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Aberrant expression and constitutive activation of STAT3 in cervical carcinogenesis: implications in high-risk human papillomavirus infection.

Shukla S, Shishodia G, Mahata S, Hedau S, Pandey A, Bhambhani S, Batra S, Basir SF, Das BC, Bharti AC - Mol. Cancer (2010)

Bottom Line: 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.In HPV16-positive cases, STAT3 expression and activity were distinctively higher in poorly-differentiated lesions with advanced histopathological grades.We 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Molecular Oncology, Institute of Cytology & Preventive Oncology, I-7, Sector-39, NOIDA, U.P., India.

ABSTRACT

Background: Recent 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.

Results: Analysis 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.

Conclusion: We 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.

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Localized overexpression of STAT3 and pSTAT3 in basal layer of early precancer lesions positive for HPV16. Immunohistochemical analysis of STAT3, pSTAT3(Y705) and pSTAT3(S727) expression in HPV negative and HPV16 positive LSILs. White arrows indicate absence of STAT3 expression in basal layer of HPV negative lesions. STAT3 and pSTAT3 showed focal positivity and were localized in the nuclei in HPV16 positive LSIL tissues (marked by black arrows).
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Figure 4: Localized overexpression of STAT3 and pSTAT3 in basal layer of early precancer lesions positive for HPV16. Immunohistochemical analysis of STAT3, pSTAT3(Y705) and pSTAT3(S727) expression in HPV negative and HPV16 positive LSILs. White arrows indicate absence of STAT3 expression in basal layer of HPV negative lesions. STAT3 and pSTAT3 showed focal positivity and were localized in the nuclei in HPV16 positive LSIL tissues (marked by black arrows).

Mentions: To analyze the effect of HPV16 infection on STAT3 expression and activity in different stages of cervical carcinogenesis, the STAT3/pSTAT3 immunoblotting data of precancer and cancer lesions were reanalyzed with respect to the status of HPV infection in the respective lesion. As shown in Table 2, HPV16+ cervical precancer and cancer tissues expressed a higher level of STAT3 and pSTAT3(Y705) as compared to that in the HPV- precancer and cancer lesions. One precancer (HSIL) and 7 carcinoma samples that were HPV L1+ but HPV16- were excluded from the analysis to avoid HPV type as a confounding variable. Nonetheless, these tissues also showed similar over-expression of active pSTAT3/STAT3. Majority of HPV- precancer, cancer and normal tissues lacked expression of STAT3 and pSTAT3 while only a small number of HPV16+ precancers (n = 6/16; 37%) and cancers (n = 12/58; 21%) had no or low STAT3 expression. Interestingly, immunohistochemical analysis of precancer lesions particularly of LSILs showed a focal positivity of STAT3 and when these cases were analyzed with respect to their HPV16 status they showed a low background staining with no nuclear positivity for STAT3 as well as pSTAT3 in HPV negative LSIL sections (Figure 4). In contrast, HPV16 positive LSIL sections revealed a strong focal positivity and nuclear localization of both STAT3 and pSTAT3 (Y705 & S727) in basal and suprabasal cell layers of cervical epithelium.


Aberrant expression and constitutive activation of STAT3 in cervical carcinogenesis: implications in high-risk human papillomavirus infection.

Shukla S, Shishodia G, Mahata S, Hedau S, Pandey A, Bhambhani S, Batra S, Basir SF, Das BC, Bharti AC - Mol. Cancer (2010)

Localized overexpression of STAT3 and pSTAT3 in basal layer of early precancer lesions positive for HPV16. Immunohistochemical analysis of STAT3, pSTAT3(Y705) and pSTAT3(S727) expression in HPV negative and HPV16 positive LSILs. White arrows indicate absence of STAT3 expression in basal layer of HPV negative lesions. STAT3 and pSTAT3 showed focal positivity and were localized in the nuclei in HPV16 positive LSIL tissues (marked by black arrows).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2984472&req=5

Figure 4: Localized overexpression of STAT3 and pSTAT3 in basal layer of early precancer lesions positive for HPV16. Immunohistochemical analysis of STAT3, pSTAT3(Y705) and pSTAT3(S727) expression in HPV negative and HPV16 positive LSILs. White arrows indicate absence of STAT3 expression in basal layer of HPV negative lesions. STAT3 and pSTAT3 showed focal positivity and were localized in the nuclei in HPV16 positive LSIL tissues (marked by black arrows).
Mentions: To analyze the effect of HPV16 infection on STAT3 expression and activity in different stages of cervical carcinogenesis, the STAT3/pSTAT3 immunoblotting data of precancer and cancer lesions were reanalyzed with respect to the status of HPV infection in the respective lesion. As shown in Table 2, HPV16+ cervical precancer and cancer tissues expressed a higher level of STAT3 and pSTAT3(Y705) as compared to that in the HPV- precancer and cancer lesions. One precancer (HSIL) and 7 carcinoma samples that were HPV L1+ but HPV16- were excluded from the analysis to avoid HPV type as a confounding variable. Nonetheless, these tissues also showed similar over-expression of active pSTAT3/STAT3. Majority of HPV- precancer, cancer and normal tissues lacked expression of STAT3 and pSTAT3 while only a small number of HPV16+ precancers (n = 6/16; 37%) and cancers (n = 12/58; 21%) had no or low STAT3 expression. Interestingly, immunohistochemical analysis of precancer lesions particularly of LSILs showed a focal positivity of STAT3 and when these cases were analyzed with respect to their HPV16 status they showed a low background staining with no nuclear positivity for STAT3 as well as pSTAT3 in HPV negative LSIL sections (Figure 4). In contrast, HPV16 positive LSIL sections revealed a strong focal positivity and nuclear localization of both STAT3 and pSTAT3 (Y705 & S727) in basal and suprabasal cell layers of cervical epithelium.

Bottom Line: 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.In HPV16-positive cases, STAT3 expression and activity were distinctively higher in poorly-differentiated lesions with advanced histopathological grades.We 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Molecular Oncology, Institute of Cytology & Preventive Oncology, I-7, Sector-39, NOIDA, U.P., India.

ABSTRACT

Background: Recent 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.

Results: Analysis 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.

Conclusion: We 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.

Show MeSH
Related in: MedlinePlus