Association of Hyaluronic Acid Family Members (HAS1, HAS2, and HYAL-1) With Bladder Cancer Diagnosis and Prognosis

Cancer. 2011 Mar 15;117(6):1197-209. doi: 10.1002/cncr.25565. Epub 2010 Oct 19.

Abstract

Background: Cancer biomarkers are the backbone for the implementation of individualized approaches to bladder cancer (BCa). Hyaluronic acid (HA) and all 7 members of the HA family, that is, HA synthases (HA1, HA2, HA3), HYAL-1 hyaluronidase, and HA receptors (CD44s, CD44v, and RHAMM), function in tumor growth and progression. However, the diagnostic and prognostic potential of these 7 HA family members has not been compared simultaneously in any cancer. We evaluated the diagnostic and prognostic potential of HA family members in BCa.

Methods: Using quantitative PCR and immunohistochemistry, expression of HA family members was evaluated in prospectively collected bladder tissues (n = 72); mean and median follow-up were 29.6 ± 5.3 and 24 months, respectively. Transcript levels were also measured in exfoliated urothelial cells from urine specimens (n = 148).

Results: Among the HA family members, transcript levels of the HA synthases, HYAL-1, CD44v, and RHAMM were 4- to 16-fold higher in BCa tissues than in normal tissues (P < .0001); however, CD44s levels were lower. In univariate and multivariate analyses, tumor stage (P = .003), lymph node invasion (P = .033), HYAL-1 (P = .019), and HAS1 (P = .027) transcript levels, and HYAL-1 staining (P = .021) were independently associated with metastasis. Tumor stage (P = .019) and HYAL-1 (P = .046) transcript levels were also associated with disease-specific mortality. Although HA synthase and HYAL-1 transcript levels were elevated in exfoliated urothelial cells from BCa patients, the combined HAS2-HYAL-1 expression detected BCa with an overall sensitivity of 85.4% and a specificity of 79.5% and predicted BCa recurrence within 6 months (P = .004; RR = 6.7).

Conclusions: HYAL-1 and HAS1 expression predicted BCa metastasis, and HYAL-1 expression also predicted disease-specific survival. Furthermore, the combined HAS2-HYAL-1 biomarker detected BCa and significantly predicted its recurrence.

Publication types

  • Evaluation Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Biomarkers, Tumor / analysis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Carcinoma / diagnosis*
  • Carcinoma / genetics
  • Carcinoma / metabolism
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Glucuronosyltransferase / genetics*
  • Glucuronosyltransferase / metabolism
  • Humans
  • Hyaluronan Synthases
  • Hyaluronic Acid / genetics
  • Hyaluronic Acid / metabolism*
  • Hyaluronoglucosaminidase / genetics*
  • Hyaluronoglucosaminidase / metabolism
  • Male
  • Middle Aged
  • Molecular Diagnostic Techniques
  • Multigene Family / genetics
  • Multigene Family / physiology
  • Prognosis
  • Recurrence
  • Urinary Bladder Neoplasms / diagnosis*
  • Urinary Bladder Neoplasms / genetics
  • Urinary Bladder Neoplasms / metabolism

Substances

  • Biomarkers, Tumor
  • Hyaluronic Acid
  • Glucuronosyltransferase
  • HAS1 protein, human
  • HAS2 protein, human
  • Hyaluronan Synthases
  • Hyaluronoglucosaminidase