title: Prolyl-4-Hydroxylase 2 Potentially Contributes to Hepatocellular Carcinoma-Associated Erythrocytosis by Maintaining Hepatocyte Nuclear Factor-4α Expression.
abstract: BACKGROUND
  Increased red blood cell count (Erythrocytosis) is an important paraneoplastic syndrome of hepatocellular carcinoma (HCC) and is a significant risk factor for lethal lung artery thromboembolism. HCC-associated erythrocytosis is partially caused by the ability of several HCC cells to produce erythropoietin (EPO). Prolyl-4-hydroxylase 2 (PHD2) is an enzyme encoded by the gene EGLN1. The best-known function of PHD2 is to mediate the oxygen-dependent degradation of the labile α-subunit of hypoxia-inducible factor (HIF). However, there is increasing evidence that PHD2 also regulates HIF-independent pathways by interacting with other substrates.
  
  
  METHODS
  In the EPO-producing human HCC cell line HepG2, the expression of PHD2 gene was silenced with siRNA. EPO production was estimated using quantitative PCR and ELISA.
  
  
  RESULTS
  In HepG2 cells, PHD2 suppresses the activity of TGF-β1 pathway and consequently maintains the expression of hepatocyte nuclear factor-4α (HNF-4α), an important transcription factor promoting the EPO expression in hepatocytes. PHD2 knockdown caused a marked reduction of EPO production. HIF seemed not to be involved in this biology.
  
  
  CONCLUSIONS
  Our findings show that PHD2 represents a potential contributing factor for HCC-associated erythrocytosis. Selective inhibition of PHD2 in HCC cells might be considered as a new way to manage erythrocytosis in HCC patients.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Sun
authors.forename: Friederike Katharina
authors.initials: FK
authors.lastname: Kosyna
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jelkmann
authors.forename: Reinhard
authors.initials: R
authors.lastname: Depping
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000150:complications* / Q000378:metabolism; D004921:Erythropoietin / Q000096:biosynthesis*; D056945:Hep G2 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000150:complications* / Q000378:metabolism; D011086:Polycythemia / Q000209:etiology* / Q000378:metabolism; D064828:Prolyl Hydroxylases / Q000378:metabolism*; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D053773:Transforming Growth Factor beta1; D004921:Erythropoietin; D064828:Prolyl Hydroxylases