Abstract
The MEN1 gene, a tumor suppressor gene that encodes the protein menin, is mutated at high frequencies in neuroendocrine (NE) tumors; however, the biological importance of this gene in NE-type lung cancer in vivo remains unclear. Here, we established an ATII-specific KrasG12D/+/Men1−/− driven genetically engineered mouse model and show that deficiency of menin results in the accumulation of DNA damage and antagonizes oncogenic Kras-induced senescence and the epithelial-to-mesenchymal transition during lung tumorigenesis. The loss of menin expression in certain human primary lung cancers correlates with elevated NE profiles and reduced overall survival.
Highlights
The multiple endocrine neoplasia type 1 (MEN1) gene, a tumor suppressor gene that encodes the protein menin, is mutated at high frequencies in neuroendocrine (NE) tumors; the biological importance of this gene in NE-type lung cancer in vivo remains unclear
The menin expression is inactivated in certain human primary lung cancers, and this low expression is further associated with elevated NE profiles and significantly reduced 9-year overall survival
Activating Hras-transduced cells upregulates the expression of vimentin and CD44 and silences the expression of NE markers, thereby resulting in an NE-to-mesenchymal transition in smallcell lung cancer (SCLC) cells[20]
Summary
The MEN1 gene, a tumor suppressor gene that encodes the protein menin, is mutated at high frequencies in neuroendocrine (NE) tumors; the biological importance of this gene in NE-type lung cancer in vivo remains unclear. Kras-activating mutation-driven genetically engineered mouse models (GEMMs) accurately reflect the biology of NSCLC with a mesenchymal profile, whereas Rb/p53 deletion produces tumors with NE-type SCLC features[6,7]. Recent studies have found that LSD1 inhibitors have excellent physicochemical properties that demonstrate efficacy in SCLC models[9] These findings indicate a potential role for chromatin remodeling in controlling the development of P-NETs and further suggest that chromatin modifications may serve as therapeutic targets. The MEN1/MLL gene is mutated at high frequencies in certain types of human NE lung cancers, such as lung carcinoids or SCLC15,16, suggesting that menin regulation is a common characteristic in NE-type neoplasms originating from multiple organs, including NE-type lung cancer
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