PAX8 expression in ovarian surface epithelial cells

Abstract

High-grade serous ovarian carcinoma (HGSOC) is usually diagnosed at a late stage and is associated with poor prognosis. Understanding early stage disease biology is essential in developing clinical biomarkers to detect HGSOC earlier. While recent studies indicate that HGSOCs arise from fallopian tube secretory epithelial cells (FTSECs), a considerable body of evidence also suggests that HGSOC can also arise from ovarian surface epithelial cells (OSECs). PAX8 is overexpressed in HGSOCs and expressed in FTSECs, but there are conflicting reports about PAX8 expression in OSECs. The purpose of this study was to comprehensively characterize PAX8 expression in a large series of OSECs, and to investigate the role of PAX8 in early HGSOC development. PAX8 protein expression was analyzed in the OSECs of 27 normal ovaries and 7 primary OSEC cultures using immunohistochemistry and immunofluorescent cytochemistry. PAX8 mRNA expression was quantified in 66 primary OSEC cultures. Cellular transformation was evaluated in OSECs expressing a PAX8 construct. PAX8 was expressed by 44-71% of OSECs. Calretinin and E-cadherin were frequently co-expressed with PAX8. Expression of PAX8 in OSECs decreased cellular migration (P=0.028), but had no other effects on cellular transformation. In addition, PAX8 expression was significantly increased (P=0.003) in an in vitro stepwise model of neoplastic transformation. In conclusion, PAX8 is frequently expressed by OSECs and endogenous levels of PAX8 expression are non-transforming. These data indicate that in OSECs PAX8 expression may represent a normal state and that OSECs may represent an origin of HGSOCs.

The conceptual advances of carcinogenic sequence model in high-grade serous ovarian cancer

“…Historically, HGSC was believed to originate from OSE cells that form CIC (2,23,27). CIC did not present before menarche and the number of CIC increased with age (28).…”

“…Investigators have characterized the stepwise changes of molecular profiles identified by genomic, proteomic and immunohistochemical approaches, including BCL2 (BCL2 apoptosis regulator), p73 (tumor protein p73), PAX2 (paired box 2), p53, PAX8 (paired box 8), H2AX (H2A histone family member X), STMN1 (stathmin 1), EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit), Ki67, ALDH1A1 (aldehyde dehydrogenase 1 family member A1), CTNNB1 (β-catenin), CCNE1 (cyclin E1), LAMC1 (Laminin γ1), and HMGA2 (high mobility group AT-hook 2) genes and telomere shortening (Table I) (3,5,12,13,16,(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37).…”

“…A member of the PAX family, PAX8, also plays a role in organogenesis of the Müllerian system and is a marker of fallopian tubal secretory cells and ovarian surface epithelium (OSE) (16,27). Other molecular characteristics identified in fallopian tube epithelium are as follows: Fallopian tubal epithelium comprises different phenotypic and molecular subtypes; secretory cells (BCL2+, PAX2+, PAX8+, HMFG2+, p73-, FOXJ1-, and acety lated tubulin-) and cilia ted cells (BCL2-, PAX2-, PAX8-, HMFG2-, p73+, FOXJ1+, LhS28+, acetylated tubulin+, and Sall2+) (16,(25)(26)(27). p73 is a homologue of the p53 and induces cell cycle arrest, conferring its tumor suppressive activity.…”

“…OSE/CIC. OSE did not exhibit tubal biomarkers, BCL2, p73, FOXJ1 and phospho-Smad2, while PAX8 was expressed by OSE (27). Steroid hormones convert mesothelial-derived OSE to Müllerian-type tissues including CIC (28).…”

“…Immunohistochemical studies demonstrated that HGSC exhibited p53+, PAX8+, BCL2+, HMGA2+, STMN1+, EZH2+, PAX2-and ALDH1A1- (3,12,25,27,29,31,33,34,37). Since PAX8 is frequently expressed by secretory cells of the normal fallopian tube and OSE, these cells are thought to be the origin of HGSC.…”