Lack of Period1 accelerates colorectal tumorigenesis in ApcMin/+ mice

Abstract

The circadian clock coordinates physiology and behavior through [~]24-h rhythms, and disruption of core clock genes has been implicated in tumorigenesis. However, the impact of Per1, a major clock gene, on colorectal tumor development remains unclear. Here, we investigated how Per1 deletion influences intestinal tumorigenesis using the ApcMin/+ mouse model and ApcMin/+Per1-/-mice generated by crossing ApcMin/+ and Per1-/- lines (C57BL/6J background). Mice were maintained under controlled light-dark conditions, and we assessed survival, intestinal polyp burden, histopathology using Swiss-roll sections, {beta}-catenin protein abundance (immunofluorescence and western blotting), Ctnnb1 mRNA expression (RT-qPCR), and crypt proliferation (5-bromo-2-deoxyuridine (BrdU) immunohistochemistry). Per1 deletion did not significantly alter overall survival in ApcMin/+ mice but increased inter-individual variability. In contrast, polyp number was markedly increased by Per1 deletion, affecting both small (<2 mm) and large ([≥]2 mm) polyps across intestinal segments. Histology confirmed aberrant crypt foci and polyps in both ApcMin/+ genotypes. {beta}-Catenin protein levels in the whole intestine were significantly increased by Per1 deficiency and Apc mutation (two-way ANOVA), whereas Ctnnb1 mRNA was largely unchanged across regions. BrdU-based crypt proliferation was increased by the Apc mutation but not by Per1 deletion. These results indicate that Per1 loss exacerbates intestinal polyp formation and elevates {beta}-catenin predominantly through non-transcriptional mechanisms, supporting a tumor-suppressive role of Per1 in colorectal tumorigenesis.