Altered expression of inflammation-associated genes in oviductal cells following follicular fluid exposure: Implications for ovarian carcinogenesis

Abstract

Evidence indicates that high-grade serous ovarian carcinoma (HGSOC) may originate from lesions within the distal fallopian tube epithelium (FTE). Our previous studies indicate that fallopian tube epithelial cells from carriers of germline mutations in breast cancer susceptibility genes exhibit a pro-inflammatory gene expression signature during the luteal phase, suggesting that delayed resolution of postovulatory inflammatory signaling may contribute to predisposition to this ovarian cancer histotype. To determine whether exposure of tubal epithelial cells to periovulatory follicular fluid alters expression of inflammation-associated genes, we used an ex vivo culture system of bovine oviductal epithelial cells. Oviductal cells grown on collagen IV-coated transwell membranes assumed a cobblestone appearance and immunocytochemistry for FoxJ1 and Pax8 indicated that both ciliated and secretory epithelial cells were maintained in the cultures. Oviductal cells were exposed to human follicular fluid or culture medium for 24 h following which total cellular RNA was extracted at various time points. Expression of genes associated with inflammation was determined by quantitative real-time RT-PCR. Exposure to follicular fluid transiently increased the transcript levels of interleukin 8 ( IL8) and cyclooxygenase 2 ( PTGS2), and decreased the expression of mitochondrial superoxide dismutase ( SOD2) , glutathione peroxidase 3 ( GPX3), disabled homolog 2 ( DAB2), and glucocorticoid receptor ( NR3C1). Tumor necrosis factor ( TNF) and IL6 levels were also decreased while those of nicotinomide phosphoribosyltransferase ( NAMPT) were unaffected. This study demonstrates that periovulatory follicular fluid can act directly upon oviductal epithelial cells to alter gene expression that might contribute to early carcinogenic events. Furthermore, these findings illustrate the potential use of bovine oviductal cells to study signaling events implicated in ovarian carcinogenesis.