title: The tumor-suppressive function of UNC5D and its repressed expression in renal cell carcinoma.
abstract: OBJECTIVE
  As a newly added member of the UNC5H receptors, the function of UNC5D/H4 in tumorigenesis remains poorly defined. The aim of this study was to examine the expression of UNC5D in primary renal cell carcinomas (RCC), analyze the mechanisms responsible for its downregulation in RCC, and assess its functional relevance to tumor growth and migration.
  
  
  METHODS
  Forty-four paired primary RCCs and corresponding adjacent noncancerous tissues were collected. The mRNA and protein expression level of UNC5D was assessed by reverse transcriptase-PCR, real-time PCR, or immunohistochemistry. Epigenetic alterations in UNC5D promoter and LOH in the UNC5D locus were also analyzed. Ectopic expression of UNC5D in renal cancer cells with silenced expression of UNC5D was used for analysis of the biologic functions of UNC5D.
  
  
  RESULTS
  UNC5D expression was attenuated in multiple carcinoma cell lines including renal cancer cells. Similar reduction was also observed in primary RCC tissues as compared with paired adjacent noncancerous tissues. Methylation-specific PCR showed hypermethylation in UNC5D promoter in a significant proportion (18 of 44) of tumor tissue (40.9%). LOH of UNC5D was observed in 13 of 44 patients with RCCs (29.5%). Restoration of UNC5D expression in renal cancer cells significantly inhibited cell proliferation, anchorage-dependent and -independent growth, as well as migration and invasion, whereas knockdown of UNC5D promoted cell growth. Furthermore, ectopic expression of UNC5D induced G2-M cell-cycle arrest.
  
  
  CONCLUSIONS
  UNC5D is a functional tumor suppressor that is frequently downregulated in RCCs due to promoter hypermethylation and LOH.
authors.affiliation: Department of Immunology, Key Laboratory of Medical Immunology (Ministry of Health), Peking University Health Science Center, Beijing, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Lu
authors.forename: Dong
authors.initials: D
authors.lastname: Dong
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.forename: Xue-Wen
authors.initials: XW
authors.lastname: Pang
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Tian
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D018899:CpG Islands; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D019656:Loss of Heterozygosity; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism*; D014410:Tumor Stem Cell Assay
chemical_list: D011956:Receptors, Cell Surface; C529231:UNC5D protein, human