p62/SQSTM1通过wnt/β-catenin通路促进鼻咽癌转移的分子机制

Distant metastasis is the leading cause of death of nasopharyngeal carcinoma (NPC). Therefore, early prediction of NPC metastasis and development of new treatment strategies are of vital importance. In our previous studies, we have identified that p62 was overexpressed in NPC cell lines and clinical samples. Over-expression of p62 was significantly correlated with patients’ poor prognosis. A newly developed metastasis prediction model based on p62 and N stage could effectively stratify NPC patients by metastasis risk. The results showed that only high-risk metastasis patients identified by the model received survival benefits from induction chemotherapy(IC), whereas patients in the low- and intermediate-risk groups did not benefit from combined IC. The model may reduce excessive treatment as a consequence of the effective selectivity. We also discovered that silencing p62 suppressed the epithelial–mesenchymal transition (EMT) process of NPC cells accompanied by activation of the epithelial marker E-cadherin and down-regulation of the mesenchymal-related N-cadherin. In addition, silencing p62 enhanced and impaired the migration and invasion in vitro and the lung metastasis in vivo of NPC cells. Furthermore, we found that silencing p62 suppressed the wnt/β-catenin signaling pathway, while the mechanism remains unkown. The purpose of this study is to find the molecular mechanism of how silencing p62 suppresses the wnt/β-catenin signaling pathway, decreases the entry of β-catenin into nuclears and suppresses EMT of NPC by a series of cytological, molecular biology and animal experiments. We will also verify the corelation between the p62 expression and wnt/β-catenin pathway in clinical samples to further improve the metastasis prediction model. Taken together, our study will provide new prediction model and new target for early detection of NPC metastasis.

远处转移是鼻咽癌患者的主要死因，如何早期预测转移及发展新的治疗策略尤为重要。我们前期发现：p62在鼻咽癌中高表达并与病人不良预后密切相关，联合p62表达水平及临床N分期构建的鼻咽癌转移预测模型，可将患者有效地分成高低转移风险组，高风险组中联合诱导化疗可提高疗效，低风险组无需诱导化疗可减少过度治疗；在鼻咽癌细胞中沉默p62能上调E-cadherin、下调Vimentin、抑制EMT，从而减弱其迁移、侵袭和转移能力，同时也抑制了Wnt/β-catenin信号通路。本项目拟进一步在细胞水平和动物模型中明确p62具有促进鼻咽癌转移的功能；研究p62抑制E-cadherin、诱导EMT的分子机制；在鼻咽癌临床标本中分析p62、β-catenin、E-cadherin之间的相关性，进一步完善转移预测模型。本项目的完成将阐明p62促进鼻咽癌转移的分子机制，为鼻咽癌转移提供新的早期预测模型和治疗靶点。

远处转移是鼻咽癌患者死亡的主要原因，筛选和鉴定转移相关分子标志物、研究转移的分子机制和开发鼻咽癌新的治疗策略至关重要。基于该项目，我们发现p62通过NF-κB 信号通路促进鼻咽癌细胞发生上皮间质转化（EMT）进而促进远处转移的分子机制，基于转移相关蛋白p62和N分期的预后预测模型，可筛选高危转移潜能鼻咽癌患者接受诱导化疗，从而实现鼻咽癌的精准化疗；发现CTC和EBV DNA治疗前后动态变化对鼻咽癌转移具有预测作用，基于CTC、EBV DNA以及影像学评估的动态变化建立预后预测模型，可筛选高危进展患者；我们首次描绘了转移鼻咽癌新抗原全景图，发现鼻咽癌在转移过程中中存在新抗原的丢失，这些新抗原有望成为鼻咽癌转移的新型分子诊断标志物，并为鼻咽癌的治疗提供潜在靶标。依托本项目，发表第一作者/通讯作者SCI论文17篇，分别为：JAMA oncology（IF:31.777，1篇）、Cell Research（IF:25.617，1篇）、Journal for Immunotherapy of Cancer（IF:13.751，1篇）、Cancer Research（IF:12.701，1篇）、Clinical Cancer Research（IF:12.531，1篇）、Theranostics（IF:11.556，1篇）、Cancer Communications（IF:10.392，2篇）、European Journal of Cancer（IF:9.162，1篇）、International Journal of Cancer（IF:7.396，1篇）、Oral Oncology（IF:5.337，2篇）、Journal of Cancer（IF:4.207，1篇）、Otolaryngology--Head and Neck Surgery（IF:3.497，1篇）、Laryngoscope（IF:3.325，1篇）、Head & Neck（IF:3.147，2篇）。基于本项目的研究发现，负责人陈明远继续作为主持人获得各级科研项目资助5项，总经费达2030万元，并入选第四批国家“万人计划”科技创新领军人才、科技部创新人才推进计划中青年科技创新领军人才、广东省“杰出青年医学人才”、中山大学肿瘤防治中心高层次人才特殊支持计划领军人才等。