Exosome long non-coding RNA SOX2-OT contributes to ovarian cancer malignant progression by miR-181b-5p/SCD1 signaling
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ABSTRACT:
SUBMITTER: Lai Y
PROVIDER: S-EPMC8580347 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The involvement of LncRNA SOX2-overlapping transcript (SOX2-OT), SOX2, and GLI-1 transcription factors in cancer has been well documented. Nonetheless, it is still unknown whether co-expressed SOX2-OT/SOX2 or SOX2-OT/SOX2/GLI-1 axes are epigenetically/transcriptionally involved in terms of resistance to oncology therapy and in poorer clinical outcomes for patients with lung cancer. We evaluated the role of SOX2-OT/SOX2 and SOX2-OT/SOX2/GLI-1 axes using RT-qPCR, western blot, immunofluorescence analyses, gene silencing, cellular cytotoxic, and ChIP-qPCR assays on human cell lines, solid lung malignant tumors, and normal lung tissue. We detected that the SOX2-OT/SOX2/GLI-1 axis promotes resistance to tyrosine kinase inhibitor (TKI)-erlotinib and cisplatin-based therapy. Evidence from this study show that SOX2-OT modulates the expression/activation of EGFR-pathway members AKT/ERK. Further, both SOX2-OT and GLI-1 genes are epigenetically regulated at their promoter sequences, in an LncRNA SOX2-OT-dependent manner, mainly through modifying the enrichment of the activation histone mark H3K4me3/H3K27Ac, versus the repressive histone mark H3K9me3/H3K27me3. In addition, we identified that inhibition of SOX2-OT and reduced expression of SOX2/GLI-1 sensitizes lung cancer cells to EGFR/TKI-erlotinib or cisplatin-based treatment. Finally, we show that high co-expression of SOX2-OT/SOX2 transcripts and SOX2/GLI-1 proteins appears to correlate with a poor clinical prognosis and lung malignant phenotype. Collectively, these results present evidence that LncRNA SOX2-OT modulates an orchestrated resistance mechanism, promoting poor prognosis and human lung malignancy through genetic, epigenetic, and post-translational mechanisms.
| S-EPMC8024737 | biostudies-literature
Project description:The oncogenic role of long non-coding RNA SOX2 overlapping transcript (SOX2-OT) has been demonstrated as a miRNA decay system that sponges tumor suppressor miRNA, including miR-122-3p in glioblastoma and miR-194-5p in glioblastoma, gastric, and colorectal cancers. However, the molecular function of SOX2-OT remains unknown in most cancers, including lung cancer. In the current study, we aimed to evaluate the downstream regulatory function of SOX2-OT in A549 and Calu-3 lung cancer cell lines. We knocked down SOX2-OT expression using an RNA interference system, which significantly decreased expression in A549 and Calu-3 cells. The expression of down-regulating miRNAs (miR-122-3p and miR-194-5p) was evaluated, revealing increased expression of miR-122-3p and miR-194-5p. Additionally, the expression of miRNAs downstream mRNA, including FOXO1 (Forkhead Box O1) and FOXA1 (Forkhead Box O1), changed. Recently, critical roles of FOXO1 and FOXA1 proteins in pathways involved in proliferation, metastasis and apoptosis have been demonstrated. Downstream changes in cellular traits were assessed using MTT, flow cytometry, metastasis and apoptosis assays. These assessments confirmed that the biological behaviors of lung cancer cells were influenced after SOX2-OT knockdown. In summary, the present study highlights the oncogenic role of SOX2-OT through the regulation of miR-122-3p/FOXO1 and miR-194-5p/FOXA1 pathways.
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Project description:ObjectivesLong non-coding RNAs (lncRNAs) are emerging RNA regulators in cancer progression, including in hepatocellular carcinoma (HCC). Recently, insufficient radiofrequency ablation (RFA) has been reported to lead to recurrence and metastasis of residual HCC tumours. Herein, we aimed to the role of ASMTL-AS1 in residual HCC after insufficient RFA.Materials and methodsIn vitro insufficient RFA model was simulated in Huh7 cells and subsequently named Huh7-H cells. In vitro and in vivo assays were conducted to investigate ASMTL-AS1 function in HCC.ResultsLncRNA ASMTL-AS1 low expressed in normal human liver was found to be highly expressed in HCC tissues and further increased in tumours after insufficient RFA. ASMTL-AS1 expression was related to stage, metastasis and prognosis in HCC. Huh7-H possessed higher ASMTL-AS1 level and more aggressive than Huh7 cells. ASMTL-AS1 contributed to the malignancy of HCC cells both in vitro and in vivo. Mechanistically, ASMTL-AS1 was trans-activated by MYC and promoted NLK expression to activate YAP signalling via sequestering miR-342-3p in HCC. Interestingly, ASMTL-AS1 could be wrapped by exosomes and then convey malignancy through NLK/YAP axis between cells even in residual HCC after insufficient RFA.ConclusionsExosomal ASMTL-AS1 aggravates the malignancy in residual HCC after insufficient RFA via miR-342-3p/NLK/YAP signalling, opening a new road for the treatment of HCC and the prevention of recurrence or metastasis of residual HCC after insufficient RFA.
