WW45通过Hedgehog-Gli1信号通路抑制乳腺癌细胞增殖的机制研究

WW45 is a new tumor suppressor gene discovered in recent years. Recent research has shown that overexpression of WW45 was found to significantly weaken the proliferation rate and colony formation in human breast cancer cell line, but the molecular mechanism of WW45’s inhibition effect in the proliferation of breast cancer cell is not clear yet. As a key transcription factor of the Hedgehog signaling pathway, Gli1 plays a very important role in promoting breast cancer proliferation, but the mechanism of its upstream protein in regulating Gli1’s nuclear import is not clear. Our Previous study showed that WW45 sequesters Gli1 in the cytoplasm，but the mechanism and significance are unknown and further investigation is needed. Focus on the regulation of WW45 on Gli1, this project is to reveal the mechanism of proliferation of breast cancer cell that inhibited by WW45, which will provide experimental evidence for the individual treatment of breast cancer. This project includes the following aspects: 1. the influence of WW45 on the expression of Gli1 and its downstream proteins; 2. the mechanism of interactions between WW45 and Gli1; 3. the effect of WW45’s regulation on Hedgehog signaling pathway in the proliferation of breast cancer cell.

WW45是近年来新发现的抑癌基因，研究表明在人乳腺癌细胞中过表达WW45发现其增殖速度、克隆形成能力均明显减弱，但是WW45抑制乳腺癌细胞增殖的分子机制尚未明确。Gli1作为Hedgehog信号通路的关键性核转录因子，在促进乳腺癌细胞增殖中发挥重要作用，但是其上游蛋白如何调控其入核发挥生物学功能的机制尚不明确。我们的前期数据表明WW45可以通过与Gli1结合把其锚定在胞浆中，并且Gli1可以部分逆转WW45的抑癌功能，但是具体机制及生物学意义还有待进一部探讨。本课题以WW45对Gli1入核调控为切入点，探索WW45与Gli1相互作用作用位点，旨在阐明WW45抑制乳腺癌细胞增殖的分子机制。本研究包括以下3个方面：1）研究乳腺癌中WW45对Gli1及其下游蛋白表达的影响；2）阐明WW45与Gli1相互作用机制；3）探讨WW45调控Hedgehog信号通路对乳腺癌细胞增殖的影响。

WW45是近年来新发现的抑癌基因，研究表明在人乳腺癌细胞中过表达WW45发现其增殖速度、克隆形成能力均明显减弱，但是WW45抑制乳腺癌细胞增殖的分子机制尚未明确。Gli1作为Hedgehog信号通路的关键性核转录因子，在促进乳腺癌细胞增殖中发挥重要作用，但是其上游蛋白如何调控其入核发挥生物学功能的机制尚不明确。我们的前期数据表明WW45可以通过与Gli1结合把其锚定在胞浆中，并且Gli1可以部分逆转WW45的抑癌功能，但是具体机制及生物学意义还有待进一部探讨。本课题以WW45对Gli1入核调控为切入点，探索WW45与Gli1相互作用作用位点，阐明了WW45抑制乳腺癌细胞增殖的分子机制。