PMID- 31436357
OWN - NLM
STAT- MEDLINE
DCOM- 20200124
LR  - 20200124
IS  - 1098-2744 (Electronic)
IS  - 0899-1987 (Linking)
VI  - 58
IP  - 11
DP  - 2019 Nov
TI  - Macrophage HIF-2alpha regulates tumor-suppressive Spint1 in the tumor 
      microenvironment.
PG  - 2127-2138
LID - 10.1002/mc.23103 [doi]
AB  - In solid tumors, tumor-associated macrophages (TAMs) commonly accumulate within 
      hypoxic areas. Adaptations to such environments evoke transcriptional changes by 
      the hypoxia-inducible factors (HIFs). While HIF-1alpha is ubiquitously expressed, 
      HIF-2alpha appears tissue-specific with consequences of HIF-2alpha expression in TAMs 
      only being poorly characterized. An E0771 allograft breast tumor model revealed 
      faster tumor growth in myeloid HIF-2alpha knockout (HIF-2alpha(LysM-/-) ) compared with 
      wildtype (wt) mice. In an RNA-sequencing approach of FACS sorted wt and HIF-2alpha 
      (LysM-/-) TAMs, serine protease inhibitor, Kunitz type-1 ( Spint1) emerged as a 
      promising candidate for HIF-2alpha-dependent regulation. We validated reduced Spint1 
      messenger RNA expression and concomitant Spint1 protein secretion under hypoxia 
      in HIF-2alpha-deficient bone marrow-derived macrophages (BMDMs) compared with wt 
      BMDMs. In line with the physiological function of Spint1 as an inhibitor of 
      hepatocyte growth factor (HGF) activation, supernatants of hypoxic HIF-2alpha 
      knockout BMDMs, not containing Spint1, were able to release proliferative 
      properties of inactive pro-HGF on breast tumor cells. In contrast, hypoxic wt 
      BMDM supernatants containing abundant Spint1 amounts failed to do so. We propose 
      that Spint1 contributes to the tumor-suppressive function of HIF-2alpha in TAMs in 
      breast tumor development.
CI  - (c) 2019 The Authors. Molecular Carcinogenesis published by Wiley Periodicals, Inc.
FAU - Susen, Rosa M
AU  - Susen RM
AD  - Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 
      Frankfurt, Germany.
FAU - Bauer, Rebekka
AU  - Bauer R
AD  - Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 
      Frankfurt, Germany.
FAU - Olesch, Catherine
AU  - Olesch C
AD  - Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 
      Frankfurt, Germany.
FAU - Fuhrmann, Dominik C
AU  - Fuhrmann DC
AD  - Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 
      Frankfurt, Germany.
FAU - Fink, Annika F
AU  - Fink AF
AD  - Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 
      Frankfurt, Germany.
FAU - Dehne, Nathalie
AU  - Dehne N
AD  - Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 
      Frankfurt, Germany.
FAU - Jain, Arpit
AU  - Jain A
AD  - Applied Bioinformatics Group, Institute of Cell Biology and Neuroscience, 
      Goethe-University Frankfurt, Frankfurt, Germany.
FAU - Ebersberger, Ingo
AU  - Ebersberger I
AD  - Applied Bioinformatics Group, Institute of Cell Biology and Neuroscience, 
      Goethe-University Frankfurt, Frankfurt, Germany.
AD  - Senckenberg Biodiversity and Climate Research Centre (BiK-F), Frankfurt, Germany.
FAU - Schmid, Tobias
AU  - Schmid T
AUID- ORCID: 0000-0002-1952-5259
AD  - Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 
      Frankfurt, Germany.
FAU - Brune, Bernhard
AU  - Brune B
AUID- ORCID: 0000-0001-8237-2841
AD  - Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 
      Frankfurt, Germany.
AD  - German Cancer Consortium (DKTK), Partner Site Frankfurt, Frankfurt, Germany.
AD  - Frankfurt Cancer Institute, Goethe-University Frankfurt, Frankfurt, Germany.
AD  - Project Group Translational Medicine and Pharmacology TMP, Fraunhofer Institute 
      for Molecular Biology and Applied Ecology, Frankfurt, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190822
PL  - United States
TA  - Mol Carcinog
JT  - Molecular carcinogenesis
JID - 8811105
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Proteinase Inhibitory Proteins, Secretory)
RN  - 0 (RNA, Messenger)
RN  - 0 (Spint1 protein, mouse)
RN  - 1B37H0967P (endothelial PAS domain-containing protein 1)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
SB  - IM
MH  - Allografts
MH  - Animals
MH  - Basic Helix-Loop-Helix Transcription Factors/*genetics
MH  - Cell Line, Tumor
MH  - Gene Expression Regulation, Neoplastic/genetics
MH  - Hepatocyte Growth Factor/genetics
MH  - Humans
MH  - Macrophages/metabolism/pathology
MH  - Membrane Glycoproteins/genetics
MH  - Mice
MH  - Neoplasms/*genetics/pathology
MH  - Proteinase Inhibitory Proteins, Secretory/*genetics
MH  - RNA, Messenger
MH  - Tumor Microenvironment/*genetics
OTO - NOTNLM
OT  - HAI-1
OT  - HGF
OT  - hypoxia
OT  - proliferation
OT  - tumor-associated macrophages
EDAT- 2019/08/23 06:00
MHDA- 2020/01/25 06:00
CRDT- 2019/08/23 06:00
PHST- 2019/05/14 00:00 [received]
PHST- 2019/08/06 00:00 [revised]
PHST- 2019/08/06 00:00 [accepted]
PHST- 2019/08/23 06:00 [pubmed]
PHST- 2020/01/25 06:00 [medline]
PHST- 2019/08/23 06:00 [entrez]
AID - 10.1002/mc.23103 [doi]
PST - ppublish
SO  - Mol Carcinog. 2019 Nov;58(11):2127-2138. doi: 10.1002/mc.23103. Epub 2019 Aug 22.