Abstract

Mounting evidence from large-scale association studies has identified transmembrane BAX inhibitor motif-containing 1 (TMBIM1) as a promising candidate gene in colorectal cancer (CRC) pathogenesis. Our clinical analysis confirmed this association, demonstrating significantly reduced TMBIM1 expression in human colon cancer tissues. To elucidate its functional role, we employed complementary experimental approaches across different cellular contexts. In normal colonic epithelial cells (NCM460), TMBIM1 deficiency triggered distinct morphological changes and suppressed cellular growth. Conversely, in malignant HCT-116 cells, TMBIM1 knockdown paradoxically enhanced proliferation and other pro-tumorigenic characteristics, suggesting context-dependent functions. Transcriptomic profiling via RNA-seq revealed that TMBIM1 suppression enhances cell viability, and the specific mutational background of HCT-116 cells appears to exploit the consequent loss of E-cadherin to further drive progression. Mechanistic investigations further identified E-cadherin (CDH1) as a key downstream effector, showing significant down-regulation following TMBIM1 knockdown. We therefore define a context-dependent tumor-suppressive mechanism for TMBIM1, wherein its loss in MSI-H cells promotes tumorigenesis via E-cadherin suppression and the consequent loss of epithelial integrity.