Inflammation-associated gene expression is altered between normal human ovarian surface epithelial cells and cell lines derived from ovarian adenocarcinomas

Abstract

Ovulation is believed to contribute to the development of ovarian cancers that derive from the ovarian surface epithelium (OSE). The process of ovulation is synonymous with inflammation and inflammatory cytokines such as interleukin-1a (IL-1a) have recently been shown to induce both inflammatory and anti-inflammatory responses in human OSE (HOSE) cells. In this study we directly compared levels of IL-1a-induced gene expression by analysing the levels of 11b-hydroxysteroid dehydrogenase (11bHSD) types 1 (11bHSD-1) and 2 (11bHSD-2), cyclooxygenase-2 (COX-2), IL-1 receptor (IL-1R) and glucocorticoid receptor a (GRa) mRNA between normal HOSE cells and cell lines derived from poorly differentiated (SKOV-3, BG-1, PEO-4) and well-differentiated (PEO-14) ovarian adenocarcinoma. In HOSE cell cultures, and to a lesser extent PEO-14 cells, the basal mRNA levels of COX-2 and 11bHSD-1 were relatively high and further shown to be induced in response to IL-1a (for HOSE cells; 420-fold, Po0.05 and PEO-14 cells; 43fold, Po0.05). However, whereas HOSE cells expressed a low level of 11bHSD-2 mRNA that was only mildly responsive to IL-1a (1.3-fold, Po0.001), all cell lines exhibited a higher basal level of 11bHSD-2 mRNA that was in some cases further stimulated in PEO-4 cells (five-fold; Po0.05) or suppressed in SKOV-3 cells (two-fold; Po0.01) in response to IL-1a. All cells tested expressed IL-1R and, with the exception of BG-1, GRa. These results indicate that cell lines derived from ovarian cancers have lost the ability to respond normally to inflammatory cytokines such as IL-1a. The finding that normal OSE cells, in contrast to cell lines derived from patients with ovarian adenocarcinoma, abundantly express 11bHSD-1 mRNA but are essentially devoid of 11bHSD-2 mRNA supports the concept that the pattern of 11bHSD isoform gene expression is a defining feature of neoplastic cellular transformation, which might have particular relevance to the ovary.

Glucocorticoid receptor-mediated regulation of MMP9 gene expression in human ovarian surface epithelial cells

“…Ovarian cancer has an inflammatory basis (19), therefore anti-inflammatory regulation of MMP9 expression through locally regenerated glucocorticoids has both physiological (ovulation) and pathological (cancer spread) implications. We have noted previously that human ovarian cancer cell lines are generally deficient in 11bHSD1 gene expression relative to normal OSE cells (20). If this translates into deficient glucocorticoid suppression of MMP9 in primary ovarian cancer, this could be a mechanism of promoting metastatic tumor spread in vivo.…”

A polymorphism at miRNA-122-binding site in the IL-1α 3′UTR is associated with risk of epithelial ovarian cancer

“…Ovulation is believed to be an important factor in the development of ovarian cancer that derives from the ovarian surface epithelium (OSE). The process of ovulation is shown to be synonymous with inflammation and inflammatory cytokines such as IL-1a [18][19][20]. The study of Keita et al [21] found that endometrioid ovarian cancer exhibited a decrease in the expression of IL-1RA compared with other cancer ovarian cells.…”

Neutrophil gelatinase‐associated lipocalin (NGAL) an early‐screening biomarker for ovarian cancer: NGAL is associated with epidermal growth factor‐induced epithelio‐mesenchymal transition

“…As cancer and inflammation are related, it is reasonable to expect an upregulation of NGAL expression in premalignant and early-stage ovarian malignancies when the inflammatory process is heightened. 41 A number of lipocalins have unusual expression during neoplasia and tumor growth. 8 NGAL has been found in human primary breast cancers, 9 with large amounts detected in the lumen of normal breast ducts close to NGAL-expressing tumors.…”