Hsa_circ_0005576 promotes osimertinib resistance through the miR-512-5p/IGF1R axis in lung adenocarcinoma cells.
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ABSTRACT:
SUBMITTER: Liu S
PROVIDER: S-EPMC8748248 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Breast cancer (BC) is one of the most fatal diseases among women all over the world. Non-coding RNAs including circular RNAs (circRNAs) have been reported to be involved in different aspects during tumorigenesis and progression. In this study, we aimed to explore the biological functions and underlying mechanism of circRPPH1 in BC. Candidate circRNAs were screened in dataset GSE101123 from Gene Expression Omnibus (GEO) database and a differentially expressed circRNA, circRPPH1, was discovered in BC. CircRPPH1 expression was higher in the cancerous tissue compared to paired adjacent tissue. Further in vitro and in vivo experiments indicated that circRPPH1 acted as an oncogene in BC. In addition, circRPPH1 was mainly localized in cytoplasm and played the role of miR-512-5p sponge. By sequestering miR-512-5p from the 3'-UTR of STAT1, circRPPH1 inhibited the suppressive role of miR-512-5p, stabilized STAT1 mRNA in BC and finally affected BC progression. In conclusion, these findings indicated that circRPPH1 acted as an oncogene and regulated BC progression via circRPPH1-miR-512-5p-STAT1 axis, which might provide a potential therapeutic target for BC treatment.
| S-EPMC8648777 | biostudies-literature
Project description:Emerging research indicates that circRNAs serve a crucial role in occurrence and development of cancers. This study aimed to uncover the biological role of hsa_circ_0000519 in the progression of LUAD (lung adenocarcinoma). hsa_circ_0000519 was identified by bioinformatic analysis, and its differential expression was validated in LUAD tissues and cell lines. CCK8, colony formation, wound healing, transwell assays, and xenograft tumor models were used to observe the biological functions of hsa_circ_0000519. FISH, RIP, dual luciferase reporter assays, and recovery experiments were implemented to explore the underlying mechanisms of hsa_circ_0000519. hsa_circ_0000519 was significantly upregulated in LUAD tissues and cell lines. The expression of hsa_circ_0000519 was positively correlated with T grade and TNM stage in patients with LUAD. Downregulation of hsa_circ_0000519 remarkably reduced cell proliferation, migration, invasion in vitro, and tumor growth in vivo. Mechanistic investigation demonstrated that hsa_circ_0000519 directly sponged hsa-miR-1296-5p to reduce its repressive impact on DARS as well as activate the PI3K/AKT/mTOR signaling pathway. The malignant phenotypes of LUAD cells induced by upregulation of hsa_circ_0000519 could be rescued by hsa-miR-1296-5p overexpression or knockdown of DARS. In conclusion, hsa_circ_0000519 promotes LUAD progression through the hsa-miR-1296-5p/DARS axis and may be expected as a novel biomarker and therapeutic for LUAD.
| S-EPMC10492121 | biostudies-literature
Project description:BackgroundMounting evidence has shown circular RNAs (circRNAs) play an important role in the initiation and progression of pancreatic cancer (PC). Meanwhile, circRNAs may serve as the biomarkers for the diagnosis, treatment, and prognosis of PC. Therefore, it is urgent to elucidate the function and underlying mechanism of circRNAs in the development of PC.MethodsThe Cancer-Specific CircRNA Database (CSCD), Circular RNA Interactome database (circinteractome database), and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to verify the expression level of circRNF13 in PC cell lines. Fluorescence in situ hybridization (FISH) and RNase protection assay were used to detect the localization and structure of circRNF13. Then, cell functional experiments were employed to estimate the proliferated, migrated, and invasive abilities in PC. Furthermore, bioinformatic tools, luciferase dual reporter assay, and RT-qPCR were used to investigate the interaction among circRNF13, miR-139-5p, and IGF1R. Eventually, the rescue functional experiments were employed to confirm that circRNF13 targeted the miR-139-5p/IGF1R axis to participate in the development of PC.ResultsCircRNF13 was overexpressed in PC cell lines compared with the normal pancreatic duct cell line. Additionally, inhibition of circRNF13 impaired the proliferation, migration, and invasion of PC cells. CircRNF13 could serve as the molecular sponge of miR-139-5p to inhibit its association with IGF1R that eventually accelerated the malignant progression of PC.ConclusionCircRNF13 serves as a competitive endogenous RNA of IGF1R to inhibit the function of miR-139-5p that eventually reinforces the malignant phenotype of PC.
