CircRNA_103615 contributes to tumor progression and cisplatin resistance in NSCLC by regulating ABCB1.
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ABSTRACT:
SUBMITTER: Liang H
PROVIDER: S-EPMC8281253 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) is a recently identified gene associated with malignant tumor progression and patient chemotherapy resistance in human hepatocellular carcinoma (HCC). Previously, we found an association between CHD1L overexpression and poor patient survival in non-small-cell lung cancer (NSCLC). However, little is known about the relationship between CHD1L expression and chemotherapy resistance of NSCLC. By employing immunohistochemistry, we analyzed the expression of CHD1L in NSCLC samples and elucidated the roles and mechanism of CHD1L in NSCLC chemoresistance. We found that the increased expression of CHD1L is positively correlated with a shorter survival time of patients who had received chemotherapy after surgery. We also found that the expression of CHD1L was increased after cisplatin treatment in A549 cells. Conversely, the depletion of CHD1L in cisplatin-resistance cells increased the cell sensitivity to cisplatin, indicating that CHD1L plays a critical role in cisplatin resistance of NSCLC cells. Importantly, we identified the ATP-Binding Cassette Sub-Family B Member (ABCB1) gene as a potential downstream target of CHD1L in NSCLC cells. Knocking down ABCB1 coupled with ectopic expression of CHD1L enhanced the effect of cisplatin on NSCLC cells apoptosis. In addition, overexpressed CHD1L increase the transcription of c-Jun which targeted directly to the promoter of ABCB1. Our data demonstrate that CHD1L could induce cisplatin resistance in NSCLC via c-Jun-ABCB1-NF-?B axis, and may serve as a novel predictive marker and the potential therapeutic target for cisplatin resistance in NSCLC.
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Project description:To identify genes associated with lung cancer progression, we examined gene expression profiles of tumor cells from 20 patients with primary, untreated non-small cell lung cancer (10 adenocarcinomas (AC) and 10 squamous cell carcinomas (SCC)) in comparison to lung tissue of 23 patients with stage IIIB or stage IV non-small cell lung cancer (15 AC and 8 SCC). Bronchoscopical biopsies from patient with recurrent lung tumor were taken after initial treatment. Cancer cells were isolated using laser capture microdissection in order to obtain pure samples of tumor cells. For expression analysis, microarrays covering 8793 defined genes (Human HG Focus Array, Affymetrix) were used. Array data were normalized and analysed for significant differences using variance stabilizing transformation (VSN) and significance analysis of microarrays (SAM), respectively. Genes were considered to be up- or down-regulated when the ratio between primary and recurrent tumor samples were at least 1.5-fold differentially expressed with an estimated false discovery rate: < 5%. Based on differentially expressed genes, primary cancer samples could be separated from recurrent tumor samples. We identified 115 and 124 significantly regulates genes in AC and SCC, respectively. For example, in recurrent AC we found increased expression of genes related to the wingless (FZD6, RYK, MYC) and calcium (CALM1, ATB2B1, S100A2) signalling pathways which might play a role in metastasis of tumor cells. Other differentially expressed genes were related to cell cycle (CCND1, CDK2), transcription factors (TTF1, TAF2, YY1), nuclear mRNA splicing and mRNA processing (SFRS1, HNRPL), protein-nucleus import (NUTF2, KPNB1, NUP50) and chromatin modification (HIST1H4C, SMARCC1). In SCC, we found an increased expression of CTNNB1, an important mediator in wingless signalling pathway. Among the down-regulated genes in SCC, the utmost fraction belonged to genes coding for ubiquitin mediated proteolysis (UCHL1, PSMA3, COPS6) and ribosomal proteins (RPS26, RPL7A, RPS15). Other down regulated genes were related to transcription factors (TCEA2, TAF10), nuclear mRNA splicing and mRNA processing (SNRPD2, HNRPM). In conclusion, a distinct pattern of gene expression is found during the progression from primary carcinoma to recurrent NSCLC. Our microarray-based expression profiling revealed interesting novel candidate genes and pathways that may contribute to lung cancer progression. Experiment Overall Design: - 20 patients with primary, untreated non-small cell lung cancer (10adenocarcinomas (AC) and 10 squamous cell carcinomas (SCC)) in comparison to lung tissue of 23 patients with stage IIIB or stage IV non-small cell lung cancer (15 AC and 8 SCC) Experiment Overall Design: - Human HG Focus Array, Affymetrix) were used Experiment Overall Design: - Array data were normalized and analysed for significant differences using variance stabilizing transformation (VSN) and significance analysis of microarrays (SAM) Experiment Overall Design: - Genes were considered to be up- or down-regulated when the ratio between primary and recurrent tumor samples were at least 1.5-fold differentially expressed with an estimated false discovery rate: < 5%
