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

被引:20
作者
Bowman, Brittany M. [1 ]
Montgomery, Stephanie A. [1 ,2 ]
Schrank, Travis P. [1 ,3 ]
Simon, Jeremy M. [1 ,4 ,5 ]
Ptacek, Travis S. [1 ,5 ]
Tamir, Tigist Y. [6 ]
Muvlaney, Kathleen M. [7 ]
Weir, Seth J. [1 ]
Tuong T Nguyen [8 ]
Murphy, Ryan M. [6 ]
Makowski, Liza [9 ,10 ]
Hayes, D. Neil [9 ]
Chen, Xiaoxin L. [11 ,12 ]
Randell, Scott H. [1 ,7 ,13 ]
Weissman, Bernard E. [1 ,2 ]
Major, Michael B. [1 ,6 ,13 ,14 ]
机构
[1] Univ N Carolina, Lineberger Comprehens Canc Ctr, Sch Med, Chapel Hill, NC 27599 USA
[2] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA
[3] Univ N Carolina, Dept Otolaryngol Head & Neck Surg, Sch Med, Chapel Hill, NC 27599 USA
[4] Univ N Carolina, Dept Genet, Sch Med, Chapel Hill, NC 27599 USA
[5] Univ N Carolina, UNC Neurosci Ctr, Chapel Hill, NC 27599 USA
[6] Univ N Carolina, Dept Pharmacol, Sch Med, Chapel Hill, NC 27599 USA
[7] Broad Inst MIT & Harvard, Canc Program, Cambridge, MA 02142 USA
[8] Univ N Carolina, Marsico Lung Inst, Sch Med, Chapel Hill, NC 02142 USA
[9] Univ Tennessee, Hlth Sci Ctr Canc Res, Dept Med, Div Hematol & Oncol, Memphis, TN USA
[10] Univ Tennessee, Coll Pharm, Dept Pharmaceut Sci, Memphis, TN USA
[11] North Carolina Cent Univ, Canc Res Program, Julius L Chambers Biomed Biotechnol Res Inst, Durham, NC USA
[12] Univ N Carolina, Dept Med, Div Gastroenterol & Hepatol, Ctr Esophageal Dis & Swallowing, Chapel Hill, NC 27599 USA
[13] Univ N Carolina, Sch Med, Dept Cell Biol & Physiol, Chapel Hill, NC 27599 USA
[14] Washington Univ, Dept Cell Biol & Physiol, St Louis, MO 63110 USA
关键词
Nfe2l2; NRF2; KEAP1; esophagus; mouse; adipose; ESCC; GEMM; E79Q; TRANSCRIPTION FACTOR NRF2; CUL3-BASED E3 LIGASE; GENOMIC CHARACTERIZATION; PROTEASOMAL DEGRADATION; CYSTEINE RESIDUES; SUBCUTANEOUS FAT; KEAP1; GENE; ADAPTER; PROTEIN;
D O I
10.1002/path.5504
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Activation of thenuclearfactor (erythroid-derived2)-like2(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 theNFE2L2oncogene or inactivating mutations or deletions ofKEAP1orCUL3, 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 endogenousNfe2l2genomic locus to create a conditional mutantLSL-Nrf2(E79Q)mouse model. The E79Q mutation, one of the most commonly observedNRF2-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. (c) 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
引用
收藏
页码:125 / 137
页数:13
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