Expression of Hyaluronan Synthases (HAS1–3) and Hyaluronidases (HYAL1–2) in Serous Ovarian Carcinomas: Inverse Correlation between HYAL1 and Hyaluronan Content

Timo K Nykopp,Kirsi Rilla,Raija H Tammi,Veli-Matti Kosma,Reijo Sironen,Maarit Anttila,Marja Komulainen,Anna-Mari Heikkinen,Kirsi Hämäläinen,Markku I Tammi

doi:10.1186/1471-2407-9-143

Timo K Nykopp, Kirsi Rilla + Show 8 more

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https://doi.org/10.1186/1471-2407-9-143

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Abstract

BackgroundHyaluronan, a tumor promoting extracellular matrix polysaccharide, is elevated in malignant epithelial ovarian tumors, and associates with an unfavorable prognosis. To explore possible contributors to the accumulation of hyaluronan, we examined the expression of hyaluronan synthases (HAS1, HAS2 and HAS3) and hyaluronidases (HYAL1 and HYAL2), correlated with hyaluronidase enzyme activity hyaluronan content and HAS1–3 immunoreactivity.MethodsNormal ovaries (n = 5) and 34 serous epithelial ovarian tumors, divided into 4 groups: malignant grades 1+2 (n = 10); malignant grade 3 (n = 10); borderline (n = 4) and benign epithelial tumors (n = 10), were analyzed for mRNA by real-time RT-PCR and compared to hyaluronidase activity, hyaluronan staining, and HAS1–3 immunoreactivity in tissue sections of the same specimens.ResultsThe levels of HAS2 and HAS3 mRNA (HAS1 was low or absent), were not consistently increased in the carcinomas, and were not significantly correlated with HAS protein or hyaluronan accumulation in individual samples. Instead, the median of HYAL1 mRNA level was 69% lower in grade 3 serous ovarian cancers compared to normal ovaries (P = 0.01). The expression of HYAL1, but not HYAL2, significantly correlated with the enzymatic activity of tissue hyaluronidases (r = 0.5; P = 0.006). An inverse correlation was noted between HYAL1 mRNA and the intensity of hyaluronan staining of the corresponding tissue sections (r = -0.4; P = 0.025).ConclusionThe results indicate that in serous epithelial ovarian malignancies HAS expression is not consistently elevated but HYAL1 expression is significantly reduced and correlates with the accumulation of hyaluronan. (233 words)

Highlights

Hyaluronan, a tumor promoting extracellular matrix polysaccharide, is elevated in malignant epithelial ovarian tumors, and associates with an unfavorable prognosis
We have found a 49-fold increase in the median concentration of hyaluronan in grade 3 ovarian carcinomas, and an 89-fold increase in the corresponding metastases compared to normal ovary
Hyaluronan content The level of hyaluronan accumulation in the present set of tumors was scored from tissue sections using a biotinylated probe that binds hyaluronan [1]

Summary

Introduction

Hyaluronan, a tumor promoting extracellular matrix polysaccharide, is elevated in malignant epithelial ovarian tumors, and associates with an unfavorable prognosis. One of the suggested contributors for this spreading is the CD44 receptor on cell surface and its ligand, the extracellular matrix polysaccharide hyaluronan [1,2]. [3] This is consistent with the fact that hyaluronan is an independent, unfavorable prognostic factor in epithelial ovarian cancer [1], and suggests that hyaluronan is involved in the progression of this, and other malignancies [4]. Upregulation of HAS expression is a likely contributor to the hyaluronan accumulation in tissues, and promotes tumor growth [7] and metastasis in experimental animals, in particular when coexpressed with hyaluronidase [8]

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