A conditional mouse expressing an activating mutation in NRF2 displays hyperplasia of the upper gastrointestinal tract and decreased white adipose tissue

Brittany M Bowman; Stephanie A Montgomery; Travis P Schrank; Jeremy M Simon; Travis S Ptacek; Tigist Y Tamir; Kathleen M Mulvaney; Seth J Weir; Tuong T Nguyen; Ryan M Murphy; Liza Makowski; D Neil Hayes; Xiaoxin L Chen; Scott H Randell; Bernard E Weissman; Michael B Major

doi:10.1002/path.5504

A conditional mouse expressing an activating mutation in NRF2 displays hyperplasia of the upper gastrointestinal tract and decreased white adipose tissue

J Pathol. 2020 Oct;252(2):125-137. doi: 10.1002/path.5504. Epub 2020 Aug 29.

Authors

Brittany M Bowman¹, Stephanie A Montgomery^{1

2}, Travis P Schrank^{1

3}, Jeremy M Simon^{1

4

5}, Travis S Ptacek^{1

5}, Tigist Y Tamir⁶, Kathleen M Mulvaney⁷, Seth J Weir¹, Tuong T Nguyen⁸, Ryan M Murphy⁶, Liza Makowski^{9

10}, D Neil Hayes⁹, Xiaoxin L Chen^{11

12}, Scott H Randell^{1

7

13}, Bernard E Weissman^{1

2}, Michael B Major^{1

6

13

14}

Affiliations

¹ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
² Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
³ Department of Otolaryngology/Head and Neck Surgery, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
⁴ Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
⁵ UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶ Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
⁷ Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁸ Marsico Lung Institute, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
⁹ University of Tennessee Health Science Center for Cancer Research, Department of Medicine, Division of Hematology and Oncology, University of Tennessee, Memphis, TN, USA.
¹⁰ Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, Memphis, TN, USA.
¹¹ Cancer Research Program, Julius L Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, USA.
¹² Center for Esophageal Disease and Swallowing, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹³ Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
¹⁴ Department of Cell Biology and Physiology, Washington University, St Louis, MO, USA.

Abstract

Activation of the nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or NRF2) transcription factor is a critical and evolutionarily conserved cellular response to oxidative stress, metabolic stress, and xenobiotic insult. Deficiency of NRF2 results in hypersensitivity to a variety of stressors, whereas its aberrant activation contributes to several cancer types, most commonly squamous cell carcinomas of the esophagus, oral cavity, bladder, and lung. Between 10% and 35% of patients with squamous cell carcinomas display hyperactive NRF2 signaling, harboring activating mutations and copy number amplifications of the NFE2L2 oncogene or inactivating mutations or deletions of KEAP1 or CUL3, the proteins of which co-complex to ubiquitylate and degrade NRF2 protein. To better understand the role of NRF2 in tumorigenesis and more broadly in development, we engineered the endogenous Nfe2l2 genomic locus to create a conditional mutant LSL-Nrf2^E79Q mouse model. The E79Q mutation, one of the most commonly observed NRF2-activating mutations in human squamous cancers, codes for a mutant protein that does not undergo KEAP1/CUL3-dependent degradation, resulting in its constitutive activity. Expression of NRF2 E79Q protein in keratin 14 (KRT14)-positive murine tissues resulted in hyperplasia of squamous cell tissues of the tongue, forestomach, and esophagus, a stunted body axis, decreased weight, and decreased visceral adipose depots. RNA-seq profiling and follow-up validation studies of cultured NRF2^E79Q murine esophageal epithelial cells revealed known and novel NRF2-regulated transcriptional programs, including genes associated with squamous cell carcinoma (e.g. Myc), lipid and cellular metabolism (Hk2, Ppard), and growth factors (Areg, Bmp6, Vegfa). These data suggest that in addition to decreasing adipogenesis, KRT14-restricted NRF2 activation drives hyperplasia of the esophagus, forestomach, and tongue, but not formation of squamous cell carcinoma. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: E79Q; ESCC; GEMM; KEAP1; NRF2; Nfe2l2; adipose; esophagus; mouse.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adipose Tissue, White / pathology*
Animals
Carcinogenesis / genetics*
Carcinoma, Squamous Cell / genetics
Disease Models, Animal*
Esophagus / pathology
Humans
Hyperplasia / genetics
Mice
Mutation
NF-E2-Related Factor 2 / genetics*
Precancerous Conditions / genetics*
Tongue / pathology
Upper Gastrointestinal Tract / pathology*

Substances

NF-E2-Related Factor 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding