Abstract
Estrogens and estrogen receptors (ERs), such as ERα and ERβ, prolactin (PRL) and prolactin receptor (PRLR) have been reported to be involved in the physiopathology of uterine cervical cancer (UCC). The 60kDa PRL is an isoform of PRL, which is produced by UCC‑derived cells. The present study aimed to evaluate the expression of hormonal receptors in different degrees of cervical lesions, and to determine whether 60kDa PRL and 17β‑estradiol (E2) modulated cell survival and metabolism in UCC cells, and in HaCaT cells transduced with human papillomavirus (HPV)16 and18E6/E7 oncogenes. ERα, ERβ, PRLR, Ki67 and B‑cell lymphoma2 expression levels were analyzed in biopsies of precursor lesions and UCC using immunohistochemistry. In addition, HeLa, SiHa and C33A cells, and transduced HaCaT cells, were stimulated with 60kDa PRL, E2 or a combination of both. Proliferation was evaluated using the xCELLigence platform, apoptosis was analyzed by flow cytometry and cell metabolism was determined using the MTT assay. The results revealed that ERα, ERβ, PRLR and Ki67 expression levels were increased during the progression of cancer. Invitro, 60kDa PRL alone significantly increased proliferation of SiHa cells. Furthermore, E2 alone or in combination with 60kDa PRL increased the sensitivity of SiHa cells to cisplatin and increased the percentage of apoptosis; in HaCaT cells, these treatment strategies had the opposite effect on cisplatin sensitivity. Treatment with E2 increased mitochondrial activity in HeLa and SiHa cells, and in HaCaT cells transduced with HPV16E6/E7 and HPV18E6 oncogenes. PRL had a similar effect on HeLa cells, and on HaCaT cells transduced with HPV18E6 and HPV16E7. The co‑expression of these receptors demonstrated the hormonal dependence of UCC. In addition, E2 and the 60kDa PRL significantly impacted the metabolism, but not the survival, of cells.
Highlights
Uterine cervical cancer (UCC) is a global health problem and one of the most challenging medical issues, due to the complexity of the pathophysiological mechanisms that are involved [1]
Treatment of C33A with the hormones had no significant effect, whereas in HaCaT cells it produced a decrease in mitochondrial activity
Previous studies have suggested that estrogen exposure may be a critical factor for the development of uterine cervical cancer (UCC) [5,6,7,8,9,10]; the participation of estrogen and its role in the control of certain processes, such as proliferation, apoptosis, migration and metastasis, remains to be elucidated
Summary
Uterine cervical cancer (UCC) is a global health problem and one of the most challenging medical issues, due to the complexity of the pathophysiological mechanisms that are involved [1]. This complexity limits the ability to determine molecular, biochemical and clinical markers that allow for adequate classification of precursor lesions. Due to the almost constant presence of the human papillomavirus (HPV) in premalignant and malignant lesions of the cervix, this infection is among the most prevalent sexually transmitted diseases. Previous studies have revealed that HPV is associated with UCC; its presence is insufficient, and it requires cofactors for its permanence and for the initiation of carcinogenesis [7,8]
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