TP63基因编码的新环状RNA促进鼻咽癌放疗抵抗的机制及其作为新型分子标志物的临床价值研究

环状RNA没有游离的5’和3’末端因而比线性RNA更稳定、更适合作为分子标记；且它们广泛参与细胞内基因表达调控，从而影响了恶性肿瘤等人类疾病发生发展，已成为医学领域新前沿和热点。我们通过RNA-seq发现TP63基因编码一个新环状RNA在鼻咽癌中高表达；细胞实验证实它可以影响代谢、增强鼻咽癌的放疗抵抗；进一步分析发现它可以编码一个与TAp63蛋白同框的小肽。根据初步实验结果，本项目的科学假说是：TP63编码的新环状RNA翻译出小肽，与p53蛋白竞争，解除p53对LDHA的转录抑制，TP63的另一转录本ΔNp63则通过超级增强子协同上调LDHA表达，LDHA驱动鼻咽癌细胞代谢重编程，增强放疗抵抗；新环状RNA翻译的小肽还可能通过p53下游的DNA损伤修复及凋亡相关通路调控鼻咽癌放疗抵抗。本项目还将探讨该环状RNA及小肽作为鼻咽癌新型分子标记，特别是作为放疗敏感性分子标记的临床价值和应用前景。

Circular RNAs (circRNAs) are a new class of RNA molecules that do not have free 5' and 3' ends and are therefore more stable than linear RNA and more suitable as molecular markers. Moreover, they are also widely involved in the regulation of gene expression in cells, thus affecting the occurrence and development of human diseases, including malignant tumors, and they have become a new frontier and a popular focus in the field of biomedicine. Through RNA sequencing, we found that a novel circRNA encoded by the TP63 gene, which we designated as circTP63-N, was highly expressed in nasopharyngeal carcinoma. In vitro experiments have confirmed that circTP63-N can enhance the radiotherapy resistance of nasopharyngeal carcinoma. Further analysis revealed that circTP63-N can encode a small peptide that has a high similarity to the TAp63 protein, which we designated as circTP63-p. Based on our preliminary results, the scientific hypothesis of this project is that the peptide encoded by the circTP63-p competes with p53 protein, which releases the transcriptional inhibition of p53 on the LDHA gene, while another TP63 transcript, ΔNp63, also regulates the expression of LDHA through the superenhancer in cooperation with this small peptide. The high expression of LDHA drives the metabolic reprogramming of the nasopharyngeal carcinoma cells, ultimately enhancing the radiotherapy resistance of nasopharyngeal carcinoma. This project will verify this hypothesis through a series of in vivo and in vitro experiments and explore the clinical value and application prospects of circTP63-N/circTP63-p as a novel molecular marker for nasopharyngeal carcinoma, especially as a molecular marker for the prediction of radiation therapy sensitivity.