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LKB1 Loss induces characteristic patterns of gene expression in human tumors associated with NRF2 activation and attenuation of PI3K-AKT.
Abstract
Inactivation of serine/threonine kinase 11 (STK11 or LKB1) is common in lung cancer,
and understanding the pathways and phenotypes altered as a consequence will aid the
development of targeted therapeutic strategies. Gene and protein expressions in a
murine model of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (Kras)-mutant
lung cancer have been studied to gain insight into the biology of these tumors. However,
the molecular consequences of LKB1 loss in human lung cancer have not been fully characterized.We
studied gene expression profiles associated with LKB1 loss in resected lung adenocarcinomas,
non-small-cell lung cancer cell lines, and murine tumors. The biological significance
of dysregulated genes was interpreted using gene set enrichment and transcription
factor analyses and also by integration with somatic mutations and proteomic data.Loss
of LKB1 is associated with consistent gene expression changes in resected human lung
cancers and cell lines that differ substantially from the mouse model. Our analysis
implicates novel biological features associated with LKB1 loss, including altered
mitochondrial metabolism, activation of the nuclear respiratory factor 2 (NRF2) transcription
factor by kelch-like ECH-associated protein 1 (KEAP1) mutations, and attenuation of
the phosphatidylinositiol 3-kinase and v-akt murine thymoma viral oncogene homolog
(PI3K/AKT) pathway. Furthermore, we derived a 16-gene classifier that accurately predicts
LKB1 mutations and loss by nonmutational mechanisms. In vitro, transduction of LKB1
into LKB1-mutant cell lines results in attenuation of this signature.Loss of LKB1
defines a subset of lung adenocarcinomas associated with characteristic molecular
phenotypes and distinctive gene expression features. Studying these effects may improve
our understanding of the biology of these tumors and lead to the identification of
targeted treatment strategies.
Type
Journal articleSubject
Cell Line, TumorMitochondria
Animals
Humans
Mice
Adenocarcinoma
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
ras Proteins
Protein-Serine-Threonine Kinases
Receptor, Epidermal Growth Factor
Intracellular Signaling Peptides and Proteins
Adaptor Proteins, Signal Transducing
Cytoskeletal Proteins
Proto-Oncogene Proteins
RNA, Messenger
Signal Transduction
Phosphorylation
Mutation
Multigene Family
Tumor Suppressor Protein p53
Proto-Oncogene Proteins p21(ras)
Proto-Oncogene Proteins c-akt
NF-E2-Related Factor 2
GA-Binding Protein Transcription Factor
AMP-Activated Protein Kinases
Phosphatidylinositol 3-Kinase
Transcriptome
Ataxia Telangiectasia Mutated Proteins
Kelch-Like ECH-Associated Protein 1
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https://hdl.handle.net/10161/17310Published Version (Please cite this version)
10.1097/jto.0000000000000173Publication Info
Kaufman, Jacob M; Amann, Joseph M; Park, Kyungho; Arasada, Rajeswara Rao; Li, Haotian;
Shyr, Yu; & Carbone, David P (2014). LKB1 Loss induces characteristic patterns of gene expression in human tumors associated
with NRF2 activation and attenuation of PI3K-AKT. Journal of thoracic oncology : official publication of the International Association
for the Study of Lung Cancer, 9(6). pp. 794-804. 10.1097/jto.0000000000000173. Retrieved from https://hdl.handle.net/10161/17310.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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