Hyaluronan accumulation is associated with reduced hyaluronidase expression in renal cell carcinoma, with <scp>CD44</scp>, <scp>HAS1</scp>, and <scp>HYAL2</scp> emerging as prognostic markers

Hyaluronan (HA), a large extracellular matrix glycosaminoglycan, is associated with malignant features in several human cancers. The accumulation of HA in renal cell carcinomas (RCC) correlates with unfavorable outcomes, higher tumor grade, and more advanced disease stages. However, the mechanisms responsible for HA buildup in these neoplasms remain unclear, and studies on the expression of hyaluronan-metabolizing and -degrading enzymes are either lacking or conflicting. This study aims to address this knowledge gap. Formalin-fixed paraffin-embedded (FFPE) RCC samples of various histological subtypes from 315 patients were immunohistochemically stained for CD44 (the main receptor of HA), hyaluronan-synthesizing enzymes HAS1-3, and degrading enzymes HYAL1-2. Protein expression levels were correlated with clinicopathological variables and their prognostic significance was evaluated. Additionally, the mRNA expression levels of these proteins were examined using RNA extracted from the same samples and publicly available data from the cancer genome atlas (TCGA). CD44 protein expression was associated with increased tumoral HA content, poor prognosis, higher tumor grade, advanced stage, and sarcomatoid/rhabdoid changes. HYAL1 and HYAL2 protein levels were reduced in HA-positive tumors, and low HYAL2 expression predicted worse prognosis. Elevated HAS2 protein expression was associated with poor differentiation, while low HAS1 protein levels were associated with reduced survival. mRNA levels of CD44 and HYAL2 correlated with their respective protein expression levels, and CD44 mRNA expression was also associated with HA content. In RCC, HA accumulation appears to be primarily driven by decreased degradation. HAS1 and HYAL2 were identified as novel prognostic biomarkers. These findings provide new insights into HA metabolism in RCC and open potential avenues for better understanding and management of these tumors.