Department of Molecular Pathology, Nara Medical University School of Medicine, Kashihara 634-8521, Japan.
Int J Mol Sci. 2021 Dec 25;23(1):225. doi: 10.3390/ijms23010225.
Cancer dormancy is a state characterized by the quiescence of disseminated cancer cells, and tumor recurrence occurs when such cells re-proliferate after a long incubation period. These cancer cells tend to be treatment resistant and one of the barriers to successful therapeutic intervention. We have previously reported that long-term treatment of cancer cells with linoleic acid (LA) induces a dormancy-like phenotype. However, the mechanism underpinning this effect has not yet been clarified. Here, we investigate the mechanism of LA-induced quiescence in cancer cells. We first confirmed that long-term treatment of the mouse colorectal cancer cell line CT26 with LA induced quiescence. When these cells were inoculated subcutaneously into a syngeneic mouse and fed with an LA diet, the inoculated cancer cells maintained the quiescent state and exhibited markers of dormancy. LA-treated CT26 cells showed reduced oxidative phosphorylation, glycolysis, and energy production as well as reduced expression of the regulatory factors and . MicroRNA expression profiling revealed that LA induced an upregulation in miR-494. The expression of and were both induced by an miR-494 mimic, and the LA-induced decrease in gene expression was abrogated by an miR-494 inhibitor. The expression of miR-494 was enhanced by the mitochondrial oxidative stress produced by LA. In a syngeneic mouse subcutaneous tumor model, growth suppression by an LA diet and growth delay by LA pretreatment + LA diet were found to have similar effects as administration of an miR-494 mimic. In contrast, the effects of LA were abrogated by an miR-494 inhibitor. Analysis of human colorectal cancer tissue revealed that miR-494 was present at low levels in non-metastatic cases and cases with simultaneous liver metastases but was expressed at high levels in cases with delayed liver metastases, which also exhibited reduced expression of and . These results suggest that miR-494 is involved in cancer dormancy induced by high levels of LA intake and that this microRNA may be valuable in targeting dormant cancer cells.
癌症休眠是一种特征为播散性癌细胞静止的状态，当这些细胞在长时间潜伏期后重新增殖时，肿瘤就会复发。这些癌细胞往往对治疗具有抗性，是成功治疗干预的障碍之一。我们之前报道过，长期用亚油酸（LA）处理癌细胞会诱导出一种类似休眠的表型。然而，这种效应的机制尚未阐明。在这里，我们研究了 LA 诱导癌细胞静止的机制。我们首先证实，长期用 LA 处理小鼠结直肠癌细胞系 CT26 可诱导其静止。当这些细胞被皮下接种到同基因小鼠中，并给予 LA 饮食时，接种的癌细胞保持静止状态，并表现出休眠的标志物。LA 处理的 CT26 细胞表现出氧化磷酸化、糖酵解和能量产生减少，以及调节因子 和 的表达降低。miRNA 表达谱分析显示，LA 诱导 miR-494 的上调。miR-494 模拟物诱导 和 的表达，而 miR-494 抑制剂则消除了 LA 诱导的基因表达下调。LA 产生的线粒体氧化应激增强了 miR-494 的表达。在同基因小鼠皮下肿瘤模型中，LA 饮食的生长抑制作用和 LA 预处理+LA 饮食的生长延迟作用与 miR-494 模拟物的给药效果相似。相比之下，miR-494 抑制剂则消除了 LA 的作用。对人类结直肠癌组织的分析表明，miR-494 在非转移性病例和同时有肝转移的病例中表达水平较低，但在延迟性肝转移的病例中表达水平较高，这些病例中 和 的表达也降低。这些结果表明，miR-494 参与了高水平 LA 摄入诱导的癌症休眠，这种 microRNA 可能对靶向休眠癌细胞具有价值。
