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

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....

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Autores principales:	Jingyu Chen, Anketse Debebe, Ni Zeng, Janel Kopp, Lina He, Maike Sander, Bangyan L. Stiles
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1db28909f5914c96b75d5b4abc666999
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spelling	oai:doaj.org-article:1db28909f5914c96b75d5b4abc6669992021-12-02T15:57:20ZTransformation of SOX9+ cells by Pten deletion synergizes with steatotic liver injury to drive development of hepatocellular and cholangiocarcinoma10.1038/s41598-021-90958-12045-2322https://doaj.org/article/1db28909f5914c96b75d5b4abc6669992021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90958-1https://doaj.org/toc/2045-2322Abstract 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.Jingyu ChenAnketse DebebeNi ZengJanel KoppLina HeMaike SanderBangyan L. StilesNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jingyu Chen Anketse Debebe Ni Zeng Janel Kopp Lina He Maike Sander Bangyan L. Stiles Transformation of SOX9+ cells by Pten deletion synergizes with steatotic liver injury to drive development of hepatocellular and cholangiocarcinoma
description	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.
format	article
author	Jingyu Chen Anketse Debebe Ni Zeng Janel Kopp Lina He Maike Sander Bangyan L. Stiles
author_facet	Jingyu Chen Anketse Debebe Ni Zeng Janel Kopp Lina He Maike Sander Bangyan L. Stiles
author_sort	Jingyu Chen
title	Transformation of SOX9+ cells by Pten deletion synergizes with steatotic liver injury to drive development of hepatocellular and cholangiocarcinoma
title_short	Transformation of SOX9+ cells by Pten deletion synergizes with steatotic liver injury to drive development of hepatocellular and cholangiocarcinoma
title_full	Transformation of SOX9+ cells by Pten deletion synergizes with steatotic liver injury to drive development of hepatocellular and cholangiocarcinoma
title_fullStr	Transformation of SOX9+ cells by Pten deletion synergizes with steatotic liver injury to drive development of hepatocellular and cholangiocarcinoma
title_full_unstemmed	Transformation of SOX9+ cells by Pten deletion synergizes with steatotic liver injury to drive development of hepatocellular and cholangiocarcinoma
title_sort	transformation of sox9+ cells by pten deletion synergizes with steatotic liver injury to drive development of hepatocellular and cholangiocarcinoma
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/1db28909f5914c96b75d5b4abc666999
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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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