The feedback loop between miR-222-3p and ZEB1 harnesses metastasis in renal cell carcinoma

Renal cell carcinoma (RCC) is an aggressive malignancy originating from the renal parenchyma, often leading to high mortality due to local invasion and distant metastasis. MicroRNAs (miRNAs) play essential roles in RCC progression. Through miRNA sequencing, we identified significant upregulation of miR-222-3p in metastatic RCC tissues. Exosomes from highly metastatic RCC cells were found to transfer miR-222-3p to low-metastatic cells, enhancing their migration and invasion. Mechanistically, miR-222-3p directly targets the 3' untranslated region (3'UTR) of the tumor-suppressor TRPS1, reducing its expression. TRPS1 downregulation releases its inhibitory effect on ZEB1, a key regulator of epithelial-mesenchymal transition (EMT), thereby promoting EMT and metastatic traits. ZEB1 further transactivates miR-222-3p, establishing a positive feedback loop. Additionally, miR-222-3p promotes a pre-metastatic niche by inducing M2 macrophage polarization, facilitating distant metastasis. These findings highlight miR-222-3p as a critical driver of RCC metastasis and suggest its potential as a diagnostic marker and therapeutic target for RCC.