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Cited by 54Genomics, phytochemicals, and oxidative stressWnt/β-catenin signaling in development and cancerHepatocellular Carcinoma Treatment and Prognosis

Nuclear factor erythroid 2–related factor 2 and β‐Catenin Coactivation in Hepatocellular Cancer: Biological and Therapeutic Implications

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Tao, Junyan, Krutsenko, Yekaterina, Moghe, Akshata, Singh, Sucha, Poddar, Minakshi, Bell, Aaron, Oertel, Michael, Singhi, Aatur D. +5 more·2021·Hepatology
DOI 10.1002/hep.31730PMC PMC8326305
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Abstract

Background and Aims: HCC remains a major unmet clinical need. Although activating catenin beta‐1 ( CTNNB1 ) mutations are observed in prominent subsets of HCC cases, these by themselves are insufficient for hepatocarcinogenesis. Coexpression of mutant CTNNB1 with clinically relevant co‐occurrence has yielded HCCs. Here, we identify cooperation between β‐catenin and nuclear factor erythroid 2–related factor 2 (Nrf2) signaling in HCC. Approach and Results: Public HCC data sets were assessed for concomitant presence of CTNNB1 mutations and either mutations in nuclear factor erythroid‐2–related factor‐2 ( NFE2L2 ) or Kelch like‐ECH‐associated protein 1 ( KEAP1 ), or Nrf2 activation by gene signature. HCC development in mice and similarity to human HCC subsets was assessed following coexpression of T41A‐ CTNNB1 with either wild‐type (WT)‐, G31A‐, or T80K‐ NFE2L2 . Based on mammalian target of rapamycin complex 1 activation in CTNNB1 ‐mutated HCCs, response of preclinical HCC to mammalian target of rapamycin (mTOR) inhibitor was investigated. Overall, 9% of HCC cases showed concomitant CTNNB1 mutations and Nrf2 activation, subsets of which were attributable to mutations in NFE2L2 / KEAP1 . Coexpression of mutated CTNNB1 with mutant NFE2L2 , but not WT‐NFE2L2, led to HCC development and mortality by 12‐14 weeks. These HCCs were positive for β‐catenin targets, like glutamine synthetase and cyclin‐D1, and Nrf2 targets, like NAD(P)H quinone dehydrogenase 1 and peroxiredoxin 1. RNA‐sequencing and pathway analysis showed high concordance of preclinical HCC to human HCC subset showing activation of unique (iron homeostasis and glioblastoma multiforme signaling) and expected (glutamine metabolism) pathways. NFE2L2‐CTNNB1 HCC mice were treated with mTOR inhibitor everolimus (5‐mg/kg diet ad libitum ), which led to >50% decrease in tumor burden. Conclusions: Coactivation of β‐catenin and Nrf2 is evident in 9% of all human HCCs. Coexpression of mutant NFE2L2 and mutant CTNNB1 led to clinically relevant HCC development in mice, which responded to mTOR inhibitors. Thus, this model has both biological and therapeutic implications.

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  • An in vivo Keap1 siRNA positive control led to increased LW/BW ratios and microtumor burden.

    “An in vivo Keap1 siRNA, used as a positive control known to increase HCC through up-regulation of NRF2 (46), led to increased LW/BW ratios and microtumor burden (Fig. 4, M to O).”

    From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [46]

    The Results section links KEAP1 loss of function to NRF2 activation, and the Discussion reports HCC development when mutant NRF2 and β-catenin were co-expressed. But the Discussion explicitly says KEAP1 silencing was not directly tested. The cited paper therefore supports the rationale for the positive control, not an established effect of Keap1 siRNA; the LW/BW and microtumor results are attributed to the citing paper’s Figure 4. (LLM, conf=0.88)

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Authors
Tao, J., Krutsenko, Y., Moghe, A., Singh, S., Poddar, M., Bell, A., Oertel, M., Singhi, A. D., Geller, D., Chen, X., Lujambio, A., Liu, S., & Monga, S. P.
Affiliations
  • University of Pittsburgh (US)
  • University of California, San Francisco (US)
  • Tisch Cancer Institute (US)
Corresponding author
Monga, Satdarshan P.
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2021-06-21
Volume
74
Issue
2
Pages
741-759
ISSN
  • 0270-9139 (ISSN-L)
  • 1527-3350
DOI
10.1002/hep.31730
PMC
PMC8326305
OpenAlex
W3129162214
Cited by
54
References
45
Citations by year
2026: 6 · 2025: 10 · 2024: 10 · 2023: 11 · 2022: 10 · 2021: 7
FWCI
2.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Cancer Institute (R01CA204586, R01CA251155, R01CA250227)
  • National Institute of Diabetes and Digestive and Kidney Diseases (1 R01 DK62277, P30DK120531, P30DK026743, R01DK062277)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
Keywords
hepatocellular carcinoma, β-catenin, Nrf2, CTNNB1 mutation, Keap1, mTOR inhibition, everolimus, glutamine metabolism, iron homeostasis, hepatocarcinogenesis
MeSH terms
Adolescent, Aged, Aged, 80 and over, Animals, Disease Models, Animal, Female, Carcinoma, Hepatocellular, Humans, Liver, Liver Neoplasms, Male, Middle Aged, Mutation, Signal Transduction, Gene Expression Regulation, Neoplastic, Tumor Burden, beta Catenin, NF-E2-Related Factor 2, Mice, Carcinogenesis, Datasets as Topic

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