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

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。

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.