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Project description:PurposePeritoneal carcinomatosis in gastric cancer (GC) patients results in extremely poor prognosis. Malignant ascites samples are the most appropriate biological material to use to evaluate biomarkers for peritoneal carcinomatosis. This study identified exosomal MicroRNAs (miRNAs) differently expressed between benign liver cirrhosis-associated ascites (LC-ascites) and malignant gastric cancer-associated ascites (GC-ascites), and validated their role as diagnostic biomarkers for GC-ascites.Materials and methodsTotal RNA was extracted from exosomes isolated from 165 ascites samples (73 LC-ascites and 92 GC-ascites). Initially, microarrays were used to screen the expression levels of 2,006 miRNAs in the discovery cohort (n=22). Subsequently, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) analyses were performed to validate the expression levels of selected exosomal miRNAs in the training (n=70) and validation (n=73) cohorts. Furthermore, carcinoembryonic antigen (CEA) levels were determined in ascites samples.ResultsThe miR-574-3p, miR-181b-5p, miR-4481, and miR-181d were significantly downregulated in the GC-ascites samples compared to the LC-ascites samples, and miR-181b-5p showed the best diagnostic performance for GC-ascites (area under the curve [AUC]=0.798 and 0.846 for the training and validation cohorts, respectively). The diagnostic performance of CEA for GC-ascites was improved by the combined analysis of miR-181b-5p and CEA (AUC=0.981 and 0.946 for the training and validation cohorts, respectively).ConclusionsWe identified exosomal miRNAs capable of distinguishing between non-malignant and GC-ascites, showing that the combined use of miR-181b-5p and CEA could improve diagnosis.
| S-EPMC6769363 | biostudies-literature
Project description:Cholangiocarcinoma is an extremely malignant cancer with poor prognosis. Finding efficient diagnosis and treatment is the indispensable way to improve the prognosis of CCA patients. Therefore, exploring molecular abnormalities in CCA development is urgently needed. DLEU1 is a potential tumor-related lncRNA and abnormally expressed in multiple cancers. In this study, TCGA data analysis showed upregulation of DLEU1 expression in CCA. Furthermore, we confirmed that DLEU1 expression was increased in CCA tissues and cells compared with corresponding controls. Upregulated DLEU1 was related to poor clinicopathological characteristics. Functionally, silencing DLEU1 inhibited CCA proliferation, invasion, stemness maintenance and chemo-resistance, whereas amplifying DLEU1 promoted malignant biological behavior of CCA cells. Mechanistically, DLEU1 expression was transcriptionally facilitated by transcription factor YY1. Moreover, DLEU1 promoted oncogene YAP1 expression by functioning as a sponge to competitively bind to miR-149-5p. YAP1 promoted CCA proliferation, invasion and stemness maintenance, whereas miR-149-5p inhibited malignant biological behavior of CCA. Rescue experiments confirmed that the cancer-promoting effect of DLEU1 was saved by interfering miR-149-5p or YAP1. Furthermore, YAP1 promoted tumor stemness maintenance partly by acting as a transcriptional coactivator to promote TEAD2-induced SOX2 expression. These findings indicated that YY1-induced DLEU1 played a crucial role in CCA progression via miR-149-5p/YAP1/TEAD2/SOX2 axis.
