Sesn3 deficiency promotes carcinogen-induced hepatocellular carcinoma via regulation of the hedgehog pathway

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1865

Article

Liu, Yunjian^1,2  Kim, Hyeong Geug²  Dong, Edward³  Dong, Chuanpeng⁴  Huang, Menghao^2,5  Liu, Yunlong^4,6  Liangpunsakul, Suthat^2,5  Dong, Xiaocheng Charlie^2,4 

[1] Jiujiang Univ, Affiliated Hosp, Dept Hepatobiliary Surg, Jiujiang 332000, Jiangxi, Peoples R China

[2] Indiana Univ Sch Med, Dept Biochem & Mol Biol, 635 Barnhill Dr,Room MS-1021D, Indianapolis, IN 46202 USA

[3] Cannel High Sch, Cannel, IN 46032 USA

[4] Indiana Univ Purdue Univ Indianapolis, Sch Informat & Comp, Dept BioHlth Informat, Indianapolis, IN 46202 USA

[5] Indiana Univ Sch Med, Dept Med, Div Gastroenterol & Hepatol, Indianapolis, IN 46202 USA

[6] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA

关键词: Sestrin;    Liver cancer;    Hepatocellular carcinoma;    Hedgehog signaling;    Cancer stem cell;   

DOI  :  10.1016/j.bbadis.2019.07.011

来源: Elsevier

【 摘 要 】

Sestrin 3 (Sesn3) belongs to a small protein family that has been implicated in multiple biological processes including anti-oxidative stress, anti-aging, cell signaling, and metabolic homeostasis. However, the role of Sesn3 in hepatocellular carcinoma (HCC) remains unclear. Here we generated a Sesn3 knockout mouse model and induced HCC development by a combination of a single dose of diethylnitrosamine and chronic feeding of a choline deficient-high fat diet. After 6 months of the dietary treatment, Sesn3 knockout mice developed more severe HCC with higher levels of alpha-fetoprotein, arginase 1, and cytokeratin 19, but also higher metastatic rates than wild-type mice. Histological analysis revealed elevated extracellular matrix and cancer stem cell markers including Acta2, Cd44, and Cd133. Signaling analysis showed activated IL6-Stat3 and Akt pathways. Biochemical and microscopic analyses uncovered a novel inhibitory regulation of Gli2, a downstream transcription factor of the hedgehog signaling, by Sesn3. Two of the Gli2-regulated genes - Pdgfrb and Cd44 were upregulated in the Sesn3-deficient liver tissue. In conclusion, our data suggest that Sesn3 plays a critical tumor suppressor role in the liver partly through the inhibition of the hedgehog signaling.

【 授权许可】

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