Reversion of tumor hepatocytes to normal hepatocytes during liver tumor regression in an oncogene transgenic zebrafish model

Li, Y., Agrawal, I., Gong, Z.
Disease models & mechanisms   12(10): (Journal)
Registered Authors
Gong, Zhiyuan, Li, Yan
Cre/loxP, Hepatocellular carcinoma (HCC), Oncogene addiction, Tumor regression, Zebrafish, xmrk/egfr
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Apoptosis
  • Carcinoma, Hepatocellular/genetics
  • Carcinoma, Hepatocellular/pathology
  • Cell Differentiation
  • Cell Line, Transformed
  • Cell Lineage
  • Cell Proliferation
  • Gene Expression Regulation, Neoplastic
  • Hepatocytes/metabolism
  • Hepatocytes/pathology*
  • Integrases/metabolism
  • Liver Neoplasms/genetics
  • Liver Neoplasms/pathology*
  • Oncogenes*
  • Signal Transduction/genetics
  • Transcriptome/genetics
  • Zebrafish/genetics*
31515263 Full text @ Dis. Model. Mech.
Tumors are frequently addicted to primary oncogenes to maintain their malignant properties. We have previously established several inducible hepatocellular carcinoma (HCC) models in zebrafish by transgenic expression of an oncogene. These tumor models are strongly oncogene-addicted, as the induced and histologically proven liver tumors are regressed after suppression of oncogene expression by removing chemical inducer. However, the question remains unanswered is whether the liver tumor cells are eliminated or reverted to normal cells. In the present study, we generated a novel Cre/loxP transgenic zebrafish line, Tg(fabp10: loxP-EGFP-stop-loxP-DsRed; TRE: CreERT2) (abbreviated to CreER), in order to trace tumor cell lineage during tumor regression after crossing with the xmrk (activated EGFR homolog) oncogene transgenic line, Tg(fabp10: rtTA; TRE: xmrk; krt4: EGFP) We found that, during HCC regression, restored normal liver was contributed by both reversion of tumor hepatocytes (RFP+) and newly differentiated hepatocytes (GFP+). RNA-seq analyses of the RFP+ and GFP+ hepatocytes populations after tumor regression confirmed their conversion to normal hepatocytes as most of the tumor deregulated genes and pathways in the tumor stages have been reverted to normal conditions in the tumor-reverted hepatocytes. Thus, our lineage tracing studies demonstrated the possibility of transformed tumor cells to revert to normal cells after the suppression of expression of a primary oncogene and this observation may provide a basis for development of therapeutic approach targeting to addicted oncogenes or oncogenic pathways.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes