TY - JOUR
T1 - Prolyl-4-hydroxylase 2 potentially contributes to hepatocellular carcinoma-associated erythrocytosis by maintaining hepatocyte nuclear Factor-4α expression
AU - Sun, Wenwen
AU - Kosyna, Friederike Katharina
AU - Jelkmann, Wolfgang
AU - Depping, Reinhard
N1 - Funding Information:
We thank G Huck and P Rouina for excellent technical support. The project was financially supported by Werner und Klara Kreitz-Stiftung. W.S. performed the experiments, analysed the results and prepared the figures. W.S., F.K.K., W.J. and R.D. designed the research and/or wrote the paper.
Publisher Copyright:
© 2015 S. Karger AG, Basel.
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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. Conclusion: 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.
AB - 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. Conclusion: 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.
UR - http://www.scopus.com/inward/record.url?scp=84949568308&partnerID=8YFLogxK
U2 - 10.1159/000438581
DO - 10.1159/000438581
M3 - Journal articles
C2 - 26624507
AN - SCOPUS:84949568308
SN - 1015-8987
VL - 37
SP - 2257
EP - 2264
JO - Cellular Physiology and Biochemistry
JF - Cellular Physiology and Biochemistry
IS - 6
ER -