Department of Pharmaceutical Engineering, Inner Mongolia Agricultural University, Hohhot 010018, China.
Biomed Res Int. 2020 Oct 3;2020:2616930. doi: 10.1155/2020/2616930. eCollection 2020.
Blocking glioma cell invasion has been challenging due to cancer cells that can swiftly switch their migration mode, and agents that can block more than one migration mode are sought after. We found that small molecule 2-(1H-indole-3-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), an endogenous aryl hydrocarbon receptor (AHR) agonist, can block more than one mode of glioma cell migration, based on cultured cell behavior captured by videos. Data from wound-healing assays and mouse xenograft glioma models corroborated ITE's migration-inhibiting effects while knocking down AHR by siRNA abolished these effects. To identify genes that mediated ITE-AHR's effect, we first collected gene expression changes upon ITE treatment by RNA-seq, then compared them against literature reported migration-related genes in glioma and that were potentially regulated by AHR. MYH9, a component of nonmuscle myosin IIA (NMIIA), was confirmed to be reduced by ITE treatment. When MYH9 was overexpressed in the glioma cells, a good correlation was observed between the expression level and the cell migration ability, determined by wound-healing assay. Correspondingly, overexpression of MYH9 abrogated ITE's migration-inhibiting effects, indicating that ITE-AHR inhibited cell migration via inhibiting MYH9 expression. MYH9 is essential for cell migration in 3D confined space and not a discovered target of AHR; the fact that ITE affects MYH9 via AHR opens a new research and development avenue.
阻断神经胶质瘤细胞的侵袭一直具有挑战性，因为癌细胞可以迅速切换其迁移模式，因此人们正在寻找可以阻断多种迁移模式的药物。我们发现，小分子 2-(1H-吲哚-3-羰基)-噻唑-4-羧酸甲酯（ITE）是一种内源性芳烃受体（AHR）激动剂，能够阻断多种神经胶质瘤细胞迁移模式，这是基于视频中捕捉到的培养细胞行为得出的。划痕实验和小鼠异种移植神经胶质瘤模型的数据证实了 ITE 具有抑制迁移的作用，而通过 siRNA 敲低 AHR 则消除了这些作用。为了鉴定介导 ITE-AHR 作用的基因，我们首先通过 RNA-seq 收集 ITE 处理后的基因表达变化，然后将其与文献中报道的神经胶质瘤迁移相关基因进行比较，这些基因可能受 AHR 调节。肌球蛋白重链 9（MYH9）是非肌肉肌球蛋白 IIA（NMIIA）的组成部分，被证实被 ITE 处理所减少。当 MYH9 在神经胶质瘤细胞中过表达时，通过划痕实验确定细胞迁移能力与表达水平之间存在良好的相关性。相应地，过表达 MYH9 会消除 ITE 对迁移的抑制作用，表明 ITE-AHR 通过抑制 MYH9 的表达来抑制细胞迁移。MYH9 对于 3D 受限空间中的细胞迁移是必需的，而不是 AHR 的已发现靶点；ITE 通过 AHR 影响 MYH9 的事实为研究和开发开辟了新途径。
