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

• Published in: Cell biochemistry and function Vol. 43; no. 3; pp. e70065 - n/a
• Main Authors: Arvizu‐Hernandez, Erandi, Ocadiz‐Delgado, Rodolfo, Gariglio, Patricio
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.03.2025
• Subjects: Animals; Cell Proliferation - drug effects; CIN 1; Estradiol - pharmacology; Female; Gene Expression Regulation, Neoplastic - drug effects; HPV; Human papillomavirus 16 - genetics; Humans; Kcnma1; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; miR‐21; miR‐218; Papillomavirus E7 Proteins - genetics; Papillomavirus E7 Proteins - metabolism; Uterine Cervical Dysplasia - genetics; Uterine Cervical Dysplasia - metabolism; Uterine Cervical Dysplasia - pathology; Uterine Cervical Dysplasia - virology; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology; Uterine Cervical Neoplasms - virology; CIN 1; miR‐218; miR‐21; Kcnma1; HPV
• ISSN: 0263-6484; 1099-0844; 1099-0844
• DOI: 10.1002/cbf.70065

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. Summary This work represents an important study on the early stages of cervical carcinogenesis related to the effect of the E7 oncoprotein of the Human Papillomavirus and the hormonal environment. It is proposed that the validation of this murine model will be useful both for early diagnosis and for establishing possible treatments for early lesions of the cervix.