CIP2A在肝癌侵袭及复发转移中的作用和机制

Cancerous inhibitor of protein phosphatase 2A (CIP2A) promote cell proliferation and tumorigenesis by inhibiting to phosphatase 2A (PP2A). Recent studies show that CIP2A is over-expressed and has also been found to be a prognostic factor in various human malignancies。Expression and biological function(such as HCC invasion, recurrence and metastasis)of CIP2A in hepatocellular carcinoma (HCC) has so far not been investigated. In our previous research, we found that CIP2A was high expression in HCC tissue and HCC cells. Its high expression can promote HCC invasion, recurrence and metastasis.We also found that CIP2A can activate the PI3K-Akt signal. We also found CIP2A binding to PTEN, which can activate PI3K/Akt signal pathway. We intend to figure out the effcet and the mechanism of CIP2A in HCC invasion, recurrence and metastasis. In future, we want:(1)to figure out the association between CIP2A and HCC invasion,recurrence and metastasis by using large human HCC tissue samples; (2)to observe the phenotypic changes in cell invasion, metastasis by using high or low-CIP2A expression cells;(3)to figure out the effect of CIP2A on HCC invasion,recurrence and metastasis by animal experiments; (4)to explore the molecule mechanism of activating PI3K-Akt signal by CIP2A-PTEN complex, and also to find a group which can work as a guidline of therapy included CIP2A and other prognostic molecules which will be found in this study. The project will take full advantage of translational medicine research strategy, through multiple levels of "cells - animals - patients" to demonstrate the mechanism of the CIP2A in the HCC invasion, recurrence and metastasis process. Its completion will provide new candidate markers for HCC treatment, and new potential drug targets for treatment of HCC.

CIP2A是抑癌基因PP2A的内源性抑制因子，可促进细胞增殖及肿瘤形成，但其在肝癌侵袭、复发转移中的作用及分子机制尚不清楚。我们前期研究发现CIP2A在高侵袭性及高转移性的肝癌组织中高表达；CIP2A在体外可诱导肝癌细胞上皮间质转分化、血管生成及细胞外基质降解，并增强肝癌细胞的侵袭能力；并且CIP2A可与PTEN形成复合体，并激活PI3K-Akt信号通路。本项目拟开展：(1)明确CIP2A在肝癌组织和癌旁组织中的内源性表达水平及其与患者临床病理特征和预后的相关性，阐明CIP2A在肝癌中的临床意义。2）上调/沉默肝癌细胞株CIP2A表达水平，通过体内和体外实验探讨其对肝癌侵袭转移能力的影响。3）分子水平重点探讨CIP2A-PTEN复合体的形成及其结合位点，靶向激活PI3K-Akt信号通路调控肝癌侵袭复发转移的机制，为抑制CIP2A临床防治肝癌提供科学依据。

CIP2A是抑癌基因PP2A的内源性抑制因子，可促进细胞增殖及肿瘤形成，但其在肝癌侵袭、复发转移中的作用及分子机制尚不清楚。本项目在人体、动物、细胞和分子水平探讨了CIP2A在肝癌侵袭转移中的作用及机制：（1）：利用人体标本了阐明CIP2A表达与肝癌临床指标的相关性，提示CIP2A高表达与肝癌低分化程度、高肝内转移(包括合并门静脉癌栓和卫星灶形成)、肝外转移、微血管浸润呈正相关，并提示高CIP2A表达与低生存时间及短复发时间呈正相关；（2）成功构建过表达及低表达CIP2A稳转细胞株后，应用整体动物模型，阐明了CIP2A可促进肿瘤的生长及转移；（3）上调或沉默CIP2A蛋白的表达，在细胞水平探讨CIP2A对肝癌细胞侵袭转移能力的影响，发现CIP2A可诱导肝癌细胞上皮间质转分化、血管生成及细胞外基质降解，并增强肝癌细胞的侵袭能力；（4）分子水平探讨CIP2A促进肝癌侵袭转移的可能机制，发现CIP2A可与PTEN形成复合体，靶向激活PI3K-Akt信号通路进而调控肝癌侵袭复发转移。这些结果将确立抑制CIP2A作为新的肝癌治疗途径提供更充分的科学依据。