LMP1调控Siah/HIF-1α通路诱导鼻咽癌上皮间质转化的分子机制研究

Latent membrane protein-1(LMP-1) is one of the major transformation-related, Epstein-Barr virus(EBV) encoded genes. It has been identified as encoding an oncoprotein that is thought to be a key modulator in NPC pathogenesis and progression, especially in invasion and metastasis. Epithelial-mesenchymal transition (EMT) is one of the mechanisms induced by LMP1 to promote metastasis in NPC, however, the actual mechanism of EMT regulated by LMP1 has not been fully addressed. Siah, which is one member of the Seven in absentia family, has been confirmed to be aberrantly expressed in many solid tumors, including NPC, and have been proved to be associated with metastasis. Siah have been shown to be involved in the response to hypoxic response, and (Siah)-family proteins contribute to the stabilisation of HIF-1α under hypoxic conditions. We proposed that LMP1 would induced EMT through Siah/HIF-1α pathway.This study will detect the expression of LMP1, Siah、HIF-1α and EMT related markers in the tissue of NPC patients,their relationship would be analyzed as well. In this study, we will evaluate the role of siah during EMT caused by LMP1, aim to provide new clues for the research of LMP1's role during NPC metastasis.

EB病毒潜伏膜蛋白1（LMP1）是鼻咽癌重要的病毒癌基因，被证实在鼻咽癌的转移过程中发挥了重要的作用。有报道LMP1可以诱导上皮细胞间质转化（EMT）来增加转移潜能，但LMP1引起EMT的分子机制仍不完全清楚。Siah是Seven in absentia家族成员之一，已证实在包括鼻咽癌的实体瘤中表达异常，且与肿瘤的转移有关。研究还报道Siah与肿瘤的乏氧反应通路密切相关，Siah可以调节HIF-1α蛋白的水平。据此我们推测LMP1可以通过Siah/HIF-1α来引起EMT现象。本研究拟在人体水平研究LMP1、Siah、HIF-1α及EMT特征性指标的相关性，初步探讨Siah在LMP1引起的EMT过程中的作用，旨在为LMP1引起鼻咽癌转移的分子机制研究提供新的线索。

EB病毒潜伏膜蛋白1（LMP1）是鼻咽癌重要的病毒癌基因，与鼻咽癌的转移潜能密切相关，可以诱导上皮间质转化（EMT）以增加转移潜能，但具体机制目前仍不完全清楚。Siah1是Seven in absentia家族成员之一，其表达水平受到LMP1的调节，该基因与肿瘤的乏氧反应通路密切相关，可以调节HIF-1α蛋白的稳定性，有报道在包括鼻咽癌的实体瘤中表达异常。我们推测LMP1可以通过Siah1/HIF-1α来引起EMT现象。本探索性项目在人体组织学水平利用免疫组化的方法检测鼻咽癌组织芯片中LMP1、HIF-1α、Siah1及EMT相关蛋白的表达情况，分析其相关性，旨在为进一步在细胞学及动物学水平的实验提供线索。首先，我们发现LMP1的表达与患者的无远处转移生存相关(p=0.059)，LMP1与Siah1（r=0.507，p=0.000）、Siah1和HIF-1α（r=0.489，p=0.000）的表达均存在正相关，且LMP1、Siah1和HIF-1α的表达均与EMT现象中的间质表型N-钙粘蛋白的表达存在正相关，我们推测LMP1可能通过Siah1/HIF-1α来调节鼻咽癌中EMT现象的发生。此外，本探索性项目还分析了Siah1与患者远期生存的关系，发现Siah1高表达者具有较好的预后，Siah1阳性表达组其无进展生存率及无远处转移生存明显高于阴性表达组(p分别为0.031和0.041)，Siah1是总生存、无进展生存及无远处转移生存的独立预测因子。本探索性项目为进一步在细胞学水平及动物水平研究LMP1引起鼻咽癌的EMT现象中是否有Siah1/HIF-1α的参与奠定基础，也为进一步研究Siah1在鼻咽癌发生发展中的机制提供探索方向。