Apical Enrichment of the RNA Interference Machinery in Oral Stratified Epithelia Is Disrupted in Oral Cancer

Head and neck squamous cell carcinoma (HNSC) is characterized by low survival rates, which exposes gaps in understanding of the disease. Although the role of several miRNAs has been described in HNSC, the status of the RNA interference (RNAi) machinery that regulates biogenesis and function of miRNAs is largely understudied. This study shows that the core RNAi components drosha ribonuclease III (DROSHA) and argonaute RISC catalytic component 2 (AGO2), together with the adherens junction component pleckstrin homology domain containing A7 (PLEKHA7), are enriched at the apical areas of cell-cell contact in fully polarized stratified oral epithelial cells and normal human tissues, but not in oral cells that have not been stratified. This apical localization of PLEKHA7, DROSHA, and AGO2 is disrupted in HNSC, whereas PLEKHA7, which has previously been shown to recruit DROSHA and AGO2 to adherens junctions, is consistently down-regulated across all HNSC stages and grades, independently of demographic factors or human papillomavirus status. Additionally, the data reveal an association of the oral pathogen Fusobacterium with PLEKHA7 loss in oral tumors, as well as high levels of Fusobacterium infiltration in the tumors with disrupted apical RNAi localization. Together, this work sheds light on the status of key RNAi components in normal oral epithelia and reveals their disruption in HNSC tumors.