PUBLICATION

ahctf1 and kras mutations combine to amplify oncogenic stress and restrict liver overgrowth in a zebrafish model of hepatocellular carcinoma

Authors
Morgan, K.J., Doggett, K., Geng, F., Mieruszynski, S., Whitehead, L., Smith, K.A., Hogan, B.M., Simons, C., Baillie, G.J., Molania, R., Papenfuss, A.T., Hall, T.E., Ober, E.A., Stainier, D.Y.R., Gong, Z., Heath, J.K.
ID
ZDB-PUB-230118-6
Date
2023
Source
eLIFE   12: (Journal)
Registered Authors
Doggett, Karen, Geng, Fansuo, Gong, Zhiyuan, Hall, Thomas, Heath, Joan K., Hogan, Ben M., Morgan, Kimberly, Ober, Elke, Stainier, Didier
Keywords
cancer biology, cell biology, zebrafish
Datasets
GEO:GSE220282
MeSH Terms
  • Animals
  • Carcinoma, Hepatocellular*/genetics
  • Carcinoma, Hepatocellular*/pathology
  • Hyperplasia
  • Liver Neoplasms*/genetics
  • Liver Neoplasms*/pathology
  • Mutation
  • Nuclear Pore Complex Proteins/genetics
  • Nuclear Pore Complex Proteins/metabolism
  • Proto-Oncogene Proteins p21(ras)/genetics
  • Proto-Oncogene Proteins p21(ras)/metabolism
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed
36648336 Full text @ Elife
Abstract
The nucleoporin (NUP) ELYS, encoded by AHCTF1, is a large multifunctional protein with essential roles in nuclear pore assembly and mitosis. Using both larval and adult zebrafish models of hepatocellular carcinoma (HCC), in which the expression of an inducible mutant kras transgene (krasG12V) drives hepatocyte-specific hyperplasia and liver enlargement, we show that reducing ahctf1 gene dosage by 50% markedly decreases liver volume, while non-hyperplastic tissues are unaffected. We demonstrate that in the context of cancer, ahctf1 heterozygosity impairs nuclear pore formation, mitotic spindle assembly and chromosome segregation, leading to DNA damage and activation of a Tp53-dependent transcriptional program that induces cell death and cell cycle arrest. Heterozygous expression of both ahctf1 and ranbp2 (encoding a second nucleoporin), or treatment of heterozygous ahctf1 larvae with the nucleocytoplasmic transport inhibitor, Selinexor, completely blocks krasG12V-driven hepatocyte hyperplasia. Gene expression analysis of patient samples in the Liver hepatocellular carcinoma (LIHC) dataset in The Cancer Genome Atlas shows that high expression of one or more of the transcripts encoding the ten components of the NUP107-160 sub-complex, which includes AHCTF1, is positively correlated with worse overall survival. These results provide a strong and feasible rationale for the development of novel cancer therapeutics that target ELYS function and suggest potential avenues for effective combinatorial treatments.
Genes / Markers
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Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping