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Recently, epidemiological evidence of high-risk human papillomavirus (hrHPV) and its association with the increasing risk of esophageal cancer (EC) have been described. However, the involvement of such a virus in the pathogenesis of EC is still inconclusive in the literature. Therefore, our objective was to clarify the epidemiology of HPV infections in primarily diagnosed EC cases and validate this correlation with hospital-based control patients using a retrospective study with a case--control model. Here, we reported that the overall prevalence of HPV DNA was statistically associated with an increased risk of EC (OR, 3.3; 95% CI, 2.5--4.3). Interestingly, a history of gastroesophageal reflux disease (GERD) was constituted and significantly associated with HPV prevalence (adjusted OR, 4.6; 95% CI, 2.2--9.5). Furthermore, our meta-analysis in public databases also indicated that the combined OR and 95% CI between HPV infection and EC risk were 3.31 and 2.53--4.34, respectively, with significant heterogeneity (I2 =78%). Variations in the geographic study, tissue type, and detection method remain potential predictors of heterogeneity. In addition, publication bias and sensitivity analysis were not observed, and the results exhibited stable outcomes. Collectively, we specify the recent epidemiological evidence in a validation of the distributed HPV, which might be statistically associated with an increased risk of EC. However, additional high-quality studies with larger sample sizes are needed to further verify the link between HPV and EC. [ABSTRACT FROM AUTHOR]

Simple Summary: There is still limited knowledge of the critical pathogenic processes by which HPV16 induces oral carcinogenesis. Therefore, we aimed to illuminate the oncogenic role of HPV16 in the context of oral squamous cell carcinomas (OSCCs). Using human tongue keratinocyte cells, we demonstrated that HPV16 E6 promotes LTα1β2 and LTβR expression, thus promoting the lymphotoxin signaling pathway and leading to suppression of the transporter associated with the antigen-processing complex (TAPs; TAP1 and TAP2). Additionally, in vitro, we also demonstrated regulation of the antigenic peptide-loaded machinery in HPV-infected OSCC tissues through analysis of the transcriptomic profiles of the head and neck squamous cell carcinoma (HNSCC) cohort from the TCGA database, which was validated using fresh biopsied specimens. Thus, our study enhances the proposed functional role of HPV16 E6-associated immune-evasive properties in oral epithelial cells, revealing a possible mechanism underlying the development of HPV-mediated OSCCs. Infection by high-risk human papillomaviruses (hrHPVs), including HPV type 16 (HPV16), is a major risk factor for oral squamous cell carcinomas (OSCCs). However, the pathogenic mechanism by which hrHPVs promote oral carcinogenesis remains to be elucidated. Here, we demonstrated that the suppression of a transporter associated with the antigen-processing complex (TAPs; TAP1 and TAP2), which is a key molecule in the transportation of viral antigenic peptides into MHC class-I cells, is affected by the E6 protein of HPV16. Mechanistically, HPV-mediated immune evasion is principally mediated via the signal-transduction network of a lymphotoxin (LT) pathway, in particular LTα1β2 and LTβR. Our analysis of transcriptomic data from an HNSCC cohort from the Cancer Genome Atlas (TCGA) indicated that expression of TAP genes, particularly TAP2, was downregulated in HPV-infected cases. We further demonstrated that LTα1β2 and LTβR were upregulated, which was negatively correlated with TAP1 and TAP2 expression in HPV-positive clinical OSCC samples. Taken together, our findings imply that HPV16 E6 regulates the machinery of the antigenic peptide-loading system and helps to clarify the role of oncogenic viruses in the context of oral carcinoma. [ABSTRACT FROM AUTHOR]