Interleukin‐6 production mediated by the IRE1‐XBP1 pathway confers radioresistance in human papillomavirus‐negative oropharyngeal carcinoma

摘要

Endoplasmic reticulum stress (ERS) plays a key role in the pathogenesis and development of tumors and protects tumor cells from radiation damage and drug‐induced stress. We previously demonstrated that EGFR confers radioresistance in human papillomavirus (HPV)‐negative human oropharyngeal carcinoma by activating ERS signaling through PERK and IRE1α. In addition, PERK confers radioresistance by activating the inflammatory cytokine NF‐κB. However, the effect of IRE1 on radiosensitivity has not yet been fully elucidated. Here, we clarified that IRE1 overexpression was associated with poor outcome in HPV‐negative patients treated with radiotherapy (P = 0.0001). In addition, a significantly higher percentage of radioresistant HPV‐negative patients than radiosensitive HPV‐negative patients exhibited high IRE expression (66.7% vs 27.8%, respectively; P = 0.001). Silencing IRE1 and XBP1 increased style="fixed-case">DNA double‐strand break ( style="fixed-case">DSB) and radiation‐induced apoptosis, thereby increasing the radiosensitivity of style="fixed-case">HPV‐negative oropharyngeal carcinoma cells. style="fixed-case">IRE1‐ style="fixed-case">XBP1 silencing also inhibited radiation‐induced style="fixed-case">IL‐6 expression at both the style="fixed-case">RNA and protein levels. The regulatory effect of style="fixed-case">IRE1‐ style="fixed-case">XBP1 silencing on style="fixed-case">DNA DSB‐induced and radiation‐induced apoptosis was inhibited by pretreatment with style="fixed-case">IL‐6. These data indicate that style="fixed-case">IRE1 regulates radioresistance in style="fixed-case">HPV‐negative oropharyngeal carcinoma through style="fixed-case">IL‐6 activation, enhancing X‐ray‐induced style="fixed-case">DNA DSB and cell apoptosis.