| S-EPMC8664507 | biostudies-literature
Project description:Long noncoding RNAs (lncRNAs) possessed essential functions in the biological behaviors of various human cancers. SLCO4A1 antisense RNA 1 (SLCO4A1-AS1) is a lncRNA that has been reported as a oncogenic regulator in colorectal cancer and bladder cancer. However, whether it exerted functions in the gene expression and cellular processes in lung adenocarcinoma (LUAD) remains still obscure. In the present research, we unveiled the high level of SLCO4A1-AS1 in LUAD tissues and cells. Moreover, functional assays indicated that SLCO4A-AS1 facilitated LUAD cell proliferation, motility, and cisplatin-resistance. Besides, mechanism investigation revealed that miR-4701-5p could interact with SLCO4A1-AS1 and directly target to NFE2L1. The expression correlation between miR-4701-5p and SLCO4A1-AS1 or NFE2L1 was found to be negative. Moreover, NFE2L1 was expressed at a same tendency with SLCO4A1-AS1 in LUAD tissues and cells. In addition, it was confirmed that NFE2L1 was involved in SLCO4A1-AS1-mediated activation of WNT pathway. According to rescue assays, NFE2L1 could involve in SLCO4A1-AS1-mediated LUAD cell growth. Conclusively, our study demonstrated that SLCO4A1-AS1 facilitated cell growth and enhanced the resistance of LUAD cells to chemotherapy via activating WNT pathway through miR-4701-5p/NFE2L1 axis.
| S-EPMC7541149 | biostudies-literature
Project description:Gastric adenocarcinoma, which originates from the gastric mucosal epithelium, has the highest incidence among various malignant tumours in China. As a crucial long non-coding RNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been suggested to play an important role in many tumours. Here, we aimed to investigate the role and underlying mechanism of MALAT1 in gastric adenocarcinoma. Quantitative reverse transcription polymerase chain reaction was applied to determine the expression levels of MALAT1 in serum and cell lines. A CCK-8 assay and a clonogenic survival assay were used to examine cell proliferation and apoptosis. The protein level of RAC-γ serine/threonine-specific protein kinase (AKT3) was determined by western blot. Our results showed that MALAT1 was highly expressed in the serum of patients with gastric adenocarcinoma and in cell lines. Downregulating MALAT1 inhibited proliferation and promoted apoptosis of MGC-803 cells. In addition, MALAT1 directly targeted and decreased the expression of miR-181a-5p, which in turn upregulated the expression of AKT3. Further, overexpressing miR-181a-5p or directly inhibiting the AKT pathway with the inhibitor ipatasertib exhibited similar effects to MALAT1 knockdown. Our research proposes a novel mechanism where the role of MALAT1 is dependent on the MALAT1/miR-181a-5p/AKT3 axis. MALAT1 competes with AKT3 for miR-181a-5p binding, thereby upregulating the AKT3 protein level and ultimately promoting the growth of gastric adenocarcinoma.
