The circTIMP2/miR-106a/TIMP2 tumor-suppressive axis versus tumor-derived exosomal counteraction in gastric cancer

Gastric cancer is a multifactorial disease and remains one of the leading causes of cancer-related deaths worldwide. CircRNAs have emerged as critical regulators in various cancers, while exosomes play essential roles in shaping the tumor microenvironment. However, the function of circTIMP2 and its interaction with exosomes are largely unknown. In this study, we evaluated the expression of circTIMP2 and investigated its biological roles in gastric cancer through a series of in vitro and in vivo experiments. The sponge mechanism of circTIMP2 for miR-106a, together with the target TIMP2, was validated using bioinformatics, luciferase, RNA immunoprecipitation, and fluorescence in situ hybridization assays. The involvement of exosomes and the influence on circTIMP2 were further explored. We found that circTIMP2 was significantly downregulated in gastric cancer, whereas miR-106a was upregulated, accompanied by downregulation of TIMP2. Overexpression of circTIMP2 attenuated malignant behaviors of cancer cells and suppressed subcutaneous tumor growth by upregulating its host gene TIMP2, coinciding with reduced miR-106a and inhibition of Wnt/β-catenin signaling pathway. Mechanistically, circTIMP2 acts as a competitive endogenous RNA by sequestering miR-106a to release its target TIMP2, thereby forming a circTIMP2/miR-106a/TIMP2 feedback loop that suppresses gastric cancer through inhibition of Wnt/β-catenin signaling. Importantly, tumor-derived exosomes counteracted the suppressive effects of circTIMP2, promoting orthotopic tumor progression by inhibiting TIMP2 and reactivating Wnt/β-catenin signaling. Our findings unveil a novel circRNA-guided feedback loop in gastric cancer and highlight how exosome-mediated mechanisms counteract this axis, providing new insights into the molecular pathogenesis of gastric cancer and suggesting potential therapeutic targets.