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Aims Esophageal cancer ( EC) is one of the most prevalent and deadly cancers worldwide. Along with nutrition, smoking and alcohol consumption, human papillomavirus ( HPV) infection is one of the major risk factors, which is modulated by host immune response. This study is aimed at elucidating how HPV modifies host immune system in the EC pathogenesis. Methods The HPV and HLA- DQB1 levels in primary esophageal squamous cell (ESC) cancer cells from Han, Khazak and Uygur patients were analyzed by quantitative real-time PCR and immunoblotting. The ability of HPV16 E6/E7 to transform normal primary ESCs was investigated by infecting ESC with pMSCVpuro-carried E6 or E7. The shRNA against HPV16 E6 or E7 was delivered by adenovirus into esophageal squamous cell carcinoma ( ESCC) cells with high HPV content. The DNA methylation level of HLA- DQB1 was measured by methylation-specific PCR. Results The HLA- DQB1 expression level was correlated with the levels of HPV and inversely related to DNA methylation level of HLA- DQB1. Overexpressing HPV16 E6 or E7 alone was enough to transform normal primary ESCs. However, single knockdown of either E6 or E7 in ESC cancer cells did not reduce HLA- DQB1 expression. Conclusions Oncogenic HPV E6 and E7 genes promoted ESCC pathogenesis by upregulating susceptible HLA- DQB1 via DNA demethylation. [ABSTRACT FROM AUTHOR]