Department of Radiotherapy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang, 110042, Liaoning, China.
Gene Ther. 2022 Feb;29(1-2):28-40. doi: 10.1038/s41434-020-0167-3. Epub 2020 Jun 12.
MicroRNAs (miRNAs) are considered important in the pathogenesis of colon cancer. But the mechanism of their role in colon cancer is still largely unknown. Here, we aimed to explore the function of miR-503-5p in the pathogenesis of colon cancer. This study analyzed miRNA microarray of colon cancer. Then, we performed EdU, CCK-8, flow cytometry, Transwell invasion assays and in vivo assays to explore the exact role of miR-503-5p in colon cancer. We observed considerable downregulation of miR-503-5p expression in colon cancer cells and tissues and significant correlation with the TNM stage, differentiation grade and lymph node metastasis of colon cancer. Overexpression of miR-503-5p promoted the apoptosis and G1 arrest of colon cancer cells, and inhibited migration, proliferation, invasion and colony formation. Interestingly, ectopic miR-503-5p overexpression could significantly inhibit vascular endothelial growth factor (VEGF)-A expression and reduce the activity of a luciferase reporter containing the VEGF-A 3'-untranslated region. Furthermore, overexpressed miR-503-5p in human umbilical vein endothelial cells (HUVECs) and colon cancer cells resulted in lower expression levels of VEGFR-2, and subsequently inhibited AKT signaling pathway. Additionally, overexpression of miR-503-5p suppressed both lymphangiogenesis and angiogenesis in vivo and significantly inhibited the tumorigenicity of HT-29 cells in nude mice. In summary, our study shows downregulation of miR-503-5p at least partially contributes to the tumorigenesis of colon cancer through modulating the angiogenesis and lymphangiogenesis by targeting VEGF-A while stimulating AKT signaling pathways. Therapeutic strategies to restore miR-503-5p in colon cancer could be useful to inhibit tumor progression.
微小 RNA（miRNAs）被认为在结肠癌的发病机制中起重要作用。但它们在结肠癌中的作用机制在很大程度上仍然未知。在这里，我们旨在探索 miR-503-5p 在结肠癌发病机制中的作用。本研究分析了结肠癌的 miRNA 微阵列。然后，我们进行了 EdU、CCK-8、流式细胞术、Transwell 侵袭实验和体内实验，以探讨 miR-503-5p 在结肠癌中的确切作用。我们观察到 miR-503-5p 在结肠癌细胞和组织中的表达明显下调，并且与结肠癌的 TNM 分期、分化程度和淋巴结转移显著相关。miR-503-5p 的过表达促进了结肠癌细胞的凋亡和 G1 期阻滞，并抑制了迁移、增殖、侵袭和集落形成。有趣的是，外源性 miR-503-5p 过表达可显著抑制血管内皮生长因子（VEGF-A）的表达，并降低含有 VEGF-A 3'-非翻译区的荧光素酶报告基因的活性。此外，过表达 miR-503-5p 可导致人脐静脉内皮细胞（HUVECs）和结肠癌细胞中 VEGFR-2 的表达水平降低，进而抑制 AKT 信号通路。此外，miR-503-5p 的过表达在体内抑制淋巴管生成和血管生成，并显著抑制裸鼠 HT-29 细胞的肿瘤发生。总之，我们的研究表明，miR-503-5p 的下调至少部分通过靶向 VEGF-A 调节血管生成和淋巴管生成，同时刺激 AKT 信号通路，有助于结肠癌的发生。在结肠癌中恢复 miR-503-5p 的治疗策略可能有助于抑制肿瘤进展。
