?-3 polyunsaturated fatty acids upregulate 15-PGDH expression in cholangiocarcinoma cells by inhibiting miR-26a/b expression.

Cancer Research

PubMedID: 25691459

Yao L, Han C, Song K, Zhang J, Lim K, Wu T. ?-3 polyunsaturated fatty acids upregulate 15-PGDH expression in cholangiocarcinoma cells by inhibiting miR-26a/b expression. Cancer Res. 2015;75(7):1388-98.
Prostaglandin E2 (PGE2) is a pro-inflammatory lipid modifier that promotes cancer growth. The hydroxyprostaglandin dehydrogenase 15-PGDH catalyzes oxidation of the 15(S)-hydroxyl group of PGE2, leading to its enzymatic inactivation. Therefore, 15-PGDH induction may offer a strategy to treat cancers that are driven by PGE2, such as human cholangiocarcinoma. Here we report that ?-3 polyunsaturated fatty acids (?-3 PUFA) upregulate 15-PGDH expression by inhibiting miR26a and miR26b, thereby contributing to ?-3 PUFA-induced inhibition of human cholangiocarcinoma cell growth. Genetic or pharmacological tactics increase ?-3 PUFA levels increased 15-PGDH enzyme levels in cholangiocarcinoma cell, but with little effect on the activity of the 15-PGDH gene promoter. Mechanistic investigations revealed that this increase in 15-PGDH levels in cells was mediated by a reduction in the expression of miRNA26a and miRNA26b, two microRNAs each known to target 15-PGDH mRNA and inhibit 15-PGDH translation. These findings were extended by the demonstration that overexpressing miR26a or miR26b decreased 15-PGDH protein levels, reversed ?-3 PUFA-induced accumulation of 15-PGDH protein and prevented ?-3 PUFA-induced inhibition of cholangiocarcinoma cell growth. We further observed that ?-3 PUFA suppressed miRNA26a and miRNA26b by inhibiting c-myc, a transcription factor that regulates miR-26a/b. Accordingly, c-myc overexpression enhanced expression of miRNA26a/b and ablated the ability of ?-3 PUFA to inhibit cell growth. Taken together, our results reveal a lipid modifier pathway in human cholangiocarcinoma and provide a preclinical rationale for the evaluation of ?-3 PUFA in treatment of this malignancy.