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1.
Oncogene ; 39(5): 1152-1164, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31570790

RESUMO

Non-small cell lung cancer remains a highly lethal malignancy. Using the tamoxifen inducible Hnf1b:CreERT2 (H) transgenic mouse crossed to the LsL-KrasG12D (K) transgenic mouse, we recently discovered that an Hnf1b positive cell type in the lung is sensitive to adenoma formation when expressing a mutant KrasG12D allele. In these mice, we observe adenoma formation over a time frame of three to six months. To study specificity of the inducible Hnf1b:CreERT2 in the lung, we employed lineage tracing using an mTmG (G) reporter allele. This technique revealed recombined, GFP+ cells were predominantly SPC+. We further employed this technique in HKG mice to determine Hnf1b+ cells give rise to adenomas that express SPC and TTF1. Review of murine lung tissue confirmed a diagnosis of adenoma and early adenocarcinoma, a pathologic subtype of non-small cell lung cancer. Our expanded mouse model revealed loss of Mst1/2 promotes aggressive lung adenocarcinoma and large-scale proteomic analysis revealed upregulation of PKM2 in the lungs of mice with genetic deletion of Mst1/2. PKM2 is a known metabolic regulator in proliferating cells and cancer. Using a human lung adenocarcinoma cell line, we show pharmacologic inhibition of Mst1/2 increases the abundance of PKM2, indicating genetic loss or pharmacologic inhibition of Mst1/2 directly modulates the abundance of PKM2. In conclusion, here we report a novel model of non-small cell lung cancer driven by a mutation in Kras and deletion of Mst1/2 kinases. Tumor development is restricted to a subset of alveolar type II cells expressing Hnf1b. Our data show loss of Mst1/2 regulates levels of a potent metabolic regulator, PKM2.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Transformação Celular Neoplásica , Modelos Animais de Doenças , Neoplasias Pulmonares/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas ras/genética , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Deleção de Genes , Fator 1-beta Nuclear de Hepatócito/genética , Peptídeos e Proteínas de Sinalização Intracelular , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Serina-Treonina Quinase 3 , Hormônios Tireóideos/metabolismo , Proteínas de Ligação a Hormônio da Tireoide
2.
Cancer Lett ; 453: 122-130, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30946870

RESUMO

Pancreatic cancer remains a highly lethal malignancy. We have recently shown that simultaneous expression of Kras and mutant Tp53R175H promotes invasive ductal adenocarcinoma from pancreatic ductal cells. We hypothesized specific mutations in TP53 have divergent mechanisms of transforming ductal cells. In order to understand the role of mutant TP53 in transforming pancreatic ductal cells, we used a lentiviral system to express mutant TP53R175H and TP53R273H, two of the most frequently mutated TP53 alleles in pancreatic cancer patients, in immortalized, but not transformed, pancreatic ductal epithelial cells carrying a KRAS mutation (HPNE:KRASG12D). Mutant TP53 expression enhanced colony formation and an RPPA assay results revealed TP53R175H uniquely induced HSP70 expression in HPNE:KRASG12D cells. In the context of TP53R175H expression; we observed nuclear localization of HSP70. We performed immunoprecipitation experiments to show mutant p53R175H binds to HSP70. We also provide evidence mutant p53R175H is important for HSP70 stability and, more importantly, HSP70 is required for mutant p53 stability. These data are critical in the context of events leading to cellular transformation in the pancreas.


Assuntos
Proteínas de Choque Térmico HSP70/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Carcinogênese , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Sobrevivência Celular/fisiologia , Proteínas de Choque Térmico HSP70/biossíntese , Proteínas de Choque Térmico HSP70/genética , Humanos , Mutação , Neoplasias Pancreáticas/patologia , Proteômica
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