The SLC35B2/YAP1 axis contributes to the inhibitory effects of CLIC-2-overexpressing cancer-associated fibroblast-derived exosomes on gastric cancer progression

作者：Cong X, Zhang X, Yang H, Zhao Q, Gao Y, Jiang Z, Lv J, Guo H, Li S · 发表于：Cellular signalling · 年份：2026 · DOI：10.1016/j.cellsig.2026.112809 · 研究领域：CLIC-2、Cancer-associated fibroblasts、Gastric cancer、SLC35B2、YAP1 signaling

Cancer-associated fibroblasts (CAFs) are key regulators of tumor progression within the gastric cancer microenvironment. Chloride Intracellular Channel-2 (CLIC-2), a member of the CLIC protein family, has been implicated in tumor biology. However, its role in CAFs remains unclear. In this study, we found that CLIC-2 expression was significantly reduced in gastric CAFs and that low CLIC-2 levels were associated with poor patient prognosis. Loss-of-function experiments demonstrated that CLIC-2 deficiency promoted CAF-like activation of non-cancer fibroblasts (NFs), whereas CLIC-2 overexpression attenuated the activated phenotype of CAFs. Conditioned medium from CLIC-2-knockdown fibroblasts enhanced the viability, migratory, and invasion of gastric cancer cells, while conditioned medium from CLIC-2-overexpressing CAFs suppressed these malignant phenotypes. In vivo, co-injection of MKN-45 cells with CLIC-2-deficient fibroblasts promoted tumor growth and liver metastasis, whereas CLIC-2 overexpression in CAFs exerted tumor-suppressive effects. Proteomic analysis of CAF-derived exosomes identified Solute Carrier Family 35 Member B2 (SLC35B2) as a candidate downstream component associated with CLIC-2-regulated exosomal alterations. Exosomes derived from CLIC-2-overexpressing CAFs exhibited reduced SLC35B2 levels and inhibited malignant behaviors in gastric cancer cells. Mechanistically, SLC35B2 promoted YAP1 activation, as evidenced by enhanced nuclear accumulation of YAP1 and upreg...