pathway via regulating miR-545-5p/c-Met axis

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