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.
Copyright © 2019 Elsevier B.V. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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AC133 Antigen / metabolism
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Actins / metabolism
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Animals
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Arginase / metabolism
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Carcinogens / metabolism*
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism*
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Carcinoma, Hepatocellular / pathology
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Diet, High-Fat
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Disease Models, Animal
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Gene Expression Regulation, Neoplastic
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Genetic Predisposition to Disease / genetics*
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Heat-Shock Proteins / genetics*
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Heat-Shock Proteins / metabolism*
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Hedgehog Proteins / metabolism*
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Hyaluronan Receptors / genetics
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Hyaluronan Receptors / metabolism
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Interleukin-6 / metabolism
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Keratin-19 / metabolism
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Liver / metabolism
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Liver / pathology
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism*
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Liver Neoplasms / pathology
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Mice
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Mice, Knockout
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Receptor, Platelet-Derived Growth Factor beta / metabolism
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STAT3 Transcription Factor / metabolism
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Signal Transduction / genetics
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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Up-Regulation
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Zinc Finger Protein Gli2 / metabolism
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alpha-Fetoproteins / metabolism
Substances
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AC133 Antigen
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Acta2 protein, mouse
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Actins
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Carcinogens
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Cd44 protein, mouse
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Gli2 protein, mouse
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Heat-Shock Proteins
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Hedgehog Proteins
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Hyaluronan Receptors
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Interleukin-6
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Keratin-19
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Prom1 protein, mouse
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STAT3 Transcription Factor
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Sesn3 protein, mouse
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Stat3 protein, mouse
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Tumor Suppressor Proteins
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Zinc Finger Protein Gli2
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alpha-Fetoproteins
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interleukin-6, mouse
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Receptor, Platelet-Derived Growth Factor beta
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Arg1 protein, mouse
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Arginase