title: Alterations in microRNAs miR-21 and let-7a correlate with aberrant STAT3 signaling and downstream effects during cervical carcinogenesis.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Molecular Oncology, Institute of Cytology and Preventive Oncology, I - 7, Sector -39, Noida, 201301, Uttar Pradesh, India. gaurishishodia@gmail.com.|Dr. B.R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, 110007, New Delhi, India. gaurishishodia@gmail.com.|Present Address: Louisiana State University Health Sciences Center, Shreveport, LA, USA. gaurishishodia@gmail.com.
authors.forename: Gauri
authors.initials: G
authors.lastname: Shishodia
authors.affiliation: Division of Molecular Oncology, Institute of Cytology and Preventive Oncology, I - 7, Sector -39, Noida, 201301, Uttar Pradesh, India. shirishshukla31@gmail.com.|Present Address: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA. shirishshukla31@gmail.com.
authors.forename: Shirish
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Division of Molecular Oncology, Institute of Cytology and Preventive Oncology, I - 7, Sector -39, Noida, 201301, Uttar Pradesh, India. yansh111@gmail.com.
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Srivastava
authors.affiliation: Division of Molecular Oncology, Institute of Cytology and Preventive Oncology, I - 7, Sector -39, Noida, 201301, Uttar Pradesh, India. masaldan@gmail.com.
authors.forename: Shashank
authors.initials: S
authors.lastname: Masaldan
authors.affiliation: Department of Obstetrics and Gynecology, University College of Medical Sciences and Associated Guru Teg Bahadur Hospital, Shahdara, Delhi, New Delhi, India. sumitadr@gmail.com.
authors.forename: Sumita
authors.initials: S
authors.lastname: Mehta
authors.affiliation: Division of Cytopathology, Institute of Cytology and Preventive Oncology, I - 7, Sector - 39, Noida, 201301, Uttar Pradesh, India. sureshib@yahoo.com.
authors.forename: Suresh
authors.initials: S
authors.lastname: Bhambhani
authors.affiliation: Division of Epidemiology and Biostatistics, Institute of Cytology and Preventive Oncology, I - 7, Sector -39, Noida, 201301, Uttar Pradesh, India. datta582002@yahoo.co.in.
authors.forename: Shashi
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Division of Cytopathology, Institute of Cytology and Preventive Oncology, I - 7, Sector - 39, Noida, 201301, Uttar Pradesh, India. rm8509@gmail.com.
authors.forename: Ravi
authors.initials: R
authors.lastname: Mehrotra
authors.affiliation: Dr. B.R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, 110007, New Delhi, India. bcdas48@hotmail.com.
authors.forename: Bhudev Chandra
authors.initials: BC
authors.lastname: Das
authors.affiliation: Division of Molecular Oncology, Institute of Cytology and Preventive Oncology, I - 7, Sector -39, Noida, 201301, Uttar Pradesh, India. alokchandrab@yahoo.com.
authors.forename: Alok Chandra
authors.initials: AC
authors.lastname: Bharti
mesh_terms: D001706:Biopsy; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002584:Cervix Uteri / Q000378:metabolism / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052162:Human papillomavirus 16; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D009856:Oncogene Proteins, Viral; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: C068651:E6 protein, Human papillomavirus type 16; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D009856:Oncogene Proteins, Viral; D012333:RNA, Messenger; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C487931:mirnlet7 microRNA, human