masaldan-alterationsinmicro-2015.pdf (2.29 MB)
Alterations in microRNAs miR-21 and let-7a correlate with aberrant STAT3 signaling and downstream effects during cervical carcinogenesis
journal contribution
posted on 2015-01-01, 00:00 authored by G Shishodia, S Shukla, Y Srivastava, Shashank Masaldan, S Mehta, S Bhambhani, S Sharma, R Mehrotra, B C Das, A C BhartiBACKGROUND: Present study provides clinical evidence of existence of a functional loop involving miR-21 and let-7a as potential regulators of aberrant STAT3 signaling recently reported by our group in an experimental setup (Shishodia et al. BMC Cancer 2014, 14:996). The study is now extended to a set of cervical tissues that represent natural history of human papillomavirus (HPV)-induced tumorigenic transformation. MATERIALS AND METHODS: Cervical tissues from histopathologically-confirmed pre-cancer (23) and cancer lesions (56) along with the normal control tissues (23) were examined for their HPV infection status, expression level of miR-21 & let-7a and STAT3 & pSTAT3 (Y705) by PCR-based genotyping, quantitative real-time PCR and immunoblotting. RESULTS: Analysis of cancer tissues revealed an elevated miR-21 and reduced let-7a expression that correspond to the level of STAT3 signaling. While miR-21 showed direct association, let-7a expression was inversely related to STAT3 expression and its activation. In contrast, a similar reciprocal expression kinetics was absent in LSIL and HSIL tissues which overexpressed let-7a. miR-21 was found differentially overexpressed in HPV16-positive lesions with a higher oncoprotein E6 level. Overexpression of miR-21 was accompanied by elevated level of other STAT3-regulated gene products MMP-2 and MMP-9. Enhanced miR-21 was found associated with decreased level of STAT3 negative regulator PTEN and negative regulator of MMPs, TIMP-3. CONCLUSION: Overall, our study suggests that the microRNAs, miR-21 and let-7a function as clinically relevant integral components of STAT3 signaling and are responsible for maintaining activated state of STAT3 in HPV-infected cells during cervical carcinogenesis.
History
Journal
Molecular cancerVolume
14Pagination
116 - 129Publisher
BioMed CentralLocation
London, Eng.Publisher DOI
ISSN
1476-4598eISSN
1476-4598Language
engPublication classification
C Journal article; C1.1 Refereed article in a scholarly journalCopyright notice
2015, The AuthorsUsage metrics
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No categories selectedKeywords
BiopsyCarcinogenesisCell Line, TumorCervix UteriFemaleGene Expression ProfilingGene Expression Regulation, NeoplasticHuman papillomavirus 16HumansMicroRNAsModels, BiologicalOncogene Proteins, ViralPhosphorylationRNA, MessengerRepressor ProteinsSTAT3 Transcription FactorSignal TransductionUterine Cervical NeoplasmsScience & TechnologyLife Sciences & BiomedicineBiochemistry & Molecular BiologyOncologyHPVLSILHSILCervical cancerSTAT3pSTAT3miR-21let-7aMMPsPTENTIMP-3HUMAN-PAPILLOMAVIRUS INFECTIONSQUAMOUS-CELL CARCINOMANF-KAPPA-BONCOSTATIN-MCONSTITUTIVE ACTIVATIONTISSUE INHIBITORGENE-EXPRESSIONTRANSCRIPTION 3CANCER CELLSTRANSDUCER
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