ISL1 and AQP5 complement each other to enhance gastric cancer cell stemness by regulating CD44 expression.

Background: Gastric cancer, a prevalent and life-threatening malignancy, is believed to involve cancer stem cells (CSCs) as a contributing factor to tumor progression. Insulin gene enhancer binding protein-1 (ISL1) is a transcription factor, and it has not been elucidated how ISL1 regulates gastric carcinogenesis. The aim of this paper is to investigate the role of ISL1 in gastric cancer development.

Methods: In this study, we investigated the effects of ISL1 on the stem-like properties of human gastric cancer cells by applying transcriptional, flow, and immunofluorescence techniques.

Results: In human gastric cancer samples, there is an observed elevation in ISL1 expression, which correlates with the expression of stem cell markers, notably LGR5. Functionally, ISL1 fosters the self-renewal, cell proliferation, migration, and the clonogenic potential of gastric cancer cells in vitro. Furthermore, it enhances the ability of these cells to form tumors and metastasize in vivo. Additionally, ISL1 collaborates with AQP5, collectively intensifying the tumorigenicity of gastric cancer cells. Mechanistically, transcriptomic analysis of cells overexpressing ISL1 unveils a notable activation of the forkhead box O (FOXO) pathway. This activation leads to increased nuclear expression of forkhead box O3 (FOXO3), subsequently resulting in elevated expression of the stemness-associated gene CD44 in gastric cancer cells.

Conclusions: These findings shed light on the role of ISL1 in promoting the stem-like characteristics of gastric cancer cells and emphasize the connection between ISL1 and AQP5 as a novel therapeutic target for individuals with gastric cancer.