Omega-3 Polyunsaturated Fatty Acids Upregulate 15-PGDH Expression in Cholangiocarcinoma Cells by Inhibiting miR-26a/b Expression.

Abstract

Prostaglandin E2 (PGE2) is a proinflammatory lipid mediator that promotes cancer growth. The 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes oxidation of the 15(S)-hydroxyl group of PGE2, leading to its 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 omega-3 polyunsaturated fatty acids (ω-3 PUFA) upregulate 15-PGDH expression by inhibiting miR-26a and miR-26b, thereby contributing to ω-3 PUFA-induced inhibition of human cholangiocarcinoma cell growth. Treatment of human cholangiocarcinoma cells (CCLP1 and TFK-1) with ω-3 PUFA (DHA) or transfection of these cells with the Fat-1 gene (encoding Caenorhabditis elegans desaturase, which converts ω-6 PUFA to ω-3 PUFA) significantly increased 15-PGDH enzymes levels, 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 miR-26a and miR-26b, which target 15-PGDH mRNA and inhibit 15-PGDH translation. These findings were extended by the demonstration that overexpressing miR-26a or miR-26b decreased 15-PGDH protein levels, reversed ω-3 PUFA-induced accumulation of 15-PGDH protein, and prevented ω-3 PUFA-induced inhibition of cholangiocarcinoma cell growth. We further observed that ω-3 PUFA suppressed miR-26a and miR-26b by inhibiting c-myc, a transcription factor that regulates miR-26a/b. Accordingly, c-myc overexpression enhanced expression of miR-26a/b and ablated the ability of ω-3 PUFA to inhibit cell growth. Taken together, our results reveal a novel mechanism for ω-3 PUFA-induced expression of 15-PGDH in human cholangiocarcinoma and provide a preclinical rationale for the evaluation of ω-3 PUFA in treatment of this malignancy.

• Authors: Lu Yao, Chang Han, Kyoungsub Song, Jinqiang Zhang, Kyu Lim, Tong Wu
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 7 Pg. 1388-98 (Apr 01 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 25691459 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• MIRN26A microRNA, human
• MYC protein, human
• MicroRNAs
• Proto-Oncogene Proteins c-myc
• Docosahexaenoic Acids
• Arachidonic Acid
• Hydroxyprostaglandin Dehydrogenases
• 15-hydroxyprostaglandin dehydrogenase

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Arachidonic Acid (pharmacology)
• Base Sequence
• Bile Duct Neoplasms (drug therapy, enzymology, pathology)
• Bile Ducts, Intrahepatic (enzymology, pathology)
• Binding Sites
• Cell Line, Tumor
• Cell Proliferation
• Cholangiocarcinoma (drug therapy, enzymology, pathology)
• Docosahexaenoic Acids (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Hydroxyprostaglandin Dehydrogenases (genetics, metabolism)
• Mice, Inbred NOD
• Mice, SCID
• MicroRNAs (genetics, metabolism)
• Proto-Oncogene Proteins c-myc (metabolism)
• RNA Interference
• Transcriptional Activation
• Tumor Burden (drug effects)
• Up-Regulation
• Xenograft Model Antitumor Assays