Tumor-initiating cell-specific miR-1246 and miR-1290 converge to promote non-small cell lung cancer progression
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE69631 | GEO | 2015/11/30
SECONDARY ACCESSION(S): PRJNA286042
REPOSITORIES: GEO
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Project description:The tumour-initiating cell (TIC) model accounts for phenotypic and functional heterogeneity among tumour cells. MicroRNAs (miRNAs) are regulatory molecules frequently aberrantly expressed in cancers, and may contribute towards tumour heterogeneity and TIC behaviour. More recent efforts have focused on miRNAs as diagnostic or therapeutic targets. Here, we identified the TIC-specific miRNAs, miR-1246 and miR-1290, as crucial drivers for tumour initiation and cancer progression in human non-small cell lung cancer. The loss of either miRNA impacted the tumour-initiating potential of TICs and their ability to metastasize. Longitudinal analyses of serum miR-1246 and miR-1290 levels across time correlate their circulating levels to the clinical response of lung cancer patients who were receiving ongoing anti-neoplastic therapies. Functionally, direct inhibition of either miRNA with locked nucleic acid administered systemically, can arrest the growth of established patient-derived xenograft tumours, thus indicating that these miRNAs are clinically useful as biomarkers for tracking disease progression and as therapeutic targets.
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Project description:The tumor-initiating cell (TIC) model accounts for the phenotypic and functional heterogeneity among cancer cells found within human cancers. MicroRNAs (miRNAs) are key regulatory molecules frequently aberrantly expressed in tumors, and may play important roles in contributing towards tumor heterogeneity and TIC behavior. More recent efforts have focused on miRNAs for diagnosis and as targets for novel therapies. In this study, we identified the miRNAs, miR-1246 and miR-1290, which are crucial for the function of TICs, thereby driving cancer progression in human non-small cell lung cancer (NSCLC). These miRNAs are restricted to patient-derived tumorspheres and CD166+ primary tumor cells, both enriched for TICs. Loss of either miRNA impacted the tumorigenic potential of TICs and their ability to metastasize. Interestingly, longitudinal analyses of serum miR-1246 and miR-1290 levels correlated circulating levels of either miRNA to the clinical response seen in lung cancer patients to epidermal growth factor receptor (EGFR) tyrosine kinase inhibition, chemotherapy and radiotherapy. Functionally, direct inhibition of miR-1246 or miR-1290 with locked nucleic acid (LNA) administered systemically, could arrest the growth of established patient-derived tumors xenografted in immunocompromised mice, thus indicating these miRNAs are clinically useful as biomarkers for tracking disease progression and as therapeutic targets.
2015-11-30 | GSE69630 | GEO
Project description:The tumor-initiating cell (TIC) model accounts for the phenotypic and functional heterogeneity among cancer cells found within human cancers. MicroRNAs (miRNAs) are key regulatory molecules frequently aberrantly expressed in tumors, and may play important roles in contributing towards tumor heterogeneity and TIC behavior. More recent efforts have focused on miRNAs for diagnosis and as targets for novel therapies. In this study, we identified the miRNAs, miR-1246 and miR-1290, which are crucial for the function of TICs, thereby driving cancer progression in human non-small cell lung cancer (NSCLC). These miRNAs are restricted to patient-derived tumorspheres and CD166+ primary tumor cells, both enriched for TICs. Loss of either miRNA impacted the tumorigenic potential of TICs and their ability to metastasize. Interestingly, longitudinal analyses of serum miR-1246 and miR-1290 levels correlated circulating levels of either miRNA to the clinical response seen in lung cancer patients to epidermal growth factor receptor (EGFR) tyrosine kinase inhibition, chemotherapy and radiotherapy. Functionally, direct inhibition of miR-1246 or miR-1290 with locked nucleic acid (LNA) administered systemically, could arrest the growth of established patient-derived tumors xenografted in immunocompromised mice, thus indicating these miRNAs are clinically useful as biomarkers for tracking disease progression and as therapeutic targets.
