NFIB overexpression cooperates with Rb/p53 deletion to promote small cell lung cancer.
Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor type that is typically metastatic upon diagnosis. We have a poor understanding of the factors that control SCLC progression and metastasis. TheNFIB transcription factor is frequently amplified in mouse models of SCLC, but clear evidence that NFIB promotes SCLC in vivo is lacking. We report that in mouse models, Nfib amplifications are far more frequent in liver metastases over primary SCLC, suggesting roles in tumor progression/metastasis. Overexpression of Nfib in a sensitized mouse model led to acceleration of SCLC, indicating that Nfib functions as a bona fide oncogene. Suppression of Nfib expression in cell lines derived from the doxycycline-inducible Rb/p53/TET-Nfib model led to increased apoptosis and suppression of proliferation. Transcriptional analysis revealed that Nfib regulates the expression of genes related to axon guidance, focal adhesion and extracellular matrix-receptor interactions. These data indicate that Nfib is a potent oncogene in SCLC, and the enrichment of Nfib amplifications in liver metastases over primary SCLC points to Nfib as a candidate driver of SCLC metastasis.
Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Nan
N
Wu
Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Deshui
D
Jia
Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Ali H
AH
Ibrahim
Division of Pulmonary Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA.
Cindy J
CJ
Bachurski
Department of Biochemistry, Program in Genetics, Genomics & Bioinformatics, University at Buffalo, Buffalo, NY, USA.
Richard M
RM
Gronostajski
Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Department of Genome Sciences, University of Washington, Seattle, WA, USA.
David
D
MacPherson
D000483:Alleles; D000818:Animals; D017209:Apoptosis; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D004195:Disease Models, Animal; D018450:Disease Progression; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D051839:NFI Transcription Factors / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009857:Oncogenes; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D055752:Small Cell Lung Carcinoma / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D051839:NFI Transcription Factors; C484683:Nfib protein, mouse; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53
NFI; metastasis; mouse model; nuclear factor I; oncogene