Alterations in microRNAs miR-21 and let-7a correlate with aberrant STAT3 signaling and downstream effects during cervical carcinogenesis

Shishodia, Gauri, Shukla, Shirish, Srivastava, Yogesh, Masaldan, Shashank, Mehta, Sumita, Bhambhani, Suresh, Sharma, Shashi, Mehrotra, Ravi, Das, Bhudev Chandra and Bharti, Alok Chandra 2015, Alterations in microRNAs miR-21 and let-7a correlate with aberrant STAT3 signaling and downstream effects during cervical carcinogenesis, Molecular cancer, vol. 14, pp. 116-129, doi: 10.1186/s12943-015-0385-2.

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Title Alterations in microRNAs miR-21 and let-7a correlate with aberrant STAT3 signaling and downstream effects during cervical carcinogenesis
Author(s) Shishodia, Gauri
Shukla, Shirish
Srivastava, Yogesh
Masaldan, ShashankORCID iD for Masaldan, Shashank
Mehta, Sumita
Bhambhani, Suresh
Sharma, Shashi
Mehrotra, Ravi
Das, Bhudev Chandra
Bharti, Alok Chandra
Journal name Molecular cancer
Volume number 14
Start page 116
End page 129
Total pages 13
Publisher BioMed Central
Place of publication London, Eng.
Publication date 2015
ISSN 1476-4598
Keyword(s) Biopsy
Cell Line, Tumor
Cervix Uteri
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Human papillomavirus 16
Models, Biological
Oncogene Proteins, Viral
RNA, Messenger
Repressor Proteins
STAT3 Transcription Factor
Signal Transduction
Uterine Cervical Neoplasms
Summary BACKGROUND: 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.
Language eng
DOI 10.1186/s12943-015-0385-2
Field of Research 060199 Biochemistry and Cell Biology not elsewhere classified
1112 Oncology And Carcinogenesis
Socio Economic Objective 920102 Cancer and Related Disorders
HERDC Research category C1.1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2015, The Authors
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