title: Decreased hyaluronidase 1 expression is associated with early disease recurrence in human endometrial cancer.
abstract: OBJECTIVE
  Hyaluronidases (HYAL1 and HYAL2) are key enzymes in the degradation of hyaluronan, and their expression has been altered in various cancer types. We previously showed that hyaluronan accumulation in endometrial carcinomas was correlated with decreased mRNA expression of the HYAL genes. In this study, we analyzed HYAL1 and HYAL2 protein expressions in normal and precancerous endometrial tissues and in endometrial carcinomas. We also investigated whether the protein levels were associated with clinicopathological factors, invasion, and disease recurrence.
  
  
  METHODS
  A total of 343 tissue specimens from normal, atrophic, hypertrophic, and neoplastic endometria were analyzed immunohistochemically for HYAL1 and HYAL2 expressions. The results were correlated with clinicopathological factors, the expression of the epithelial-mesenchymal transition marker, E-cadherin, and disease recurrence.
  
  
  RESULTS
  Reduced HYAL1 expression was associated with the progression of endometrial carcinomas towards higher grades and also with large tumor sizes, lymph node metastasis, and lymphovascular invasion. Reduced expression of both HYAL1 and HYAL2 was associated with deep myometrial invasion. HYAL2 expression was primarily constant in neoplastic tissues, but its expression was altered in different phases of the endometrial cycle. In addition, a reduction in HYAL1 expression was associated with the depletion of E-cadherin. In a multivariate analysis, reduced HYAL1 expression was an independent prognostic factor for early disease recurrence (HR 5.13, 95% CI: 1.131-23.270, p=0.034).
  
  
  CONCLUSIONS
  This study showed that reduced HYAL1 expression was associated with endometrial carcinoma aggressiveness, which further supported the role of hyaluronan degradation in cancer progression.
authors.affiliation: Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland; Department of Surgery, Kuopio University Hospital, Kuopio, Finland; Biocenter Kuopio and Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland; Department of Gynecology and Obstetrics, Kuopio University Hospital, Kuopio, Finland. Electronic address: timo.nykopp@kuh.fi.
authors.forename: Timo K
authors.initials: TK
authors.lastname: Nykopp
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland; Biocenter Kuopio and Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.
authors.forename: Sanna
authors.initials: S
authors.lastname: Pasonen-Seppänen
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland; Biocenter Kuopio and Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.
authors.forename: Markku I
authors.initials: MI
authors.lastname: Tammi
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland; Biocenter Kuopio and Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.
authors.forename: Raija H
authors.initials: RH
authors.lastname: Tammi
authors.affiliation: Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland; Biocenter Kuopio and Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland; Imaging Center, Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Kosma
authors.affiliation: Biocenter Kuopio and Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland; Department of Gynecology and Obstetrics, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Maarit
authors.initials: M
authors.lastname: Anttila
authors.affiliation: Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland; Biocenter Kuopio and Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland; Imaging Center, Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Reijo
authors.initials: R
authors.lastname: Sironen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000201:enzymology* / Q000473:pathology; D005260:Female; D058851:GPI-Linked Proteins / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism; D006821:Hyaluronoglucosaminidase / Q000096:biosynthesis* / Q000378:metabolism; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000201:enzymology* / Q000473:pathology
chemical_list: D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; D006820:Hyaluronic Acid; C473096:Hyal2 protein, human; D006821:Hyaluronoglucosaminidase
keywords: E-cadherin; Endometrial carcinoma; Hyaluronan; Hyaluronidase; Menstrual cycle