Ahmadizad Firouzjaei Ali, Sharifi Kazem, Khazaei Majid, Mohammadi-Yeganeh Samira, Aghaee-Bakhtiari Seyed Hamid
Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
Curr Med Chem. 2025;32(13):2608-2625. doi: 10.2174/0109298673300320240604062533.
microRNA (miRNA) levels are dysregulated in many cancers, suggesting that miRNA-based therapy may be effective. The molecular pathways of colorectal cancer (CRC) development are unknown.
Understanding miRNAs implicated in CRC formation may reveal new diagnostic and therapeutic targets. Angiogenesis is a key mechanism in tumor growth. CRC treatment may involve inhibiting angiogenesis, but existing drugs can cause negative effects. Tranexamic acid, an FDA-approved medication, may reduce the adverse effects of angiogenesis inhibitors. This work examined miRNAs implicated in CRC angiogenesis and how miR-16 and tranexamic acid may synergistically decrease CRC cell migration and angiogenesis. We identified miRNAs targeting CRC angiogenesis genes using bioinformatic databases. Proteins were docked with tranexamic acid utilizing the PyRx software. Quantitative Real-time PCR was used to analyze the effects of overexpressed miRNA and tranexamic acid on the expression of target genes. Scratch, transwell migration, and Chicken Chorioallantoic Membrane (CAM) assays were used to evaluate the effect of selected miRNA and tranexamic acid on the invasion and angiogenesis of CRC cells. in silico studies identified hsa-miR-16-5p, -101-3p, and 34a-5p as possible CRC angiogenesis modulators.
The study found that miR-16 and tranexamic acid influence the expression of VEGFA, ANGPT2, MMP9, and HIF1A. miR-16 and tranexamic acid influenced CRC cell movement in scratch tests and transwell migration assays. Furthermore, the CAM assay results demonstrated that miR-16 and tranexamic acid can alter angiogenesis in CRC.
These findings highlight the potential of miR-16 and tranexamic acid as combination therapeutic agents for CRC, with the ability to simultaneously target tumorigenesis and angiogenesis.
微小RNA（miRNA）水平在许多癌症中失调，这表明基于miRNA的治疗可能有效。结直肠癌（CRC）发展的分子途径尚不清楚。
了解与CRC形成相关的miRNA可能会揭示新的诊断和治疗靶点。血管生成是肿瘤生长的关键机制。CRC治疗可能涉及抑制血管生成，但现有药物会产生负面影响。氨甲环酸是一种经美国食品药品监督管理局（FDA）批准的药物，可能会减少血管生成抑制剂的不良反应。这项研究探讨了与CRC血管生成相关的miRNA，以及miR-16和氨甲环酸如何协同降低CRC细胞迁移和血管生成。我们使用生物信息学数据库鉴定了靶向CRC血管生成基因的miRNA。利用PyRx软件将蛋白质与氨甲环酸进行对接。采用定量实时聚合酶链反应（qRT-PCR）分析过表达的miRNA和氨甲环酸对靶基因表达的影响。划痕实验、Transwell迁移实验和鸡胚绒毛尿囊膜（CAM）实验用于评估所选miRNA和氨甲环酸对CRC细胞侵袭和血管生成的影响。计算机模拟研究确定hsa-miR-16-5p、-101-3p和34a-5p为可能的CRC血管生成调节剂。
研究发现miR-16和氨甲环酸影响血管内皮生长因子A（VEGFA）、血管生成素2（ANGPT2）、基质金属蛋白酶9（MMP9）和缺氧诱导因子1α（HIF1A）的表达。在划痕实验和Transwell迁移实验中，miR-16和氨甲环酸影响CRC细胞运动。此外，CAM实验结果表明，miR-16和氨甲环酸可改变CRC中的血管生成。
这些发现突出了miR-16和氨甲环酸作为CRC联合治疗药物的潜力，它们能够同时靶向肿瘤发生和血管生成。
