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Transformation of SOX9(+) cells by Pten deletion synergizes with steatotic liver injury to drive development of hepatocellular and cholangiocarcinoma

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Item Type:Article
Title:Transformation of SOX9(+) cells by Pten deletion synergizes with steatotic liver injury to drive development of hepatocellular and cholangiocarcinoma
Creators Name:Chen, J., Debebe, A., Zeng, N., Kopp, J., He, L., Sander, M. and Stiles, B.L.
Abstract:SOX9 (Sex-determining region Y Box 9) is a well-characterized transcription factor that is a marker for progenitor cells in various tissues. In the liver, cells delineated by SOX9 are responsible for regenerating liver parenchyma when cell proliferation is impaired following chronic injury. However, whether these SOX9(+) cells play a role in liver carcinogenesis has not been fully understood, although high SOX9 expression has been linked to poor survival outcome in liver cancer patients. To address this question, we developed a liver cancer mouse model (Pten(loxP/loxP); Sox9-Cre(ERT+); R26R(YFP)) where tumor suppressor Pten (phosphatase and tensin homolog deleted on chromosome ten) is deleted in SOX9(+) cells following tamoxifen injection. In this paper, we employ lineage-tracing to demonstrate the tumorigenicity potential of the Pten(-), SOX9(+) cells. We show that these cells are capable of giving rise to mixed-lineage tumors that manifest features of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA). Our results suggest that PTEN loss induces the transformation of SOX9(+) cells. We further show that to activate these transformed SOX9(+) cells, the presence of liver injury is crucial. Liver injury, induced by hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or high-fat diet (HFD), substantially increases tumor incidence and accelerates liver carcinogenesis from SOX9(+) cells in Pten null mice but not in control mice. We further examine the mechanisms underlying tumor formation in this model to show that concurrent with the induction of niche signal (i.e., Wnt signaling), liver injury significantly stimulates the expansion of tumor-initiating cells (TICs). Together, these data show that (1) SOX9(+) cells have the potential to become TICs following the primary transformation (i.e. Pten deletion) and that (2) liver injury is necessary for promoting the activation and proliferation of transformed SOX9(+) cells, resulting in the genesis of mixed-lineage liver tumors.
Keywords:Cancer, Cell Biology, Gastroenterology, Molecular Biology, Animals, Mice
Source:Scientific Reports
ISSN:2045-2322
Publisher:Nature Publishing Group
Volume:11
Number:1
Page Range:11823
Date:3 June 2021
Official Publication:https://doi.org/10.1038/s41598-021-90958-1
PubMed:View item in PubMed

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