Department of Stem Cells and Regenerative Medicine, Institute for Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Box: 14965-161, Tehran, Iran.
Department of Stem Cells and Regenerative Medicine, Institute for Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Box: 14965-161, Tehran, Iran.
Tissue Cell. 2021 Dec;73:101654. doi: 10.1016/j.tice.2021.101654. Epub 2021 Sep 20.
CXCR4 plays an important role in colorectal cancer (CRC) development and metastasis. Some previous studies have indicated CXCR4 as a therapeutic target in cancer. CXCR4 is known as a direct target of miR-146a. The present study aimed to investigate how exogenous induction of miR-146a affects CXCR4 gene and protein expression and also proliferation, apoptosis and migration of CRC cells. Transfection of Caco-2 and SW480 cells by a synthetic miR-146a mimic led to downregulation of CXCR4 expression at both gene and protein levels. It also downregulated expression of several miR-146a targets, including GSK3B, IRAK1, TRAF6, AKT2, SMAD4, EGFR and NFKB1, mostly in SW480 cells. Overexpression of miR-146a resulted in a partial cell cycle arrest in the both cell lines, while the apoptotic rate was also decreased. In regards to epithelial-mesenchymal transition factors, VIM was downregulated in the both cell lines, but SNAI1 was upregulated in Caco-2 cells. The wound closure assay showed a reduction in cell migration in SW480 cells, but an opposite effect was detected in Caco-2 cells following transfection with miR-146a mimic. Therefore, our results are indicating that overexpression of miR-146a, despite downregulation of oncogenic CXCR4, may not lead to a universal tumor suppressive effect in all CRC cells, and this is possibly due to differences in miR-146a effects on signaling pathways in each cell type. Selection of miR-146a for tumor suppression requires enough details regarding the signaling profile of cancer cells otherwise it may produce unexpected outcome.
趋化因子受体 4（CXCR4）在结直肠癌（CRC）的发展和转移中发挥重要作用。一些先前的研究表明，CXCR4 是癌症的治疗靶点。CXCR4 是 miR-146a 的直接靶标。本研究旨在探讨外源性诱导 miR-146a 如何影响 CRC 细胞的 CXCR4 基因和蛋白表达以及增殖、凋亡和迁移。用合成的 miR-146a 模拟物转染 Caco-2 和 SW480 细胞，导致 CXCR4 基因和蛋白水平的表达下调。它还下调了几个 miR-146a 靶基因的表达，包括 GSK3B、IRAK1、TRAF6、AKT2、SMAD4、EGFR 和 NFKB1，主要在 SW480 细胞中。miR-146a 的过表达导致两个细胞系的细胞周期部分停滞，而凋亡率也降低。关于上皮-间充质转化因子，VIM 在两个细胞系中下调，但 SNAI1 在 Caco-2 细胞中上调。划痕闭合实验显示，SW480 细胞的细胞迁移减少，但转染 miR-146a 模拟物后 Caco-2 细胞的迁移则相反。因此，我们的结果表明，尽管 CXCR4 的致癌作用下调，但过表达 miR-146a 可能不会导致所有 CRC 细胞产生普遍的肿瘤抑制作用，这可能是由于 miR-146a 对每种细胞类型的信号通路的影响存在差异。选择 miR-146a 进行肿瘤抑制需要足够的关于癌细胞信号谱的细节，否则可能会产生意想不到的结果。