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Project description:Background:Circular RNA downstream neighbor of SON (circDONSON) has been revealed to promote gastric cancer (GC) growth and invasion, while the role and molecular mechanism underlying circDONSON in GC cisplatin (DDP) resistance remain unclear. Methods:Levels of circDONSON, microRNA (miR)-802, and B lymphoma Mo-MLV insertion region 1 (BMI1) mRNA were detected using quantitative real-time polymerase chain reaction. Cell viability and apoptosis were measured by cell counting kit-8 assay, colony formation assay and flow cytometry, respectively. Protein levels of BMI1, Cyclin D1, p27, Caspase-3 Cleavage and Caspase-9 Cleavage were determined by western blot. The interaction between miR-802 and circDONSON or BMI1 was confirmed by dual-luciferase reporter assay. In vivo experiments were conducted via the murine xenograft model. Results:CircDONSON was elevated in GC tissues and cell lines, especially in DDP-resistant GC tissues and cells. Knockdown of circDONSON sensitized GC cells to DDP by inhibiting cell viability and promoting cell apoptosis in vitro. Further mechanism-related investigations suggested that circDONSON functioned as "sponge" by competing for miR-802 binding to modulate its target BMI1. Silencing miR-802 reversed the inhibition of DDP-resistance in GC cells induced by circDONSON down-regulation. Besides, miR-802 alleviated DDP resistance in GC cells by targeting BMI1. Functionally, circDONSON knockdown enhanced the cytotoxicity of DDP in GC in vivo. Conclusion:Our findings demonstrated circDONSON promoted cisplatin resistance in gastric cancer cells by regulating miR-802/BMI1 axis, shedding light on the development of a novel therapeutic strategy to overcome chemoresistance in gastric cancer patients.
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Project description:Background:Cisplatin (DDP) is the first-line chemotherapeutic drug for non-small cell lung cancer (NSCLC), and long-term DDP stimulation increased resistance of NSCLC cells to this drug by enriching cancer stem cells (CSCs), which contributed to recurrence and worse prognosis of NSCLC, but the molecular mechanisms are still not fully delineated. Methods:Real-Time qPCR and Western Blot analysis were conducted to examine gene expressions at mRNA and protein levels, respectively. Dual-luciferase reporter gene system was used to validate the targeting sites among circRNA CDR1as, miR-641 and HOXA9 mRNA. Cell growth was evaluated by CCK-8 assay, trypan blue staining assay and colony formation assay. The Annexin V-FITC/PI double staining method was employed to measure cell apoptosis ratio. Spheroid formation and flow cytometer assay was used to evaluate cell stemness. Xenograft mice models were established to measure tumorgenicity in vivo, and Ki67 expressions in mice tumor tissues were examined by immunohistochemistry (IHC). Results:Here we identified a novel circRNA CDR1as/miR-641/Homeobox protein Hox-A9 (HOXA9) pathway regulated stemness and DDP chemoresistance in NSCLC. Mechanistically, circRNA CDR1as and HOXA9 were high-expressed, while miR-641 was low-expressed in DDP-resistant NSCLC cells, instead of their corresponding parental DDP-sensitive NSCLC cells. Additionally, we validated that circRNA CDR1as positively regulated HOXA9 in NSCLC cells by serving as an RNA sponge for miR-641, and knock-down of circRNA CDR1as increased the sensitivity of DDP-resistant NSCLC cells, which were reversed by downregulating miR-641 and upregulating HOXA9. Consistently, overexpression of circRNA CDR1as increased drug resistance of DDP-sensitive NSCLC cells by regulating miR-641/HOXA9 axis. In addition, the expression levels of stemness signatures (SOX2, OCT4 and Nanog) were higher in DDP-resistant NSCLC cells, which also tended to form spheres and enrich CD44+CD166+ population compared to their parental DDP-sensitive NSCLC cells, suggesting that CSCs were enriched in DDP-resistant NSCLC cells. Notably, knock-down of circRNA CDR1as inhibited stemness of DDP-resistant NSCLC cells by inhibiting HOXA9 through upregulating miR-641. Conclusions:Taken together, this study identified that circRNA CDR1as regulated stemness and DDP chemoresistance in NSCLC cells by targeting miR-641/HOXA9 axis.
