Nucleus-targeted Silencer nanoplatform regulating ZEB1-AS1 in head and neck squamous cell carcinoma therapy
Haojie Yang,
Yangfan Zhang,
Zicong Tan,
Zihao Liu,
Yingzhe Yan,
Qin Li,
Phei Er Saw,
Ning Liufu,
Fengtao Ji
Affiliations
Haojie Yang
Department of Anesthesia, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University
Yangfan Zhang
Department of Anesthesia, Guangzhou Women and Children’s Medical Center
Zicong Tan
Department of Anesthesia, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University
Zihao Liu
Department of Breast Surgery, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Beijing University Cancer Hospital Yunnan Hospital
Yingzhe Yan
Department of Anesthesia, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University
Qin Li
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University
Phei Er Saw
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University
Ning Liufu
Department of Anesthesia, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University
Fengtao Ji
Department of Anesthesia, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University
Abstract Long noncoding RNAs have emerged as key players in the progression of head and neck squamous cell carcinoma (HNSC). Among them, ZEB1-AS1 was identified as an upregulated candidate in HNSC through comprehensive analysis of RNA-sequencing datasets. Here, elevated ZEB1-AS1 expression was correlated with poor prognosis in HNSC patients. Further investigations demonstrated that downregulation of ZEB1-AS1 induced epithelial-mesenchymal transition and increased sensitivity to cisplatin in Cal27 cells, while its upregulation reversed these effects, underscoring its pivotal role in tumor metastasis and cisplatin resistance in Cal27 cells. Mechanistically, ZEB1-AS1, located in cytoplasm and nucleus, directly regulated the expression of ZEB1, thereby influencing the expression of μ opioid receptor (MOR) and implicating in cancer progression. To advance clinical translation, we employed a nucleus-targeting nanoparticle platform for efficient delivery of a mixture of antisense oligonucleotides and siRNA (Silencer), effectively manipulating ZEB1-AS1 expression in vitro and in vivo. Besides, a predictive model for HNSC patients was developed by analyzing the expression levels of ZEB1-AS1, ZEB1, and MOR in the HNSC datasets. Our study underscored the critical role of ZEB1-AS1 in HNSC and its potential as a therapeutic target. By elucidating its functional mechanisms and utilizing a nucleus-targeting nanoparticle platform for efficient delivery, we proved the potential of ZEB1-AS1-targeted therapies in HNSC.
