Aberrant expression and constitutive activation of STAT3 in cervical carcinogenesis: implications in high-risk human papillomavirus infection.
Aberrant expression and constitutive activation of STAT3 in cervical carcinogenesis: implications in high-risk human papillomavirus infection.
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DOI：
10.1186/1476-4598-9-282
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发表时间：
2010-10-27
期刊：
影响因子：
37.3
通讯作者：
Bharti AC
中科院分区：
文献类型：
--
作者：
Shukla S;Shishodia G;Mahata S;Hedau S;Pandey A;Bhambhani S;Batra S;Basir SF;Das BC;Bharti AC
最近的观察表明转录因子STAT3在宫颈癌发展中的潜在作用，但其在HPV感染中的具体作用尚不清楚。本研究旨在探讨STAT3在宫颈癌前期和癌中的表达和激活与宫颈癌发生过程中HPV感染的关系。对已建立的宫颈癌细胞系和前瞻性收集的宫颈癌前病变组织和癌组织进行HPV阳性分析，并通过免疫印迹和免疫组织化学评估STAT3的表达及其磷酸化，同时通过凝胶转移法检测STAT3特异性DNA结合活性。对120例宫颈癌前病变和癌灶组织及正常子宫颈组织的分析显示，在宫颈癌前病变和癌灶组织中，组成型活性STAT3水平存在差异，而在正常对照中则不存在。同样，与hpv阴性细胞相比，在hpv阳性宫颈癌细胞系中观察到高水平的组成活性STAT3表达。STAT3的表达和活性随着宫颈病变从癌前病变到癌前病变的严重程度而变化。活跃的pSTAT3在宫颈癌前病变和HPV16癌灶中表达特别高。有趣的是，在hpv16阳性的早期癌前病变的基底和基底上层观察到STAT3的特异位点积累，这表明STAT3可能参与了HPV感染的建立。在hpv16阳性病例中，STAT3的表达和活性在组织病理分级较高的低分化病变中明显较高。我们证明，在HPV16存在的情况下，STAT3在宫颈癌中异常表达和组成性激活，并随着病变的进展而增加，从而表明其在HPV16介导的宫颈癌发生进展中的潜在作用。
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. 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. 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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