Linoleic Acid Upregulates Microrna-494 to Induce Quiescence in Colorectal Cancer

• Published in: International journal of molecular sciences 2021-12, Vol.23 (1), p.225
• Main Authors: Ogata, Ruiko, Mori, Shiori, Kishi, Shingo, Sasaki, Rika, Iwata, Naoya, Ohmori, Hitoshi, Sasaki, Takamitsu, Nishiguchi, Yukiko, Nakashima, Chie, Goto, Kei, Kawahara, Isao, Fujiwara-Tani, Rina, Kuniyasu, Hiroki
• Format: Article
• Language: English
• Subjects: Animals; Cancer; Cell cycle; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Proliferation - genetics; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; delayed metastasis; Dormancy; energy metabolism; Fatty acids; Gene expression; Glycolysis; Glycolysis - drug effects; Glycolysis - genetics; Humans; Inhibitors; Linoleic acid; Linoleic Acid - pharmacology; Liver; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Male; Metabolism; Metastases; Metastasis; Mice; Mice, Inbred BALB C; MicroRNAs; MicroRNAs - genetics; miRNA; Mitochondria; Mitochondria - drug effects; Mitochondria - genetics; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - genetics; Oxidative phosphorylation; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - genetics; Phenotypes; Phosphorylation; quiescence; Transcriptome - drug effects; Transcriptome - genetics; Tumors; Up-Regulation - drug effects; Up-Regulation - genetics
• ISSN: 1422-0067; 1661-6596; 1422-0067
• 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.