Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
Department of Medical Laboratory Science, Faculty of Paramedical Science, Jiroft University of Medical Sciences, Jiroft, Iran.
Eur J Pharmacol. 2020 Aug 15;881:173282. doi: 10.1016/j.ejphar.2020.173282. Epub 2020 Jun 21.
Vasculogenic mimicry (VM) play an important role in breast cancer metastasis and anti- angiogenic drugs resistance. Hypoxia, the epithelial-mesenchymal transition (EMT), and cancer stem cells (CSCs) are known as essential factors for VM formation. Also, melatonin is an amino acid-derived hormone with many anti-tumor effects. Despite the antitumor effects of melatonin, its effect on VM formation in breast cancer has not been considered yet, so we investigated the effect of melatonin on VM formation through EMT process under hypoxia conditions in breast CSCs. The CSCs percentage and VM formation were determined in MCF-7 and MDA-MB-231, respectively. Also, analysis of HIF-1α expression under hypoxia in MDA-MB-231 and MCF-7 cell lines was performed using Western blot. The effect of melatonin on the VM formation, invasion, and migration was also investigated. Moreover, the effect of melatonin on the expression EMT markers was evaluated. CD44 CD24phenotype as CSCs marker in MDA-MB-231 cell line, was 80.8%, while it was 11.1% in MCF-7 cell line. HIF-1α expression was up-regulated in the VM-positive breast cancer cell line MDA-MB-231, and consequently, affected the expression of the EMT markers E-cadherin, vimentin, snail, and MMP9. Melatonin had significant effect on EMT and formations of VM in breast CSCs. Melatonin could prevent the formation of VM by affecting the important molecules involved in the formation of VM structures and the EMT. Moreover, our data clearly showed that, melatonin represents molecule with significant anti-cancer activities that may potentially optimize the management of breast cancer through the overcoming drug resistance in anti-angiogenic drugs.
血管生成拟态 (VM) 在乳腺癌转移和抗血管生成药物耐药中起重要作用。缺氧、上皮-间充质转化 (EMT) 和癌症干细胞 (CSC) 被认为是 VM 形成的重要因素。褪黑素是一种氨基酸衍生的激素，具有许多抗肿瘤作用。尽管褪黑素具有抗肿瘤作用，但尚未考虑其对乳腺癌中 VM 形成的影响，因此我们研究了在缺氧条件下通过 EMT 过程在乳腺癌 CSC 中褪黑素对 VM 形成的影响。通过流式细胞术分别确定 MCF-7 和 MDA-MB-231 中 CSC 的百分比和 VM 形成。还使用 Western blot 分析 MDA-MB-231 和 MCF-7 细胞系在缺氧下 HIF-1α 的表达。还研究了褪黑素对 VM 形成、侵袭和迁移的影响。此外，还评估了褪黑素对 EMT 标志物表达的影响。在 MDA-MB-231 细胞系中，CD44 CD24 表型作为 CSC 标志物的比例为 80.8%，而在 MCF-7 细胞系中为 11.1%。HIF-1α 在 VM 阳性乳腺癌细胞系 MDA-MB-231 中的表达上调，从而影响 EMT 标志物 E-钙粘蛋白、波形蛋白、snail 和 MMP9 的表达。褪黑素对乳腺癌 CSC 中的 EMT 和 VM 形成有显著影响。褪黑素通过影响参与 VM 结构形成和 EMT 的重要分子来防止 VM 的形成。此外，我们的数据清楚地表明，褪黑素代表具有显著抗癌活性的分子，通过克服抗血管生成药物中的耐药性，可能潜在地优化乳腺癌的管理。
