ZLM-7靶向β-tubulin双抑制Sp1/HIF-1α信号的抗肿瘤血管生成机制研究

Anti-angiogenesis is a new targeted cancer therapy strategy. In the early stage, we synthesized ZLM-7, a target microtubule compound with independent intellectual property rights. It has high anti-tumor activity, good water solubility and stability. It was reported that ZLM-7 has anti-angiogenesis effect, but the upstream regulation mechanism is still unclear. Evidence showed that ZLM-7 inhibited microtubule aggregation, then β-tubulin binding to Sp1 and HIF-1α respectively, down-regulated their protein levels, inhibited tumor angiogenesis, and simultaneously over-expression of both Sp1 and HIF-1a restored the protein level of VEGF/VEGFR2. Therefore we put forward that ZLM-7 targeting β-tubulin, inhibits microtubule aggregation, down-regulates Sp1/HIF-1α protein level, and then reduces the transcriptional expression of VEGF/VEGFR2, ultimately inhibits tumor angiogenesis. In this project, we firstly identify the binding sites of ZLM-7 and beta-tubulin, then discuss the interaction between β-tubulin and Sp1/HIF-1a and their binding domain, finally verify the anti-angiogenesis effect of ZLM-7 mediated by β-tubulin—Sp1/HIF-1α. Therefore, our studies provided proof of concept for further drug discovery efforts that may lead to novel strategies and new therapeutics for the treatment of human cancer.

抗肿瘤血管生成是一种新的靶向治疗策略，课题组前期合成了自主知识产权的靶向微管化合物ZLM-7，其抗肿瘤活性高，水溶性和稳定性好，并报道ZLM-7有抗肿瘤血管生成作用，但其上游调控机制尚不明确。预实验发现ZLM-7抑制微管聚合，β-tubulin分别与Sp1和HIF-1α结合并下调其蛋白水平，抑制肿瘤血管生成，同时过表达Sp1/HIF-1α可回复VEGF/VEGFR2蛋白水平。据此提出假说：ZLM-7靶向β-tubulin，抑制微管聚合，下调Sp1/HIF-1α蛋白水平，进而降低VEGF/VEGFR2转录表达，最终抑制肿瘤血管生成。为此本项目首先明确ZLM-7与β-tubulin的结合位点，再探讨β-tubulin与Sp1/HIF-1α的互作及其结合结构域，最后验证β-tubulin—Sp1/HIF-1α介导ZLM-7抗肿瘤血管生成作用，为靶向抗肿瘤血管生成的新药研发提供重要理论与科学依据。

抗肿瘤血管生成是一种新的靶向治疗策略，课题组前期合成了自主知识产权的靶向微管化合物ZLM-7，其抗肿瘤活性高，水溶性和稳定性好，并报道ZLM-7有抗肿瘤血管生成作用，但其上游调控机制尚不明确。项目组前期工作发现 Sp1 可以直接促进 VEGFA 的表达， 而 ZLM-7可以上调 miR-212 在乳腺癌细胞中的表达， 因此我们首先研究 ZLM-7 在乳腺癌中对 miR-212/Sp1/VEGFA 信号轴的分子调控机制，再探讨ZLM-7抑制微管聚合，下调Sp1/HIF-1α蛋白水平及相互作用关系。本研究发现ZLM-7 上调了 miR-212 在乳腺癌细胞中的表达， 抑制了乳腺癌细胞的增殖、迁移、 侵袭和血管生成； miR-212 通过靶向 Sp1 抑制 VEGFA 的表达；从而通过 Sp1/ VEGFA 轴抑制乳腺癌细胞的增殖、 迁移、 侵袭和血管生成；ZLM-7 通过上调体内 miR-212 的表达来抑制 Sp1 和 VEGFA 的表达，从而抑制了乳腺癌的生长。本项目的开展为靶向抗肿瘤血管生成的新药研发提供重要理论与科学依据。

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