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

Yunjian Liu, Hyeong Geug Kim, Edward Dong, Chuanpeng Dong, Menghao Huang, Yunlong Liu, Suthat Liangpunsakul, X. Dong

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2685-2693
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1865
Issue number10
DOIs
StatePublished - Oct 1 2019

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Hedgehogs
Carcinogens
Hepatocellular Carcinoma
Knockout Mice
Keratin-19
Biological Phenomena
Diethylnitrosamine
Arginase
Neoplastic Stem Cells
Cell Aging
Liver
alpha-Fetoproteins
High Fat Diet
Choline
Extracellular Matrix
Interleukin-6
Oxidative Stress
Homeostasis
Transcription Factors
Genes

Keywords

  • Cancer stem cell
  • Hedgehog signaling
  • Hepatocellular carcinoma
  • Liver cancer
  • Sestrin

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

Cite this

Sesn3 deficiency promotes carcinogen-induced hepatocellular carcinoma via regulation of the hedgehog pathway. / Liu, Yunjian; Kim, Hyeong Geug; Dong, Edward; Dong, Chuanpeng; Huang, Menghao; Liu, Yunlong; Liangpunsakul, Suthat; Dong, X.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1865, No. 10, 01.10.2019, p. 2685-2693.

Research output: Contribution to journalArticle

Liu, Yunjian ; Kim, Hyeong Geug ; Dong, Edward ; Dong, Chuanpeng ; Huang, Menghao ; Liu, Yunlong ; Liangpunsakul, Suthat ; Dong, X. / Sesn3 deficiency promotes carcinogen-induced hepatocellular carcinoma via regulation of the hedgehog pathway. In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 2019 ; Vol. 1865, No. 10. pp. 2685-2693.
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