Abstract
BackgroundEpithelial ovarian cancer (EOC) is morphologically heterogeneous being classified as serous, endometrioid, clear cell, or mucinous. Molecular genetic analysis has suggested a role for tumor suppressor genes located at chromosome 3p in serous EOC pathogenesis. Our objective was to evaluate the expression of HYAL1, located at chromosome 3p21.3, in these EOC subtypes, and to investigate its correlation with the expression of steroid hormone receptors.Methodology/Principal FindingsWe determined the mRNA expression of HYAL1, estrogen receptor (ER)-α, ERβ and progesterone receptor (PR) in EOC tumor samples and cell lines using quantitative RT-PCR. We also examined the expression of these genes in a publicly available microarray dataset. HYAL-1 enzyme activity was measured in EOC cell lines and in plasma samples from patients. We found that HYAL1 mRNA expression was elevated in clear cell and mucinous EOC tissue samples, but not in serous and endometrioid samples, normal ovaries or benign tumors. Similar results were obtained by two different techniques and with tissue sample cohorts from two independent institutions. Concordantly, HYAL1 mRNA levels and enzymatic activity were elevated only in EOC cell lines derived from clear cell and mucinous subtypes. We also showed that HYAL1 mRNA was inversely correlated to that of ERα specifically in clear cell and mucinous EOCs. Additionally, ectopic expression of ERα in a clear cell EOC cell line (ER- and PR-negative) induced 50% reduction of HYAL1 mRNA expression, supporting a role of ERα in HYAL1 gene regulation. Significantly, HYAL-1 activity was also high in the plasma of patients with these EOC subtypes.Conclusions/SignificanceThis is the first report showing high HYAL-1 levels in EOC and demonstrating HYAL1 gene repression by ERα. Our results identify Hyaluronidase-1 as a potential target/biomarker for clear cell and mucinous EOCs and especially in tumors with low ERα levels.
Highlights
Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic cancer in most Western countries [1]
In the present study we analysed the mRNA expression of this enzyme by Quantitative real-time RT-PCR (Q-PCR) in ovarian cancer tissue samples obtained from patients with different morphological subtypes of this disease, e.g. serous (11 samples), endometrioid (9 samples), clear cell (11 samples) and mucinous (8 samples)
There are more than 190,000 new cases of epithelial ovarian cancer (EOC) each year worldwide and this malignancy represents the leading cause of death from gynaecological cancers [1,2]
Summary
Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic cancer in most Western countries [1]. EOCs are morphologically heterogeneous, and different histopathological subtypes have distinct molecular characteristics and diverse response to treatment [3]. EOC can be classified as serous, endometrioid, clear cell or mucinous which correspond to the different types of epithelia present in the female reproductive tract [4]. Differences in chemotherapy response and patient outcomes probably result from the molecular heterogeneity of these morphologically distinct EOCs [3]. TP53 mutations are frequently observed in serous and endometrioid cancers, but are scarcely detected in clear cell and mucinous EOCs [3]. Epithelial ovarian cancer (EOC) is morphologically heterogeneous being classified as serous, endometrioid, clear cell, or mucinous. Molecular genetic analysis has suggested a role for tumor suppressor genes located at chromosome 3p in serous EOC pathogenesis. Our objective was to evaluate the expression of HYAL1, located at chromosome 3p21.3, in these EOC subtypes, and to investigate its correlation with the expression of steroid hormone receptors
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