Hyaluronic Acid Synthase-1 Expression Regulates Bladder Cancer Growth, Invasion, and Angiogenesis through CD44

Abstract

Hyaluronic acid (HA) promotes tumor metastasis and is an accurate diagnostic marker for bladder cancer. HA is synthesized by HA synthases HAS1, HAS2, or HAS3. We have previously shown that HAS1 expression in tumor tissues is a predictor of bladder cancer recurrence and treatment failure. In this study, we stably transfected HT1376 bladder cancer cells with HAS1-sense (HAS1-S), HAS1-antisense (HAS1-AS), or vector cDNA constructs. Whereas HAS1-S transfectants produced f1.7-fold more HA than vector transfectants, HA production was reduced by f70% in HAS1-AS transfectants. HAS1-AS transfectants grew 5-fold slower and were f60% less invasive than vector and HAS1-S transfectants. HAS1-AS transfectants were blocked in G 2 -M phase of the cell cycle due to down-regulation of cyclin B1, cdc25c, and cyclin-dependent kinase 1 levels. These transfectants were also 5-to 10-fold more apoptotic due to the activation of the Fas-Fas ligandmediated extrinsic pathway. HAS1-AS transfectants showed a f4-fold decrease in ErbB2 phosphorylation and downregulation of CD44 variant isoforms (CD44-v3, CD44-v6, and CD44-E) both at the protein and mRNA levels. However, no decrease in RHAMM levels was observed. The decrease in CD44-v mRNA levels was not due to increased mRNA degradation. Whereas CD44 small interfering RNA (siRNA) transfection decreased cell growth and induced apoptosis in HT1376 cells, HA addition modestly increased CD44 expression and cell growth in HAS1-AS transfectants, which could be blocked by CD44 siRNA. In xenograft studies, HAS1-AS tumors grew 3-to 5-fold slower and had f4-fold lower microvessel density. These results show that HAS1 regulates bladder cancer growth and progression by modulating HA synthesis and HA receptor levels. [Cancer Res 2008;68(2):483-91]

Cellular heterogeneity profiling by hyaluronan probes reveals an invasive but slow-growing breast tumor subset

“…We chose HA because the production and metabolism of this glycosaminoglycan is linked to cancer progression and poor clinical outcome (20,21,71,72). We profiled multivalent interactions of F-HA and HA receptors in live cells.…”

Hyaluronic Acid Promotes Angiogenesis by Inducing RHAMM-TGFβ Receptor Interaction via CD44-PKCδ

“…Hyaluronic acid synthase-1 (HAS-1) promotes angiogenesis through CD44 (Golshani et al, 2008). There are three HAS isoforms, HAS1, HAS2, and HAS3, which synthesize HA at different catalytic rates, resulting in different size polymers (Itano et al, 1999).…”

“…Hyaluronic acid (HA) is involved in various cellular processes, such as cellular invasion (Bourguignon et al, 2007;Golshani et al, 2008;, tissue regeneration (Contreras et al, 2009) and angiogenesis (Savani et al, 2001). HA suppresses NGF-induced cell differentiation through RHAMM (Washio et al, 2009).…”

“…HA also promotes angiogenesis through recruitment of stromal cells (Koyama et al, 2007). HA employs CD44 and RHAMM to induce angiogenesis (Golshani et al, 2008). RHAMM compensates for the loss of CD44 in inflamed CD44 knock out mice (Nedvetzki et al, 2004) and is necessary for basic FGF-induced neovascularization in mice (Savani et al, 2001).…”

A Global Gene Expression Analysis of the Peripheral Blood Mononuclear Cells Reveals the Gene Expression Signature in Psoriasis

“…CD44 is a typical receptor for HA and it can bind with osteoponin, collagens and matrix metalloproteinases (MMPs). The interaction of CD44 with its ligand regulates the lymphocyte activation and this leads to the migration of skin-homing T cells 13,14 . Another cell surface molecule CD56 was also identified as an up-regulated gene in the psoriatic PBMCs in this study.…”