P0031 The role of LAT1 in colitis and colitis-associated tumourigenesis
Authors: Sui Y , Okamoto N , Hoshi N , Inoue Y , Funatsu T , Ku Y , Ooi M , Watanabe D , Miyazaki H , Agawa M , Nakamura H , Yang H , Kodama Y ,   IBD group
Published: January 2025

Abstract

Background
Inflammatory bowel disease (IBD) remains a public health challenge, with its incidence and prevalence increasing globally [1]. IBD is known to have an increasing risk of developing colitis-associated cancer (CAC) [2], and it is important to elucidate the pathophysiology of CAC to invent a counteraction to prevent it. L-type amino acid transporter 1 (LAT1) has been reported to be upregulated during the active phase of ulcerative colitis [3] and colorectal cancer (CRC) [4]. However, its role and mechanisms in the progression of colitis and CRC development from a chronic inflammatory background remain unclear.

Methods
To investigate the role of LAT1 in tumour development with a colitis background, mice with intestinal epithelium-specific deletions of LAT1 (LAT1fl/fl; vil-cre) were subjected to azoxymethane/ dextran sulfate sodium (AOM/DSS) CAC model. Organoids derived from these mice were also analysed.

Results
LAT1 was detected at the base of colonic crypts and upregulated in DSS-induced colitis. Deletion of LAT1 in intestinal epithelium led to more severe inflammatory injury and delayed tissue repair following DSS treatment. Crypts derived from LAT1fl/fl; vil-cre mice formed fewer colonic organoids than LAT1fl/fl crypts. Furthermore, LAT1 was also upregulated in AOM/DSS-induced tumour tissues. The expression of inflammatory cytokine genes was significantly increased in LAT1-deleted tumours; however, no overall difference in colon tumour number or size was observed between the two groups. Accordingly, cell proliferation and apoptotic cell number were similar between LAT1-deleted tumours and those with sufficient LAT1.

Conclusion
The results of this study showed that LAT1 deficiency exacerbated intestinal inflammatory injury and delayed tissue repair by impairing the maturity of colonic crypt cells. Contrary to the expectation, however, LAT1 deficiency did not phenotypically affect overall colonic tumour development in the AOM/DSS-induced model. It may be partly because of the severe chronic colitis and increased inflammatory status within the tumours due to LAT1 deficiency in LAT1fl/fl; vil-cre mice, which might have compensated for tumour growth advantage of sufficient amino acid supplementation in LAT1 expressing control mice. Our results offer insights into how nutrient intake, such as daily diet, may influence the progression of colitis, and provide insights into the potential of LAT1-targeted therapies for clinical CRC treatment.

References
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[3]Sakata T, Hana K, Mikami T, et al. Positive correlation of expression of L-type amino-acid transporter 1 with colorectal tumor progression and prognosis: Higher expression in sporadic colorectal tumors compared with ulcerative colitis-associated neoplasia. Pathol Res Pract. 2020;216(6):152972.
[4]Najumudeen AK, Ceteci F, Fey SK, et al. The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer. Nat Genet. 2021;53(1):16-26.