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Article: Epigenetic silencing of microRNA-199b-5p is associated with acquired chemoresistance via activation of JAG1-Notch1 signaling in ovarian cancer.

TitleEpigenetic silencing of microRNA-199b-5p is associated with acquired chemoresistance via activation of JAG1-Notch1 signaling in ovarian cancer.
Authors
Issue Date2014
PublisherImpact Journals LLC. The Journal's web site is located at http://www.impactjournals.com/oncotarget/index.html
Citation
Oncotarget, 2014, v. 5 n. 4, p. 944-958 How to Cite?
AbstractEpithelial ovarian cancer is a highly lethal and aggressive gynecological malignancy. The high mortality rate is due in part to the fact that many advanced cancer patients become refractory to current chemotherapeutic agents, leading to tumor recurrence and death. However, the underlying mechanisms leading to chemoresistance remain obscure. Here, we report that the loss of miR-199b-5p due to progressive epigenetic silencing leads to the activation of the JAG1-mediated Notch1 signaling cascade, thereby leading to the development of acquired chemoresistance in ovarian cancer. Using miRCURY LNATM microRNA array and Q-PCR analyses of two pairs of cisplatin-sensitive and -resistant ovarian cancer cell lines, we identified miR-199b-5p as significantly down-regulated in cisplatin-resistant ovarian cancer cells and confirmed that miR-199b-5p is clinically associated with advanced and poor survival ovarian cancers. Interestingly, the loss of miR-199b-5p could be restored by 5-Aza-dC-mediated demethylation, and methylated specific PCR (MS-PCR), bisulfite-sequencing and pyrosequencing revealed that the promoter region of miR-199b-5p was hypermethylated. Computational and mechanistic analyses identified JAG1 as a primary target of miR-199b-5p. Notably, the reduced expression of miR-199b-5p was found to be inversely correlated with the increased expression of JAG1 using an ovarian cancer tissue array. Enforced expression of miR-199b-5p sensitized ovarian cancer cells to cisplatin-induced cytotoxicity both in vitro and in vivo. Conversely, re-expression of miR-199b-5p and siRNA-mediated JAG1 knockdown or treatment with Notch specific inhibitor γ-secretase (GSI) attenuated JAG1-Notch1 signaling activity, thereby enhancing cisplatin-mediated cell cytotoxicity. Taken together, our study suggests that the epigenetic silencing of miR-199b-5p during tumor progression is significantly associated with acquired chemoresistance in ovarian cancer through the activation of JAG1-Notch1 signaling.
Persistent Identifierhttp://hdl.handle.net/10722/197655
ISSN
2015 Impact Factor: 5.008
2015 SCImago Journal Rankings: 2.294
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLiu, Xen_US
dc.contributor.authorSiu, KYen_US
dc.contributor.authorLiu, Sen_US
dc.contributor.authorYam, JWPen_US
dc.contributor.authorNgan, HYSen_US
dc.contributor.authorChan, DWen_US
dc.date.accessioned2014-05-29T08:36:50Z-
dc.date.available2014-05-29T08:36:50Z-
dc.date.issued2014en_US
dc.identifier.citationOncotarget, 2014, v. 5 n. 4, p. 944-958en_US
dc.identifier.issn1949-2553en_US
dc.identifier.urihttp://hdl.handle.net/10722/197655-
dc.description.abstractEpithelial ovarian cancer is a highly lethal and aggressive gynecological malignancy. The high mortality rate is due in part to the fact that many advanced cancer patients become refractory to current chemotherapeutic agents, leading to tumor recurrence and death. However, the underlying mechanisms leading to chemoresistance remain obscure. Here, we report that the loss of miR-199b-5p due to progressive epigenetic silencing leads to the activation of the JAG1-mediated Notch1 signaling cascade, thereby leading to the development of acquired chemoresistance in ovarian cancer. Using miRCURY LNATM microRNA array and Q-PCR analyses of two pairs of cisplatin-sensitive and -resistant ovarian cancer cell lines, we identified miR-199b-5p as significantly down-regulated in cisplatin-resistant ovarian cancer cells and confirmed that miR-199b-5p is clinically associated with advanced and poor survival ovarian cancers. Interestingly, the loss of miR-199b-5p could be restored by 5-Aza-dC-mediated demethylation, and methylated specific PCR (MS-PCR), bisulfite-sequencing and pyrosequencing revealed that the promoter region of miR-199b-5p was hypermethylated. Computational and mechanistic analyses identified JAG1 as a primary target of miR-199b-5p. Notably, the reduced expression of miR-199b-5p was found to be inversely correlated with the increased expression of JAG1 using an ovarian cancer tissue array. Enforced expression of miR-199b-5p sensitized ovarian cancer cells to cisplatin-induced cytotoxicity both in vitro and in vivo. Conversely, re-expression of miR-199b-5p and siRNA-mediated JAG1 knockdown or treatment with Notch specific inhibitor γ-secretase (GSI) attenuated JAG1-Notch1 signaling activity, thereby enhancing cisplatin-mediated cell cytotoxicity. Taken together, our study suggests that the epigenetic silencing of miR-199b-5p during tumor progression is significantly associated with acquired chemoresistance in ovarian cancer through the activation of JAG1-Notch1 signaling.en_US
dc.languageengen_US
dc.publisherImpact Journals LLC. The Journal's web site is located at http://www.impactjournals.com/oncotarget/index.htmlen_US
dc.relation.ispartofOncotargeten_US
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.titleEpigenetic silencing of microRNA-199b-5p is associated with acquired chemoresistance via activation of JAG1-Notch1 signaling in ovarian cancer.en_US
dc.typeArticleen_US
dc.identifier.emailSiu, KY: mkysiu@hkucc.hku.hken_US
dc.identifier.emailLiu, S: stephasl@hku.hken_US
dc.identifier.emailYam, JWP: judyyam@pathology.hku.hken_US
dc.identifier.emailNgan, HYS: hysngan@hkucc.hku.hken_US
dc.identifier.emailChan, DW: dwchan@hku.hken_US
dc.identifier.authoritySiu, KY=rp00275en_US
dc.identifier.authorityLiu, S=rp00372en_US
dc.identifier.authorityYam, JWP=rp00468en_US
dc.identifier.authorityNgan, HYS=rp00346en_US
dc.identifier.authorityChan, DW=rp00543en_US
dc.description.naturepublished_or_final_version-
dc.identifier.pmid24659709-
dc.identifier.pmcidPMC401159-
dc.identifier.hkuros228887en_US
dc.identifier.hkuros232568-
dc.identifier.volume5en_US
dc.identifier.spage944en_US
dc.identifier.epage958en_US
dc.identifier.isiWOS:000336962300009-
dc.publisher.placeUnited Statesen_US

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