title: Functional regulatory role of STAT3 in HPV16-mediated cervical carcinogenesis.
abstract: Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor constitutively active and aberrantly expressed in cervical cancer. However, the functional role of STAT3 in regulation of HPV's viral oncogene expression and downstream events associated with cervical carcinogenesis is not known. Our present study performed on HPV16-positive cervical cancer cell lines (SiHa and CaSki) and primary tumor tissues revealed a strong positive correlation of constitutively active STAT3 with expression of HPV16 E6 and E7 oncoproteins and a negative association with levels of p53 and pRB. Pharmacologic targeting of STAT3 expression in cervical cancer cell lines either by STAT3-specific siRNA or blocking its tyrosine phosphorylation by AG490 or curcumin led to dose-dependent accumulation of p53 and pRb in cervical cancer cells. Interestingly, the suppression of STAT3 expression or activation was associated with the gradual loss of HPV16 E6 and E7 expression and was accompanied by loss of cell viability. The viability loss was specifically high in HPV16-positive cells as compared to HPV negative C33a cells. These findings substantiate the regulatory role of STAT3 in HPV16-mediated cervical carcinogenesis. Leads obtained from the present study provide a strong rationale for developing novel STAT3-based approaches for therapeutic interventions against HPV infection to control cervical cancer.
authors.affiliation: Division of Molecular Oncology, Institute of Cytology and Preventive Oncology, NOIDA, Uttar Pradesh, India.
authors.forename: Shirish
authors.initials: S
authors.lastname: Shukla
authors.forename: Sutapa
authors.initials: S
authors.lastname: Mahata
authors.forename: Gauri
authors.initials: G
authors.lastname: Shishodia
authors.forename: Arvind
authors.initials: A
authors.lastname: Pandey
authors.forename: Abhishek
authors.initials: A
authors.lastname: Tyagi
authors.forename: Kanchan
authors.initials: K
authors.lastname: Vishnoi
authors.forename: Seemi F
authors.initials: SF
authors.lastname: Basir
authors.forename: Bhudev C
authors.initials: BC
authors.lastname: Das
authors.forename: Alok C
authors.initials: AC
authors.lastname: Bharti
mesh_terms: D063646:Carcinogenesis / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D003474:Curcumin; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005434:Flow Cytometry; D015967:Gene Expression Regulation, Viral / Q000235:genetics*; D052162:Human papillomavirus 16; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013778:Tetrazolium Salts; D013844:Thiazoles; D020032:Tyrphostins; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000821:virology*
chemical_list: D009856:Oncogene Proteins, Viral; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013778:Tetrazolium Salts; D013844:Thiazoles; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D053148:Caspase 3; C022616:thiazolyl blue; D003474:Curcumin