Dataset Information

CircAR-E2E4-miR-665-STAT3 axis is a potential regulatory network in triple-negative breast cancer.

ABSTRACT: Circular RNAs (circRNAs) are a novel type of endogenous non-coding RNAs (ncRNA). Many studies showed that circRNAs played different biological functions in triple-negative breast cancer (TNBC). However, the potential molecular mechanism of circRNAs in TNBC still remains to be investigated. In this study, circAR-E2E4 was defined as a novel circRNA involved in TNBC progression, derived from and regulated by androgen receptor (AR). CCK-8 assay showed circAR-E2E4 regulated TNBC cell proliferation. Potential binding miRNAs of circAR-E2E4 were predicted and miR-665 was identified to have a great prognosis value. Three databases were employed to predict target genes of miR-665, and STAT3 was regarded as the most potential downstream genes analyzed by protein-protein interaction (PPI), hub gene screening, correlation analysis, and survival analysis. Finally, knockdown of circAR-E2E4 led to the decrease of STAT3 expression. Collectively, the regulatory network circAR-E2E4-miR-665-STAT3 axis we constructed was associated with TNBC progression, providing a promising diagnostic, prognostic, and therapeutic target in future treatment for TNBC.

SUBMITTER: Xu H

PROVIDER: S-EPMC9860453 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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circAR-E2E4-miR-665-STAT3 axis is a potential regulatory network in triple-negative breast cancer.

Xu Hao H Fang Mengdie M Zuo Bowen B Yao Wanxin W Ren Juan J Zhang Yanmei Y

Heliyon 20221223 1

Circular RNAs (circRNAs) are a novel type of endogenous non-coding RNAs (ncRNA). Many studies showed that circRNAs played different biological functions in triple-negative breast cancer (TNBC). However, the potential molecular mechanism of circRNAs in TNBC still remains to be investigated. In this study, circAR-E2E4 was defined as a novel circRNA involved in TNBC progression, derived from and regulated by androgen receptor (AR). CCK-8 assay showed circAR-E2E4 regulated TNBC cell proliferation. P ...[more]

PMID: 36691537

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Project description:BackgroundFamilial triple-negative breast cancers are often linked to mutations in the BRCA1 tumor suppressor gene. In sporadic triple-negative breast cancers BRCA1 is frequently inactivated at the transcriptional level, and it has been reported that this inactivation may be brought about by promoter methylation. More recently, it was found that BRCA1 may also be regulated at the post-transcriptional level by miRNAs. Here, we explored the expression of putative BRCA1-regulating miRNAs in sporadic human triple-negative breast cancer cells.MethodsNine sporadic human breast cancer-derived cell lines and one benign breast epithelium-derived cell line were assessed for their hormone receptor, growth factor receptor and cytokeratin status by immunocytochemistry. The expression of 5 selected miRNAs predicted to target BRCA1 was assessed using qRT-PCR in the 10 cell lines. In addition, expression profiles of 84 known breast cancer-associated miRNAs were established in these 10 cell lines using PCR Array and qRT-PCR, respectively. The putative role of pre-selected candidate miRNAs in breast cancer development was assessed through exogenous expression of these miRNAs and their anti-miRNAs ('antagomirs') in MDA-MB-231 and MCF7 breast cancer-derived cells.ResultsBased on our expression profiling results, four candidate miRNAs (miR-10b, miR-26a, miR-146a and miR-153) were selected as being potentially involved in triple-negative breast cancer development. Exogenous expression assays revealed that miR-10b and miR-26a, but not miR-146a, can down-regulate the expression of BRCA1 in both triple-negative MDA-MB-231 and luminal epithelial MCF7 breast cancer-derived cells, whereas miR-153 could down-regulate BRCA1 expression only in MCF7 cells. In silico analysis of The Cancer Genome Atlas (TCGA) data confirmed that miR-146a is significantly higher expressed in triple-negative breast tumors compared to other (non triple-negative) breast tumors.ConclusionOur work provides evidence for the involvement of specific miRNAs in triple-negative breast cancer development through regulating BRCA1 expression.

Project description:PurposeTriple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer that is frequently treated with chemotherapy. However, many patients exhibit either de novo chemoresistance or ultimately develop resistance to chemotherapy, leading to significantly high mortality rates. Therefore, increasing the efficacy of chemotherapy has potential to improve patient outcomes.MethodsHere, we performed whole transcriptome sequencing (both RNA and small RNA-sequencing), coupled with network simulations and patient survival data analyses to build a novel miRNA-mRNA interaction network governing chemoresistance in TNBC. We performed cell proliferation assay, Western blotting, RNAi/miRNA mimic experiments, FN coating, 3D cultures, and ChIP assays to validate the interactions in the network, and their functional roles in chemoresistance. We developed xenograft models to test the therapeutic potential of the identified key miRNA/proteins in potentiating chemoresponse in vivo. We also analyzed several patient datasets to evaluate the clinical relevance of our findings.ResultsWe identified fibronectin (FN1) as a central chemoresistance driver gene. Overexpressing miR-326 reversed FN1-driven chemoresistance by targeting FN1 receptor, ITGA5. miR-326 was downregulated by increased hypoxia/HIF1A and ECM stiffness in chemoresistant tumors, leading to upregulation of ITGA5 and activation of the downstream FAK/Src signaling pathways. Overexpression of miR-326 or inhibition of ITGA5 overcame FN1-driven chemotherapy resistance in vitro by inhibiting FAK/Src pathway and potentiated the efficacy of chemotherapy in vivo. Importantly, lower expression of miR-326 or higher levels of predicted miR-326 target genes was significantly associated with worse overall survival in chemotherapy-treated TNBC patients.ConclusionFN1 is central in chemoresistance. In chemoresistant tumors, hypoxia and resulting ECM stiffness repress the expression of the tumor suppressor miRNA, miR-326. Hence, re-expression of miR-326 or inhibition of its target ITGA5 reverses FN1-driven chemoresistance making them attractive therapeutic approaches to enhance chemotherapy response in TNBCs.

Dataset Information

CircAR-E2E4-miR-665-STAT3 axis is a potential regulatory network in triple-negative breast cancer.

Publications

circAR-E2E4-miR-665-STAT3 axis is a potential regulatory network in triple-negative breast cancer.

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