Gankyrin结合SMADs调控TGF-β诱导宫颈癌上皮间充质转化的机制研究

Epithelial-mesenchymal transition of cervical cancer cells is considered the key step in cervical cancer metastasis, but the exact mechanism remains unknown. Recently, an oncogenic protein Gankyrin has been shown playing an important way in tumorigenesis and metastasis through protein-protein interactions and post-translational modification. In previous research we found the abnormal high expression of Gankyrin in cervical cancer tissues, and the up-regulation of Gankyrin in TGF-β1-induced EMT process of cervical cancer cells. According to these results, we postulated that Gankyrin is probably a key factor in TGF-β-induced EMT process of cervical cancer. Further experiments found that Gankyrin can form a complex with SMAD3. However, the underlying mechanism of how Gankyrin interacting with SMAD3 keeps unclear. Meanwhile, it is considerably worthwhile to explore the detailed function of Gankyrin/SMADs complex during the process of TGF-β-induced EMT. In this research project, we aim to further investigate the mechanism of the interaction between Gankyrin and SMADs, and reveal the function of Gankyrin in TGF-β/SMADs pathway, thus elaborating Gankyrin is another important modulator of TGF-β-induced EMT process.

宫颈癌上皮间充质转化（EMT）被认为是宫颈癌发生转移的关键步骤，但调控机制仍不清楚。近年来研究表明，癌蛋白Gankyrin所介导的蛋白间相互结合与翻译后修饰是引起肿瘤发生和转移的重要分子机制。我们前期研究发现，Gankyrin在宫颈癌组织中存在异常高表达，而TGF-β1诱导宫颈癌细胞EMT的同时伴随Gankyrin表达上调。因此我们提出假说：Gankyrin可能是TGF-β信号通路诱导宫颈癌发生EMT的关键分子。进一步实验表明，Gankyrin能与SMAD3形成复合体，但两者之间相互作用的机制尚不明确，Gankyrin是如何通过SMADs调控TGF-β信号通路的也有待继续研究。为此在本课题中，我们拟进一步明确Gankyrin与SMADs蛋白相互作用的方式，确定Gankyrin在TGF-β/SMADs信号通路中的功能，阐明Gankyrin调控TGF-β信号通路促进宫颈癌发生EMT的新机制。

上皮间质转化（EMT）在宫颈癌侵袭转移中发挥重要作用，其调控机制值得深入探索。我们前期研究表明：癌蛋白Gankyrin在宫颈癌组织中存在异常高表达，并能诱导宫颈癌细胞发生EMT。在本项目中，我们证实了TGF-β促进宫颈癌细胞发生EMT的同时能诱导Gankyrin表达上调，敲减Gankyrin能削弱TGF-β诱导的EMT。进一步研究发现，Gankyrin能增加SMAD3的磷酸化水平并调控TGF-β介导的转录活性。我们在本项目中亦发现Gankyrin在巨噬细胞移动抑制因子（MIF）诱导EMT中发挥调控作用。此外，通过生物信息学分析，我们对Gankyrin的上游调控分子进行探索，发现染色质重构复合体SWI/SNF的亚基ACTL6A能通过促进Gankyrin的表达诱导EMT发生。通过本项目的开展，我们进一步丰富了Gankyrin调控EMT的分子机制，并可能为转移性宫颈癌治疗的药物研发提供新的靶点。