Tao Qianying, Qi Yingxue, Gu Jiayi, Yu Die, Lu Yuxin, Liu Jianwen, Liang Xin
Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China; Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China.
Toxicol Appl Pharmacol. 2022 Apr 1;440:115927. doi: 10.1016/j.taap.2022.115927. Epub 2022 Feb 19.
The metastasis and angiogenesis of breast cancer has always been a difficult problem for treatment. It has recently been discovered that Von Willebrand Factor (vWF), in addition to hemostasis, also plays a role in tumor metastasis and angiogenesis. We noticed that besides endothelial cells, breast cancer cells (MDA-MB-231 and MCF-7) could also express vWF. In vitro experiments showed that knocking down vWF inhibited breast cancer cell metastasis. And we found that overexpression of vWF significantly promoted VEGF-A-dependent vascular proliferation in vitro by activating the PI3K/Akt signaling pathway. Further studies indicated that inhibition of PI3K/Akt signaling pathway up-regulated the expression of miR-205-5p, and miR-205-5p could bind to the 3'UTR region of VEGF-A to hinder the production of VEGF-A. Furthermore, when a spontaneous lung metastasis model was established in Balb/c female mice, knockdown of vWF in 4 T1 cells resulted in a decrease in tumor blood vessel density and effectively inhibited lung metastasis, accompanied by a decrease in the expression level of VEGF-A and an increase in the expression level of miR-205-5p. In summary, our findings provide experimental evidence that overexpression of vWF in breast cancer cells down-regulates the expression of miR-205-5p and up-regulates the expression of VEGF-A through the PI3K/Akt signaling pathway, thereby promoting tumor angiogenesis and metastasis.
乳腺癌的转移和血管生成一直是治疗中的难题。最近发现，血管性血友病因子（vWF）除了在止血过程中发挥作用外，在肿瘤转移和血管生成中也起作用。我们注意到，除了内皮细胞外，乳腺癌细胞（MDA-MB-231和MCF-7）也能表达vWF。体外实验表明，敲低vWF可抑制乳腺癌细胞转移。并且我们发现，vWF的过表达通过激活PI3K/Akt信号通路在体外显著促进了VEGF-A依赖的血管增殖。进一步研究表明，抑制PI3K/Akt信号通路可上调miR-205-5p的表达，且miR-205-5p可与VEGF-A的3'UTR区域结合以阻碍VEGF-A的产生。此外，当在Balb/c雌性小鼠中建立自发肺转移模型时，敲低4T1细胞中的vWF会导致肿瘤血管密度降低并有效抑制肺转移，同时伴有VEGF-A表达水平降低和miR-205-5p表达水平升高。总之，我们的研究结果提供了实验证据，即乳腺癌细胞中vWF的过表达通过PI3K/Akt信号通路下调miR-205-5p的表达并上调VEGF-A的表达，从而促进肿瘤血管生成和转移。
