PMID- 23225569
OWN - NLM
STAT- MEDLINE
DCOM- 20130612
LR  - 20160303
IS  - 1097-0215 (Electronic)
IS  - 0020-7136 (Linking)
VI  - 132
IP  - 12
DP  - 2013 Jun 15
TI  - Knockdown of prolyl-4-hydroxylase domain 2 inhibits tumor growth of human breast 
      cancer MDA-MB-231 cells by affecting TGF-beta1 processing.
PG  - 2787-98
LID - 10.1002/ijc.27982 [doi]
AB  - The prolyl-4-hydroxylase domain 1-3 (PHD1-3) enzymes are regulating the protein 
      stability of the alpha-subunit of the hypoxia-inducible factor-1 (HIF-1), which 
      mediates oxygen-dependent gene expression. PHD2 is the main isoform regulating 
      HIF-1alpha hydroxylation and thus stability in normoxia. In human cancers, HIF-1alpha is 
      overexpressed as a result of intratumoral hypoxia which in turn promotes tumor 
      progression. The role of PHD2 for tumor progression is in contrast far from being 
      thoroughly understood. Therefore, we established PHD2 knockdown clones of 
      MDA-MB-231 breast cancer cells and analyzed their tumor-forming potential in a 
      SCID mouse model. Tumor progression was significantly impaired in the PHD2 
      knockdown MDA-MB-231 cells, which could be partially rescued by re-establishing 
      PHD2 expression. In a RNA profile screen, we identified the secreted 
      phosphoprotein 1 (SPP1) as one target, which is differentially regulated as a 
      consequence of the PHD2 knockdown. Knockdown of PHD2 drastically reduced the SPP1 
      expression in MDA-MB-231 cells. A correlation of SPP1 and PHD2 expression was 
      additionally verified in 294 invasive breast cancer biopsies. In subsequent 
      analyses, we identified that PHD2 alters the processing of transforming growth 
      factor (TGF)-beta1, which is highly involved in SPP1 expression. The altered 
      processing capacity was associated with a dislocation of the pro-protein 
      convertase furin. Thus, our data demonstrate that in MDA-MB-231 cells PHD2 might 
      affect tumor-relevant TGF-beta1 target gene expression by altering the TGF-beta1 
      processing capacity.
CI  - Copyright (c) 2012 UICC.
FAU - Wottawa, Marieke
AU  - Wottawa M
AD  - Department of Cardiovascular Physiology, University Medical Center, Georg-August 
      University of Gottingen, D-37073 Gottingen, Germany.
FAU - Leisering, Pia
AU  - Leisering P
FAU - Ahlen, Melanie von
AU  - Ahlen Mv
FAU - Schnelle, Moritz
AU  - Schnelle M
FAU - Vogel, Sabine
AU  - Vogel S
FAU - Malz, Cordula
AU  - Malz C
FAU - Bordoli, Mattia Renato
AU  - Bordoli MR
FAU - Camenisch, Gieri
AU  - Camenisch G
FAU - Hesse, Amke
AU  - Hesse A
FAU - Napp, Joanna
AU  - Napp J
FAU - Alves, Frauke
AU  - Alves F
FAU - Kristiansen, Glen
AU  - Kristiansen G
FAU - Farhat, Katja
AU  - Farhat K
FAU - Katschinski, Dorthe Magdalena
AU  - Katschinski DM
LA  - eng
PT  - Journal Article
DEP - 20121227
PL  - United States
TA  - Int J Cancer
JT  - International journal of cancer
JID - 0042124
RN  - 0 (SPP1 protein, human)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 106441-73-0 (Osteopontin)
RN  - EC 1.14.11.2 (EGLN1 protein, human)
RN  - EC 1.14.11.2 (Procollagen-Proline Dioxygenase)
RN  - EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases)
SB  - IM
MH  - Animals
MH  - Breast Neoplasms/*genetics/*metabolism/pathology
MH  - Disease Models, Animal
MH  - Female
MH  - Gene Expression Regulation, Neoplastic
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Hypoxia-Inducible Factor-Proline Dioxygenases
MH  - Mice
MH  - Osteopontin/genetics
MH  - Procollagen-Proline Dioxygenase/*genetics
MH  - Signal Transduction
MH  - Transforming Growth Factor beta1/*metabolism
MH  - Tumor Burden/genetics
MH  - Xenograft Model Antitumor Assays
EDAT- 2012/12/12 06:00
MHDA- 2013/06/13 06:00
CRDT- 2012/12/11 06:00
PHST- 2012/06/13 00:00 [received]
PHST- 2012/11/21 00:00 [accepted]
PHST- 2012/12/11 06:00 [entrez]
PHST- 2012/12/12 06:00 [pubmed]
PHST- 2013/06/13 06:00 [medline]
AID - 10.1002/ijc.27982 [doi]
PST - ppublish
SO  - Int J Cancer. 2013 Jun 15;132(12):2787-98. doi: 10.1002/ijc.27982. Epub 2012 Dec 
      27.