NFIB overexpression cooperates with Rb/p53 deletion to promote small cell lung cancer

// Nan Wu 1 , Deshui Jia 1 , Ali H. Ibrahim 1 , Cindy J. Bachurski 2 , Richard M. Gronostajski 3 and David MacPherson 1,4 1 Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA 2 Division of Pulmonary Biology, Cincinnati Children’s Hospital Research Foundation, Cincinnati, OH, USA 3 Department of Biochemistry, Program in Genetics, Genomics & Bioinformatics, University at Buffalo, Buffalo, NY, USA 4 Department of Genome Sciences, University of Washington, Seattle, WA, USA Correspondence to: David MacPherson, email: // Keywords : oncogene, metastasis, mouse model, nuclear factor I, NFI Received : June 28, 2016 Accepted : August 20, 2016 Published : August 24, 2016 Abstract 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.