PMID- 24762440
OWN - NLM
STAT- MEDLINE
DCOM- 20140818
LR  - 20220408
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 124
IP  - 6
DP  - 2014 Jun
TI  - ZEB1 sensitizes lung adenocarcinoma to metastasis suppression by PI3K antagonism.
PG  - 2696-708
LID - 72171 [pii]
LID - 10.1172/JCI72171 [doi]
AB  - Epithelial tumor cells that have undergone epithelial-to-mesenchymal transition 
      (EMT) are typically prone to metastasis and drug resistance and contribute to a 
      poor clinical outcome. The transcription factor ZEB1 is a known driver of EMT, 
      and mediators of ZEB1 represent potential therapeutic targets for metastasis 
      suppression. Here, we have shown that phosphatidylinositol 3-kinase-targeted 
      (PI3K-targeted) therapy suppresses metastasis in a mouse model of 
      Kras/Tp53-mutant lung adenocarcinoma that develops metastatic disease due to high 
      expression of ZEB1. In lung adenocarcinoma cells from Kras/Tp53-mutant animals 
      and human lung cancer cell lines, ZEB1 activated PI3K by derepressing miR-200 
      targets, including amphiregulin (AREG), betacellulin (BTC), and the transcription 
      factor GATA6, which stimulated an EGFR/ERBB2 autocrine loop. Additionally, 
      ZEB1-dependent derepression of the miR-200 and miR-183 target friend of GATA 2 
      (FOG2) enhanced GATA3-induced expression of the p110alpha catalytic subunit of PI3K. 
      Knockdown of FOG2, p110alpha, and RHEB ameliorated invasive and metastatic 
      propensities of tumor cells. Surprisingly, FOG2 was not required for mesenchymal 
      differentiation, suggesting that mesenchymal differentiation and invasion are 
      distinct and separable processes. Together, these results indicate that ZEB1 
      sensitizes lung adenocarcinoma cells to metastasis suppression by PI3K-targeted 
      therapy and suggest that treatments to selectively modify the metastatic behavior 
      of mesenchymal tumor cells are feasible and may be of clinical value.
FAU - Yang, Yanan
AU  - Yang Y
FAU - Ahn, Young-Ho
AU  - Ahn YH
FAU - Chen, Yulong
AU  - Chen Y
FAU - Tan, Xiaochao
AU  - Tan X
FAU - Guo, Lixia
AU  - Guo L
FAU - Gibbons, Don L
AU  - Gibbons DL
FAU - Ungewiss, Christin
AU  - Ungewiss C
FAU - Peng, David H
AU  - Peng DH
FAU - Liu, Xin
AU  - Liu X
FAU - Lin, Steven H
AU  - Lin SH
FAU - Thilaganathan, Nishan
AU  - Thilaganathan N
FAU - Wistuba, Ignacio I
AU  - Wistuba II
FAU - Rodriguez-Canales, Jaime
AU  - Rodriguez-Canales J
FAU - McLendon, Georgia
AU  - McLendon G
FAU - Creighton, Chad J
AU  - Creighton CJ
FAU - Kurie, Jonathan M
AU  - Kurie JM
LA  - eng
GR  - P30 CA016672/CA/NCI NIH HHS/United States
GR  - P50 CA70907/CA/NCI NIH HHS/United States
GR  - P30 CA125123/CA/NCI NIH HHS/United States
GR  - R01 CA157450/CA/NCI NIH HHS/United States
GR  - T32 CA009299/CA/NCI NIH HHS/United States
GR  - P50 CA070907/CA/NCI NIH HHS/United States
GR  - K08 CA151651/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 - 20140424
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Gonanes)
RN  - 0 (Homeodomain Proteins)
RN  - 0 (Kruppel-Like Transcription Factors)
RN  - 0 (PX-866)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Transcription Factors)
RN  - 0 (ZEB1 protein, human)
RN  - 0 (ZEB1 protein, mouse)
RN  - 0 (Zinc Finger E-box-Binding Homeobox 1)
RN  - EC 2.7.10.1 (EGFR protein, mouse)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Erbb2 protein, mouse)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 3.6.5.2 (Hras protein, mouse)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
SB  - IM
MH  - Adenocarcinoma/drug therapy/*metabolism/*secondary
MH  - Adenocarcinoma of Lung
MH  - Animals
MH  - Cell Line, Tumor
MH  - Enzyme Inhibitors/pharmacology
MH  - Epithelial-Mesenchymal Transition
MH  - ErbB Receptors/metabolism
MH  - Gene Expression Regulation, Enzymologic
MH  - Gene Expression Regulation, Neoplastic
MH  - Genes, p53
MH  - Gonanes/pharmacology
MH  - Homeodomain Proteins/*metabolism
MH  - Humans
MH  - Kruppel-Like Transcription Factors/*metabolism
MH  - Lung Neoplasms/drug therapy/*metabolism/*secondary
MH  - Mice
MH  - Mutation
MH  - Neoplasm Metastasis/prevention & control
MH  - Phosphatidylinositol 3-Kinases/genetics
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Proto-Oncogene Proteins p21(ras)/genetics
MH  - Receptor, ErbB-2/metabolism
MH  - Transcription Factors/*metabolism
MH  - Zinc Finger E-box-Binding Homeobox 1
PMC - PMC4038569
EDAT- 2014/04/26 06:00
MHDA- 2014/08/19 06:00
PMCR- 2014/04/24
CRDT- 2014/04/26 06:00
PHST- 2014/04/26 06:00 [entrez]
PHST- 2014/04/26 06:00 [pubmed]
PHST- 2014/08/19 06:00 [medline]
PHST- 2014/04/24 00:00 [pmc-release]
AID - 72171 [pii]
AID - 10.1172/JCI72171 [doi]
PST - ppublish
SO  - J Clin Invest. 2014 Jun;124(6):2696-708. doi: 10.1172/JCI72171. Epub 2014 Apr 24.