| S-EPMC9295058 | biostudies-literature
Project description:BackgroundGliomas are based on a genetic abnormality and present with a dismal prognosis. MicroRNAs (miRNAs) are considered to be important mediators of gene expression in glioma tissues.MethodsReal-time PCR was used to analyze the expression of microRNA-423-5p (miR-423-5p) in human glioma samples and normal brain tissue. Apoptosis, cell cycle, proliferation, immunostaining, transwell, in vitro 2D and 3D migration, and chemosensitivity assays were performed to assess the phenotypic changes in glioma cells overexpressing miRNA-423-5p. Western blotting was used to determine the expression of inhibitor of growth 4 (ING-4)in glioma tissues, and a luciferase reporter assay was conducted to confirm whether ING-4 is a direct target of miR-423-5p. Western blotting was used to identify the potential signaling pathways that are affected in glioma cell growth by miR-423-5p. Xenograft tumors were examined in vivo for the carcinogenic effects of miR-423-5p in glioma tissues.ResultsWe first reported that miR-423-5p expression was increased in gliomas and was a potential tumor promoter via targeting ING-4. The overexpression of miR-423-5p resulted in upregulation of important signaling molecules such as p-AKT and p-ERK1/2. In clinical samples, miR-423-5p was dysregulated, and a corresponding alteration in ING-4 expression was observed (P = .0207). Furthermore, the overexpression of miR-423-5p strengthened glioma cell proliferation, angiogenesis, and invasion. Finally, miR-423-5p overexpression also strengthened GBM neurosphere formation and rendered glioma cells resistant to temozolomide (TMZ).ConclusionThis study establishes that miR-423-5p functions as an oncogene in glioma tissues by suppressing ING-4 and suggests that it has therapeutic potential for glioma.
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Project description:SRY-box transcription factor 2 (SOX2) overlapping transcript (SOX2-OT) is an evolutionarily conserved long noncoding RNA. Its intronic region contains the SOX2 gene, the major regulator of the pluripotency of embryonic stem cells. The human SOX2-OT gene comprises multiple exons and has multiple transcription start sites and generates hundreds of transcripts. Transcription factors (IRF4, AR, and SOX3), transcriptional inhibitors (NSPc1, MTA3, and YY1), and miRNAs (miR-211 and miR-375) have been demonstrated to control certain SOX2-OT transcript level at the transcriptional or posttranscriptional levels. Accumulated evidence indicates its crucial roles in the regulation of the SOX2 gene, miRNAs, and transcriptional process. Restricted expression of SOX2-OT transcripts in the brain results in the association between SOX2-OT single nucleotide polymorphisms and mental illnesses such as schizophrenia and anorexia nervosa. SOX2-OT is notably elevated in tumor tissues, and a high level of SOX2-OT is well correlated with poor clinical outcomes in cancer patients, leading to the establishment of its role as an oncogene and a prognostic or diagnostic biomarker for cancers. The emerging evidence supports that SOX2-OT mediates diabetic complications. In summary, SOX2-OT has diversified functions and could be a therapeutic target for various diseases.
| S-EPMC7718063 | biostudies-literature
Project description:BackgroundCircular RNAs (circRNAs) play important regulatory roles in multiple human malignancies, including non-small cell lung cancer (NSCLC). Here, we explored the role of circRNA vacuole membrane protein 1 (circVMP1) in NSCLC progression and cisplatin (DDP) resistance.MethodsThe DDP resistance, proliferation, sphere formation ability, migration, invasion, and apoptosis of NSCLC cells were analyzed by Cell Counting Kit-8 (CCK8) assay, 5-ethynyl-2'-deoxyuridine (EdU) assay, sphere formation assay, wound healing assay, Transwell assay, and flow cytometry. Methylated RIP-qPCR (MeRIP-qPCR) was conducted to analyze the m6A modification level of SRY-box transcription factor 2 (SOX2). Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay, and RNA-pull down assay were performed to confirm the intermolecular interaction. Exosomes were identified by transmission electron microscopy (TEM) and characterized by nanoparticle tracking analysis (NTA).ResultsCircVMP1 expression was markedly elevated in DDP-resistant NSCLC cell lines compared with their parental cell lines. CircVMP1 absence restrained the proliferation, sphere formation, migration, invasion, and DDP resistance and promoted the apoptosis of DDP-resistant NSCLC cells. CircVMP1 acted as microRNA-524-5p (miR-524-5p) sponge to up-regulate the expression of methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit (METTL3) and SOX2. CircVMP1 silencing restrained the malignant behaviors and DDP resistance of A549/DDP and H1299/DDP cells by targeting miR-524-5p. Exosomal circVMP1 disseminated the malignant properties and DDP resistance to DDP-sensitive cells. Exosomal circVMP1 elevated the DDP resistance of xenograft tumors in vivo. Exosomal circVMP1 was up-regulated in the serum samples of DDP-resistant NSCLC patients compared with DDP-sensitive patients.ConclusionExosome-mediated transmission of circVMP1 promoted NSCLC progression and DDP resistance by targeting miR-524-5p-METTL3/SOX2 axis.HighlightsCircVMP1 level is up-regulated in DDP-resistant NSCLC cell lines compared with DDP-sensitive cell lines.CircVMP1 absence restrains the malignant behaviors and DDP resistance of A549/DDP and H1299/DDP cells.CircVMP1-miR-524-5p/METTL3/SOX2 axis is identified for the first time.CircVMP1 plays an oncogenic role by targeting miR-524-5p-METTL3/SOX2 axis in A549/DDP and H1299/DDP cells.Exosomal circVMP1 transmits the malignant properties and DDP resistance to DDP-sensitive cells.
