ARF介导RAF-1苏木化修饰激活ERK促骨肉瘤细胞失巢凋亡抵抗机制的研究

约15%-20%的骨肉瘤（Osteosarcoma，OS）患者初次就诊时就已存在肺部转移。明确OS转移机制是提高OS临床疗效的重要途径。RAS-RAF-MEK-ERK信号通路介导的失巢凋亡抵抗已证实在肿瘤转移中发挥重要作用。申请者在美国访学期间及发表在ATM的研究显示ARF可在特定条件下发挥促癌作用。但ARF与OS细胞失巢凋亡抵抗的关系目前国内外无相关研究。我们预实验显示ARF能以RAF-1依赖性的方式激活ERK促OS细胞失巢凋亡抵抗，但潜在机制不明确。由于ARF可通过增强其结合蛋白的苏木化修饰，而蛋白相互作用预测网站STRING显示ARF与RAF-1存在结合，且苏木化修饰预测软件GPS-SUMO1.0 显示RAF-1上存在苏木化修饰位点，因此我们推测ARF可能通过增强RAF-1苏木化修饰激活ERK促OS失巢凋亡抵抗，明确该机制将为提高骨肉瘤临床疗效提供新的思路。

Almost 15%-20% Osteosarcoma(OS) patients were combined with lung metastasis when they were diagnosed with OS in clinical. Uncovering the underlying mechanism of metastasis in OS is the key method to improve the clinical outcome. Anoikis resistance mediated by RAS-RAF-MEK-ERK signal has already been approved to play vital roles in tumor metastasis. Our previous study in MD Anderson Cancer Center and paper published in Annals of Translational Medicine demonstrated that ARF could exert oncogenic roles in some special situation. However, there are no papers related to ARF and anoikis resistance in OS cancer cells all over the world. Our primary data showed that ARF could promotes OS cancer cells anoikis resistance through activating ERK in a RAF-1 dependent manner, but the underlying mechanism is still unknown. As ARF could interact with numerous proteins and regulate their activity through triggering SUMOylation and website STRING showed that ARF could bind with RAF-1 and there are several SUMOylation sites in RAF-1 through GPS-SUMO1.0, so, we hypothesize that ARF may promote OS cancer cells anoikis resistance through activating ERK through enhancing RAF-1 SUMOylation. But the underlying mechanism is still unknown. Understanding this mechanism will provide new insights to improve the OS clinical outcome.