Abstract
BackgroundCervical cancer is a chronic inflammatory disease of multifactorial etiology usually presenting in sexually active women. Exposure of neoplastic cervical epithelial cells to seminal plasma (SP) has been shown to promote the growth of cancer cells in vitro and tumors in vivo by inducing the expression of inflammatory mediators including pro-inflammatory cytokines. IL-1α is a pleotropic pro-inflammatory cytokine induced in several human cancers and has been associated with virulent tumor phenotype and poorer prognosis. Here we investigated the expression of IL-1α in cervical cancer, the role of SP in the regulation of IL-1α in neoplastic cervical epithelial cells and the molecular mechanism underlying this regulation.Methods and resultsReal-time quantitative RT-PCR confirmed the elevated expression of IL-1α mRNA in cervical squamous cell carcinoma and adenocarcinoma tissue explants, compared with normal cervix. Using immunohistochemistry, IL-1α was localized to the neoplastically transformed squamous, columnar and glandular epithelium in all cases of squamous cell carcinoma and adenocarcinomas explants studied. We found that SP induced the expression of IL-α in both normal and neoplastic cervical tissue explants. Employing HeLa (adenocarcinoma) cell line as a model system we identified PGE2 and EGF as possible ligands responsible for SP-mediated induction of IL-1α in these neoplastic cells. In addition, we showed that SP activates EP2/EGFR/PI3kinase-Akt signaling to induce IL-1α mRNA and protein expression. Furthermore, we demonstrate that in normal cervical tissue explants the induction of IL-1α by SP is via the activation of EP2/EGFR/PI3 kinase-Akt signaling.ConclusionSP-mediated induction of IL-1α in normal and neoplastic cervical epithelial cells suggests that SP may promote cervical inflammation as well as progression of cervical cancer in sexually active women.
Highlights
Cervical cancer is a chronic inflammatory disease of multifactorial etiology usually presenting in sexually active women
seminal plasma (SP)-mediated induction of Interleukin 1α (IL-1α) in normal and neoplastic cervical epithelial cells suggests that SP may promote cervical inflammation as well as progression of cervical cancer in sexually active women
IL-1α is up-regulated in cervical cancer Prior studies have shown that a major agonist protein of the interleukin 1 family (i.e. IL-1α) is present in abundance in tumor microenvironment where it plays a major role in tumourigenesis [14]
Summary
Cervical cancer is a chronic inflammatory disease of multifactorial etiology usually presenting in sexually active women. Exposure of neoplastic cervical epithelial cells to seminal plasma (SP) has been shown to promote the growth of cancer cells in vitro and tumors in vivo by inducing the expression of inflammatory mediators including pro-inflammatory cytokines. Cervical cancer is a disease of multifactorial etiology usually presenting in sexually active women. The inflammatory milieu of most cancer microenvironment has been shown to consist of tumor cells, surrounding stromal, immune and inflammatory cells which all interact intimately to produce cytokines/chemokines, growth factors, and adhesion molecules in a bid to promote tumorigenesis and metastasis [13]. Of special relevance within this milieu are pro-inflammatory cytokines which are important mediators of chronic inflammatory responses, and have cardinal effects on malignant processes
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