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

Abstract

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 Pgc1α and MycC. MicroRNA expression profiling revealed that LA induced an upregulation in miR-494. The expression of Pgc1α and MycC 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 PGC1α and MYCC. 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.

An Axis between the Long Non-Coding RNA HOXA11-AS and NQOs Enhances Metastatic Ability in Oral Squamous Cell Carcinoma

“…Suppression of miR-494 by the lncRNA PCAT29 promotes PTEN expression [27], while a similar action by the lncRNA SBF2-AS1 promotes FGFR2 expression [28]. The downregulation of NQO1 by miR-494 has been shown to inhibit the Nrf2 signaling pathway [20], and we previously reported that miR-494 induces a quiescent state in cancer cells by suppressing oxidative phosphorylation [29].…”

Identification of metabolism terms significantly affecting hepatocellular carcinoma immune microenvironment and immunotherapy response

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Anti-proliferation and apoptosis-inducing effects of dihydroartemisinin on SH-SY5Y cells and metabolomic analysis

“…Numerous epidemiological and animal experimental studies have shown that polyunsaturated fatty acids (PUFAs) have a growth-inhibitory effect on mammary ( 38 ) and colorectal cancer ( 39 ). One of the important PUFAs commonly present in diets is linoleic acid.…”