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Mol Cancer. 2015 Jun 9;14:116. doi: 10.1186/s12943-015-0385-2.

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

Author information

1
Division of Molecular Oncology, Institute of Cytology and Preventive Oncology, I - 7, Sector -39, Noida, 201301, Uttar Pradesh, India. gaurishishodia@gmail.com.
2
Dr. B.R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, 110007, New Delhi, India. gaurishishodia@gmail.com.
3
Present Address: Louisiana State University Health Sciences Center, Shreveport, LA, USA. gaurishishodia@gmail.com.
4
Division of Molecular Oncology, Institute of Cytology and Preventive Oncology, I - 7, Sector -39, Noida, 201301, Uttar Pradesh, India. shirishshukla31@gmail.com.
5
Present Address: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA. shirishshukla31@gmail.com.
6
Division of Molecular Oncology, Institute of Cytology and Preventive Oncology, I - 7, Sector -39, Noida, 201301, Uttar Pradesh, India. yansh111@gmail.com.
7
Division of Molecular Oncology, Institute of Cytology and Preventive Oncology, I - 7, Sector -39, Noida, 201301, Uttar Pradesh, India. masaldan@gmail.com.
8
Department of Obstetrics and Gynecology, University College of Medical Sciences and Associated Guru Teg Bahadur Hospital, Shahdara, Delhi, New Delhi, India. sumitadr@gmail.com.
9
Division of Cytopathology, Institute of Cytology and Preventive Oncology, I - 7, Sector - 39, Noida, 201301, Uttar Pradesh, India. sureshib@yahoo.com.
10
Division of Epidemiology and Biostatistics, Institute of Cytology and Preventive Oncology, I - 7, Sector -39, Noida, 201301, Uttar Pradesh, India. datta582002@yahoo.co.in.
11
Division of Cytopathology, Institute of Cytology and Preventive Oncology, I - 7, Sector - 39, Noida, 201301, Uttar Pradesh, India. rm8509@gmail.com.
12
Dr. B.R. Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, 110007, New Delhi, India. bcdas48@hotmail.com.
13
Division of Molecular Oncology, Institute of Cytology and Preventive Oncology, I - 7, Sector -39, Noida, 201301, Uttar Pradesh, India. alokchandrab@yahoo.com.

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.

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.

PMID:
26051842
PMCID:
PMC4459448
DOI:
10.1186/s12943-015-0385-2
[Indexed for MEDLINE]
Free PMC Article

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