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Article: Deregulated miR-155 promotes Fas-mediated apoptosis in human intervertebral disc degeneration by targeting FADD and caspase-3

TitleDeregulated miR-155 promotes Fas-mediated apoptosis in human intervertebral disc degeneration by targeting FADD and caspase-3
Authors
Keywordsapoptosis
caspase-3
disc degeneration
FADD
miR-155
miRNAs
nucleus pulposus
Issue Date2011
PublisherJohn Wiley & Sons. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/1130
Citation
Journal Of Pathology, 2011, v. 225 n. 2, p. 232-242 How to Cite?
AbstractThe role of apoptosis in the pathogenesis of intervertebral disc degeneration (IDD) remains enigmatic. Accumulating evidence has shown that the apoptotic machinery is regulated by miRNAs. We hypothesized that miRNAs might contribute to apoptosis in IDD. We have found that 29 miRNAs were differentially expressed and miR-155 was down-regulated in degenerative nucleus pulposus (NP). The deregulation of miR-155 was further verified using real-time PCR (0.56 fold, p < 0.05). Bioinformatics target prediction identified FADD and caspase-3 as putative targets of miR-155. Furthermore, miR-155 inhibited FADD and caspase-3 expression by directly targeting their 3′-UTRs, which was abolished by mutation of the miR-155 binding sites. In vitro up-regulation of miR-155 in human NP cells by transfection with lentiviral pre-miR-155 resulted in repression of FADD and caspase-3; whereas knockdown of miR-155 with lentiviral antigomiR-155 led to over-expression of FADD and caspase-3. Also, Fas-mediated apoptosis was increased when antagonizing miR-155 and decreased when using pre-miR-155 in human NP cells. In addition, we presented direct evidence of NP cells undergoing apoptosis in IDD tissues using transmission electron microscopy analysis. Moreover, a combination of in situ hybridization (ISH) and immunohistochemistry (IHC) revealed that miR-155 expressed in the cytoplasm of human NP cells with reverse correlation with FADD and caspase-3. In summary, this is the first study addressing the underlying mechanisms of IDD in terms of apoptosis and miRNAs. Furthermore, caspase-3 is identified as a novel target of miR-155. Our results suggest that deregulated miR-155 promotes Fas-mediated apoptosis in human IDD by targeting FADD and caspase-3, implicating an aetiological and therapeutic role of miR-155 in IDD. Copyright © 2011 Pathological Society of Great Britain and Ireland. Copyright © 2011 Pathological Society of Great Britain and Ireland.
Persistent Identifierhttp://hdl.handle.net/10722/137446
ISSN
2014 Impact Factor: 7.429
ISI Accession Number ID
Funding AgencyGrant Number
Chinese National Natural Science Foundation30901509
30770571
30973052
Key Technologies R&D Programme of Shaanxi Province2008K10-02
Chinese National Basic Research Program2009CB521700
Funding Information:

This study was supported by the Chinese National Natural Science Foundation (Grant Nos 30901509, 30770571 and 30973052), the Key Technologies R&D Programme of Shaanxi Province (Grant No. 2008K10-02) and the Chinese National Basic Research Program (Grant No. 2009CB521700). We thank Dr Yan-Yan Wei for her assistance in ISH and IHC staining; our clinical staff for helping obtain specimens; our office secretary Dan Geng for her coordination of the experimentation; laboratory members Li-Feng Lan, Jie Wu and Jing Li for their assistance in the experimentation; and Kang Chen Bio-tech (Shanghai, China) for their skillful assistance on microRNA microarray.

References

 

