转录辅助因子CITED4调控Claudin-3参与肺腺癌转移的机制研究

Recurrence and metastasis were the most important prognostic factors for lung adenocarcinoma patients, but the underlying mechanism was not clear. Previous study had demonstrated that CBP/p300-interacting transactivator CITED4 was generally overexpression in lung adenocarcinoma, and was an important indicator for recurrence and metastasis in lung adenocarcinoma patients. The further studies had found that the expression of CITED4 affected the invasion and metastasis in vitro and vivo. These suggesting that CITED4 may play a key role in metastasis, but its regulatory mechanism was not identified. Furthermore, our previous work found that upregulation of Claudin-3 was induced the proliferation and invasion of lung adenocarcinoma cells. More importantly, the expression of CITED4 affected Claudin-3 levels significantly and suggested that CITED4 could interact directly with CTNNB1 (β-catenin), a transcription factor could bind directly to the promoter of Claudin-3 and activate its transcription. Based on the preliminary work, the role of CITED4 in the metastasis of lung adenocarcinoma and the mechanism of claudin-3 expression regulated by CITED4 binding to β-catenin would be further discussed in this topic. From the clinical specimen, cell molecular and animal model, the relationship between the CITED4 and Claudin-3 expression and lung adenocarcinoma metastasis and prognosis would be further illustrated. This study aims to gain insight into its regulatory mechanisms and find new targets for lung adenocarcinoma metastasis.

肿瘤复发和转移是影响肺腺癌患者预后的最重要因素，但其机制尚未明确。前期的实验结果发现转录辅助因子CITED4在肺腺癌中普遍高表达，并且可以预测腺癌患者的复发转移，进一步体内外实验发现CITED4水平影响肺腺癌细胞的侵袭能力，但其调控机制尚不明确，在既往的工作中发现紧密连接蛋白claudin-3是增强肺腺癌细胞的增殖及侵袭能力的关键分子，体外实验证实CITED4的表达显著影响claudin-3的水平，并初步证实CITED4能与claudin-3的结合分子CTNNB1(β-catenin)直接相互作用，本课题拟在前期工作基础上，研究CITED4在肺腺癌转移中的作用及CITED4结合β-catenin调控claudin-3水平进而影响转移的机制，在临床病例分析、细胞分子水平及动物转移模型三方面深入探讨二者的表达与肺腺癌转移和临床预后的相关性，为深入了解其调控机制及预测肺腺癌转移发现新的靶标。

目前，肺癌是世界范围内肿瘤死亡的首要原因。肺腺癌是肺癌重要病理类型之一，近年来发病率逐年上升，转移是肺腺癌临床治疗的一个难题，是影响患者生存质量和预后的最重要因素，前期研究发现改变Claudin-3表达水平可以影响肺腺癌细胞的增殖和侵袭迁移能力，因此，Claudin-3可能参与了肺腺癌转移的恶性行为。本研究的核心转录辅助因子CITED4的表达与Claudin-3的水平在肺腺癌组织中存在“同升共降”的趋势；体外实验证实，CITED4依赖于Claudin-3水平影响肺腺癌细胞的侵袭迁移能力，进一步机制研究，CITED4可以与CTNNB1（β-Catenin）相互作用入核，进而结合CTNNB1（β-Catenin）依赖的Claudin-3启动子区，从而诱导Claudin-3的表达，参与肺腺癌的转移过程，最终影响肺癌患者的预后。我们证实CITED4在肺腺癌转移中的作用，并在基因转录水平、蛋白水平深入研究CITED4参与调控Claudin-3及其下游基因、蛋白影响肺腺癌侵袭和迁移的分子调控机制，为肺腺癌转移的诊治提供新的理论基础。