Excessive proliferation, metastasis and immune escape are considered to be hallmarks of cancer contributing to tumor progression. Split hand and foot malformation 1 (SHFM1) is highly expressed in various cancers and has been reported to increase malignant behaviors. However, the biological functions of SHFM1 in esophageal squamous cell carcinomas (ESCC) progression remain to be elucidated. An integrated bioinformatics analysis was performed to identify candidate genes in ESCC progression based on GSE microarrays. SHFM1 was found to be profoundly upregulated in ESCC tissues compared with normal tissues and SHFM1 expression was positively associated with poor prognosis. The biological effects of SHFM1 on cell growth, metastasis and immune escape were investigated following depletion or overexpression of SHFM1 in vitro. A xenograft mouse model was established to investigate the effect of SHFM1 on ESCC progression in vivo. SHFM1 overexpression promoted ESCC cell proliferation and migration in vitro as well as tumorigenesis in vivo, while SHFM1 knockdown restored those phenotype changes. Additionally, the present study demonstrated that the effects of SHFM1 on malignant behaviors of ESCC cells were achieved by activating the NF-κB signaling accompanied by increased P65 phosphorylation and nuclear translocation. Furthermore, SHFM1 was also found to regulate the sensitivity of cancer cells to natural killer (NK) cells. Specifically, inhibition of SHFM1 enhanced cell-mediated cell apoptosis and increased NK toxicity, which might involve the downregulation of c-Myc and programmed death-ligand 1, key targets in cancer immunotherapy. In conclusion, these findings suggested that SHFM1 probably promoted ESCC progression by activating the NF-κB pathway and enhancing the resistance of ESCC cells to NK cell cytotoxicity, indicating that SHFM1 may be a promising target for ESCC treatment.Copyright: © Wu et al.