鼻咽癌中LMP1介导的SUMO1修饰翻转Klf4抑癌功能的作用及机制

Klf4是诱导多潜能干细胞的“山中伸弥”四因子之一，在肿瘤中的研究存在促癌和抑癌的矛盾现象。SUMO1修饰能使Klf4从细胞核内转位至细胞浆，并导致了其双向功能效应。病毒癌基因LMP1能劫持宿主细胞内SUMO修饰系统致靶蛋白的SUMO1修饰。我们前期在鼻咽癌细胞中也证实LMP1促进了Klf4的SUMO1修饰，且促进了细胞增殖和迁移；但是不表达LMP1的鼻咽癌细胞中Klf4抑制了细胞增殖、上皮-间充质转化（EMT）和肿瘤干性特征。由此我们推测LMP1介导的SUMO1修饰逆转了Klf4的抑癌功能，进而促进鼻咽癌恶性进展。本项目拟采用体外细胞培养、裸鼠移植瘤模型，过表达或敲低LMP1，同时抑制Klf4的SUMO1修饰，并观察增殖、EMT和肿瘤干性特征的改变。并采用免疫组化、蛋白印迹等技术在人体组织标本中验证该机制。以期阐明LMP1劫持宿主SUMO修饰系统逆转抑癌蛋白功能的促癌新机制。

Krüppel-like factor 4 (Klf4) is one of the four “Yamanaka” factors, which reprogrammed fibroblasts into induced pluripotent stem cells (iPSCs). In the fucntional researh of tumor, Klf4 showed divergent functions as promoting or inhibiting tumor. Sumoylated by small ubiquitin-like modifier 1 (SUMO1), Klf4 tanslocate from nuclear into cytoplasm and contribute to its bidirectional function. Viral oncogene latent membrane protein 1 (LMP1) could hijacked the SUMO modification system of host cells to modifier target proteins. Previously, we also confirmed LMP1 promoted the sumoylation of Klf4 by SUMO1, and further enhanced cell proliferation and migration. Whereas Klf4 inhibited proliferation, epithelial-to-mesenchymal transition (EMT) and stemness of nasopharyngeal carcinoma (NPC). So we postulated that sumoylation with SUMO1, which mediated by LMP1, lead to the turnover of tumor-inhibiting function of Klf4 and then promote the malignant progression of NPC. This proposal aimed to elucidate the new tumor-promoting mechanism of LMP1 hijacked the host cell SUMO modification system to reverse the funtion of tumor suppressor. Cultured cells, xenografted mice were used to observe the cell proliferation, EMT-like molecular phenotype, and stemness charachers through ectopic expression and knockdown of Klf4, and inhibiting sumoylation. The mechanism will be verified in human tissues by detecting the expression of associtaed proteins by immunohistochemistry and western blotting.