Department of Gastrointestinal and Anal Diseases Surgery of the Affiliated Hospital, Weifang Medical University, China.
Department of General Surgery, The Affiliated Jiangning Hospital with Nanjing Medical University, 168 Gushan Road, Nanjing, 210000, China.
Cancer Lett. 2020 Sep 28;488:18-26. doi: 10.1016/j.canlet.2020.04.021. Epub 2020 May 27.
MicroRNAs (miRNAs) are gene modulators essential for biological processes. However, the precise functions of miRNAs in growth and development of colon cancer are still elusive. To clarify their role, here we analyzed a miRNA microarray of colon cancer. MiR-182-5p was found markedly downregulated in colon cancer tissues and cells, and strongly correlated with pathological stage, differentiation, and lymphatic metastasis. In vitro, miR-182-5p overexpression repressed colon cancer cell proliferation, colony formation, migration, and invasion, and triggered G1 arrest and apoptosis. MiR-182-5p overexpression also downregulated vascular endothelial growth factor (VEGF)-C and inhibited the activity of a luciferase reporter containing the VEGF-C 3'-untranslated region. Moreover, miR-182-5p overexpression in colon cancer cells and human umbilical vein endothelial cells (HUVECs) downregulated VEGF-A as well as VEGF receptor (VEGFR)-2 and VEGFR-3, thereby inhibiting the phosphorylation of ERK and AKT. In vivo, miR-182-5p overexpression strikingly suppressed oncogenicity of SW620 cells as well as angiogenesis and lymphangiogenesis of xenograft tumors in nude mice. These data indicate that miR-182-5p regulates colon cancer tumorigenesis partially through modulating angiogenesis and lymphangiogenesis by targeting VEGF-C, and inhibiting ERK and AKT signaling pathways.
微小 RNA（miRNAs）是生物过程中必不可少的基因调节剂。然而，miRNAs 在结肠癌生长和发育中的精确功能仍不清楚。为了阐明其作用，我们在这里分析了结肠癌的 miRNA 微阵列。miR-182-5p 在结肠癌组织和细胞中明显下调，与病理分期、分化和淋巴转移强烈相关。在体外，miR-182-5p 的过表达抑制了结肠癌细胞的增殖、集落形成、迁移和侵袭，并引发了 G1 期阻滞和细胞凋亡。miR-182-5p 的过表达还下调了血管内皮生长因子（VEGF）-C，并抑制了包含 VEGF-C 3'-非翻译区的荧光素酶报告基因的活性。此外，在结肠癌细胞和人脐静脉内皮细胞（HUVEC）中过表达 miR-182-5p 也下调了 VEGF-A 以及血管内皮生长因子受体（VEGFR）-2 和 VEGFR-3，从而抑制了 ERK 和 AKT 的磷酸化。在体内，miR-182-5p 的过表达显著抑制了 SW620 细胞的致瘤性以及裸鼠异种移植肿瘤的血管生成和淋巴管生成。这些数据表明，miR-182-5p 通过靶向 VEGF-C 调节血管生成和淋巴管生成，并抑制 ERK 和 AKT 信号通路，部分调节结肠癌的肿瘤发生。
