肝癌的转移和复发是肝癌临床治疗的瓶颈问题，其分子机制的阐释是分子靶向治疗的前提和基础。我们课题组和王红阳院士课题组都研究发现：免疫负调控因子A20可以抑制肝癌转移，但是作用机制不清楚。细胞迁移是肿瘤转移的基础，其动态过程由RhoGTP酶家族严密调控，RAC1是其中重要成员。我们前期研究提示A20通过抑制RAC1活化抑制肝癌细胞的迁移，但是A20直接作用的靶分子是什么？生化实质为泛素编辑酶的A20如何对靶分子发挥作用？具体的分子机制仍然不明确。依据RAC1活化的信号通路：活化的RAS—导致PI3K/AKT活化—作用于RAC1调控因子—导致RAC1活化，我们前期研究初步锁定A20的直接作用靶点可能是RAC1调控因子。就此提出假说：A20通过泛素编辑特定的RAC1调控因子，抑制RAC1活化，进而抑制肝癌细胞迁移。本项目将阐释A20抑制肝癌转移的分子机制，为临床肝癌防治提供新的思路和理论依据。

HCC is one of the most common malignancies globally, ranking fifth in incidence and third in cancer-related deaths. Despite the recent advance in diagnosis and treatment of HCC, it remains a highly lethal disease due to metastasis and consequent recurrence after curative therapies. Understanding the metastatic mechanisms is a prerequisite for developing targeted molecular therapy to improve patients’ survival. . Both Lab of Professor Hongyang Wang and our lab find that A20, a critical immune negative regulator, inhibits the metastasis of HCC. But the mechanism is largely unknown. . The cell motility is the basis of cancer metastasis and controlled tightly by RhoGTPase family. RAC1 is the important member of RhoGTPase family responsible for lamellipodia formation occurring at the first step of tumor cell migration in the mode of mesenchamal movement. Our preliminary research suggested that A20 inhibited the formation of ruffling lamellipodia and the activation of RAC1 in HCC cells. However, what is the direct target of A20? How does A20 modify the RAC1 modulator since it is an ubiquitin editor? Both of the questions are intriguing. . The RAC1 activation is due to RAS activation in most cancer cells. RAS can be activated either by its gene mutation or by stimulation from environmental signals , such as EGF, PDGF and HGF. The activated RAS leads to activation of PI3K/AKT, which interacts with RAC1 modulators , including GEFs, GAPs and GDIs. These RAC1 modulators directly control the RAC1 activity. Our preliminary data suggested that A20 overexpression did not influenced the activation of PI3K/AKT. In addition, our immunoprecipitation experiment showed that A20 seemed not to combine with RAC1. Therefore, the target of A20 should be located between PI3K/AKT and RAC1. That is, it may be the RAC1 modulators. . Based on all these preliminary data, we propose the hypothesis that A20 modifies certain RAC1 modulators as an ubiquitin-editor so as to inhibit the RAC1 activity and HCC cell motility.. In the present project, we will confirm that A20 restrain HCC cell motility by its inhibiting RAC1 activity. The specific RAC1 modulators will be identified and the way for A20 to modify the RAC1 modulators will be clarified.