Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
J Cell Physiol. 2020 Feb;235(2):920-931. doi: 10.1002/jcp.29007. Epub 2019 Jun 26.
MicroRNAs (miRNAs) are important molecular regulatorsof cellular signaling and behavior. They alter gene expression by targeting messenger RNAs, including those encoding transcriptional regulators, such as HMGA2. While HMGA2 is oncogenic in various tumors, miRNAs may be oncogenic or tumor suppressive. Here, we investigate the expression of HMGA2 and the miRNA miR-330 in a patient with colorectal cancer (CRC) samples and their effects on oncogenic cellular phenotypes. We found that HMGA2 expression is increased and miR-330 expression is decreased in CRCs and each predicts poor long-term patient survival. Stably increased miR-330 expression in human colorectal cancer cells (HCT116) and SW480 CRC cell lines downregulate the oncogenic expression of HMGA2, a predicted miR-330 target. Additionally, this promotes apoptosis and decreases cell migration and viability. Consistently, it also decreases protein-level expression of markers for epithelial-to-mesenchymal-transition (Snail-1, E-cadherin, and Vascular endothelial growth factor receptors) and transforming growth factor β signaling (SMAD3), as well as phospho- Protein kinase B (AKT) and phospho-STAT3 levels. We conclude that miR-330 acts as a tumor suppressor miRNA in CRC by suppressing HMGA2 expression and reducing cell survival, proliferation, and migration. Thus, we identify miR-330 as a promising candidate for miRNA replacement therapy for patients with CRC.
微小 RNA（miRNAs）是细胞信号和行为的重要分子调节剂。它们通过靶向信使 RNA 来改变基因表达，包括那些编码转录调节剂的信使 RNA，如 HMGA2。虽然 HMGA2 在各种肿瘤中具有致癌性，但 miRNAs 可能具有致癌性或肿瘤抑制作用。在这里，我们研究了 HMGA2 和 miRNA miR-330 在结直肠癌（CRC）样本中的表达及其对致癌细胞表型的影响。我们发现，HMGA2 的表达在 CRC 中增加，miR-330 的表达减少，并且每个都预测患者的长期生存不良。稳定增加人结直肠癌细胞（HCT116）和 SW480 CRC 细胞系中的 miR-330 表达下调 HMGA2 的致癌表达，HMGA2 是 miR-330 的预测靶标。此外，这还促进了细胞凋亡，并减少了细胞迁移和活力。一致地，它还降低了上皮-间充质转化（Snail-1、E-钙粘蛋白和血管内皮生长因子受体）和转化生长因子 β 信号（SMAD3）的标志物以及磷酸化蛋白激酶 B（AKT）和磷酸化 STAT3 水平的蛋白表达。我们得出结论，miR-330 通过抑制 HMGA2 表达和降低细胞存活、增殖和迁移，在 CRC 中充当肿瘤抑制 miRNA。因此，我们将 miR-330 鉴定为 CRC 患者 miRNA 替代治疗的有前途的候选物。
