Targeted BMI1 inhibition impairs tumor growth in lung adenocarcinomas with low CEBPα expression
| Autor: | Pu Zhang, Atsushi Iwama, Meritxell Alberich-Jorda, Maria Cristina Magli, Junyan Zhang, Daniel G. Tenen, Christopher J. Hetherington, Henry Yang, Min Ye, Daniela S. Basseres, Thomas W. Davis, Kol Jia Yong, Elena Levantini, Lorena Lobo de Figueiredo-Pontes, Bing Lim, Alain C. Borczuk, Hong Zhang, Giorgia Maroni, Ross A. Soo, Wen Cai Zhang, Benedict Yan, Balazs Halmos, Liangxian Cao, Donna Neuberg, Nadiya Sydorenko, Robert S. Welner, Olivier Kocher, Young Choon Moon, Chiara Battelli, Karen B. O'Brien, Lyuba Varticovski, Bhavin Thakkar |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Oncology medicine.medical_specialty Lung Neoplasms xenograft mice cebpa tumor suppressor Adenocarcinoma of Lung macromolecular substances Tumor initiation Adenocarcinoma transgenic mice Biology Article novel therapeutic treatment for lung cancer Mice 03 medical and health sciences 0302 clinical medicine Proto-Oncogene Proteins Internal medicine Enhancer binding CCAAT-Enhancer-Binding Protein-alpha medicine Animals Humans Lung cancer Transcription factor Mice Knockout Polycomb Repressive Complex 1 preclinical murine models of disease Regulation of gene expression BMI1 oncogene as novel therapeutic target in lung cancer knock out mice Cancer in vivo drug treatment General Medicine medicine.disease PROLIFERAÇÃO CELULAR Gene Expression Regulation Neoplastic 030104 developmental biology BMI1 030220 oncology & carcinogenesis Mutation Cancer research |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP Science translational medicine 8 (2016): 350ra104. doi:10.1126/scitranslmed.aad6066 info:cnr-pdr/source/autori:Yong K.J.; Basseres D.S.; Welner R.S.; Zhang W.C.; Yang H.; Yan B.; Alberich-Jorda M.; Zhang J.; De Figueiredo-Pontes L.L.; Battelli C.; Hetherington C.J.; Ye M.; Zhang H.; Maroni G.; O'Brien K.; Magli M.C.; Borczuk A.C.; Varticovski L.; Kocher O.; Zhang P.; Moon Y.-C.; Sydorenko N.; Cao L.; Davis T.W.; Thakkar B.M.; Soo R.A.; Iwama A.; Lim B.; Halmos B.; Neuberg D.; Tenen D.G.; Levantini E./titolo:Targeted BMI1 inhibition impairs tumor growth in lung adenocarcinomas with low CEBPa expression/doi:10.1126%2Fscitranslmed.aad6066/rivista:Science translational medicine/anno:2016/pagina_da:350ra104/pagina_a:/intervallo_pagine:350ra104/volume:8 Sci Transl Med |
| ISSN: | 1946-6242 1946-6234 |
| Popis: | Lung cancer is the most common cause of cancer deaths. The expression of the transcription factor C/EBPα (CCAAT/enhancer binding protein α) is frequently lost in non-small cell lung cancer, but the mechanisms by which C/EBPα suppresses tumor formation are not fully understood. In addition, no pharmacological therapy is available to specifically target C/EBPα expression. We discovered a subset of pulmonary adenocarcinoma patients in whom negative/low C/EBPα expression and positive expression of the oncogenic protein BMI1 (B lymphoma Mo-MLV insertion region 1 homolog) have prognostic value. We also generated a lung-specific mouse model of C/EBPα deletion that develops lung adenocarcinomas, which are prevented by Bmi1 haploinsufficiency. BMI1 activity is required for both tumor initiation and maintenance in the C/EBPα-null background, and pharmacological inhibition of BMI1 exhibits antitumor effects in both murine and human adenocarcinoma lines. Overall, we show that C/EBPα is a tumor suppressor in lung cancer and that BMI1 is required for the oncogenic process downstream of C/EBPα loss. Therefore, anti-BMI1 pharmacological inhibition may offer a therapeutic benefit for lung cancer patients with low expression of C/EBPα and high BMI1. |
| Databáze: | OpenAIRE |
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