Targeted BMI1 inhibition impairs tumor growth in lung adenocarcinomas with low CEBP alpha expression

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F16%3A00473109" target="_blank" >RIV/68378050:_____/16:00473109 - isvavai.cz</a>

Výsledek na webu

<a href="http://dx.doi.org/10.1126/scitranslmed.aad6066" target="_blank" >http://dx.doi.org/10.1126/scitranslmed.aad6066</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1126/scitranslmed.aad6066" target="_blank" >10.1126/scitranslmed.aad6066</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Targeted BMI1 inhibition impairs tumor growth in lung adenocarcinomas with low CEBP alpha expression

Popis výsledku v původním jazyce

Lung cancer is the most common cause of cancer deaths. The expression of the transcription factor C/EBP alpha (CCAAT/enhancer binding protein a) is frequently lost in non-small cell lung cancer, but the mechanisms by which C/EBP alpha suppresses tumor formation are not fully understood. In addition, no pharmacological therapy is available to specifically target C/EBP alpha expression. We discovered a subset of pulmonary adenocarcinoma patients in whom negative/low C/EBP alpha 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/EBP alpha deletion that develops lung adenocarcinomas, which are prevented by Bmi1 haploinsufficiency. BMI1 activity is required for both tumor initiation and maintenance in the C/EBP alpha-null background, and pharmacological inhibition of BMI1 exhibits antitumor effects in both murine and human adenocarcinoma lines. Overall, we show that C/EBP alpha is a tumor suppressor in lung cancer and that BMI1 is required for the oncogenic process downstream of C/EBP alpha loss. Therefore, anti-BMI1 pharmacological inhibition may offer a therapeutic benefit for lung cancer patients with low expression of C/EBP alpha and high BMI1.

Název v anglickém jazyce

Targeted BMI1 inhibition impairs tumor growth in lung adenocarcinomas with low CEBP alpha expression

Popis výsledku anglicky

Lung cancer is the most common cause of cancer deaths. The expression of the transcription factor C/EBP alpha (CCAAT/enhancer binding protein a) is frequently lost in non-small cell lung cancer, but the mechanisms by which C/EBP alpha suppresses tumor formation are not fully understood. In addition, no pharmacological therapy is available to specifically target C/EBP alpha expression. We discovered a subset of pulmonary adenocarcinoma patients in whom negative/low C/EBP alpha 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/EBP alpha deletion that develops lung adenocarcinomas, which are prevented by Bmi1 haploinsufficiency. BMI1 activity is required for both tumor initiation and maintenance in the C/EBP alpha-null background, and pharmacological inhibition of BMI1 exhibits antitumor effects in both murine and human adenocarcinoma lines. Overall, we show that C/EBP alpha is a tumor suppressor in lung cancer and that BMI1 is required for the oncogenic process downstream of C/EBP alpha loss. Therefore, anti-BMI1 pharmacological inhibition may offer a therapeutic benefit for lung cancer patients with low expression of C/EBP alpha and high BMI1.

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

EB - Genetika a molekulární biologie

OECD FORD obor

—

Projekt

<a href="/cs/project/LK21307" target="_blank" >LK21307: C/EBPg v normální hematopoéze a akutní myeloidní leukémii: identifikace molekulárních mechanismů zapojených do buněčné transformace</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2016

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Science Translational Medicine

ISSN

1946-6234

e-ISSN

—

Svazek periodika

8

Číslo periodika v rámci svazku

350

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

10

Strana od-do

—

Kód UT WoS článku

000380780000006

EID výsledku v databázi Scopus

—