A study from Dr. Edward Prochownik’s group published a manuscript in Cellular and Molecular Gastroenterology and Hepatology entitled, “Patient-Derived Mutant Forms of NFE2L2/NRF2 Drive Aggressive Murine Hepatoblastomas.”
Cell Mol Gastroenterol Hepatol. 2021 Feb 19:S2352-345X(21)00037-0. doi: 10.1016/j.jcmgh.2021.02.004. Online ahead of print.PMID: 33618031
Background and aims: Hepatoblastoma (HB), the most common pediatric liver cancer, often bears β-catenin mutations and deregulates the Hippo tumor suppressor pathway. Murine HBs can be generated by co-expressing β-catenin mutants and the constitutively active Hippo effector YAPS127A. Some HBs and other cancers also express mutants of NFE2L2/NRF2 (NFE2L2), a transcription factor that tempers oxidative and electrophilic stress. In doing so, NFE2L2 either suppresses or facilitates tumorigenesis.
Methods: We evaluated NFE2L2‘s role in HB pathogenesis by co-expressing all combinations of mutant β-catenin, YAPS127A and the patient–derived NFE2L2 mutants L30P and R34P in murine livers. We evaluated growth, biochemical and metabolic profiles and transcriptomes of the ensuing tumors.
Results: In association with β-catenin+YAPS127A, L30P and R34P markedly accelerated HB growth and generated widespread cyst formation and necrosis, which are otherwise uncommon features. Surprisingly, any two members of the mutant β-catenin-YAPS127A-L30P/R34P triad were tumorigenic, thus directly establishing NFE2L2‘s oncogenicity. Each tumor group displayed distinct features but shared 22 similarly deregulated transcripts, 10 of which perfectly correlated with survival in human HBs and 17 of which correlated with survival in multiple adult cancers. One highly up-regulated transcript encoded serpin E1, a serine protease inhibitor that regulates fibrinolysis, growth and extracellular matrix. The combination of mutant β-catenin, YAPS127A and Serpin E1, while not accelerating cystogenic tumor growth, did promote the wide-spread necrosis associated with mutant β-catenin-YAPS127A-L30P/R34P tumors.
Conclusions: Our findings establish the direct oncogenicity of NFE2L2 mutants and key transcripts, including serpin E1, that drive specific HB features.
Keywords: KEAP1; Warburg effect; hepatocellular carcinoma; plasminogen activator inhibitor.