Bone marrow tyrosine kinase on chromosome X promotes epithelial-mesenchymal transition through signal transducer and activator of transcription 3 in colorectal cancer

Epithelial-mesenchymal transition (EMT) is a key driver of colorectal cancer (CRC) metastasis, contributing significantly to the high mortality rate in CRC patients. Bone marrow tyrosine kinase on chromosome X (BMX), a non-receptor tyrosine kinase, is broadly expressed in bone marrow epithelial cells, hematopoietic cells, and endothelial cells. While BMX has been implicated as an oncogenic factor in multiple malignancies, its functional role in CRC remains poorly understood. In this study, we demonstrated that BMX expression was significantly upregulated in CRC tissues. Genetic silencing of BMX by siRNA or pharmacological inhibition with BMX-IN-1 markedly attenuated the proliferation, migration, and invasion capacity of CRC cells. Consistently, BMX knockdown or inhibition potently suppressed tumor growth in cell line-derived xenograft models. Mechanically, β-catenin directly binds to the BMX promoter region, transcriptionally activating BMX expression. Furthermore, BMX physically interacts with signal transducer and activator of transcription 3 (STAT3) and enhances its phosphorylation at the Y705 residue, facilitating nuclear translocation of p-STAT3. Notably, nuclear p-STAT3 binds to E-cadherin promoter to suppress its transcription, thereby promoting EMT. Critically, the STAT3 inhibitor S3I-201 abrogated the pro-tumorigenic effects of BMX overexpression on HT29 cell proliferation, migration, and invasion. In conclusion, our findings establish that BMX drives CRC progression by activating STAT3 signaling pathway, which subsequently suppresses E-cadherin expression to induce EMT. • In CRC, β-catenin directly binds to the promoter region of BMX and upregulates BMX expression. • BMX decreased the expression of E-cadherin through STAT3 signaling, which ultimately contributes to epithelial-mesenchymal transition in colorectal cancer. • Knockdown or inhibition of BMX suppresses CRC progression both in vitro and vivo.