2015-11-30 | GSE69574 | GEO
Project description:Tumor-initiating cell-specific miR-1246 and miR-1290 converge to promote non-small cell lung cancer progression
| PRJNA286042 | ENA
Project description:Background: Pancreatic cancer (PC) is a highly malignant tumor with no effective early diagnostic biomarkers. This study was performed to screen and identify serum microRNAs (miRNAs) as noninvasive biomarkers for PC diagnosis. Methods: Two upregulated miRNAs were selected by integrated analysis of three independent GEO datasets. Then, the expressions of two miRNAs in serum were determined by quantitative reverse-transcription PCR among 120 PC patients, 40 benign disease controls and 40 healthy controls. The correlation between serum miRNAs and clinical characteristics was analyzed. The diagnostic utility of miRNAs was compared to CA19-9 using receiver operating characteristic curve analysis. Results: We discovered miR-1290 and miR-1246 were upregulated in PC patients through GEO datasets analysis. Serum miR-1290 and miR-1246 expression levels were elevated in PC patients compared to all controls and dramatically decreased after tumor resection (all P<0.001). The area under the curve (AUC) for miR-1290 was larger than miR-1246 and CA19-9 (miR-1290: 0.91; miR-1246: 0.81; CA19-9: 0.82). The combined diagnosis of individual or both miRNAs with CA19-9 was more effective for discriminating PC from all controls than the single CA19-9 assay (miR-1290+CA19-9: 0.96, miR-1246+CA19-9: 0.93, miR-1290+miR-1246+CA19-9: 0.97). The abundance of serum miR-1290 and miR-1246 was associated with tumor stage and size respectively and logistic modeling proved that both of them were independent risk factors for PC. Conclusion: Serum miR-1290 and miR-1246 might be promising biomarkers for PC diagnosis and the combined detection of CA19-9, together with miR-1290 or miR-1246, could improve the diagnostic accuracy of PC.
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Project description:Circular RNAs (CircRNAs) are reported to exert vital regulatory roles in the occurrence and development of various human malignancies, including non-small cell lung cancer (NSCLC). Bioinformatics methods identified the down-regulation of circSCN8A (circBase ID: hsa_circ_0026337) in NSCLC tissues. However, its biological functions and molecular mechanisms in NSCLC remain unknown. In this study, we found that circSCN8A expression was down-regulated in NSCLC tissues and cells. Low circSCN8A expression was positively associated with aggressive clinicopathological characteristics and poor prognosis in NSCLC patients. CircSCN8A suppressed cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro and blocked tumor growth in vivo. Moreover, circSCN8A promoted cell ferroptosis in NSCLC. Mechanistically, circSCN8A acted as a competing endogenous RNA (ceRNA) by sponging miR-1290 to enhance the expression of long-chain acyl-CoA synthetase-4 (ACSL4). Furthermore, the knockdown of ACSL4 or overexpression of miR-1290 reversed the effect of circSCN8A on facilitating ferroptosis and inhibiting cell proliferation and metastasis. In summary, circSCN8A represses cell proliferation and metastasis in NSCLC by regulating the miR-1290/ACSL4 axis to induce ferroptosis. Thus, circSCN8A may represent a promising therapeutic target against NSCLC.
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Project description:Lung cancer remains the leading cause of cancer-associated death worldwide. MiR-21 and miR-155 are the most amplified miRNAs in non-small cell lung carcinoma (NSCLC), and are critical promoters of NSCLC progression. However, it remains unclear how miR-21 and miR-155 induce cancer progression, and whether these miRNAs share common targets, such as tumor suppressor genes required to prevent NSCLC. Here we report that miR-21 and miR-155 levels are elevated in NSCLC and are proportional to the progression of the disease. In addition, miR-21 and miR-155 share nearly 30% of their predicted target genes, including SOCS1, SOCS6, and PTEN, three tumor suppressor genes often silenced in NSCLC. Consequently, antagonizing miR-21, miR-155 or both potently inhibited tumor progression in xenografted animal models of NSCLC. Treatment with miR-21 and miR-155 inhibitors in combination was always more effective against NSCLC than treatment with a single inhibitor. Furthermore, levels of miR-21 and miR-155 expression correlated inversely with overall and disease-free survival of NSCLC patients. Our findings reveal that miR-21 and miR-155 promote the development of NSCLC, in part by downregulating SOCS1, SOCS6, and PTEN. Combined inhibition of miR-21 and miR-155 could improve the treatment of NSCLC.
