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Article: Identification of miR-29c and its Target FBXO31 as a Key Regulatory Mechanism in Esophageal Cancer Chemoresistance: Functional Validation and Clinical Significance

TitleIdentification of miR-29c and its Target FBXO31 as a Key Regulatory Mechanism in Esophageal Cancer Chemoresistance: Functional Validation and Clinical Significance
Authors
Keywordsdiagnosis and prognosis
chemoresistance
p38 signaling
STAT5A
microRNA therapy
Issue Date2019
PublisherIvyspring International Publisher. The Journal's web site is located at http://www.thno.org/
Citation
Theranostics, 2019, v. 9 n. 6, p. 1599-1613 How to Cite?
AbstractRationale: Dysregulated microRNA (miRNA) expressions in cancer can contribute to chemoresistance. This study aims to identify miRNAs that are associated with fluorouracil (5-FU) chemoresistance in esophageal squamous cell carcinoma (ESCC). The potential of miR-29c as a novel diagnostic, prognostic and treatment-predictive marker in ESCC, and its mechanisms and therapeutic implication in overcoming 5-FU chemoresistance were explored. Methods: The miRNA profiles of an ESCC cell model with acquired chemoresistance to 5-FU were analyzed using a Taqman miRNA microarray to identify novel miRNAs associated with 5-FU chemoresistance. Quantitative real-time PCR was used to determine miR-29c expression in tissue and serum samples of patients. Bioinformatics, gain- and loss-of-function experiments, and luciferase reporter assay were performed to validate F-box only protein 31 (FBXO31) as a direct target of miR-29c, and to identify potential transcription factor binding events that control miR-29c expression. The potential of systemic miR-29c oligonucleotide-based therapy in overcoming 5-FU chemoresistance was evaluated in tumor xenograft model. Results: MiR-29c, under the regulatory control of STAT5A, was frequently downregulated in tumor and serum samples of patients with ESCC, and the expression level was correlated with overall survival. Functional studies showed that miR-29c could override 5-FU chemoresistance in vitro and in vivo by directly interacting with the 3'UTR of FBXO31, leading to repression of FBXO31 expression and downstream activation of p38 MAPK. Systemically administered miR-29c dramatically improved response of 5-FU chemoresistant ESCC xenografts in vivo. Conclusions: MiR-29c modulates chemoresistance by interacting with FBXO31, and is a promising non-invasive biomarker and therapeutic target in ESCC.
Persistent Identifierhttp://hdl.handle.net/10722/271188
ISSN
2017 Impact Factor: 8.537
2015 SCImago Journal Rankings: 2.702
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorLi, B-
dc.contributor.authorHong, P-
dc.contributor.authorZheng, C-C-
dc.contributor.authorDai, W-
dc.contributor.authorChen, W-Y-
dc.contributor.authorYang, Q-S-
dc.contributor.authorHAN, L-
dc.contributor.authorTsao, SW-
dc.contributor.authorChan, KT-
dc.contributor.authorLee, NPY-
dc.contributor.authorLaw, S-
dc.contributor.authorXu, LY-
dc.contributor.authorLi, EM-
dc.contributor.authorChan, KW-
dc.contributor.authorQin, YR-
dc.contributor.authorGuan, XY-
dc.contributor.authorLung, ML-
dc.contributor.authorHe, Q-Y-
dc.contributor.authorXu, W-
dc.contributor.authorCheung, ALM-
dc.date.accessioned2019-06-24T01:05:03Z-
dc.date.available2019-06-24T01:05:03Z-
dc.date.issued2019-
dc.identifier.citationTheranostics, 2019, v. 9 n. 6, p. 1599-1613-
dc.identifier.issn1838-7640-
dc.identifier.urihttp://hdl.handle.net/10722/271188-
dc.description.abstractRationale: Dysregulated microRNA (miRNA) expressions in cancer can contribute to chemoresistance. This study aims to identify miRNAs that are associated with fluorouracil (5-FU) chemoresistance in esophageal squamous cell carcinoma (ESCC). The potential of miR-29c as a novel diagnostic, prognostic and treatment-predictive marker in ESCC, and its mechanisms and therapeutic implication in overcoming 5-FU chemoresistance were explored. Methods: The miRNA profiles of an ESCC cell model with acquired chemoresistance to 5-FU were analyzed using a Taqman miRNA microarray to identify novel miRNAs associated with 5-FU chemoresistance. Quantitative real-time PCR was used to determine miR-29c expression in tissue and serum samples of patients. Bioinformatics, gain- and loss-of-function experiments, and luciferase reporter assay were performed to validate F-box only protein 31 (FBXO31) as a direct target of miR-29c, and to identify potential transcription factor binding events that control miR-29c expression. The potential of systemic miR-29c oligonucleotide-based therapy in overcoming 5-FU chemoresistance was evaluated in tumor xenograft model. Results: MiR-29c, under the regulatory control of STAT5A, was frequently downregulated in tumor and serum samples of patients with ESCC, and the expression level was correlated with overall survival. Functional studies showed that miR-29c could override 5-FU chemoresistance in vitro and in vivo by directly interacting with the 3'UTR of FBXO31, leading to repression of FBXO31 expression and downstream activation of p38 MAPK. Systemically administered miR-29c dramatically improved response of 5-FU chemoresistant ESCC xenografts in vivo. Conclusions: MiR-29c modulates chemoresistance by interacting with FBXO31, and is a promising non-invasive biomarker and therapeutic target in ESCC.-
dc.languageeng-
dc.publisherIvyspring International Publisher. The Journal's web site is located at http://www.thno.org/-
dc.relation.ispartofTheranostics-
dc.rightsTheranostics. Copyright © Ivyspring International Publisher.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectdiagnosis and prognosis-
dc.subjectchemoresistance-
dc.subjectp38 signaling-
dc.subjectSTAT5A-
dc.subjectmicroRNA therapy-
dc.titleIdentification of miR-29c and its Target FBXO31 as a Key Regulatory Mechanism in Esophageal Cancer Chemoresistance: Functional Validation and Clinical Significance-
dc.typeArticle-
dc.identifier.emailTsao, SW: gswtsao@hku.hk-
dc.identifier.emailChan, KT: ktchan66@hku.hk-
dc.identifier.emailLee, NPY: nikkilee@hku.hk-
dc.identifier.emailLaw, S: slaw@hku.hk-
dc.identifier.emailChan, KW: kwchan@pathology.hku.hk-
dc.identifier.emailGuan, XY: xyguan@hku.hk-
dc.identifier.emailLung, ML: mlilung@hku.hk-
dc.identifier.emailCheung, ALM: lmcheung@hku.hk-
dc.identifier.authorityTsao, SW=rp00399-
dc.identifier.authorityLee, NPY=rp00263-
dc.identifier.authorityLaw, S=rp00437-
dc.identifier.authorityChan, KW=rp00330-
dc.identifier.authorityGuan, XY=rp00454-
dc.identifier.authorityLung, ML=rp00300-
dc.identifier.authorityCheung, ALM=rp00332-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.7150/thno.30372-
dc.identifier.pmid31037126-
dc.identifier.pmcidPMC6485198-
dc.identifier.scopuseid_2-s2.0-85065493868-
dc.identifier.hkuros298162-
dc.identifier.hkuros302815-
dc.identifier.volume9-
dc.identifier.issue6-
dc.identifier.spage1599-
dc.identifier.epage1613-
dc.publisher.placeAustralia-

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