LIF promotes colorectal tumorigenesis via STAT3-mediated DNMT1 upregulation and subsequent tumor suppressor gene silencing

Although early screening, chemotherapy, and targeted therapies directed against specific oncoproteins and downstream signaling pathways have improved the prevention and treatment of colorectal cancer (CRC) to some extent, the incidence and mortality rates of CRC continue to increase. Thus, there is a pressing need to further elucidate the molecular mechanisms driving CRC pathogenesis and to develop novel therapeutic strategies. Leukemia inhibitory factor (LIF), a multifunctional cytokine that is frequently overexpressed in CRC and other malignancies, has recently emerged as a critical regulator of tumor progression. In this investigation, we examined the role of LIF in promoting malignant phenotypes in CRC cells. RNA-sequencing was performed on LIF-overexpressing CRC cell clones to identify downstream molecular changes. The relationship between LIF and DNA methyltransferase 1 (DNMT1) was further investigated, including the involvement of the JAK/STAT3 signaling pathway. In addition, a subcutaneous xenograft model was used to evaluate the therapeutic effect of an anti-LIF neutralizing antibody in vivo. We found that LIF promotes malignant phenotypes in CRC cells. RNA-sequencing identified a pronounced upregulation of DNMT1 in LIF-overexpressing CRC cell clones, suggesting its involvement in mediating epigenetic alterations within the tumor microenvironment and in maintaining methylation patterns during cell proliferation. LIF was shown to enhance stem-like properties in CRC cells, which was associated with DNMT1 expression. Mechanistically, LIF induced nuclear accumulation of DNMT1 and regulated its expression via the JAK/STAT3 signaling pathway. Furthermore, LIF-mediated upregulation of DNMT1 led to promoter hypermethylation and transcriptional silencing of tumor suppressor genes including PTPRO, RERG, and SCN4B. In a subcutaneous xenograft model, systemic administration of an anti-LIF neutralizing antibody significantly suppressed tumor growth and reduced DNMT1 expression in vivo. Collectively, these findings identify the LIF/DNMT1 axis as a critical driver of CRC progression and suggest that targeting this pathway represents a promising therapeutic strategy.