title: Inactivation of the von Hippel-Lindau tumour suppressor gene induces Neuromedin U expression in renal cancer cells.
abstract: BACKGROUND
  209 000 new cases of renal carcinoma are diagnosed each year worldwide and new therapeutic targets are urgently required. The great majority of clear cell renal cancer involves inactivation of VHL, which acts as a gatekeeper tumour suppressor gene in renal epithelial cells. However how VHL exerts its tumour suppressor function remains unclear. A gene expression microarray comparing RCC10 renal cancer cells expressing either VHL or an empty vector was used to identify novel VHL regulated genes.
  
  
  RESULTS
  NMU (Neuromedin U) is a neuropeptide that has been implicated in energy homeostasis and tumour progression. Here we show for the first time that VHL loss-of-function results in dramatic upregulation of NMU expression in renal cancer cells. The effect of VHL inactivation was found to be mediated via activation of Hypoxia Inducible Factor (HIF). Exposure of VHL expressing RCC cells to either hypoxia or dimethyloxalylglycine resulted in HIF activation and increased NMU expression. Conversely, suppression of HIF in VHL defective RCC cells via siRNA of HIF-α subunits or expression of Type 2C mutant VHLs reduced NMU expression levels. We also show that renal cancer cells express a functional NMU receptor (NMUR1), and that NMU stimulates migration of renal cancer cells.
  
  
  CONCLUSIONS
  These findings suggest that NMU may act in an autocrine fashion, promoting progression of kidney cancer. Hypoxia and HIF expression are frequently observed in many non-renal cancers and are associated with a poor prognosis. Our study raises the possibility that HIF may also drive NMU expression in non-renal tumours.
authors.affiliation: Division of Medicine, University College London, London, UK. sarah.harten@qimr.edu.au
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Harten
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Esteban
authors.forename: Deepa
authors.initials: D
authors.lastname: Shukla
authors.forename: Margaret
authors.initials: M
authors.lastname: Ashcroft
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Maxwell
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing / Q000502:physiology*; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D046228:Microarray Analysis; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009479:Neuropeptides; C056900:neuromedin U; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human