Abstract
BackgroundOvarian cancer is the third most common cause of death among gynecologic malignancies worldwide. Understanding the biology and molecular pathogenesis of ovarian epithelial tumors is key to developing improved prognostic indicators and effective therapies. We aimed to determine the effects of PAX8 expression on the migrative, adhesive and survival capabilities of high-grade serous carcinoma cells.MethodsPAX8 depleted Fallopian tube secretory cells and ovarian cancer cells were generated using short interfering siRNA. Anoikis resistance, cell migration and adhesion properties of PAX8 silenced cells were analyzed by means of specific assays. Chromatin immunoprecipitation (ChIP) was carried out using a PAX8 polyclonal antibody to demonstrate that PAX8 is able to bind to the 5′-flanking region of the ITGB3 gene positively regulating its expression.ResultsHere, we report that RNAi silencing of PAX8 sensitizes non-adherent cancer cells to anoikis and affects their tumorigenic properties. We show that PAX8 plays a critical role in migration and adhesion of both Fallopian tube secretory epithelial cells and ovarian cancer cells. Inhibition of PAX8 gene expression reduces the ability of ovarian cancer cells to migrate and adhere to the ECM and specifically to fibronectin and/or collagen substrates. Moreover, loss of PAX8 strongly reduces ITGB3 expression and consequently the correct expression of the αvβ3 heterodimer on the plasma membrane.ConclusionsOur results demonstrate that PAX8 modulates the interaction of tumor cells with the extracellular matrix (ECM). Notably, we also highlight a novel pathway downstream this transcription factor. Overall, PAX8 could be a potential therapeutic target for high-grade serous carcinoma.
Highlights
Ovarian cancer is the third most common cause of death among gynecologic malignancies worldwide
Soriano et al Cancer Cell Int (2019) 19:303 by the presence of Serous Tubal Intraepithelial Carcinoma (STIC) in the Fallopian tube in ~ 68% of High-Grade Serous Ovarian Cancer (HGSC) patients [8]. Another important evidence that further strengthen this theory is the presence of the Fallopian Tube Epithelium (FTE) lineage specific marker PAX8 in almost all HGSC [9,10,11,12]
Supernatant collected after O/N digestion was centrifuged at 1200 rpm for 5 min and the pellet composed of dissociated cells was plated on collagen coated 60 mm plate supplemented with DMEM-F12 (Euroclone, Italy), 2% Ultroser G serum (PALL, France) and 1% penicillin/streptomycin (Euroclone, Italy)
Summary
Ovarian cancer is the third most common cause of death among gynecologic malignancies worldwide. PAX8 has been demonstrated to be crucial in determining cell fate during the development of thyroid, kidney, brain, eyes and Mullerian system; in adult normal tissues, it is expressed in kidney, thyroid and Fallopian tubes and not in the ovarian epithelium [13,14,15]. This could be relevant in the development of HGSC because PAX8 is neither lost, mutated or overexpressed but is functionally retained possibly due to a selective advantage that it confers upon HGSC tumor cells. We believe that PAX8 possibly continues to exert its transcriptional activity on its physiological targets and may function on newly available targets after the tumorigenic hits
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