PMID- 32576270
OWN - NLM
STAT- MEDLINE
DCOM- 20210811
LR  - 20221207
IS  - 1478-811X (Electronic)
IS  - 1478-811X (Linking)
VI  - 18
IP  - 1
DP  - 2020 Jun 23
TI  - Loss-of-function mutations in KEAP1 drive lung cancer progression via KEAP1/NRF2 
      pathway activation.
PG  - 98
LID - 10.1186/s12964-020-00568-z [doi]
LID - 98
AB  - BACKGROUND AND PURPOSE: Targeted therapy and immunotherapy have led to dramatic 
      change in the treatment of lung cancer, however, the overall 5-year survival rate 
      of lung cancer patients is still suboptimal. It is important to exploit new 
      potential of molecularly targeted therapies. High-frequency somatic mutations in 
      KEAP1/NRF2 (27.9%) have been identified in lung squamous cell carcinoma. In this 
      research, we explored the role of KEAP1 somatic mutations in the development of 
      LSCC and whether a nuclear factor erythroid 2-related factor 2(NRF2) inhibitor be 
      potential to target lung cancer carrying KEAP1/NRF2 mutations. METHODS: Lung 
      cancer cell lines A549 and H460 with loss-of-function mutations in KEAP1 stably 
      transfected with wild-type (WT) KEAP1 or somatic mutations in KEAP1 were used to 
      investigate the functions of somatic mutations in KEAP1. Flow cytometry, plate 
      clone formation experiments, and scratch tests were used to examine reactive 
      oxygen species, proliferation, and migration of these cell lines. RESULTS: The 
      expression of NRF2 and its target genes increased, and tumor cell proliferation, 
      migration, and tumor growth were accelerated in A549 and H460 cells stably 
      transfected with KEAP1 mutants compared to control cells with a loss-of-function 
      KEAP1 mutation and stably transfected with WT KEAP1 in both in vitro and in vivo 
      studies. The proliferation of A549 cell line trasfected with the R320Q KEAP1 
      mutant was inhibited more apparent than that of the A549 cell line trasfected 
      with WT KEAP1 after treatment with NRF2 inhibitor ML385. CONCLUSION: Somatic 
      mutations of KEAP1 identified from patients with LSCC likely promote 
      tumorigenesis mediated by activation of the KEAP1/NRF2 antioxidant stress 
      response pathway. NRF2 inhibition with ML385 could inhibit the proliferation of 
      tumor cells with KEAP1 mutation. Video abstract.
FAU - Gong, Meiling
AU  - Gong M
AD  - Department of Respiratory and Critical Care Medicine, Yangpu Hospital, Tongji 
      Universtiy School Of Medicine, Shanghai, China.
FAU - Li, Yan
AU  - Li Y
AD  - Shanghai Jiaotong University School of Medicine, Shanghai, China.
AD  - Shanghai Ninth People's Hospital, Shanghai Jiaotong University, Shanghai, China.
FAU - Ye, Xiaoping
AU  - Ye X
AD  - Shanghai Jiaotong University School of Medicine, Shanghai, China.
FAU - Zhang, Linlin
AU  - Zhang L
AD  - Shanghai University of Traditional Chinese Medicine, Shanghai, China.
FAU - Wang, Zhifang
AU  - Wang Z
AD  - Department of Respiratory and Critical Care Medicine, Yangpu Hospital, Tongji 
      Universtiy School Of Medicine, Shanghai, China.
FAU - Xu, Xiaowen
AU  - Xu X
AD  - Department of Respiratory and Critical Care Medicine, Yangpu Hospital, Tongji 
      Universtiy School Of Medicine, Shanghai, China.
FAU - Shen, Yejing
AU  - Shen Y
AD  - Department of Respiratory and Critical Care Medicine, Yangpu Hospital, Tongji 
      Universtiy School Of Medicine, Shanghai, China.
FAU - Zheng, Cuixia
AU  - Zheng C
AD  - Department of Respiratory and Critical Care Medicine, Yangpu Hospital, Tongji 
      Universtiy School Of Medicine, Shanghai, China. zcx9566@163.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200623
PL  - England
TA  - Cell Commun Signal
JT  - Cell communication and signaling : CCS
JID - 101170464
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (NF-E2-Related Factor 2)
SB  - IM
MH  - Animals
MH  - Asian People/genetics
MH  - Base Sequence
MH  - Carcinogenesis/genetics/pathology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/genetics
MH  - *Disease Progression
MH  - HEK293 Cells
MH  - Humans
MH  - Kelch-Like ECH-Associated Protein 1/*genetics
MH  - Loss of Function Mutation/*genetics
MH  - Lung Neoplasms/*genetics/*pathology
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - NF-E2-Related Factor 2/*metabolism
MH  - *Signal Transduction/drug effects
PMC - PMC7310414
OTO - NOTNLM
OT  - KEAP1/NRF2
OT  - Lung carcinoma
OT  - NRF2 inhibitor
OT  - Somatic mutation
OT  - Targeted therapy
COIS- The authors declare that they have no competing interests.
EDAT- 2020/06/25 06:00
MHDA- 2021/08/12 06:00
PMCR- 2020/06/23
CRDT- 2020/06/25 06:00
PHST- 2019/11/29 00:00 [received]
PHST- 2020/03/25 00:00 [accepted]
PHST- 2020/06/25 06:00 [entrez]
PHST- 2020/06/25 06:00 [pubmed]
PHST- 2021/08/12 06:00 [medline]
PHST- 2020/06/23 00:00 [pmc-release]
AID - 10.1186/s12964-020-00568-z [pii]
AID - 568 [pii]
AID - 10.1186/s12964-020-00568-z [doi]
PST - epublish
SO  - Cell Commun Signal. 2020 Jun 23;18(1):98. doi: 10.1186/s12964-020-00568-z.