Divergent Roles of PAX2 in the Etiology and Progression of Ovarian Cancer.

Ensaf M Al-Hujaily,Yong Tang,Euridice Carmona,Barbara C Vanderhyden,De-Sheng Yao,Kenneth Garson

doi:10.1158/1940-6207.capr-15-0121-t

Abstract

PAX2 is an essential transcription factor for development. Aberrant PAX2 expression in adult tissues is associated with carcinogenesis and experimental evidence shows that PAX2 generally exhibits oncogenic properties. Although PAX2 is not expressed in normal ovaries, it is highly expressed in low malignant potential and low-grade epithelial ovarian tumors, suggesting that PAX2 induction in ovarian surface epithelium (OSE) may contribute to transformation. Herein, we provide evidence that expression of PAX2 in normal murine OSE cells (mOSE) enhances their proliferation and survival and, with loss of p53, induces tumorigenicity. PAX2 expression in murine ovarian cancer cells enhanced or inhibited tumorigenicity, depending on the model system. In RM cells (mOSE transformed by K-RAS and c-MYC), PAX2 expression inhibited p53 and induced pERK1/2 and COX2, resulting in enhanced angiogenesis and decreased apoptosis of tumors arising from these cells. However, in a murine model of high-grade serous ovarian cancer (STOSE), PAX2 expression improved animal survival by reducing proliferation and metastasis, which correlated with increased Htra1 and decreased COX2. Thus, PAX2 may not be a classical oncogene or tumor suppressor but instead can act in either role by differential regulation of COX2 and/or HTRA1.

Highlights

Epithelial ovarian carcinoma (EOC) has been divided into two major subgroups with distinct molecular characteristics and clinical behavior [1]
PAX2 enhances proliferation in murine OSE cells (mOSE) cells Similar to its expression in the human reproductive tract [4, 7], PAX2 was expressed in the murine oviduct and uterus, but not the ovary (Supplementary Fig. S1)
PAX2 enhances survival in mOSE cells To determine the effect of PAX2 on cell survival, cells were challenged by deprivation of growth factors, and the percentage of viable cells was normalized to viability of cells supplemented with growth factors

Summary

Introduction

Epithelial ovarian carcinoma (EOC) has been divided into two major subgroups with distinct molecular characteristics and clinical behavior [1]. Patients with type II tumors encompass 75% of all EOC cases and include high-grade serous (HGSC), endometrioid, and undifferentiated carcinomas [1]. They frequently harbor TP53 mutations; 15% have BRCA1 or BRCA2 mutations and 20% have CCNE1 amplification [3]. They are often diagnosed at an advanced stage [2], resulting in poor understanding of the pathogenesis of EOC. The putative oncogene, PAX2, is highly expressed in low malignant potential tumors (59%) and LGSC (63%) and ciliated inclusion cysts, which are thought to be precursor lesions for ovarian carcinogenesis [4].

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