E7HPV16 Oncogene and 17beta-Estradiol Stress, Promotes Oncogenic microRNA Expression Patterns, Cell Proliferation and Cervical Intraepithelial Neoplasia 1

Abstract

Cervical cancer (CC) is the second cause of death by a neoplasia in woman in Mexico. Among the factors that contribute to its development are prolonged infection by a high-risk HPV type and the use of estrogens. It is well known that diagnosis at early stages is extremely important since, in most cases, progression towards carcinogenesis could be prevented, hence the importance of finding candidates that serve as early biomarkers. Several studies have shown that the expression level of the tumor suppressor miR-218 is diminished in CC while oncomiR miR-21 is overexpressed. On the other hand, it has been reported that the Potassium calcium-activated channel subfamily M alpha 1 (Kcnma1) oncogene, a known target gene of miR-218, is overexpressed in CC. However, there are few studies on the expression of this oncogene in Cervical Intraepithelial Neoplasia 1 (CIN 1). In this study, the analysis of the K14E7HPV16 carcinogenesis model in young mice (1.5-month-old), showed that a single-dose of 17β-estradiol (E₂) increased both the cell proliferation and the Bcl-2 oncogene expression, as well as promoted the development of CIN 1. Interestingly, the hormonal stress and the E7 expression, favor the physiological response of the organism in transgenic young mice by decreasing the expression levels of the tumor suppressor miR-218 and increasing the expression of the Kcnma1 and Bcl-2 mRNA oncogenes in both, cervical tissue and serum. This work demonstrates the significance of a single E₂ stimulation and the expression of the HPV E7 oncoprotein in the early stage of cervical carcinogenesis. In addition, we provide strong evidence about Kcnma1 oncogene as a target gene of miR-218 and that both could be used as early circulating biomarkers of CC.