Abstract
BackgroundRecent observations indicate potential role of transcription factor STAT3 in cervical cancer development but its role specifically with respect to HPV infection is not known. Present study has been designed to investigate expression and activation of STAT3 in cervical precancer and cancer in relation to HPV infection during cervical carcinogenesis. Established cervical cancer cell lines and prospectively-collected cervical precancer and cancer tissues were analyzed for the HPV positivity and evaluated for STAT3 expression and its phosphorylation by immunoblotting and immunohistochemistry whereas STAT3-specific DNA binding activity was examined by gel-shift assays.ResultsAnalysis of 120 tissues from cervical precancer and cancer lesions or from normal cervix revealed differentially high levels of constitutively active STAT3 in cervical precancer and cancer lesions, whereas it was absent in normal controls. Similarly, a high level of constitutively active STAT3 expression was observed in HPV-positive cervical cancer cell lines when compared to that of HPV-negative cells. Expression and activity of STAT3 were found to change as a function of severity of cervical lesions from precancer to cancer. Expression of active pSTAT3 was specifically high in cervical precancer and cancer lesions found positive for HPV16. Interestingly, site-specific accumulation of STAT3 was observed in basal and suprabasal layers of HPV16-positive early precancer lesions which is indicative of possible involvement of STAT3 in establishment of HPV infection. In HPV16-positive cases, STAT3 expression and activity were distinctively higher in poorly-differentiated lesions with advanced histopathological grades.ConclusionWe demonstrate that in the presence of HPV16, STAT3 is aberrantly-expressed and constitutively-activated in cervical cancer which increases as the lesion progresses thus indicating its potential role in progression of HPV16-mediated cervical carcinogenesis.
Highlights
Recent observations indicate potential role of transcription factor Signal transducer and activator of transcription 3 (STAT3) in cervical cancer development but its role with respect to human papillomavirus (HPV) infection is not known
Established cervical cancer cell lines (C33a, SiHa, CaSki, HeLa) and 100 prospectively collected biopsies from precancer and cancer lesions and 20 control specimens from histopathologically-confirmed, normal hysterectomized cervix were examined for presence of HPV infection as well as expression and activation of STAT3
Detection of HPV DNA sequences in cervical precancer and cancer tissues To determine the status of HPV infection and distribution of HPV16/18 types in study samples, HPV L1 and type-specific PCRs were performed as described in Methods
Summary
Recent observations indicate potential role of transcription factor STAT3 in cervical cancer development but its role with respect to HPV infection is not known. Present study has been designed to investigate expression and activation of STAT3 in cervical precancer and cancer in relation to HPV infection during cervical carcinogenesis. Despite availability of two HPV vaccines directed against HPV16 and HPV18 for control of cervical cancer [7] that have been licensed for clinical application in several countries including India, it is difficult to control HPV infection through vaccination. These vaccines are not just expensive but are only prophylactic in nature and do not possess any therapeutic efficacy. For effective therapeutic intervention of HPV and to prevent cervical cancer development at an early stage, it is essential to improve understanding of molecular mechanisms involved in HPV-mediated cervical carcinogenesis
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