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.

Cervical cancer is the major cancer in Indian women and a leading cause of cancer deaths. Every year, more than 130,000 new cases and about 70,000 deaths are recorded. The persistent infection by specific types of high-risk human papillomaviruses (HR-HPVs) is essential for the progression of cervical lesions (6,11,31,60), and women who are infected with HRHPVs are likely to develop cancer (3,4,27,40). Various studies have demonstrated that more than 70% of invasive cervical cancers harbor HPV type 16 (HPV-16) and 31), and the products of viral transforming E6 and E7 genes have been shown to contribute to tumorigenesis by functionally inactivating two important cellular tumor suppressor proteins, p53 and retinoblastoma (5,14,30,55).More than 100 types of HPV are known, but only about 30 types are associated with anogenital cancer. According to the Papillomavirus Nomenclature Committee, a new HPV type is defined by a nucleotide sequence variation of more than 10% compared to that of other known HPV types in the E6, E7, and L1 open reading frames. Those differing by 2 to 10% are referred to as subtypes, whereas intratype variants may vary by up to 2% in the coding region and 5% in the noncoding region compared to that of the prototype (2, 10).On the basis of sequence variations in E6, L1, L2, and the long control region (LCR), HPV-16 variants have been identified and grouped into six distinct phylogenetic branches: E (European), AA (Asian-American), Af1 (African 1), Af2 (African 2), As (Asian), and NA (North American) (54, 56, 57). These variants have been found to show different geographic distributions, with various oncogenic potentials. A number of sequence variations have been reported for HPV-16 E6, E7, and L1 genes as well as in the LCR in cervical cancer (33,39,48,55,56). Studies also have shown that specific intratype variants may influence the persistence of HPV infection and the progression of precursor lesions to cancer (27,58,59). HPV variants also may affect virus assembly, immunologic responses, pathogenicity, p53 degradation, immortalization activity, and the regulation of transcription (15,18,24,25,37,51). These variations immediately affect the sensitivity and specificity of different PCR-based genotype diagnostic methods.Of the two HPV-16 oncogenes E6 and E7, E6 has been found to show more variations than E7, which is relatively conserved (48,50,56,58,59). The analysis of the L1 gene, which codes for the viral major capsid protein, is of immense importance because of its high diagnostic value. The range of intratype variation observed in this region allows the distinction and assessment of known and novel HPV types (46). This is also an important target for the development of HPV vaccines.

Visual inspection of the cervix with acetic acid is very sensitive for ectocervical lesions. The advantages of the VIA method are its low cost and ease of use (it can be used by paramedical workers), its high sensitivity and its immediate results (it is possible to "see and treat" at the first visit). Its main limitation is a high rate of false-positive results, which may lead to overtreatment if a "see and treat" policy is applied.

BackgroundPresent study provides clinical evidence of existence of a functional loop involving miR-21 and let-7a as potential regulators of aberrant STAT3 signaling recently reported by our group in an experimental setup (Shishodia et al. BMC Cancer 2014, 14:996). The study is now extended to a set of cervical tissues that represent natural history of human papillomavirus (HPV)-induced tumorigenic transformation.Materials and methodsCervical tissues from histopathologically-confirmed pre-cancer (23) and cancer lesions (56) along with the normal control tissues (23) were examined for their HPV infection status, expression level of miR-21 & let-7a and STAT3 & pSTAT3 (Y705) by PCR-based genotyping, quantitative real-time PCR and immunoblotting.ResultsAnalysis of cancer tissues revealed an elevated miR-21 and reduced let-7a expression that correspond to the level of STAT3 signaling. While miR-21 showed direct association, let-7a expression was inversely related to STAT3 expression and its activation. In contrast, a similar reciprocal expression kinetics was absent in LSIL and HSIL tissues which overexpressed let-7a. miR-21 was found differentially overexpressed in HPV16-positive lesions with a higher oncoprotein E6 level. Overexpression of miR-21 was accompanied by elevated level of other STAT3-regulated gene products MMP-2 and MMP-9. Enhanced miR-21 was found associated with decreased level of STAT3 negative regulator PTEN and negative regulator of MMPs, TIMP-3.ConclusionOverall, our study suggests that the microRNAs, miR-21 and let-7a function as clinically relevant integral components of STAT3 signaling and are responsible for maintaining activated state of STAT3 in HPV-infected cells during cervical carcinogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0385-2) contains supplementary material, which is available to authorized users.

Fine-needle aspiration cytology of lymph nodes and extranodal swellings in 160 cases showed granulomatous reaction with or without caseation necrosis in 83%. The material was acellular or predominantly composed of necrotic material, polymorphs, and lymphocytes in 17%. The age of the patient ranged from 1.5 to 72 yr. The male to female ratio was 1:1.3. Acid-fast bacilli (AFB) could be demonstrated in 40.6% of cases. In cases associated with cellular reaction and necrosis. AFB positivity was 50.0%, while it was 66.7% in cases with acellular necrotic material.