ArticleClinical cancer research : an official journal of the American Association for Cancer Research2020
A Novel Splice Variant of HYAL-4 Drives Malignant Transformation and Predicts Outcome in Patients with Bladder Cancer.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 20 citations in OpenAlex.
- Urine cf-nucleosomes: A non-invasive window into human physiology and disease.Cell genomics · 2025Article
- Article
- Blood-based HYAL2 methylation as a potential marker for the preclinical detection of coronary heart disease and stroke.Clinical epigenetics · 2024Article
- Effect of CHST11, a novel biomarker, on the biological functionalities of clear cell renal cell carcinoma.Scientific reports · 2024Article
- The short isoform of MS4A7 is a novel player in glioblastoma microenvironment, M2 macrophage polarization, and tumor progression.Journal of neuroinflammation · 2023Article
- Characterization of Hyaluronidase 4 Involved in the Catabolism of Chondroitin Sulfate.Molecules (Basel, Switzerland) · 2022Article
- Review
- Dynamic Changes in Myofibroblasts Affect the Carcinogenesis and Prognosis of Bladder Cancer Associated With Tumor Microenvironment Remodeling.Frontiers in cell and developmental biology · 2022Article
- New Insights Into Human Hyaluronidase 4/Chondroitin Sulphate Hydrolase.Frontiers in cell and developmental biology · 2021Review
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Authors and funding
22 authors at 4 institutions in 3 countries.
Funding
Abstract
purposePoor prognosis of patients with muscle-invasive bladder cancer that often metastasizes drives the need for discovery of molecular determinants of bladder cancer progression. Chondroitin sulfate proteoglycans, including CD44, regulate cancer progression; however, the identity of a chondroitinase (Chase) that cleaves chondroitin sulfate from proteoglycans is unknown. HYAL-4 is an understudied gene suspected to encode a Chase, with no known biological function. We evaluated HYAL-4 expression and its role in bladder cancer. EXPERIMENTAL
designIn clinical specimens, HYAL-4 wild-type (Wt) and V1 expression was evaluated by RT-qPCR, IHC, and/or immunoblotting; a novel assay measured Chase activity. Wt and V1 were stably expressed or silenced in normal urothelial and three bladder cancer cell lines. Transfectants were analyzed for stem cell phenotype, invasive signature and tumorigenesis, and metastasis in four xenograft models, including orthotopic bladder.
resultsHYAL-4 expression, specifically a novel splice variant (V1), was elevated in bladder tumors; Wt expression was barely detectable. V1 encoded a truncated 349 amino acid protein that was secreted. In bladder cancer tissues, V1 levels associated with metastasis and cancer-specific survival with high efficacy and encoded Chase activity. V1 cleaved chondroitin-6-sulfate from CD44, increasing CD44 secretion. V1 induced stem cell phenotype, motility/invasion, and an invasive signature. CD44 knockdown abrogated these phenotypes. V1-expressing urothelial cells developed angiogenic, muscle-invasive tumors. V1-expressing bladder cancer cells formed tumors at low density and formed metastatic bladder tumors when implanted orthotopically.
conclusionsOur study discovered the first naturally-occurring eukaryotic/human Chase and connected it to disease pathology, specifically cancer. V1-Chase is a driver of malignant bladder cancer and potential predictor of outcome in patients with bladder cancer.
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