LAT1 expression influences Paneth cell number and tumor development in ApcMin/+ mice

• Published in: Journal of gastroenterology Vol. 58; no. 5; pp. 444 - 457
• Main Authors: Sui, Yunlong, Hoshi, Namiko, Ohgaki, Ryuichi, Kong, Lingling, Yoshida, Ryutaro, Okamoto, Norihiro, Kinoshita, Masato, Miyazaki, Haruka, Ku, Yuna, Tokunaga, Eri, Ito, Yuki, Watanabe, Daisuke, Ooi, Makoto, Shinohara, Masakazu, Sasaki, Kengo, Zen, Yoh, Kotani, Takenori, Matozaki, Takashi, Tian, Zibin, Kanai, Yoshikatsu, Kodama, Yuzo
• Format: Journal Article
• Language: English
• Published: Singapore Springer Nature Singapore 01.05.2023; Springer Nature B.V
• Subjects: Abdominal Surgery; Amino acids; Antibodies; Cell growth; Cell number; Cell proliferation; Clonal deletion; Colorectal Surgery; Cre recombinase; Epidemiology; Epithelium; Gastroenterology; Gene deletion; Gene expression; Hepatology; Laboratories; Medical research; Medicine; Medicine & Public Health; Nutrient availability; Organoids; Original Article—Alimentary Tract; Original —Alimentary Tract; Paneth cells; Small intestine; Surgical Oncology; Tumorigenesis; Tumors; University graduates; Wnt protein; β-Catenin; Paneth cells; L-type amino acid transporter 1; mTORC1; Cancer; Wnt3
• DOI: 10.1007/s00535-023-01960-5
• ISSN: 0944-1174; 1435-5922

Background Amino acid transporters play an important role in supplying nutrition to cells and are associated with cell proliferation. L-type amino acid transporter 1 (LAT1) is highly expressed in many types of cancers and promotes tumor growth; however, how LAT1 affects tumor development is not fully understood. Methods To investigate the role of LAT1 in intestinal tumorigenesis, mice carrying LAT1 floxed alleles that also expressed Cre recombinase from the promoter of gene encoding Villin were crossed to an Apc Min/+ background (LAT1 fl/fl ; vil-cre; Apc Min/+ ), which were subject to analysis; organoids derived from those mice were also analyzed. Results This study showed that LAT1 was constitutively expressed in normal crypt base cells, and its conditional deletion in the intestinal epithelium resulted in fewer Paneth cells. LAT1 deletion reduced tumor size and number in the small intestine of Apc Min/+ mice. Organoids derived from LAT1-deleted Apc Min/+ intestinal crypts displayed fewer spherical organoids with reduced Wnt/β-catenin target gene expression, suggesting a low tumor-initiation capacity. Wnt3 expression was decreased in the absence of LAT1 in the intestinal epithelium, suggesting that loss of Paneth cells due to LAT1 deficiency reduced the risk of tumor initiation by decreasing Wnt3 production. Conclusions LAT1 affects intestinal tumor development in a cell-extrinsic manner through reduced Wnt3 expression in Paneth cells. Our findings may partly explain how nutrient availability can affect the risk of tumor development in the intestines.