STAT3异常活化与肝癌密切相关，已成为治疗肝癌的一个重要靶标。当蛋白激酶活性升高和/或蛋白磷酸酶活性降低时，STAT3就过度激活，从而导致肿瘤的发生或恶化。尽管已经发现了几个磷酸酶能够调控STAT3的活性，但其特异性问题尚未解决。我们发现，GdX能够介导STAT3的去磷酸化，其机理是介导了STAT3与磷酸酶PTPTC45的特异结合。然而，GdX如何调控STAT3的去磷酸化过程仍不清楚，其在肝癌中的作用亦未见报道。本课题在前期研究基础上，提出GdX可能识别STAT3的不同二聚体，在细胞中发生核质转移，使STAT3失去活性。我们已经在GdX敲除小鼠上诱导出炎症相关结肠癌，发现GdX的缺失能够通过增强STAT3的活性，促进结肠癌发生。据此我们推测GdX能够通过调控STAT3的磷酸化影响肝癌发生。因此，本课题将利用基因敲除小鼠，结合临床病理资料，阐明GdX在抑制肝癌发生方面发挥的作用。

The aberrant activation of STAT3 is highly related to hepatocarcinogenesis and STAT3 has become an important target for the treatment of hepatocellular carcinoma (HCC).The hyper-activated STAT3 is caused by up-expression and over-activation of different kinases and/or down-regulation of several phosphatases, which together lead to tumorigenesis and metastasis. It remains unclear how STAT3 is specifically dephosphorylated although several phosphatases have been identified during the inactivation of STAT3. We have found that GdX, a ubiquitin like domain containing protein,dephosphorylates STAT3 and inhibits STAT3 activity, by specifically mediating the association of STAT3 with PTPTC45, a nuclear phosphatase, in response to cytokine stimulationis. However, it remains elusive how the dephosphorylation process occurs and the role of GdX in HCC has not been reported. This study proposes that GdX may recognize different dimers of STAT3,translocates from the nucleus to the cytoplasm and inactivates STAT3, based on our previous observations. We have established a colitis-associated colon cancer model using GdX knock-out mouse that we generated and observed that deletion of GdX resulted in an enhanced STAT3 activity in the colon cancer tissues. Therefore we prospected that GdX may regulate HCC through affecting the STAT3 de-phosphorylation process. We will use the knock-out mouse model plus clinical samples from human HCC patients to reveal the role of GdX in HCC. Our study will provide new insights in understanding regulation of STAT3 activity in HCC. We expect that GdX might be used as a marker for the diagnosis of this disease.

STAT3异常活化与肝癌密切相关，已成为肝癌治疗的一个重要靶标。我们发现，GdX能够介导STAT3的去磷酸化，其机理是介导了STAT3与磷酸酶PTPTC45的特异结合。在肝癌发生过程中，STAT3被过度激活，从而导致肿瘤的发生或恶化。实验利用GdX基因敲除小鼠，结合临床病理资料，搞清GdX在小鼠肝癌发生过程中发挥的作用。在GdX敲除小鼠上诱导出炎症相关结肠癌，发现GdX的缺失能够抑制NF-KB的活性，促进结肠癌发生。实验进一步证明GdX能够通过正调控p65的磷酸化，而Gdx作为一个调节蛋白，在NF-kB信号通路中，同样可以通过募集磷酸酶TC45来调控p65的磷酸化，从而影响炎症的发生，进一步参与结肠癌的发生发展。 GdX基因敲除后小鼠牙齿，脊柱，额面骨等骨组织出现发育异常现象。对胚胎期小鼠全身骨骼染色，发现GdX基因缺失后，小鼠部分骨组织出现成骨过程异常现象，如指骨骨化延迟，囟门闭合不全。股骨、胫骨组织学染色结果分析，发现次级骨化中心增殖区扩大，细胞增殖活性增强。GdX基因对小鼠骨发育的影响主要表现于胚胎发育早期及成熟期前。通过对生长板软骨细胞亚细胞结构的观 察发现，GdX基因敲除后内质网膨大，细胞外基质蛋白表达减少。在骨分化早期，胞外基质蛋白对骨髓间充质干细胞分化有重要影响，如 I 型胶原蛋白基因的突变， 会产生异常前α链，异常前α链会通过内质网相关的蛋白酶体降解途径被降解，若无法得到正常降解将引发多种骨发育异常相关疾病。