肝细胞癌(HCC)存在对Sorafenib的耐受是制约其在晚期HCC患者中疗效的主要原因。最新理论认为，敏感细胞产生的治疗诱导肿瘤蛋白质组(TIS)通过激活AKT通路，促进自身存活和耐药细胞增殖浸润，导致激酶抑制剂耐受。我们初步研究表明， Sorafenib作用于HCC细胞可出现AKT上调，促进肿瘤耐药。在敏感细胞和耐受细胞共培养体系中，Sorafenib可促进耐受细胞的增殖、侵袭和转移灶形成，提示Sorafenib作用于敏感HCC细胞可能产生TIS。在此基础上本项目拟明确：Sorafenib作用于HCC后是否产生TIS；TIS是否由基因转录水平调控；TIS的下游信号通路是什么； Sorafenib联合TIS下游信号通路抑制剂是否可逆转Sorafenib耐药。本项目有望以全新理论解释HCC对Sorafenib的耐受和肿瘤进展机制，为提高Sorafenib疗效、延缓肿瘤进展提供新的治疗策略。

The natural and acquired resistance against Sorafenib in hepatocellular carcinoma (HCC) is the main obstacle that limits its efficiency in patients diagnosed at advanced stages. The latest theory is that therapy-induced tumor secrectomes (TIS) which is transcriptionally regulated in sensitive tumor cells activates the downstream AKT signaling, promoting the survival of sensitive cells and proliferation and invasion of resistant cells. Our preliminary research revealed the Sorafenib could activate AKT in HCC cell which was capable of inducing drug resistance. In further experiments, we found that the incubation of Sorafenib with sensitive HCC cells and resistant HCC cell could promote the proliferation, migration, invasion of resistant HCC cell, and also promote tumor metastasis in nude mice lung. So we speculated that TIS which could be responsible for AKT activation might be involved in Sorafenib resistance. On this basis, we aim to investigate the following problems in the level of molecular, cell and animal: Whether Sorafenib induces TIS in HCC? Whether TIS was transcriptionally regulated? What is the downstream signaling responsible for TIS induced Sorafenib resistance? Whether the combination of Sorafenib and the related signaling inhibitor could enhance Sorafenib efficiency? This study is expected to reveal a novel mechanism underlying Sorafenib resistance which will provide new molecular targets and theoretical basis to improve Sorafenib efficiency and reduce HCC progression.