Level of phospho-STAT3 (Tyr705) correlates with copy number and physical state of human papillomavirus 16 genome in cervical precancer and cancer lesions

Shirish Shukla; Mohit Jadli; Kulbhushan Thakur; Gauri Shishodia; Sutapa Mahata; Seemi Farhat Basir; Bhudev Chandra Das; Alok Chandra Bharti

doi:10.1371/journal.pone.0222089

Level of phospho-STAT3 (Tyr705) correlates with copy number and physical state of human papillomavirus 16 genome in cervical precancer and cancer lesions

PLoS One. 2019 Sep 5;14(9):e0222089. doi: 10.1371/journal.pone.0222089. eCollection 2019.

Authors

Shirish Shukla¹, Mohit Jadli², Kulbhushan Thakur², Gauri Shishodia¹, Sutapa Mahata¹, Seemi Farhat Basir³, Bhudev Chandra Das⁴, Alok Chandra Bharti^{1

2}

Affiliations

¹ Division of Molecular Oncology, National Institute of Cancer Prevention and Research Noida, Uttar Pradesh, India.
² Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India.
³ Department of Biosciences, Jamia Millia Islamia, New Delhi, India.
⁴ Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR) Amity University, Noida, Uttar Pradesh, India.

Abstract

Our earlier studies indicated an important role of inducible transcription factor STAT3 in the establishment of persistent infection of human papillomavirus (HPV) type 16 and promotion of cervical carcinogenesis. Since HPV load and its physical state are two potential determinants of this virally-induced carcinogensis, though with some exceptions, we extended our study to examine the role of active STAT3 level in cervical precancer and cancer lesions and it's association with HPV viral load and physical state. An elevated level of active STAT3 was measured by assessing phospho-STAT3-Y705 (pSTAT3), in tumor tissues harboring higher viral load irrespective of the disease grade. Physical state analysis of HPV16 by assessing the degree of amplification of full length E2 and comparing it with E6 (E2:E6 ratio), which predominantly represent episomal form of HPV16, revealed low or undetectable pSTAT3. A strong pSTAT3 immunoreactivity was found in tissues those harbored either mixed or predominantly integrated form of viral genome. Cumulative analysis of pSTAT3 expression, viral load and physical state demonstrated a direct correlation between pSTAT3 expression, viral load and physical state of HPV. The study suggests that there exists a strong clinical correlation between level of active STAT3 expression and HPV genome copy number, and integrated state of the virus that may play a pivotal role in promotion/maintanence of tumorigenic phenotype.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

DNA Copy Number Variations*
DNA, Viral / genetics
Female
Genome, Viral*
Human papillomavirus 16 / isolation & purification
Humans
Middle Aged
Papillomavirus Infections / complications*
Papillomavirus Infections / virology
Phosphorylation
Precancerous Conditions / genetics
Precancerous Conditions / metabolism
Precancerous Conditions / pathology*
Precancerous Conditions / virology
Prognosis
STAT3 Transcription Factor / genetics
STAT3 Transcription Factor / metabolism*
Uterine Cervical Dysplasia / genetics
Uterine Cervical Dysplasia / metabolism
Uterine Cervical Dysplasia / pathology*
Uterine Cervical Dysplasia / virology
Uterine Cervical Neoplasms / genetics
Uterine Cervical Neoplasms / metabolism
Uterine Cervical Neoplasms / pathology*
Uterine Cervical Neoplasms / virology
Viral Load
Virus Integration

Substances

DNA, Viral
STAT3 Transcription Factor
STAT3 protein, human

Grants and funding

The study was supported by research grants from ICMR (sanction no.- 5/13/38/2014-NCD-III), and DST-SERB (EMR/2017/004018), and DBT extramural grant (6242-P34/RGCB/PMD/DBT/ALCB/2015) to ACB & ICMR-Senior Research Fellowship to MJ (3/2/2/278/2014-NCD III). Intramural funding from Delhi University (DST – PURSE Phase II/RC/2016/944) and ICMR to ACB is also acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.