title: Expression of heparanase in renal cell carcinomas: implications for tumor invasion and prognosis.
abstract: OBJECTIVE
  Heparanase activity has been detected in many malignant tumors, showing a correlation with the metastatic potential. The present study was undertaken to investigate the expression of heparanase and its prognostic significance in renal cell carcinomas (RCC).
  
  
  METHODS
  Nineteen RCCs and 6 nonneoplastic renal tissues were analyzed for heparanase mRNA expression by real-time PCR. Heparanase protein expression was semiquantitatively investigated by immunohistochemistry in 70 RCCs. Involvement of heparanase in the invasiveness of RCC cell lines, 786-O and Caki-2 cells, was examined by down-regulating the gene expression with small interfering RNA (siRNA) using the Matrigel invasion assay.
  
  
  RESULTS
  The expression level of heparanase mRNA was significantly higher in clear cell RCCs than in papillary RCCs, chromophobe RCCs, and nonneoplastic renal tissues. Heparanase was predominantly immunolocalized to cell surface and cytoplasm of clear cell RCCs and mean expression levels of heparanase were significantly higher in clear cell RCCs than in papillary and chromophobe RCCs. The protein expression levels were positively correlated with primary tumor stage, distant metastasis, and histologic grade. Targeting of heparanase mRNA expression in 786-O and Caki-2 cells with siRNA down-regulated the mRNA expression and inhibited the Matrigel invasion by these cells, whereas nonsilencing siRNA showed no effect. Multivariate Cox analysis revealed that elevated heparanase expression was a significant and an independent predictor of disease-specific survival (odds ratio, 8.814; P = 0.019).
  
  
  CONCLUSIONS
  These data suggest that heparanase plays an important role in invasion and metastasis and silencing of the gene might be a potential therapeutic target in clear cell RCCs.
authors.affiliation: Division of Diagnostic Pathology, Keio University Hospital, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan. mikami-s@sc.itc.keio.ac.jp
authors.forename: Shuji
authors.initials: S
authors.lastname: Mikami
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Oya
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shimoda
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Mizuno
authors.forename: Masaru
authors.initials: M
authors.lastname: Ishida
authors.forename: Takeo
authors.initials: T
authors.lastname: Kosaka
authors.forename: Makio
authors.initials: M
authors.lastname: Mukai
authors.forename: Motowo
authors.initials: M
authors.lastname: Nakajima
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Okada
mesh_terms: D000368:Aged; D002292:Carcinoma, Renal Cell / Q000201:enzymology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005966:Glucuronidase / Q000096:biosynthesis* / Q000502:physiology*; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011379:Prognosis; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D000099175:Heparanase