Loss of PAX8 in high-grade serous ovarian cancer reduces cell survival despite unique modes of action in the fallopian tube and ovarian surface epithelium

Abstract

High-grade serous carcinoma (HGSC) is the most common and lethal form of ovarian cancer. PAX8 is a transcription factor expressed in fallopian tube epithelial cells and in 80–96% of HGSC tumors. The ovarian surface epithelium (OSE) only acquires PAX8 expression after malignant transformation. In this study, forced PAX8 expression in OSE cells increased proliferation and migration through upregulation of EMT factors such as N-cadherin and Fibronectin. OSE cells expressing PAX8 also had an increase in the FOXM1 pathway, but PAX8 alone was not sufficient to drive tumorigenesis. PAX8 knockdown in the oviductal epithelium cells did not decrease expression of the FOXM1 pathway and induced only a slight decrease in cell proliferation. No changes in migration, cell cycle, or apoptosis were detected after PAX8 knockdown in oviductal cells. Finally, PAX8 knockdown in HGSC cell lines resulted in increased apoptosis and decreased FOXM1 levels. The results presented here suggest that PAX8 has a cell specific role in governing proliferation and migration in nontransformed ovarian surface epithelium cells compared to the oviductal cells, but its reduction in serous cancer cell lines provides a common mechanism for reducing cell survival.

PAX8 orchestrates an angiogenic program through interaction with SOX17

“…The sustained expression of PAX8 in the adult FTSEC and in nearly all HGSOCs (16), previously led us to use the PAX8 promoter to develop a genetically engineered mouse model of HGSOC (17,18). Knockdown of PAX8 in ovarian cancer cells leads to apoptosis (19)(20)(21) supporting a definitive role for PAX8 in ovarian cancer growth and progression. However, it remains unclear how PAX8 drives the development of the Mullerian reproductive tract or how it supports neoplastic growth.…”

Gonadotropins promote human ovarian cancer cell migration and invasion via a cyclooxygenase 2-dependent pathway

“…Some evidence has indicated that endocrine factors may influence the tumorigenesis of ovarian cancer (1,2). Ovarian cancer is more common in patients with elevation of the gonadotropins follicle stimulating hormone (FSH) and luteinizing hormone (LH), such as postmenopausal women or women who have received treatment for the induction of ovulation (3)(4)(5). Additionally, reduced risk for ovarian cancer is associated with multiple pregnancies, breastfeeding, and oral contraceptive use, which are all associated with lower levels of and reduced exposure to gonadotropins (1).…”

Circular RNA expression profile and potential function of hsa_circ_0045272 in systemic lupus erythematosus

“…Among them were NM_003466 [ Homo sapiens paired box 8 (PAX8), transcript variant PAX8A, mRNA], and NM_015177 [ Homo sapiens deltex E3 ubiquitin ligase 4 (DTX4), transcript variant 1, mRNA]. Published studies have shown the role of transcription factor PAX8 in inhibiting apoptosis, whereas DTX4 mediates the degradation of TANK‐binding kinase 1 (TBK1), a kinase implicated in T‐cell activation . Accordingly, we measured the mRNA levels of NM_003466 (PAX8) and NM_015177 (DTX4) as well as their corresponding protein isoform levels in cells with hsa_circ_0045272 knockdown to show the putative ceRNAs.…”

“…Silencing of Pax8 in FRTL‐5 epithelial cells induces apoptosis through a p53‐dependent pathway . Additionally, knockdown of PAX8 in high‐grade serous carcinoma cells, but not in oviductal cells, promotes apoptosis, suggesting its cell‐specific roles . NM_015177 (DTX4) encoding E3 ubiquitin ligase DTX4 is also a putative candidate.…”