The role and mechanisms of the microRNA-1180-3p/MKNK2/CREB3 signaling axis in tumor progression following insufficient radiofrequency ablation of colorectal cancer liver metastasis.

Radiofrequency ablation (RFA) is an ideal treatment method for patients with colorectal liver metastases (CRLM); however, insufficient radiofrequency ablation (IRFA) may lead to high recurrence rates of CRLM. This study investigated the mechanism of microRNA-1180-3p (miR-1180-3p) in IRFA-induced CRLM progression.We established hot shock (HS) treated colorectal cancer (CRC) cell model and found that miR-1180-3p expression levels were significantly downregulated while MAP kinase interacting serine/threonine kinase 2 (MKNK2) and cAMP responsive element binding protein 3 (CREB3) expression levels were significantly upregulated in HS-CRC cells. Additionally, through bioinformatics analysis, we identified MKNK2 as a target of miR-1180-3p and validated their interaction using dual-luciferase reporter gene assays. Further studies confirmed that MKNK2 could bind to and phosphorylate the transcription factor CREB3. Overexpression of MKNK2 reversed the inhibitory effects of miR-1180-3p overexpression on proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) processes in HS-CRC cells, besides, overexpression of CREB3 reversed the inhibitory effects of MKNK2 knockdown. CREB3 could bind to and regulate nuclear factor kappa B subunit 1 (NFKB1) expression at the transcriptional level. Overexpression of miR-1180-3p combined with knockdown of MKNK2 and CREB3 effectively inhibited CRLM tumor formation in nude mice. The nude mouse IRFA model further validated the above molecular mechanisms. This study reveals for the first time the key regulatory role of the miR-1180-3p/MKNK2/CREB3 signaling axis in CRLM recurrence after IRFA, providing a molecular theoretical basis for preventing rapid progression of CRLM after RFA.