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

Biochim Biophys Acta Mol Basis Dis. 2019 Oct 1;1865(10):2685-2693. doi: 10.1016/j.bbadis.2019.07.011. Epub 2019 Jul 24.

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.

Keywords: Cancer stem cell; Hedgehog signaling; Hepatocellular carcinoma; Liver cancer; Sestrin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen / metabolism
  • Actins / metabolism
  • Animals
  • Arginase / metabolism
  • Carcinogens / metabolism*
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Diet, High-Fat
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease / genetics*
  • Heat-Shock Proteins / genetics*
  • Heat-Shock Proteins / metabolism*
  • Hedgehog Proteins / metabolism*
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism
  • Interleukin-6 / metabolism
  • Keratin-19 / metabolism
  • Liver / metabolism
  • Liver / pathology
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Mice
  • Mice, Knockout
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Receptor, Platelet-Derived Growth Factor beta / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / genetics
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Up-Regulation
  • Zinc Finger Protein Gli2 / metabolism
  • alpha-Fetoproteins / metabolism

Substances

  • AC133 Antigen
  • Acta2 protein, mouse
  • Actins
  • Carcinogens
  • Cd44 protein, mouse
  • Gli2 protein, mouse
  • Heat-Shock Proteins
  • Hedgehog Proteins
  • Hyaluronan Receptors
  • Interleukin-6
  • Keratin-19
  • Prom1 protein, mouse
  • STAT3 Transcription Factor
  • Sesn3 protein, mouse
  • Stat3 protein, mouse
  • Tumor Suppressor Proteins
  • Zinc Finger Protein Gli2
  • alpha-Fetoproteins
  • interleukin-6, mouse
  • Receptor, Platelet-Derived Growth Factor beta
  • Arg1 protein, mouse
  • Arginase