DC FieldValueLanguage
dc.contributor.authorWang, HQen_HK
dc.contributor.authorYu, XDen_HK
dc.contributor.authorLiu, ZHen_HK
dc.contributor.authorCheng, Xen_HK
dc.contributor.authorSamartzis, Den_HK
dc.contributor.authorJia, LTen_HK
dc.contributor.authorWu, SXen_HK
dc.contributor.authorHuang, Jen_HK
dc.contributor.authorChen, Jen_HK
dc.contributor.authorLuo, ZJen_HK
dc.date.accessioned2011-08-26T14:25:18Z-
dc.date.available2011-08-26T14:25:18Z-
dc.date.issued2011en_HK
dc.identifier.citationJournal Of Pathology, 2011, v. 225 n. 2, p. 232-242en_HK
dc.identifier.issn0022-3417en_HK
dc.identifier.urihttp://hdl.handle.net/10722/137446-
dc.description.abstractThe role of apoptosis in the pathogenesis of intervertebral disc degeneration (IDD) remains enigmatic. Accumulating evidence has shown that the apoptotic machinery is regulated by miRNAs. We hypothesized that miRNAs might contribute to apoptosis in IDD. We have found that 29 miRNAs were differentially expressed and miR-155 was down-regulated in degenerative nucleus pulposus (NP). The deregulation of miR-155 was further verified using real-time PCR (0.56 fold, p < 0.05). Bioinformatics target prediction identified FADD and caspase-3 as putative targets of miR-155. Furthermore, miR-155 inhibited FADD and caspase-3 expression by directly targeting their 3′-UTRs, which was abolished by mutation of the miR-155 binding sites. In vitro up-regulation of miR-155 in human NP cells by transfection with lentiviral pre-miR-155 resulted in repression of FADD and caspase-3; whereas knockdown of miR-155 with lentiviral antigomiR-155 led to over-expression of FADD and caspase-3. Also, Fas-mediated apoptosis was increased when antagonizing miR-155 and decreased when using pre-miR-155 in human NP cells. In addition, we presented direct evidence of NP cells undergoing apoptosis in IDD tissues using transmission electron microscopy analysis. Moreover, a combination of in situ hybridization (ISH) and immunohistochemistry (IHC) revealed that miR-155 expressed in the cytoplasm of human NP cells with reverse correlation with FADD and caspase-3. In summary, this is the first study addressing the underlying mechanisms of IDD in terms of apoptosis and miRNAs. Furthermore, caspase-3 is identified as a novel target of miR-155. Our results suggest that deregulated miR-155 promotes Fas-mediated apoptosis in human IDD by targeting FADD and caspase-3, implicating an aetiological and therapeutic role of miR-155 in IDD. Copyright © 2011 Pathological Society of Great Britain and Ireland. Copyright © 2011 Pathological Society of Great Britain and Ireland.en_HK
dc.languageengen_US
dc.publisherJohn Wiley & Sons. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/1130en_HK
dc.relation.ispartofJournal of Pathologyen_HK
dc.rightsJournal of Pathology. Copyright © John Wiley & Sons.-
dc.subjectapoptosisen_HK
dc.subjectcaspase-3en_HK
dc.subjectdisc degenerationen_HK
dc.subjectFADDen_HK
dc.subjectmiR-155en_HK
dc.subjectmiRNAsen_HK
dc.subjectnucleus pulposusen_HK
dc.titleDeregulated miR-155 promotes Fas-mediated apoptosis in human intervertebral disc degeneration by targeting FADD and caspase-3en_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0022-3417&volume=225&issue=2&spage=232–242&epage=&date=2011&atitle=Deregulated+miR-155+promotes+Fas-mediated+apoptosis+in+human+intervertebral+disc+degeneration+by+targeting+FADD+and+caspase-3-
dc.identifier.emailSamartzis, D:dspine@hku.hken_HK
dc.identifier.authoritySamartzis, D=rp01430en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/path.2931en_HK
dc.identifier.pmid21706480en_HK
dc.identifier.scopuseid_2-s2.0-80052460614en_HK
dc.identifier.hkuros189129en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-80052460614&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume225en_HK
dc.identifier.issue2en_HK
dc.identifier.spage232en_HK
dc.identifier.epage242en_HK
dc.identifier.isiWOS:000295393400011-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridWang, HQ=12802248100en_HK
dc.identifier.scopusauthoridYu, XD=54394720500en_HK
dc.identifier.scopusauthoridLiu, ZH=35763861500en_HK
dc.identifier.scopusauthoridCheng, X=36717336900en_HK
dc.identifier.scopusauthoridSamartzis, D=34572771100en_HK
dc.identifier.scopusauthoridJia, LT=35285828400en_HK
dc.identifier.scopusauthoridWu, SX=35369666600en_HK
dc.identifier.scopusauthoridHuang, J=14067403800en_HK
dc.identifier.scopusauthoridChen, J=26643412500en_HK
dc.identifier.scopusauthoridLuo, ZJ=8510080000en_HK

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