Department of Oral and Maxillofacial-Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, 200011, People's Republic of China.
Department of Oral and Maxillofacial Surgery, Shanghai Stomatological Hospital, Fudan University, Shanghai, 200001, People's Republic of China.
Cell Mol Life Sci. 2024 Jun 28;81(1):282. doi: 10.1007/s00018-024-05324-x.
Cetuximab resistance has been a major challenge for head and neck squamous cell carcinoma (HNSCC) patients receiving targeted therapy. However, the mechanism that causes cetuximab resistance, especially microRNA (miRNA) regulation, remains unclear. Growing evidence suggests that miRNAs may act as "nuclear activating miRNAs" for targeting promoter regions or enhancers related to target genes. This study elucidates a novel mechanism underlying cetuximab resistance in HNSCC involving the nuclear activation of KDM7A transcription via miR-451a. Herein, small RNA sequencing, quantitative real-time polymerase chain reaction (qRT‒PCR) and fluorescence in situ hybridization (FISH) results provided compelling evidence of miR-451a nuclear enrichment in response to cetuximab treatment. Chromatin isolation via RNA purification, microarray analysis, and bioinformatic analysis revealed that miR-451a interacts with an enhancer region in KDM7A, activating its expression and further facilitating cetuximab resistance. It has also been demonstrated that the activation of KDM7A by nuclear miR-451a is induced by cetuximab treatment and is AGO2 dependent. Logistic regression analyses of 87 HNSCC samples indicated the significance of miR-451a and KDM7A in the development of cetuximab resistance. These discoveries support the potential of miR-451a and KDM7A as valuable biomarkers for cetuximab resistance and emphasize the function of nuclear-activating miRNAs.
西妥昔单抗耐药性一直是接受靶向治疗的头颈部鳞状细胞癌（HNSCC）患者的主要挑战。然而，导致西妥昔单抗耐药的机制，特别是 microRNA（miRNA）调控，仍不清楚。越来越多的证据表明，miRNAs 可能作为“核激活 miRNA”，靶向与靶基因相关的启动子区域或增强子。本研究阐明了 HNSCC 中西妥昔单抗耐药的一种新机制，涉及通过 miR-451a 对 KDM7A 转录的核激活。在此，小 RNA 测序、定量实时聚合酶链反应（qRT-PCR）和荧光原位杂交（FISH）结果提供了令人信服的证据，表明 miR-451a 在对西妥昔单抗治疗的反应中发生核富集。通过 RNA 纯化、微阵列分析和生物信息学分析进行的染色质分离揭示了 miR-451a 与 KDM7A 的增强子区域相互作用，激活其表达，并进一步促进西妥昔单抗耐药性。还表明，核 miR-451a 对 KDM7A 的激活是由西妥昔单抗治疗诱导的，并且依赖于 AGO2。对 87 例 HNSCC 样本的逻辑回归分析表明，miR-451a 和 KDM7A 在西妥昔单抗耐药性的发展中具有重要意义。这些发现支持 miR-451a 和 KDM7A 作为西妥昔单抗耐药的有价值的生物标志物的潜力，并强调了核激活 miRNA 的功能。
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