PMID- 25212966
OWN - NLM
STAT- MEDLINE
DCOM- 20150727
LR  - 20220330
IS  - 1465-542X (Electronic)
IS  - 1465-5411 (Print)
IS  - 1465-5411 (Linking)
VI  - 16
IP  - 5
DP  - 2014 Sep 9
TI  - Interleukin-like epithelial-to-mesenchymal transition inducer activity is 
      controlled by proteolytic processing and plasminogen-urokinase plasminogen 
      activator receptor system-regulated secretion during breast cancer progression.
PG  - 433
LID - 10.1186/s13058-014-0433-7 [doi]
LID - 433
AB  - INTRODUCTION: Interleukin-like epithelial-to-mesenchymal transition inducer 
      (ILEI) is an essential cytokine in tumor progression that is upregulated in 
      several cancers, and its altered subcellular localization is a predictor of poor 
      survival in human breast cancer. However, the regulation of ILEI activity and the 
      molecular meaning of its altered localization remain elusive. METHODS: The 
      influence of serum withdrawal, broad-specificity protease inhibitors, different 
      serine proteases and plasminogen depletion on the size and amount of the secreted 
      ILEI protein was investigated by Western blot analysis of EpRas cells. Proteases 
      with ILEI-processing capacity were identified by carrying out an in vitro 
      cleavage assay. Murine mammary tumor and metastasis models of EpC40 and 4T1 cells 
      overexpressing different mutant forms of ILEI were used-extended with in vivo 
      aprotinin treatment for the inhibition of ILEI-processing proteases-to test the 
      in vivo relevance of proteolytic cleavage. Stable knockdown of urokinase 
      plasminogen activator receptor (uPAR) in EpRas cells was performed to investigate 
      the involvement of uPAR in ILEI secretion. The subcellular localization of the 
      ILEI protein in tumor cell lines was analyzed by immunofluorescence. 
      Immunohistochemistry for ILEI localization and uPAR expression was performed on 
      two human breast cancer arrays, and ILEI and uPAR scores were correlated with the 
      metastasis-free survival of patients. RESULTS: We demonstrate that secreted ILEI 
      requires site-specific proteolytic maturation into its short form for its 
      tumor-promoting function, which is executed by serine proteases, most efficiently 
      by plasmin. Noncleaved ILEI is tethered to fibronectin-containing fibers of the 
      extracellular matrix through a propeptide-dependent interaction. In addition to 
      ILEI processing, plasmin rapidly increases ILEI secretion by mobilizing its 
      intracellular protein pool in a uPAR-dependent manner. Elevated ILEI secretion 
      correlates with an altered subcellular localization of the protein, most likely 
      representing a shift into secretory vesicles. Moreover, altered subcellular ILEI 
      localization strongly correlates with high tumor cell-associated uPAR protein 
      expression, as well as with poor survival, in human breast cancer. CONCLUSIONS: 
      Our findings point out extracellular serine proteases, in particular plasmin, and 
      uPAR as valuable therapeutic targets against ILEI-driven tumor progression and 
      emphasize the prognostic relevance of ILEI localization and a combined ILEI-uPAR 
      marker analysis in human breast cancer.
FAU - Csiszar, Agnes
AU  - Csiszar A
FAU - Kutay, Betul
AU  - Kutay B
FAU - Wirth, Silvia
AU  - Wirth S
FAU - Schmidt, Ulrike
AU  - Schmidt U
FAU - Macho-Maschler, Sabine
AU  - Macho-Maschler S
FAU - Schreiber, Martin
AU  - Schreiber M
FAU - Alacakaptan, Memetcan
AU  - Alacakaptan M
FAU - Vogel, Georg F
AU  - Vogel GF
FAU - Aumayr, Karin
AU  - Aumayr K
FAU - Huber, Lukas A
AU  - Huber LA
FAU - Beug, Hartmut
AU  - Beug H
LA  - eng
GR  - P 25834/FWF_/Austrian Science Fund FWF/Austria
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140909
PL  - England
TA  - Breast Cancer Res
JT  - Breast cancer research : BCR
JID - 100927353
RN  - 0 (Cytokines)
RN  - 0 (FAM3C protein, human)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Receptors, Urokinase Plasminogen Activator)
RN  - EC 3.4.21.34 (Plasma Kallikrein)
RN  - EC 3.4.21.37 (Leukocyte Elastase)
RN  - EC 3.4.21.7 (Fibrinolysin)
SB  - IM
MH  - Animals
MH  - Breast Neoplasms/*metabolism/mortality/pathology
MH  - Cell Line, Tumor
MH  - Cytokines/*physiology
MH  - Disease Progression
MH  - Epithelial-Mesenchymal Transition
MH  - Female
MH  - Fibrinolysin/metabolism
MH  - Humans
MH  - Kaplan-Meier Estimate
MH  - Leukocyte Elastase/metabolism
MH  - Lung Neoplasms/*metabolism/mortality/secondary
MH  - Mice, Nude
MH  - Neoplasm Proteins/*physiology
MH  - Neoplasm Transplantation
MH  - Plasma Kallikrein/metabolism
MH  - Protein Processing, Post-Translational
MH  - Protein Transport
MH  - Proteolysis
MH  - Receptors, Urokinase Plasminogen Activator/*metabolism
PMC - PMC4303039
EDAT- 2014/09/13 06:00
MHDA- 2015/07/28 06:00
PMCR- 2014/09/09
CRDT- 2014/09/13 06:00
PHST- 2013/09/18 00:00 [received]
PHST- 2014/08/27 00:00 [accepted]
PHST- 2014/09/13 06:00 [entrez]
PHST- 2014/09/13 06:00 [pubmed]
PHST- 2015/07/28 06:00 [medline]
PHST- 2014/09/09 00:00 [pmc-release]
AID - s13058-014-0433-7 [pii]
AID - 433 [pii]
AID - 10.1186/s13058-014-0433-7 [doi]
PST - epublish
SO  - Breast Cancer Res. 2014 Sep 9;16(5):433. doi: 10.1186/s13058-014-0433-7.