Oncogenic KRAS Requires Complete Loss of BAP1 Function for Development of Murine Intrahepatic Cholangiocarcinoma
Intrahepatic cholangiocarcinoma (ICC) is a primary biliary malignancy that harbors a dismal prognosis. Oncogenic mutations of <i>KRAS</i> and loss-of-function mutations of <i>BRCA1-associated protein 1</i> (<i>BAP1</i>) have been identified as recurrent somatic al...
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| Autores principales: | , , , , , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/a62495aad21549c2a67f379c1a441774 |
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| Sumario: | Intrahepatic cholangiocarcinoma (ICC) is a primary biliary malignancy that harbors a dismal prognosis. Oncogenic mutations of <i>KRAS</i> and loss-of-function mutations of <i>BRCA1-associated protein 1</i> (<i>BAP1</i>) have been identified as recurrent somatic alterations in ICC. However, an autochthonous genetically engineered mouse model of ICC that genocopies the co-occurrence of these mutations has never been developed. By crossing <i>Albumin</i>-Cre mice bearing conditional alleles of mutant <i>Kras</i> and/or floxed <i>Bap1,</i> Cre-mediated recombination within the liver was induced. Mice with hepatic expression of mutant <i>Kras</i><sup>G12D</sup> alone (KA), bi-allelic loss of hepatic <i>Bap1</i> (B<sup>homo</sup>A), and heterozygous loss of <i>Bap1</i> in conjunction with mutant <i>Kras</i><sup>G12D</sup> expression (B<sup>het</sup>KA) developed primary hepatocellular carcinoma (HCC), but no discernible ICC. In contrast, mice with homozygous loss of <i>Bap1</i> in conjunction with mutant <i>Kras</i><sup>G12D</sup> expression (B<sup>homo</sup>KA) developed discrete foci of HCC and ICC. Further, the median survival of B<sup>homo</sup>KA mice was significantly shorter at 24 weeks when compared to the median survival of ≥40 weeks in B<sup>het</sup>KA mice and approximately 50 weeks in B<sup>homo</sup>A and KA mice (<i>p</i> < 0.001). Microarray analysis performed on liver tissue from KA and B<sup>homo</sup>KA mice identified differentially expressed genes in the setting of BAP1 loss and suggests that deregulation of ferroptosis might be one mechanism by which loss of BAP1 cooperates with oncogenic Ras in hepato-biliary carcinogenesis. Our autochthonous model provides an in vivo platform to further study this lethal class of neoplasm. |
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