Targeting HIF1-alpha/miR-326/ITGA5 axis potentiates chemotherapy response in triple-negative breast cancer

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buir.contributor.authorAssidicky, Ridho.
buir.contributor.authorTokat, Unal Metin
buir.contributor.authorTarman, Ibrahim Oguzhan
buir.contributor.authorErsan, Pelin Gulizar
buir.contributor.authorRaza, Umar
buir.contributor.orcidTokat, Unal Metin|0000-0003-0026-368X
buir.contributor.orcidErsan, Pelin Gulizar|0000-0003-3637-4090
buir.contributor.orcidRaza, Umar|0000-0002-0081-6996
dc.citation.epage348en_US
dc.citation.issueNumber2en_US
dc.citation.spage331en_US
dc.citation.volumeNumber193en_US
dc.contributor.authorTokat, Unal Metin
dc.contributor.authorTarman, Ibrahim Oguzhan
dc.contributor.authorErsan, Pelin Gulizar
dc.contributor.authorRaza, Umar
dc.contributor.authorSaatci, O.
dc.contributor.authorSahin, O.
dc.contributor.authorOgul, H.
dc.contributor.authorRiazalhosseini, Y.
dc.contributor.authorCan, T.
dc.contributor.authorAssidicky, Ridho
dc.date.accessioned2023-02-14T09:16:29Z
dc.date.available2023-02-14T09:16:29Z
dc.date.issued2022-03-25
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.description.abstractPurpose Triple-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. Methods Here, 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. Results We 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. Conclusion FN1 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.en_US
dc.identifier.doi10.1007/s10549-022-06569-5en_US
dc.identifier.eissn1573-7217
dc.identifier.issn0167-6806
dc.identifier.urihttp://hdl.handle.net/11693/111244
dc.language.isoEnglishen_US
dc.publisherSpringer New York LLCen_US
dc.relation.isversionofhttps://www.doi.org/10.1007/s10549-022-06569-5en_US
dc.source.titleBreast Cancer Research and Treatmenten_US
dc.subjectTNBCen_US
dc.subjectmiRNA-mRNA networken_US
dc.subjectChemoresistanceen_US
dc.subjectmiR-326en_US
dc.subjectFibronectinen_US
dc.subjectIntegrinen_US
dc.subjectHypoxiaen_US
dc.subjectECM stiffnessen_US
dc.titleTargeting HIF1-alpha/miR-326/ITGA5 axis potentiates chemotherapy response in triple-negative breast canceren_US
dc.typeArticleen_US

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