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Project description:The oncogenic properties of members belonging to the forkhead box (FOX) family have been extensively documented in different types of cancers. In this study, our objective was to investigate the impact of FOXP3 on glioblastoma multiforme (GBM) cells. By conducting a screen using a small hairpin RNA (shRNA) library, we discovered a significant association between FOXP3 and ferroptosis in GBM cells. Furthermore, we observed elevated levels of FOXP3 in both GBM tissues and cell lines, which correlated with a poorer prognosis. FOXP3 was found to promote the proliferation of GBM cells by inhibiting cell ferroptosis in vitro and in vivo. Mechanistically, FOXP3 not only directly upregulated the transcription of GPX4, but also attenuated the degradation of GPX4 mRNA through the linc00857/miR-1290 axis, thereby suppressing ferroptosis and promoting proliferation. Additionally, the FOXP3 inhibitor epirubicin exhibited the ability to impede proliferation and induce ferroptosis in GBM cells both in vitro and in vivo. In summary, our study provided evidences that FOXP3 facilitates the progression of glioblastoma by inhibiting ferroptosis via the linc00857/miR-1290/GPX4 axis, highlighting FOXP3 as a potential therapeutic target for GBM.
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Project description:BackgroundNon-small cell lung cancer (NSCLC) progression is mediated by changes in gene expression induced by microRNAs. However, the underlying mechanisms remain to be elucidated. In this study, we investigated the roles of miR-183-5p and its target gene in lung cancer development.MethodsRelative levels of miR-183-5p and lysyl oxidase-like 4 (LOXL4) expression in lung cancer cells or tissues were measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR), immunofluorescence or Western blotting as appropriate. The binding of miR-183-5p to LOXL4 sequences was verified by a dual luciferase reporter assay, and cell proliferation was assessed by Cell Counting Kit-8 (CCK-8) and Edu staining. The cell cycle stage and apoptosis were detected by flow cytometry, and Transwell assays were performed to evaluate cell migration and invasion capabilities. The tumorigenic capability of cancer cells was analyzed using a cancer cell line-based xenograft nude mouse model.ResultsmiR-183-5p expression was decreased in the lung cancer tissues and cell lines and was negatively correlated with elevated LOXL4 expression. Treatment with miR-183-5p mimics suppressed LOXL4 expression, while treatment with an miR-183-5p inhibitor promoted LOXL4 expression in A549 cells. miR-183-5p was found to directly bind to the 3' UTR of the LOXL4 gene in A549 cells. Overexpression of LOXL4 enhanced cell proliferation, cell cycle progression, migration, and invasion, but repressed their apoptosis, and activated extracellular matrix (ECM) and the epithelial mesenchymal transition (EMT) process in A549 cells, while LOXL4 knockdown produced the opposite effects. Treatment with an miR-183-5P inhibitor promoted the proliferation, cell cycle progression, migration, and invasion of A549 cells but suppressed their apoptosis, and activated the ECM and EMT process, while all these effects were abrogated by LOXL4 knockdown. The tumorigenic capability of A540 cells in nude mice was greatly impaired by treatment with miR-183-5p mimics.ConclusionsmiR-183-5p repressed the proliferation, migration, invasion, ECM formation, and EMT processes, and promoted the apoptosis of lung cancer cells by targeting LOXL4 expression.
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Project description:Radiosensitivity varies among patients with non-small cell lung cancer (NSCLC). In this work, we aimed to investigate microRNAs associated with this heterogeneity among individuals. We selected miR-1246 from the microRNAs that were revealed by microarray experiments to be differentially expressed between radioresistant and parental cell lines. Both intracellular and extracellular miR-1246 was found to be upregulated after irradiation in a time-dependent pattern, resulting in increased radioresistance of NSCLC cells. We found that mTOR was a direct target gene of miR-1246, which mediated miR-1246-induced autophagy activation. Yin Yang-1 (YY1) was demonstrated to be a new transcription factor that regulates miR-1246 and CDR1as was found to be a circular RNA that sequesters miR-1246, which was confirmed in NSCLC cells and clinical samples. Finally, combining these data with the results from The Cancer Genome Atlas (TCGA), we verified that miR-1246 could be used as a biomarker to predict NSCLC patients' radiosensitivity and prognosis. Overall, our study fully investigated the effect of miR-1246 on radiosensitivity and comprehensively investigated the potential of miR-1246 as a prognostic biomarker and radiotherapy sensitization target.
| S-EPMC7017745 | biostudies-literature