顺铂
头颈部鳞状细胞癌
范科尼贫血
FANCD2
癌症研究
DNA修复
小干扰RNA
化疗增敏剂
医学
癌症
头颈部癌
化疗
内科学
化学
细胞毒性
生物
细胞培养
DNA
体外
转染
生物化学
遗传学
作者
Zheng‐Ming Huang,Yongju Chen,Rui Chen,Bin Zhou,Yongqiang Wang,Lei Hong,Yuepeng Wang,Jianguang Wang,Xiaoding Xu,Zhiquan Huang,Wei‐Liang Chen
标识
DOI:10.1002/advs.202202437
摘要
Head and neck squamous cell carcinoma (HNSCC) is the most common malignant tumor of the head and neck, and the prognosis of patients is poor due to chemotherapeutic resistance. Interestingly, patients with HNSCC induced by human papillomavirus (HPV) infection are more sensitive to chemotherapy and display a better prognosis than HPV-negative patients. The biological relevance of HPV infection and the mechanism underlying chemosensitivity to cisplatin remain unknown. Herein, SERPINB3 is identified as an important target for regulation of cisplatin sensitivity by HPV-E6/E7 in HNSCC. Downregulation of SERPINB3 inhibits cisplatin-induced DNA damage repair and enhances the cytotoxicity of cisplatin. In detail, decreasing SERPINB3 expression reduces the USP1-mediated deubiquitination of FANCD2-FANCI in the Fanconi anemia pathway, thereby interfering with cisplatin-induced DNA interstrand crosslinks repair and further contributing to HNSCC cell apoptosis. To translate this finding, pH-responsive nanoparticles are used to deliver SERPINB3 small interfering RNA in combination with cisplatin, and this treatment successfully reverses cisplatin chemotherapeutic resistance in a patient-derived xenograft model from HPV-negative HNSCC. Taken together, these findings suggest that targeting SERPINB3 based on HPV-positive HNSCC is a potential strategy to overcome cisplatin resistance in HPV-negative HNSCC and improves the prognosis of this disease.
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