Interaction between 17β-estradiol, prolactin and human papillomavirus induce E6/E7 transcript and modulate the expression and localization of hormonal receptors

Abstract

Background Cervical cancer (CC) is the second most common cancer in less developed countries and the second leading cause of death by cancer in women worldwide. The 99% of CC patients are infected with the Human Papilloma Virus (HPV), being HPV16 and HPV18 infection the most frequent. Even though HPV is considered to be a necessary factor for the development of CC, it is not enough, as it requires the participation of other factors such as the hormonal ones. Several studies have demonstrated the requirement of estrogen and its receptors (ERα, ERβ, and GPER) in the precursor lesions progress towards CC. Also, prolactin (PRL) and its receptor (PRLR) have been associated with CC. The molecular mechanisms underlying the cooperation of these hormones with the viral oncoproteins are not well elucidated. For this reason, this study focused on analyzing the contribution of 17β-estradiol (E2), PRL, and HPV on the expression and localization of hormone receptors, as well as to evaluate whether these hormones may promote greater expression of HPV oncogenes and contribute to tumor progression. Methods qPCR was used to evaluate the effect of E2 and PRL on the expression of E6 and E7 oncoproteins in HeLa and SiHa cervical cancer cells lines. HaCaT cells were transduced with the viral oncogenes E6 and E7 from HPV 16 and 18. ERα, ERβ, GPER, and PRLR expression and localization were evaluated by qPCR, Western blot and immunofluorescence. Results E2 and PRL induce E6/E7 oncogenes expression in HeLa and SiHa cells. E6 and E7 oncogenes of HPV16/18 significantly increased the protein expression of ERα, GPER, and PRLR. ERβ was positively regulated only by E6 oncogenes of HPV16/18. Besides, some of these oncogenes modify the location of PRLR toward cytoplasm, and ERα, ERβ, and GPER mainly to the nucleus. Conclusion Our studies suggest that the mutual regulation between E2, PRL, and HPV oncogenes could cooperate with the carcinogenesis process in CC.

Expression and Role of the G Protein-Coupled Estrogen Receptor (GPR30/GPER) in the Development and Immune Response in Female Reproductive Cancers

“…In another report, stimulation of GPER with G-1 was shown to inhibit cell proliferation of HeLa, SiHa, and C-33A cell lines by inducing processes such as apoptosis, necrosis, and senescence (58). Besides, it was demonstrated in a transduced non-tumorigenic keratinocyte model that E6 and E7 oncogenes from HPV 16 and HPV 18 increase GPER expression at both mRNA and protein levels and that E7 oncogene modulates GPER localization in the nucleus (61).…”

Differential modulation of natural killer cell cytotoxicity by 17β‑estradiol and prolactin through the NKG2D/NKG2DL axis in cervical cancer cells

“…Hormones, including 17β-estradiol and PRL are related to the genesis, persistence and development of CC (14,16,21,46), since in addition to being present in the TME of this cancer type, they can contribute to anti-apoptotic, proliferative, invasive, survival effects and metabolic adaptation of CC cells (10,15,21,22,25,47). In addition, they can regulate the expression of HPV oncogenes (48). The functionality of these hormones within the TME may also depend on a bilateral regulation between the two hormones, since there are studies demonstrating the possible regulation of PRLR by E2, as well as the regulation of estrogen receptors exerted by PRL effects (49)(50)(51).…”

The Relevant Participation of Prolactin in the Genesis and Progression of Gynecological Cancers

“…Besides, using HaCaT cells transduced with E6 and E7 oncogenes from HPV16 and HPV18, the authors reported that these oncogenes significantly increased the expression of PRLR (8.98–19.08 folds more than the control). Using the same cell lines, it was determined that both HPV18’s E6 and E7 oncogenes induced the relocation of this receptor from the cell membrane and from the cytoplasm to the nucleus, thus generating a loop that contributes to the development of CC, highlighting the existence of a PRL-HPV oncogenic regulation ( 61 ).…”