MCPIP1 Controls Hybrid EMT and Tumor Stemness via the IL6/JAK2/STAT3 Axis in Pancreatic Cancer

Introduction: Pancreatic Cancer (PC) is a common malignant tumor with high morbidity and mortality and a very poor prognosis, highlighting the urgent need to identify molecular therapeutic targets. Monocyte chemotactic protein-inducible protein-1 (MCPIP1) is a common inflammatory protein associated with the pathogenesis of a variety of cancers, although a comprehensive understanding of its function and the underlying mechanisms involved in PC remains unclear.

Materials and methods: Immunohistochemistry, western blotting, immunofluorescence, flow cytometry, Transwell, and the scratch assay were used to evaluate the functional role of MCPIP1 in PC. Human PC samples, PC cells, and tumor tissues from subcutaneous tumors of nude mice were examined for MCPIP1 and a panel of epithelial-mesenchymal transition (EMT) -related indicators. In the mechanistic study, the IL6/JAK/STAT3 signaling pathway was investigated as a potential downstream pathway. IL6 activity was inhibited using the pharmacological inhibitor LMT-28 and was applied to MCPIP1 gene-deficient cells to assess the reversal of the malignant phenotype.

Results: MCPIP1 was significantly downregulated in PC tissues and its expression strongly correlated with patient survival. MCPIP1 knockdown enhanced tumor cell stemness, proliferation, migration, and hybrid epithelial-mesenchymal transition (hybrid EMT) in PC cell lines, whereas overexpression suppressed these phenotypes. In xenograft models, MCPIP1 knockdown promoted tumor growth and hybrid EMT progression in mice. MCPIP1 knockdown activated the IL6/JAK/STAT3 signaling pathway, which was inhibited by MCPIP1 overexpression. LMT-28 treatment reversed the stemness and hybrid EMT phenotypes of MCPIP1-deficient cells.

Conclusion: MCPIP1 is a key regulator of PC progression, acting as a tumor suppressor by inhibiting the IL6/JAK/STAT3 signaling pathway. The findings suggest that MCPIP1 is a promising therapeutic target with potential implications for the development of new strategies for managing PC.

IL6/JAK/STAT3 axis; hybrid epithelial‐mesenchymal transition; monocyte chemotactic protein‐inducible protein‐1; pancreatic cancer; tumor stemness.