Contribution of rs2232365 Polymorphism of FOXP3 Gene in Cervical Cancer Development

Objective Cervical cancer is the second common malignancy in women. This is an immunogenic malignancy, and high-risk human papilloma virus (HPV) subtypes may cause its development. Persistent infection of high-risk HPV subtypes may significantly facilitate the development of cervical intraepithelial neoplasia, which has been confirmed as a major risk factor of cervical cancer. Regulatory T cells (Treg cells) are a group of mature T cells generated in the thymus following the induction of peripheral naïve T cells. They are essential for the inhibition of immune overreaction induced damage, but over-production of Treg cells may block the protective immune response to infection and tumors. FOXP3 (Forkhead box protein P3) is a key transcription factor in regulatory T cells (Tregs), and has important roles in the immunosuppressive functions in Tregs. The role of FOXP3 gene polymorphisms in cancer patients is not determined till now. We have investigated the association of rs2232365 (A to G) of FOXP3 gene with cervical cancer. rs2232365A/G polymorphism has been detected in cervical cancer (25 cases, 73.53% of cancer cases, p=0.03) and CIN (36 cases, 64.29% of CIN cases, p=0.02). We assume that rs2232365 polymorphism of the Foxp3 gene may contribute to the cervical cancer development.


Introduction
In 21st century cancer still remains a major cause of morbidity and mortality. Cancer incidence is increased worldwide because of high exposure to risk factors and prolonged life expectancy [1]. Surgery is the main treatment approach for primary tumor removal; however it cannot diminish the risk of metastasis development.
Cervical cancer is the second most common malignancy of the female reproductive system. While the incidence of cervical cancer is decreasing, the morbidity and mortality rates of this oncologic disease are still high. Furthermore, cervical cancer patients become younger.
Cervical cancer is an immunogenic oncology disease which can be developed as a result of the persistent infection of the high-risk human papilloma virus (HPV) subtypes. The process may include the following steps: cervical intraepithelial neoplasia (CIN), carcinoma in situ of cervix, invasive carcinoma of cervix and cervical cancer metastasis.
Persistent infection of high-risk HPV subtypes (such as HPV16) has been confirmed as a major risk factor of CIN (especially CIN2 and CIN3) and cervical cancer [2].
After exposure to HPV and as an outcome of HPV infection the immune response of the host is developed. A group of mature T cells generated in the thymus, regulatory T cells -Tregs, are responsible for the maintenance of non-response of host to autoantibodies and the inhibition of immune overreaction. However, overproduction of Tregs is inhibiting immune response during infection and cancer. Immunosupressiv function of Tregs is regulated by the transcription factor FOXP3 (Forkhead box protein P3) [3]. The high levels of FOXP3 expression in cancer cells have been reported [4][5][6]; this is an important mechanism of tumor escape [7]. FOXP3 is expressed in tumor cells as well as Tregs.
Furthermore, it has been reported, that tumor cells can transform T cells into Tregs and ensure immune escape [8][9]. The presence of Tregs in tumor microenvironment is associated with the worst clinical outcomes [10][11].
The molecular peculiarities of FOXP3 gene should be explained too. This gene is located at the short arm of X chromosome and is characterized by the complex mechanisms of regulation. The transcriptional factors bind to conserved non-coding sequences (CNS) in intronic regions; this mechanism ensures transcription of FOXP3 gene [12]. Polymorphisms of FOXP3 gene regulatory regions of FOXP3 gene may alter gene expression and Tregs function [13]. It has been reported, that rs2232365 (A to G) polymorphism, which is specific to the FOXP3 gene regulatory regions, is associated with immunologic diseases [14] and Treg function regulation. The role of this polymorphism in cancer has not been investigated till now. The determination of FOXP3 gene polymorphisms role in cancer is important for understanding of molecular mechanisms of cancer and for identification of the effective screening biomarker. Only several studies reported association of the FOXP3 gene polymorphisms with cancer [15]; this data are presented in table given below (

Results And Discussion
The present study aimed determination of FOXP3 gene rs2232365A/G polymorphism in Treg cells have the key role in the process of immune escape. Their development requires continued expression of Foxp3 [16]; attenuated Foxp3 expression results in its functional deficiency [17]. By analysis of the obtained results, we assume that polymorphisms of the Foxp3 gene may contribute to the cervical cancer development.

Conclusion
The present study revealed the link of rs2232365A/G polymorphism of FOXP3 gene with cervical cancer development.

Limitations
This study only concentrates on the rs2232365A/G polymorphism of FOXP3 gene.
Increasing of the target group size as well as the investigation of FOXP3 gene expression in case of rs2232365A/G polymorphism presence are required.