Foxm1 transcription factor is required for the initiation of lung tumorigenesis by oncogenic KrasG12D

Abstract

Lung cancer is the leading cause of deaths in cancer patients in the United States. Identification of new molecular targets is clearly needed to improve therapeutic outcomes of this devastating human disease. Activating mutations in K-Ras oncogene and increased expression of FOXM1 protein are associated with poor prognosis in patients with non-small-cell lung cancer. Transgenic expression of activated Kras(G12D) in mouse respiratory epithelium is sufficient to induce lung adenocarcinomas; however, transcriptional mechanisms regulated by K-Ras during the initiation of lung cancer remain poorly understood. Foxm1 transcription factor, a downstream target of K-Ras, stimulates cellular proliferation during embryogenesis, organ repair and tumor growth, but its role in tumor initiation is unknown. In the present study, we used transgenic mice expressing Kras(G12D) under control of Sftpc promoter to demonstrate that Foxm1 was induced in type II epithelial cells before the formation of lung tumors. Conditional deletion of Foxm1 from Kras(G12D)-expressing respiratory epithelium prevented the initiation of lung tumors in vivo. The loss of Foxm1 inhibited expression of K-Ras target genes critical for the nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) pathways, including Ikbkb, Nfkb1, Nfkb2, Rela, Jnk1, N-Myc, Pttg1 and Cdkn2a. Transgenic overexpression of activated FOXM1 mutant was sufficient to induce expression of these genes in alveolar type II cells. FOXM1 directly bound to promoter regions of Ikbkb, Nfkb2, N-Myc, Pttg1 and Cdkn2a, indicating that these genes are direct FOXM1 targets. FOXM1 is required for K-Ras-mediated lung tumorigenesis by activating genes critical for the NF-κB and JNK pathways.

Fox transcription factors: from development to disease

“…Conversely, mice lacking FoxM1 or with inhibited FoxM1 function in the tissue of interest show a reduced tumor load compared with controls when treated with carcinogens (Yoshida et al, 2007;Gusarova et al, 2007). Similar results have been observed in the lung, where increased FoxM1 activity hastens lung tumor growth in mice with induced Kras expression , while its absence inhibits lung tumorigenesis mediated by Kras (Wang et al, 2014a). Given this link between FoxM1 and tumor progression, anti-FoxM1 agents are being explored as potential cancer therapeutics (Box 1).…”

Molecular Pathways: Targeting the Cyclin D–CDK4/6 Axis for Cancer Treatment

“…This observation appears to explain why constitutive cyclin D-CDK4/6 signaling overrides the induction of senescence induced by oncogenic BRAF signaling in melanoma nevi (26). These findings have implications beyond melanoma; for example, both FOXM1 and cyclin D-CDK4 suppress cellular senescence induced by oncogenic RAS, and both are critical for KRASinduced tumorigenesis in a mouse model of lung cancer (27)(28)(29). Further studies of the contribution of increased FOXM1 activity to the therapeutic effects of cyclin D-CDK4/6 inhibitors in human cancers are clearly warranted.…”

The NF-κB Genomic Landscape in Lymphoblastoid B Cells

“…However, cross-talk between NF-κB and FOXM1 may underlie published studies. Both FOXM1 and NF-κB are implicated in the pathogenesis of K-Ras-induced non-small cell lung cancer (Wang et al, 2013). Moreover, conditional FOXM1 deletion impairs K-Ras-mediated expression of multiple NF-κB pathway components, including IKK-β, RelA, p105/p50, and p100/p52.…”