Abstract
BackgroundCervical 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.MethodsqPCR 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.ResultsE2 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.ConclusionOur studies suggest that the mutual regulation between E2, PRL, and HPV oncogenes could cooperate with the carcinogenesis process in CC.
Highlights
Cervical cancer (CC) is the second most common cancer in less developed countries and the sec‐ ond leading cause of death by cancer in women worldwide
PRL and E2 modulate the mRNA expression of E6 and E7 oncogenes on HeLa and SiHa cell lines To evaluate whether PRL and E2 modulate the mRNA expression of E6 and E7 oncogenes on HeLa and SiHa cell lines, the qRT-PCR assay was performed in cells with hormonal stimuli for 4 h; the results were analyzed by the methods 2−Δcq and 2−ΔΔcq, using RPL32 as the reference gene
E6 and E7 oncogenes modulate the expression and localization of estrogen and PRL receptors qPCR, western blot and, immunofluorescence assays were performed to evaluate if E6 and E7 oncogenes from HPV16 and HPV18 transduced in HaCaT cells can regulate the expression and localization of estrogen and PRL receptors
Summary
Cervical cancer (CC) is the second most common cancer in less developed countries and the sec‐ ond leading cause of death by cancer in women worldwide. 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. High-risk HPV16 and -18 are present in over 85% of women with CC, this is why most of the molecular research is focused on these genotypes [1, 2]. E7 oncogene induces the nuclear translocation of Smad proteins in a ligand-independent manner and interacted with MH1 Domain of SMAD3 to repress its transcription through TGF-β [6, 7]
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