PMID- 27041571
OWN - NLM
STAT- MEDLINE
DCOM- 20170906
LR  - 20220321
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 35
IP  - 43
DP  - 2016 Oct 27
TI  - SHP-2-upregulated ZEB1 is important for PDGFRalpha-driven glioma 
      epithelial-mesenchymal transition and invasion in mice and humans.
PG  - 5641-5652
LID - 10.1038/onc.2016.100 [doi]
AB  - Gliomas are highly malignant brain tumors that are highly invasive and resistant 
      to conventional therapy. Receptor tyrosine kinases (RTKs) such as PDGFRalpha 
      (platelet-derived growth factor receptor-alpha), which show frequent aberrant 
      activation in gliomas, are associated with a process of epithelial-mesenchymal 
      transition (EMT), a cellular alteration that confers a more invasive and 
      drug-resistant phenotype. Although this phenomenon is well documented in human 
      cancers, the processes by which RTKs including PDGFRalpha mediate EMT are largely 
      unknown. Here, we report that SHP-2 (encoded by PTPN11) upregulates an EMT 
      inducer, ZEB1, to mediate PDGFRalpha-driven glioma EMT, invasion and growth in glioma 
      cell lines and patient-derived glioma stem cells (GSCs) using cell culture and 
      orthotopic xenograft models. ZEB1 and activated PDGFRalpha were coexpressed in 
      invasive regions of mouse glioma xenografts and clinical glioma specimens. Glioma 
      patients with high levels of both phospho-PDGFRalpha (p-PDGFRalpha) and ZEB1 had 
      significantly shorter overall survival compared with those with low expression of 
      p-PDGFRalpha and ZEB1. Knockdown of ZEB1 inhibited PDGFA/PDGFRalpha-stimulated glioma 
      EMT, tumor growth and invasion in glioma cell lines and patient-derived GSCs. 
      PDGFRalpha mutant deficient of SHP2 binding (PDGFRalpha-F720) or phosphoinositide 
      3-kinase (PI3K) binding (PDGFRalpha-F731/42), knockdown of SHP2 or treatments of 
      pharmacological inhibitor for PDGFRalpha-signaling effectors attenuated 
      PDGFA/PDGFRalpha-stimulated ZEB1 expression, cell migration and GSC proliferation. 
      Importantly, SHP-2 acts together with PI3K/AKT to regulate a ZEB1-miR-200 
      feedback loop in PDGFRalpha-driven gliomas. Taken together, our findings uncover a 
      new pathway in which ZEB1 functions as a key regulator for PDGFRalpha-driven glioma 
      EMT, invasiveness and growth, suggesting that ZEB1 is a promising therapeutic 
      target for treating gliomas with high PDGFRalpha activation.
FAU - Zhang, L
AU  - Zhang L
AD  - State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem 
      Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, China.
FAU - Zhang, W
AU  - Zhang W
AD  - State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem 
      Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, China.
FAU - Li, Y
AU  - Li Y
AD  - Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Pediatric 
      Translational Medicine Institute, Shanghai Children's Medical Center, School of 
      Medicine, Shanghai Jiao Tong University, Shanghai, China.
FAU - Alvarez, A
AU  - Alvarez A
AD  - Department of Neurology, Northwestern Brain Tumor Institute, Center for Genetic 
      Medicine, The Robert H Lurie Comprehensive Cancer Center, Northwestern University 
      Feinberg School of Medicine, Chicago, IL, USA.
FAU - Li, Z
AU  - Li Z
AD  - State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem 
      Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, China.
FAU - Wang, Y
AU  - Wang Y
AD  - State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem 
      Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, China.
FAU - Song, L
AU  - Song L
AD  - State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem 
      Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, China.
FAU - Lv, D
AU  - Lv D
AD  - State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem 
      Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, China.
FAU - Nakano, I
AU  - Nakano I
AD  - Department of Neurosurgery, Cell Developmental and Integrative Biology, 
      Biochemistry and Molecular Genetics, University of Alabama at Birmingham, 
      Birmingham, AL, USA.
FAU - Hu, B
AU  - Hu B
AD  - Department of Neurology, Northwestern Brain Tumor Institute, Center for Genetic 
      Medicine, The Robert H Lurie Comprehensive Cancer Center, Northwestern University 
      Feinberg School of Medicine, Chicago, IL, USA.
FAU - Cheng, S-Y
AU  - Cheng SY
AD  - State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem 
      Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, China.
AD  - Department of Neurology, Northwestern Brain Tumor Institute, Center for Genetic 
      Medicine, The Robert H Lurie Comprehensive Cancer Center, Northwestern University 
      Feinberg School of Medicine, Chicago, IL, USA.
FAU - Feng, H
AU  - Feng H
AD  - State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem 
      Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong 
      University, Shanghai, China.
LA  - eng
GR  - R01 NS083767/NS/NINDS NIH HHS/United States
GR  - R01 NS095634/NS/NINDS NIH HHS/United States
GR  - R01 CA159811/CA/NCI NIH HHS/United States
GR  - R01 NS093843/NS/NINDS NIH HHS/United States
GR  - T32 CA070085/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20160404
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (MIRN200 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 0 (ZEB1 protein, human)
RN  - 0 (Zinc Finger E-box-Binding Homeobox 1)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.10.1 (Receptor, Platelet-Derived Growth Factor alpha)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11)
SB  - IM
MH  - Animals
MH  - Brain Neoplasms/genetics/metabolism/pathology
MH  - Cell Line, Tumor
MH  - Cell Movement/genetics
MH  - *Epithelial-Mesenchymal Transition/genetics
MH  - Gene Expression
MH  - Glioma/genetics/*metabolism/*pathology
MH  - Humans
MH  - Mice
MH  - MicroRNAs/genetics
MH  - Models, Biological
MH  - Neoplasm Invasiveness
MH  - Neoplastic Stem Cells/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - RNA Interference
MH  - Receptor, Platelet-Derived Growth Factor alpha/genetics/*metabolism
MH  - Signal Transduction
MH  - Tumor Stem Cell Assay
MH  - Up-Regulation
MH  - Zinc Finger E-box-Binding Homeobox 1/*metabolism
PMC - PMC5050071
MID - NIHMS780334
COIS- The authors declare no conflict of interest.
EDAT- 2016/10/28 06:00
MHDA- 2017/09/07 06:00
PMCR- 2016/11/04
CRDT- 2016/04/05 06:00
PHST- 2015/07/12 00:00 [received]
PHST- 2015/12/20 00:00 [revised]
PHST- 2016/01/19 00:00 [accepted]
PHST- 2016/10/28 06:00 [pubmed]
PHST- 2017/09/07 06:00 [medline]
PHST- 2016/04/05 06:00 [entrez]
PHST- 2016/11/04 00:00 [pmc-release]
AID - onc2016100 [pii]
AID - 10.1038/onc.2016.100 [doi]
PST - ppublish
SO  - Oncogene. 2016 Oct 27;35(43):5641-5652. doi: 10.1038/onc.2016.100. Epub 2016 Apr 
      4.