ArticleJournal of hepatology2022
Yap-Sox9 signaling determines hepatocyte plasticity and lineage-specific hepatocarcinogenesis.
Article in Journal of hepatology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.
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76 citing papers in PubMed, 137 citations in OpenAlex.
- Cell plasticity in cancer and therapy resistance.Experimental & molecular medicine · 2026Review
- Noncanonical mTORC1-TFEB activation promotes hepatocyte plasticity and high-grade malignancy in hepatocellular carcinoma.The Journal of clinical investigation · 2026Article
- Current therapeutic interventions to target cancer stem cells for metastasis.International journal of clinical oncology · 2026Review
- Specificity-driven cell-gene graph learning identifies rare cell states in single-cell and spatial transcriptomic data.Advanced biotechnology · 2026Article
- HDAC inhibitors reverse YAP-driven immune resistance in NSCLC: mechanistic and translational evidence.Journal for immunotherapy of cancer · 2026Article
- Interplay among oncogenic pathways governs hepatobiliary lineage decisions in liver cancer.iLIVER · 2026Article
- SOX9 promotes hepatocyte proliferation via upregulating TGF-α expression during liver regeneration.Hepatology international · 2026Article
- Unraveling key molecules mediating the mechanisms of YAP deletion or inhibition in liver fibrosis regression through a multi-omics approach.Histology and histopathology · 2026Article
- Palmitoylation remodeling dictates HCC heterogeneity: implications for subtype-specific prognostication and targeting the YAP-RhoA axis.BMC medical genomics · 2026Article
- How to efficiently establish animal models of cholangiocarcinoma: challenges and inspiration.Medical review (2021) · 2026Review
- ICMT deficiency ameliorates weight loss and mortality, but not tumor formation in a mouse model of liver cancer.Cell communication and signaling : CCS · 2026Article
- Preclinical mouse models for studying cholangiocarcinoma.Liver research (Beijing, China) · 2026Review
- Integrative machine learning identifies a TEAD4-driven endothelial program shaping drug sensitivity and microvascular invasion in HCC.Journal of translational medicine · 2026Article
- Phase-Separation of YAP Mediates AJUBA Super Enhancer Activation to Promote Aberrant Mitosis in Breast Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- SNORA49 negatively regulates self-renewal of liver cancer stem cells and hepatocarcinogenesis via suppressing SOX9 transcription.Nature communications · 2026Article
- Recent trends in lipid metabolism research in liver cancer: a bibliometric analysis.Frontiers in oncology · 2026Article
- Pbrm1 Loss Induces a Permissive Chromatin State for Cholangiocytic Differentiation and Cholangiocarcinoma Formation.Cellular and molecular gastroenterology and hepatology · 2026Article
- Taurochenodeoxycholic acid ameliorates liver fibrosis by regulating gut microbiota and bile acids via hippo-YAP pathway.iScience · 2025Article
- YAP-induced MAML1 cooperates with STAT3 to drive hepatocellular carcinoma progression.Experimental hematology & oncology · 2025Article
- Review
16 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 4 institutions in 1 country.
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Abstract
BACKGROUND &
aimsPrimary liver tumors comprise distinct subtypes. A subset of intrahepatic cholangiocarcinoma (iCCA) can arise from cell fate reprogramming of mature hepatocytes in mouse models. However, the underpinning of cell fate plasticity during hepatocarcinogenesis is still poorly understood, hampering therapeutic development for primary liver cancer. As YAP activation induces liver tumor formation and cell fate plasticity, we investigated the role of Sox9, a transcription factor downstream of Yap activation that is expressed in biliary epithelial cells (BECs), in Yap-induced cell fate plasticity during hepatocarcinogenesis.
methodsTo evaluate the function of Sox9 in YAP-induced hepatocarcinogenesis in vivo, we used several genetic mouse models of inducible hepatocyte-specific YAP activation with simultaneous Sox9 removal. Cell fate reprogramming was determined by lineage tracing and immunohistochemistry. The molecular mechanism underlying Yap and Sox9 function in hepatocyte plasticity was investigated by transcription and transcriptomic analyses of mouse and human liver tumors.
resultsSox9, a marker of liver progenitor cells (LPCs) and BECs, is differentially required in YAP-induced stepwise hepatocyte programming. While Sox9 has a limited role in hepatocyte dedifferentiation to LPCs, it is required for BEC differentiation from LPCs. YAP activation in Sox9-deficient hepatocytes resulted in more aggressive HCC with enhanced Yap activity at the expense of iCCA-like tumors. Furthermore, we showed that 20% of primary human liver tumors were associated with a YAP activation signature, and tumor plasticity is highly correlated with YAP activation and SOX9 expression.
conclusionOur data demonstrated that Yap-Sox9 signaling determines hepatocyte plasticity and tumor heterogeneity in hepatocarcinogenesis in both mouse and human liver tumors. We identified Sox9 as a critical transcription factor required for Yap-induced hepatocyte cell fate reprogramming during hepatocarcinogenesis. LAY SUMMARY: Sox9, a marker of liver progenitor cells and bile duct lining cells, is a downstream target of YAP protein activation. Herein, we found that YAP activation in hepatocytes leads to a transition from mature hepatocytes to liver progenitor cells and then to bile duct lining cells. Sox9 is required in the second step during mouse hepatocarcinogenesis. We also found that human YAP and SOX9 may play similar roles in liver cancers.
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