| S-EPMC9045767 | biostudies-literature
Project description:Background & Aims Treatment with non-selective beta-blockers (NSBBs) reduces the risk of ascites, which is the most common decompensating event in cirrhosis. This study aimed to assess the ability of a serum microRNA (miRNA) signature to predict ascites formation and the hemodynamic response to NSBBs in compensated cirrhosis. Methods Serum levels of miR-452-5p, miR-429, miR-885-5p, miR-181b-5p, and miR-122-5p were analyzed in patients with compensated cirrhosis (N = 105). Hepatic venous pressure gradient (HVPG) was measured at baseline, after intravenous propranolol, and 1 year after randomization to NSBBs (n = 52) or placebo (n = 53) (PREDESCI trial). miRNAs were analyzed at baseline and at 1 year. Results Nineteen patients (18%) developed ascites, of whom 17 developed ascites after 1 year. miR-181b-5p levels at 1 year, but not at baseline, were higher in patients that developed ascites. The AUC of miR-181b-5p at 1 year to predict ascites was 0.7 (95% CI 0.59–0.78). miR-429 levels were lower at baseline in acute HVPG responders to NSBBs (AUC 0.65; 95% CI, 0.53–0.76), but levels at baseline and at 1 year were not associated with the HVPG response to NSBBs at 1 year. Conclusions Serum miR-181b-5p is a promising non-invasive biomarker to identify patients with compensated cirrhosis at risk of ascites development. Lay summary Ascites marks the transition from the compensated to decompensated stage in cirrhosis and indicates a worsening in prognosis. There are currently no easily accessible tools to identify patients with compensated cirrhosis at risk of developing ascites. We evaluated the levels of novel molecules termed microRNAs in the blood of patients with compensated cirrhosis and observed that miR-181b-5p can predict which patients are going to develop ascites. Graphical abstract Highlights • miR-181b-5p appears to be a useful serum biomarker to anticipate ascites onset.• Low serum miR-181b-5p indicates low risk of ascites in compensated cirrhosis.• Low serum miR-429 reflects acute hemodynamic response to non-selective beta-blockers.
| S-EPMC8531668 | biostudies-literature
Project description:IntroductionHepatoblastoma (HB) is a malignant liver tumor predominantly found in children and tumor metastasis is one of the main causes of poor prognosis in affected patients. The precise molecular mechanisms responsible for HB metastasis remain incompletely understood. However, there is evidence suggesting a connection between the dysregulation of microRNAs (miRNAs) and the progression of tumor metastasis in HB.MethodsThe study utilized weighted gene co-expression network analysis (WGCNA) to analyze a miRNA microarray dataset of HB. The expression of miR-181b-5p in HB tissues and cells was detected using quantitative real-time PCR. The impact of miR-181b-5p on the metastatic capacity of HB was evaluated through scratch and Transwell assays. The effects of exogenously expressing miR-181b on the metastatic phenotypes of HB cells were evaluated in vivo. Furthermore, a luciferase reporter assay was performed to validate a potential target of miR-181b-5p in HB.ResultsWe found that miR-181b-5p was highly expressed in HB tissues and HB cell lines. Overexpression of miR-181b enhanced scratch healing, cell migration, and invasion abilities in vitro, as well as enhancing HB lung metastasis potential in vivo. Dual-luciferase reporter assays showed that Suppressor Of Cytokine Signaling 2 (SOCS2) was a direct target of miR-181b. The overexpression of miR-181b resulted in the suppression of SOCS2 expression, subsequently activating the epithelial-mesenchymal transition and JAK2/STAT5 signaling pathways. The rescue experiment showed that SOCS2 overexpression attenuated the effects of miR-181b on HB cells.ConclusionOur study showed that miR-181b promotes HB metastasis by targeting SOCS2 and may be a potential therapeutic target for HB.
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