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Project description:BackgroundCisplatin-based chemotherapy is recommended as the primary treatment for advanced bladder cancer (BC) with unresectable or metastatic disease. However, the benefits are limited due to the acquisition of drug resistance. The mechanisms of resistance remain unclear. Although there are some reports that some molecules are associated with cisplatin resistance in advanced BC, those reports have not been fully investigated. Therefore, we undertook a new search for cisplatin resistance-related genes targeted by tumor suppressive microRNAs as well as genes that were downregulated in cisplatin-resistant BC cells and clinical BC tissues.MethodsFirst, we established cisplatin-resistant BOY and T24 BC cell lines (CDDP-R-BOY, CDDP-R-T24). Then, Next Generation Sequence analysis was performed with parental and cisplatin-resistant cell lines to search for the microRNAs responsible for cisplatin resistance. We conducted gain-of-function analysis of microRNAs and their effects on cisplatin resistance, and we searched target genes comprehensively using Next Generation mRNA sequences.ResultsA total of 28 microRNAs were significantly downregulated in both CDDP-R-BOY and CDDP-R-T24. Among them, miR-486-5p, a tumor suppressor miRNA, was negatively correlated with the TNM classification of clinical BC samples in The Cancer Genome Atlas (TCGA) database. Transfection of miRNA-486-5p significantly inhibited cancer cell proliferation, migration, and invasion, and also improved the cells' resistance to cisplatin. Among the genes targeted by miRNA-486-5p, we focused on enoyl-CoA, hydratase/3-hydroxyacyl CoA dehydrogenase (EHHADH), which is involved in the degradation of fatty acids. EHHADH was directly regulated by miRNA-486-5p as determined by a dual-luciferase reporter assay. Loss-of-function study using EHHADH si-RNA showed significant inhibitions of cell proliferation, migration, invasion and the recovery of cisplatin sensitivity.ConclusionIdentification of EHHADH as a target of miRNA-486-5p provides novel insights into the potential mechanisms of cisplatin resistance in BC.
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Project description:Ubiquitin carboxyl terminal hydrolase 1 (UCHL1) catalyzes the hydrolysis of COOH-terminal ubiquityl esters and amides. It has been reported as either an oncogene or a tumor suppressor in cancers. However, UCHL1's role in ovarian cancer is still unclear. Therefore, we conducted an analysis to understand the role of UCHL1 in ovarian cancer. Firstly, we detected UCHL1 promoter methylation status in 7 ovarian cancer cell lines. 4 of them with UCHL1 silencing showed heavy promoter methylation while the other 3 with relative high UCHL1 expression showed little promoter methylation. Then we reduced UCHL1 expression in ovarian cancer cell line A2780 and IGROV1 and found that inhibition of UCHL1 promoted cell proliferation by increasing cells in S phases of cell cycle. Knockdown of UCHL1 also reduced cell apoptosis and contributed to cisplatin resistance. Furthermore, the expression level of UCHL1 in several ovarian cancer cell lines correlated negatively with their cisplatin resistance levels. Microarray data revealed that UCHL1 related genes are enriched in apoptosis and cell death gene ontology (GO) terms. Several apoptosis related genes were increased after UCHL1 knockdown, including apoptosis regulator BCL2, BCL11A, AEN and XIAP. Furthermore, we identified up-regulation of Bcl-2 and pAKT as well as down-regulation of Bax in UCHL1 knockdown cells, while no significant alteration of p53 and AKT1 was found. This study provides a new and promising strategy to overcome cisplatin resistance in ovarian cancer via UCHL1 mediated pathways.
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