Abstract
The present study investigated the expression and clinical role of hyaluronan synthases (HAS1-3) and hyaluronidases (Hyal1-3) in serous ovarian carcinoma. HAS and HYAL mRNA expression was analyzed in 97 tumors (61 effusions, 27 primary carcinomas, 9 solid metastases) using PCR and further studied for association with clinicopathologic parameters, including survival. HAS1 mRNA was overexpressed in effusions compared to primary carcinomas and solid metastases (p < 0.001), and an alternatively spliced HAS1 was expressed only in effusions. HAS2 mRNA was overexpressed in solid metastases and primary carcinomas compared to effusions (p = 0.043), and HAS3 mRNA was overexpressed in primary carcinomas and effusions compared to solid metastases (p = 0.008). HYAL1 mRNA was absent in all specimens, whereas HYAL2 was expressed as two splice variants, of which HYAL2-var2 was overexpressed in solid metastases compared to effusions and primary carcinomas (p < 0.001). HYAL3 mRNA was expressed as wild-type and variant 1–3 form, the latter more highly in primary carcinomas and effusions compared to solid metastases (p = 0.006). HAS1 mRNA was overexpressed in pre- compared to post-chemotherapy effusions (p < 0.001), with opposite finding for HYAL2-var1 and HYAL3-WT (p = 0.016 and p = 0.024, respectively). Higher HYAL2-var1 and HAS1 splice variant mRNA expression in effusions was associated with longer (p = 0.033) and shorter (p = 0.047) overall survival, respectively. These data are the first to document a role for HAS and Hyal members in tumor progression in ovarian carcinoma, as evidenced by their differential expression as function of anatomic site and chemotherapy exposure, with a possible prognostic role for patients with malignant effusions.
Highlights
IntroductionThe majority of patients are diagnosed with advanced-stage disease and despite aggressive surgery and adjuvant platinum-based combination therapy, succumb to their disease, primarily due to chemotherapy resistance [1,2]
Ovarian carcinoma (OC) is the most lethal gynecologic malignancy
HAS1 mRNA was detected in 47/61 (77%) effusions, 8/27 (30%) primary OC and 4/9 (44%) solid metastases, with a comparative analysis of expression levels showing significantly higher expression in effusions compared to the two other anatomic sites (p < 0.001) (Figures 1 and 2)
Summary
The majority of patients are diagnosed with advanced-stage disease and despite aggressive surgery and adjuvant platinum-based combination therapy, succumb to their disease, primarily due to chemotherapy resistance [1,2]. Despite the obvious role of FIGO stage, tumor grade, residual disease (RD) volume after surgery and the presence of ascites in providing prognostic information in OC, these factors fail to predict clinical outcome for individual patients owing to a significant degree of tumor heterogeneity. The extracellular matrix (ECM) is a critical environmental determinant of tumor cell behavior. The matrix serves as a scaffold for the tumor cells to adhere, migrate and proliferate in response to the reservoir of growth factors and cytokines stored in it. Hyaluronan ( termed hyaluronic acid or hyaluronate; HA) is a prominent component of the ECM in many tissues, in rapidly remodeling ones. Its strong negative charge attracts a large associated volume of water capable of expansion up to 10,000 times its actual polymer volume
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