Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, 650-0017, Japan.
Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan.
J Gastroenterol. 2023 May;58(5):444-457. doi: 10.1007/s00535-023-01960-5. Epub 2023 Feb 5.
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.
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 background (LAT1; vil-cre; Apc), which were subject to analysis; organoids derived from those mice were also analyzed.
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 mice. Organoids derived from LAT1-deleted Apc 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.
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.
氨基酸转运体在为细胞提供营养方面发挥着重要作用，并且与细胞增殖有关。L 型氨基酸转运体 1（LAT1）在许多类型的癌症中高度表达，促进肿瘤生长；然而，LAT1 如何影响肿瘤的发展尚不完全清楚。
为了研究 LAT1 在肠道肿瘤发生中的作用，携带 LAT1 基因 floxed 等位基因的小鼠，该基因的启动子也表达 Cre 重组酶，来自编码微管相关蛋白 villin 的基因（LAT1; vil-cre; Apc），进行了分析；还分析了来自这些小鼠的类器官。
本研究表明 LAT1 在正常隐窝基底部细胞中持续表达，其在肠上皮细胞中的条件缺失导致潘氏细胞减少。LAT1 缺失减少了 Apc 小鼠小肠中的肿瘤大小和数量。来自 LAT1 缺失的 Apc 肠隐窝的类器官显示出较少的球形类器官，Wnt/β-catenin 靶基因表达减少，表明肿瘤起始能力较低。在肠上皮细胞中缺乏 LAT1 时，Wnt3 的表达减少，这表明由于 LAT1 缺乏导致潘氏细胞减少，通过减少 Wnt3 的产生，降低了肿瘤起始的风险。
LAT1 通过减少潘氏细胞中的 Wnt3 表达，以细胞外方式影响肠道肿瘤的发展。我们的研究结果可能部分解释了营养物质的可用性如何影响肠道中肿瘤发展的风险。
