PMID- 26936993
OWN - NLM
STAT- MEDLINE
DCOM- 20171211
LR  - 20181113
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 7
IP  - 12
DP  - 2016 Mar 22
TI  - FGFR1 promotes the stem cell-like phenotype of FGFR1-amplified non-small cell 
      lung cancer cells through the Hedgehog pathway.
PG  - 15118-34
LID - 10.18632/oncotarget.7701 [doi]
AB  - Cancer stem cell-like phenotype is critical for tumor formation and treatment 
      resistance. FGFR1 is found to be amplified in non-small cell lung cancer, 
      particularly in the lung squamous cell cancer (LSCC). Whether FGFR1 contributes 
      to the maintenance of stem cell-like phenotype of FGFR1-amplified lung cancer 
      cells remains elusive. In this study, treatment with FGFR1 inhibitor AZD4547 
      suppressed the growth of tumor spheres and reduced ALDH positive proportion in 
      FGFR1-amplified lung cancer cells in vitro, as well as inhibited the growth of 
      oncospheres and parental cells in xenograft models. Knockdown of FGFR1 recaptured 
      the similar effect as AZD4547 in vitro. Furthermore, activation of FGFR1 and 
      subsequently its downstream ERK signaling enhanced the expression and 
      transcriptional activity of GLI2, which could be blocked by FGFR1 
      inhibitor/silencing or ERK inhibitor. Knockdown of GLI2 directly inhibited the 
      stem-like phenotype of FGFR1-amilified cells, whereas overexpression of GLI2 
      sufficiently rescued the phenotype caused by FGFR1 knockdown. Notably we also 
      identified a correlation between FGFR1 and GLI2 expressions from clinical data, 
      as well as an inverse relationship with progression free survival (PFS). Together 
      our study suggests that the FGFR1/GLI2 axis promotes the lung cancer stem 
      cell-like phenotype. These results support a rational strategy of combination of 
      FGFR1 and GLI inhibitors for treatment of FGFR1-amplified lung cancers, 
      especially LSCC.
FAU - Ji, Wenxiang
AU  - Ji W
AD  - Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong 
      University, Shanghai 200030, China.
AD  - State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem 
      Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, Shanghai 
      Jiao Tong University, Shanghai 200030, China.
FAU - Yu, Yongfeng
AU  - Yu Y
AD  - Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong 
      University, Shanghai 200030, China.
FAU - Li, Ziming
AU  - Li Z
AD  - Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong 
      University, Shanghai 200030, China.
FAU - Wang, Guan
AU  - Wang G
AD  - Genomics Center, WuXiAppTec Co., Ltd., Shanghai 200131, China.
FAU - Li, Fan
AU  - Li F
AD  - State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem 
      Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, Shanghai 
      Jiao Tong University, Shanghai 200030, China.
FAU - Xia, Weiliang
AU  - Xia W
AD  - State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem 
      Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, Shanghai 
      Jiao Tong University, Shanghai 200030, China.
FAU - Lu, Shun
AU  - Lu S
AD  - Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong 
      University, Shanghai 200030, China.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (GLI2 protein, human)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Zinc Finger Protein Gli2)
RN  - EC 2.7.10.1 (FGFR1 protein, human)
RN  - EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 1)
SB  - IM
MH  - Apoptosis
MH  - Biomarkers, Tumor/metabolism
MH  - Carcinoma, Non-Small-Cell Lung/genetics/metabolism/*pathology
MH  - Carcinoma, Squamous Cell/genetics/metabolism/*pathology
MH  - Cell Proliferation
MH  - Gene Amplification
MH  - Gene Expression Regulation, Neoplastic
MH  - Hedgehog Proteins/genetics/*metabolism
MH  - Humans
MH  - Lung Neoplasms/genetics/metabolism/*pathology
MH  - Neoplastic Stem Cells/metabolism/*pathology
MH  - Nuclear Proteins/*metabolism
MH  - Phenotype
MH  - Receptor, Fibroblast Growth Factor, Type 1/genetics/*metabolism
MH  - Signal Transduction
MH  - Tumor Cells, Cultured
MH  - Zinc Finger Protein Gli2/*metabolism
PMC - PMC4924774
OTO - NOTNLM
OT  - FGFR1
OT  - GLI2
OT  - lung squamous cell cancer
OT  - stem cell-like phenotype
COIS- CONFLICTS OF INTEREST The authors declare no conflict of interest.
EDAT- 2016/03/05 06:00
MHDA- 2017/12/12 06:00
PMCR- 2016/03/22
CRDT- 2016/03/04 06:00
PHST- 2015/08/22 00:00 [received]
PHST- 2016/01/29 00:00 [accepted]
PHST- 2016/03/04 06:00 [entrez]
PHST- 2016/03/05 06:00 [pubmed]
PHST- 2017/12/12 06:00 [medline]
PHST- 2016/03/22 00:00 [pmc-release]
AID - 7701 [pii]
AID - 10.18632/oncotarget.7701 [doi]
PST - ppublish
SO  - Oncotarget. 2016 Mar 22;7(12):15118-34. doi: 10.18632/oncotarget.7701.