Abstract 2719: Aberrant expression of transcription factors STAT-3 and STAT-5 and their epigenetic control by SOCS-1 gene: The STAT signaling crosstalk in HPV coupled cervical carcinogenesis
Authors: Singh Neha , Hussain Showket , Suri Vanita , Bharadwaj Mausumi , Das B C. , Sobti R C. 
Published: June 2012

Introduction: Cancer of the uterine cervix is the second most common cancer among women worldwide with more than 80% cases occurring in developing countries. The most important etiological factor in cervical cancer progression is infection of high risk human papillomaviruses (HR-HPVs). Transcriptional regulation of these HR-HPVs is controlled by a set of transcription factors such as Signal transducers and Activators of Transcription (STAT) particularly, STAT-3 and STAT-5. Activation of STATs has been shown to be negatively regulated by Suppressor of Cytokine Signaling (SOCS-1) in carcinogenesis. Also SOCS-1 is silenced due to promoter hypermethylation in a variety of cancers. We therefore, have investigated the role of STATs and SOCS-1 genes in cervical cancer.

Methods: We analyzed the expression pattern of STAT-3, STAT-5, SOCS-1 and HPV detection by RT-PCR, immunohistochemistry, western blotting and methylation-specific PCR in a total of 120 surgically resected cervical tissue biopsies comprising of 12 precancerous, 78 invasive cancer and 30 normal controls. HPV infection was detected by L1 consensus PCR and type specific PCRs.

Results: An aberrant expression pattern of STAT-3 and STAT-5 was detected in most of the cervical tumors (P &lt; 0.001), whereas it was almost undetectable in normal controls. Relative contribution of STAT-5 isoforms revealed a higher expression pattern of STAT-5b in cervical tumors. Enhanced STAT expression was also significantly associated with function of severity of cancer lesion both clinically as well as histologically (P &lt; 0.001). When we compared the expression pattern of SOCS-1 gene in normal tissues, 58% of the tumor tissues expressed either undetectable or reduced expression. Furthermore, aberrant promoter methylation of SOCS-1 was found in 54% of the cervical tumor tissues. Interestingly, most of the cases that showed loss of SOCS-1 expression had a promoter hypermethylation and overexpression of STAT-3 and STAT-5 genes. This implicates that methylation mediated gene silencing of SOCS-1 gene may act as a possible cause for overexpression of STAT in cervical carcinogenesis.

Conclusions: It is shown for the first time that transcription factors STAT-3 and STAT-5 are upregulated in cervical cancer. The findings provide an interesting clue(s) for possible role of HPV infection in overexpression of STAT-3 and STAT-5 in cervical cancer. In addition, transcriptional inactivation of SOCS-1 gene, primarily due to DNA promoter hypermethylation and the synergism with HPV infection may play an important role in cervical carcinogenesis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2719. doi:10.1158/1538-7445.AM2011-2719