Heterozygosity of Chaperone Grp78 Reduces Intestinal Stem Cell Regeneration Potential and Protects against Adenoma Formation.

Abstract

Deletion of endoplasmic reticulum resident chaperone Grp78 results in activation of the unfolded protein response and causes rapid depletion of the entire intestinal epithelium. Whether modest reduction of Grp78 may affect stem cell fate without compromising intestinal integrity remains unknown. Here, we employ a model of epithelial-specific, heterozygous <i>Grp78</i> deletion by use of <i>VillinCre^ERT2-Rosa26^ZsGreen/LacZ-Grp78^+/fl</i> mice and organoids. We examine models of irradiation and tumorigenesis, both <i>in vitro</i> and <i>in vivo</i> Although we observed no phenotypic changes in <i>Grp78</i> heterozygous mice, <i>Grp78</i> heterozygous organoid growth was markedly reduced. Irradiation of <i>Grp78</i> heterozygous mice resulted in less frequent regeneration of crypts compared with nonrecombined (wild-type) mice, exposing reduced capacity for self-renewal upon genotoxic insult. We crossed mice to <i>Apc</i>-mutant animals for adenoma studies and found that adenomagenesis in <i>Apc</i> heterozygous-<i>Grp78</i> heterozygous mice was reduced compared with <i>Apc</i> heterozygous controls (1.43 vs. 3.33; <i>P</i> < 0.01). In conclusion, epithelium-specific <i>Grp78</i> heterozygosity compromises epithelial fitness under conditions requiring expansive growth such as adenomagenesis or regeneration after γ-irradiation. These results suggest that Grp78 may be a therapeutic target in prevention of intestinal neoplasms without affecting normal tissue.<b>Significance:</b> Heterozygous disruption of chaperone protein Grp78 reduces tissue regeneration and expansive growth and protects from tumor formation without affecting intestinal homeostasis. <i>Cancer Res; 78(21); 6098-106. ©2018 AACR</i>.