| S-EPMC6769293 | biostudies-literature
Project description:Differentiation of preadipocytes into functional adipocytes could be a major target for repressing obesity-induced insulin resistance (IR). However, the molecular mechanisms involved in adipogenesis and the development of IR are unclear. We report, for the first time, that miR-574-5p, a novel miRNA, promotes adipogenesis to suppress IR. An increase in the level of miR-574-5p significantly induced the differentiation of preadipocytes into mature adipocytes. Conversely, reduction of miR-574-5p levels blocked the differentiation of preadipocytes in vitro. In a dual-luciferase reporter assay, it was shown that homeobox A5 (HOXA5) promoted the transcription of miR-574-5p to induce the differentiation of preadipocytes. Hdac9, a direct downstream target of miR-574-5p, was involved in the regulation of adipocyte differentiation. The overexpression of miR-574-5p also promoted adipogenesis in subcutaneous fat to alleviate IR in high-fat-diet-fed mice. Additionally, miR-574-5p expression was significantly higher in the subcutaneous adipose tissue of obese patients without type 2 diabetes than in those with type 2 diabetes. There was an increase in HOXA5 expression and a decrease in histone deacetylase 9 (HDAC9) expression in the subcutaneous fat of obese patients without type 2 diabetes. These results suggest that miR-574-5p may be a potential therapeutic target for combating obesity-related IR.
| S-EPMC8693313 | biostudies-literature
Project description:BackgroundLung adenocarcinoma (LUAD) is currently the leading cause of cancer-related death worldwide. Long noncoding RNAs (lncRNAs) play key roles in tumor occurrence and development as crucial cancer regulators. The present study aimed to explore the molecular mechanism and regulatory network of Linc00511 in LUAD and to identify new potential therapeutic targets for LUAD.MethodsReal-time quantitative polymerase chain reaction (RT-qPCR) was performed to determine the relative Linc00511 levels in LUAD tissues and cells. The proliferation, apoptosis, migration, and invasion abilities of LUAD cells were assessed by a Cell Counting Kit-8 (CCK-8) assay, a colony formation assay, flow cytometry, and a Transwell assay. Changes in hsa_miR-126-5p, hsa_miR-218-5p, and COL1A1 expression were analyzed using western blotting and RT-qPCR. Targeted binding between miR-126-5p/miR-218-5p and Linc00511 or COL1A1 was verified with a luciferase reporter system and confirmed by an RNA pulldown assay. The participation of the PI3K/AKT signaling pathway was confirmed via western blotting. Xenograft animal experiments were performed to detect the impact of Linc00511 on LUAD tumor growth in vivo.ResultsIn the present work, we observed that Linc00511 was upregulated in LUAD tissues and cells. Loss/gain-of-function experiments indicated that knockdown of Linc00511 significantly inhibited LUAD cell proliferation, migration and invasion and promoted LUAD cell apoptosis, whereas overexpression of Linc00511 showed the opposite effects. In addition, we determined that Linc00511 promoted COL1A1-mediated cell proliferation and cell motility by sponging miR-126-5p and miR-218-5p. Moreover, Linc00511 activated the PI3K/AKT signaling pathway through upregulation of COL1A1. Finally, silencing of Linc00511 inhibited LUAD tumor growth in vivo.ConclusionsLinc00511 acts as a competing endogenous RNA to regulate COL1A1 by targeting miR-126-5p and miR-218-5p, thereby promoting the proliferation and invasion of LUAD cells.
| S-EPMC9287882 | biostudies-literature
Project description:OBJECTIVES:Long non-coding RNAs (lncRNAs) are extensively reported as participants in the biological process of diverse malignancies, including lung squamous cell carcinoma (LUSC). Long intergenic non-protein coding RNA 519 (LINC00519) is identified as a novel lncRNA which has not yet been studied in cancers. MATERIALS AND METHODS:LINC00519 expression was detected by qRT-PCR. The effect of LINC00519 on LUSC cellular activities was determined by in vitro and in vivo assays. Subcellular fractionation and FISH assays were conducted to identify the localization of LINC00519. The interaction between miR-450b-5p/miR-515-5p and LINC00519/YAP1 was verified by RIP, RNA pull-down and luciferase reporter assays. RESULTS:Elevated level of LINC00519 was identified in LUSC tissues and cell lines. High LINC00519 level predicted unsatisfactory prognosis. Then, loss-of-function assays suggested the inhibitive role of silenced LINC00519 in cell proliferation, migration, invasion and tumour growth and promoting effect on cell apoptosis in LUSC. Mechanically, LINC00519 was activated by H3K27 acetylation (H3K27ac). Moreover, LINC00519 sponged miR-450b-5p and miR-515-5p to up-regulate Yes1 associated transcriptional regulator (YAP1). Additionally, miR-450b-5p and miR-515-5p elicited anti-carcinogenic effects in LUSC. Finally, rescue assays validated the effect of LINC00519-miR-450b-5p-miR-515-5p-YAP1 axis in LUSC. CONCLUSIONS:H3K27ac-activated LINC00519 acts as a competing endogenous RNA (ceRNA) to promote LUSC progression by targeting miR-450b-5p/miR-515-5p/YAP1 axis.
