Liu, YunjianKim, Hyeong GeugDong, EdwardDong, ChuanpengHuang, MenghaoLiu, YunlongLiangpunsakul, SuthatDong, Xiaocheng Charlie2021-08-022021-08-022019-10-01Liu, Y., Kim, H. G., Dong, E., Dong, C., Huang, M., Liu, Y., Liangpunsakul, S., & Dong, X. C. (2019). Sesn3 deficiency promotes carcinogen-induced hepatocellular carcinoma via regulation of the hedgehog pathway. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1865(10), 2685–2693. https://doi.org/10.1016/j.bbadis.2019.07.0110925-4439https://hdl.handle.net/1805/26319Sestrin 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.en-USSestrinliver cancerhepatocellular carcinomahedgehog signalingcancer stem cellArticle