title: Allele loss and down-regulation of heparanase gene are associated with the progression and poor prognosis of hepatocellular carcinoma.
abstract: OBJECTIVE
  The role of heparanase (HPSE) gene in cancers including hepatocellular carcinoma (HCC) is currently controversial. This study was aimed at investigating the impact of genetic alteration and expression change of HPSE on the progression and prognosis of HCC.
  
  
  METHODS
  The HPSE gene was studied in three different aspects: (1) loss of heterozygosity (LOH) by a custom SNP microarray and DNA copy number by real-time PCR; (2) mRNA level by qRT-PCR; and (3) protein expression by immunohistochemistry. The clinical significances of allele loss and expression change of HPSE were analyzed.
  
  
  RESULTS
  Microarray analysis showed that the average LOH frequency for 10 SNPs located within HPSE gene was 31.6%, three of which were significantly correlated with tumor grade, serum HBV-DNA level, and AFP concentration. In agreement with SNP LOH data, DNA copy number loss of HPSE was observed in 38.74% (43/111) of HCC cases. HPSE mRNA level was notably reduced in 74.1% (83/112) of tumor tissues compared with non-tumor liver tissues, which was significantly associated with DNA copy number loss, increased tumor size, and post-operative metastasis. HPSE protein level was also remarkably reduced in 66.3% (53/80) of tumor tissues, which was correlated with tumor grade. Patients with lower expression level of HPSE mRNA or protein had a significantly lower survival rate than those with higher expression. Cox regression analysis suggested that HPSE protein was an independent predictor of overall survival in HCC patients.
  
  
  CONCLUSIONS
  The results in this study demonstrate that genetic alteration and reduction of HPSE expression are associated with tumor progression and poor prognosis of HCCs, suggesting that HPSE behaves like a tumor suppressor gene and is a potential prognostic marker for HCC patients.
authors.affiliation: National Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China.
authors.forename: Guo-Liang
authors.initials: GL
authors.lastname: Huang
authors.forename: Bin-Kui
authors.initials: BK
authors.lastname: Li
authors.forename: Mei-Yin
authors.initials: MY
authors.lastname: Zhang
authors.forename: Rong-Rong
authors.initials: RR
authors.lastname: Wei
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Yuan
authors.forename: Ming
authors.initials: M
authors.lastname: Shi
authors.forename: Xiao-Qian
authors.initials: XQ
authors.lastname: Chen
authors.forename: Long
authors.initials: L
authors.lastname: Huang
authors.forename: Hui-Zhong
authors.initials: HZ
authors.lastname: Zhang
authors.forename: Wanqing
authors.initials: W
authors.lastname: Liu
authors.forename: Bi-Jun
authors.initials: BJ
authors.lastname: Huang
authors.forename: Honghua
authors.initials: H
authors.lastname: Li
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Zheng
authors.forename: Xian-Rong
authors.initials: XR
authors.lastname: Luo
authors.forename: Hui-Yun
authors.initials: HY
authors.lastname: Wang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology / Q000821:virology; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D005966:Glucuronidase / Q000235:genetics* / Q000378:metabolism; D006515:Hepatitis B virus / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000821:virology; D019656:Loss of Heterozygosity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis; D047368:Tumor Burden / Q000235:genetics; D055815:Young Adult; D000509:alpha-Fetoproteins / Q000378:metabolism; D000099175:Heparanase
chemical_list: D004279:DNA, Viral; D005966:Glucuronidase; D000509:alpha-Fetoproteins; D000099175:Heparanase