| S-EPMC7260072 | biostudies-literature
Project description:BackgroundGrowing evidences suggest that circular RNAs (circRNAs) are important factors in cancer progression. Nevertheless, the role of circRNAs in the progression of pancreatic ductal adenocarcinoma (PDAC) remains unclear.MethodsCircPTPRA was identified based on our previous circRNA array data analysis. Wound healing, transwell, and EdU assays were performed to investigate the effect of circPTPRA on the migration, invasion, and proliferation of PDAC cells in vitro. RNA pull-down, fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP), and dual-luciferase reporter assays were conducted to verify the binding of circPTPRA with miR-140-5p. Subcutaneous xenograft model was constructed for in vivo experiment.ResultsCircPTPRA was significantly upregulated in PDAC tissues and cells compared to normal controls. Moreover, circPTPRA overexpression was positively correlated with lymph node invasion and worse prognosis in PDAC patients. In addition, overexpression of circPTPRA promoted PDAC migration, invasion, proliferation, and epithelial-mesenchymal transition (EMT) in vitro and in vivo. Mechanistically, circPTPRA upregulates LaminB1 (LMNB1) expression by sponging miR-140-5p and ultimately promotes the progression of PDAC.ConclusionsThis study revealed that circPTPRA plays an important role in the progression of PDAC by sponging miR-140-5p. It can be explored as a potential prognostic marker and therapeutic target for PDAC.
| S-EPMC10242365 | biostudies-literature
Project description:BackgroundMultiple lines of evidence have demonstrated that circular RNAs (circRNAs) play oncogenic or tumor-suppressive roles in various human cancers. Nevertheless, the biological functions of circRNAs in small cell lung cancer (SCLC) are still elusive.MethodsCircVAPA (annotated as hsa_circ_0006990) was identified by mining the circRNA profiling dataset of six paired SCLC tissues and the RNA-seq data of serum samples from 36 SCLC patients and 118 healthy controls. The circVAPA expression level was evaluated using quantitative real-time PCR in SCLC cells and tissues. Cell viability, colony formation, cell cycle and apoptosis analysis assays and in vivo tumorigenesis were used to reveal the biological roles of circVAPA. The underlying mechanism of circVAPA was investigated by Western blot, RNA pulldown, RNA immunoprecipitation, dual-luciferase reporter assay and rescue experiments.ResultsWe revealed that circVAPA, derived from exons 2-4 of the vesicle-associated membrane protein-associated protein A (VAPA) gene, exhibited higher expression levels in SCLC cell lines, clinical tissues, and serum from SCLC patients than the controls, and facilitated SCLC progression in vitro and in vivo. Mechanistically, circVAPA activated the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway by modulating the miR-377-3p and miR-494-3p/insulin-like growth factor 1 receptor (IGF1R) axis to accelerate SCLC progression. Furthermore, circVAPA depletion markedly enhanced the inhibitory effects of BMS-536924, an IGF1R kinase inhibitor in cellular and xenograft mouse models.ConclusionsCircVAPA promotes SCLC progression via the miR-377-3p and miR-494-3p/IGF1R/AKT axis. We hope to develop clinical protocols of combinations of circVAPA inhibition and BMS-536924 addition for treating SCLC with circVAPA upregulation.
| S-EPMC9172052 | biostudies-literature