The role of LAT1 in AOM/DSS-induced colorectal tumorigenesis

Abstract

Amino acid transporters are essential for supplying nutrients to cells and are implicated in tumor progression. L-type amino acid transporter 1 (LAT1) is reported to be overexpressed in various cancers, affecting tumor development. However, the exact mechanisms by which LAT1 affects colorectal cancer (CRC) arising from a chronic inflammatory background are not yet fully understood. This study aimed to explore the role of LAT1 in CRC. Mice with intestinal epithelium-specific deletions of LAT1 (LAT1^fl/fl; vil-cre) were treated with azoxymethane (AOM)/dextran sulfate sodium (DSS) in a colitis-associated cancer (CAC) model. Our results demonstrated that LAT1 was detected in normal colon crypts and highly expressed in AOM/DSS-induced tumor tissue. During the chronic colitis phase, weight loss was more prominent in LAT1^fl/fl; vil-cre mice, compared with that in LAT1^fl/fl mice. IL-1β and IL-6 expressions significantly increased in LAT1-deleted tumors; however, no overall difference in colon tumor number or size was observed between LAT1^fl/fl and LAT1^fl/fl; vil-cre mice. Accordingly, cell proliferation and apoptotic cell number were similar when comparing LAT1-deleted tumors with those with sufficient LAT1. Our findings indicated that LAT1 might not phenotypically affect overall colonic tumor development in this model; however, it affected the chronic colitis phase and inflammatory status within the tumors. These findings suggest that severe inflammation in tumors might have compensated for tumor growth in defects of amino acid supplementation through LAT1 deficiency, and provide insights into the potential of LAT1-targeted therapies for clinical CRC treatment.