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Targeted BMI1 inhibition impairs tumor growth in lung adenocarcinomas with low CEBPα expression
KJ. Yong, DS. Basseres, RS. Welner, WC. Zhang, H. Yang, B. Yan, M. Alberich-Jorda, J. Zhang, LL. de Figueiredo-Pontes, C. Battelli, CJ. Hetherington, M. Ye, H. Zhang, G. Maroni, K. O'Brien, MC. Magli, AC. Borczuk, L. Varticovski, O. Kocher, P....
Science translational medicine.
2016 ;
8 (350) :
350ra104.
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem
Perzistentní odkaz
https://www.medvik.cz/link/bmc18017119
- MeSH
- adenokarcinom genetika metabolismus patologie terapie MeSH
- lidé MeSH
- mutace genetika MeSH
- myši knockoutované MeSH
- myši MeSH
- nádory plic genetika metabolismus patologie terapie MeSH
- PRC1 genetika metabolismus MeSH
- protein alfa vázající zesilovač transkripce CCAAT genetika metabolismus MeSH
- protoonkogenní proteiny genetika metabolismus MeSH
- regulace genové exprese u nádorů genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
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.
Beth Israel Deaconess Medical Center Boston MA 02215 USA Harvard Medical School Boston MA 02215 USA
Cancer Science Institute National University of Singapore Singapore 117599 Singapore
Department of Pathology Weill Cornell University Medical Center New York NY 10065 USA
Division of Hematology Oncology Montefiore Hospital Bronx NY 10461 USA
Institute of Biomedical Technologies National Research Council Pisa 56124 Italy
PTC Therapeutics 100 Corporate Court South Plainfield NJ 07080 USA
Citace poskytuje Crossref.org
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- $a 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.
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