靶向G3BP1介导Wnt/β-Catenin信号通路的抗乳腺癌作用与机制研究

It is still one of the important research tend to find new molecular targeted therapy drugs with little side effects and significant anti-tumor effects, because of the non selective toxicity and side effects of chemotherapy drugs. Our previous study found the high expression of G3BP1 in various tumors, which associated with tumor development and metastasis. G3BP1 promotes the development of tumors through regulating TGF-β and Wnt signaling pathway, and down-regulation of G3BP can inhibit tumor cell proliferation, invasion and metastasis but its mechanism is still not clear. This study is (1) for the purpose of the relationship and molecular function between G3BP1 and breast cancer cell proliferation, metastasis, and drug resistance. (2) To investigate the relationship between the expression of G3BP1 and Wnt/β-catenin signaling pathway, and the regulation of GSK-3β involved in the signal pathway. (3) To investigate the the function of G3BP1 protein interaction and find key binding sites of G3BP1 and GSK-3β, we design and synthesize antagonistic peptides of protein-protein interaction, and explore the inhibition of tumor growth by the blockage of G3BP1 binding site. (4) To investigate G3BP1 as a potential drug target, verify the effect and synergism of G3BP1 blocking agent on breast cancer, and clarify the mechanism of action. This study will provide new targets and new strategies for the treatment and combination chemotherapy of breast cancer.

由于化疗药物非选择性毒副作用，寻找毒副作用小、抗肿瘤效果显著的新分子靶向治疗药物仍然是重要研究方向之一。我们前期研究发现G3BP1在肿瘤中高表达，并与肿瘤发展和转移相关；G3BP1通过调控TGF-β和Wnt等信号通路促进肿瘤的发展，下调G3BP1能抑制肿瘤细胞增殖、侵袭和转移，但其机制不很清楚。本课题旨在①探讨G3BP1与乳腺癌细胞增殖、侵袭和转移的关系及其分子功能作用；②探明G3BP1与Wnt/β-Catenin信号通路的相互关系，以及对该信号通路中GSK-3β的调控作用；③探测G3BP1与GSK-3β蛋白相互作用功能，找出与信号分子GSK-3β的关键结合位点，进一步设计和合成拮抗多肽，并深入探索G3BP1关键位点阻断对乳腺癌生长的抑制作用；④探讨G3BP1作为潜在药物靶点，验证G3BP1阻断剂对乳腺癌的疗效和对化疗药物的增效作用。本研究将为乳腺癌的靶向治疗和联合化疗提供新靶点和新策略。

Ras-GTPase激活SH3结构域结合蛋白1（G3BP1）是一种多功能结合蛋白，参与多种人类肿瘤的发生发展。然而，G3BP1在乳腺癌进展中的作用仍不清楚。在本研究中，我们报告了G3BP1上调与乳腺癌预后不良相关。G3BP1的过度表达通过刺激β-catenin信号通路促进乳腺癌细胞增殖，β-catenin信号通路上调许多增殖相关基因。我们进一步证明G3BP1通过抑制泛素-蛋白酶体降解而不是影响β-连环蛋白的转录来提高β-连环蛋白的稳定性。机制上，G3BP1升高与GSK-3β相互作用并失活以抑制β-catenin的磷酸化和降解。干扰G3BP1-GSK-3β相互作用加速β-catenin的降解，降低乳腺癌细胞的增殖能力。我们的研究表明，G3BP1/GSK-3β/β-catenin轴的调控机制可能是乳腺癌治疗的一个潜在靶点。