title: 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.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Lu
authors.initials: L
authors.lastname: Yao
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Chang
authors.initials: C
authors.lastname: Han
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Kyoungsub
authors.initials: K
authors.lastname: Song
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
authors.forename: Jinqiang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, College of Medicine, Cancer Research Institute and Infection Signaling, Network Research Center, Chungnam National University, Daejeon, Korea.
authors.forename: Kyu
authors.initials: K
authors.lastname: Lim
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana. twu@tulane.edu.
authors.forename: Tong
authors.initials: T
authors.lastname: Wu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000494:pharmacology; D001483:Base Sequence; D001650:Bile Duct Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000201:enzymology / Q000473:pathology; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034622:RNA Interference; D015533:Transcriptional Activation; D047368:Tumor Burden / Q000187:drug effects; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016718:Arachidonic Acid; D004281:Docosahexaenoic Acids; D006911:Hydroxyprostaglandin Dehydrogenases; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; C528163:MIRN26 microRNA, human; C489427:MYC protein, human; C035859:15-hydroxyprostaglandin dehydrogenase