DHA regulates the expression of 15‐PGDH through miR 26 a/b in cholangiocarcinoma (144.12)

Abstract

DHA, the primary effector molecule of omega‐3 polyunsaturated fatty acids, may ameliorate inflammatory diseases and prevent carcinogenesis. However, the precise mechanisms by which DHA influence hepatic carcinogenesis have not been elucidated. Here we report DHA regulates PGE2 deactivator‐15‐PGDH expression through miR26a/b in cholangiocarcinoma. Human cholangiocarcinoma cell lines (CCLP‐1 and TFK‐1) treated with DHA or stably transfected with Fat‐1 gene significantly enhanced 15‐PGDH protein expression while had little effect on its mRNA level. MiR26a/b, which putatively binds to 15‐PGDH 3’UTR, are significantly down‐regulated in DHA‐treated or Fat‐1 expression cells. MiR26a/b overexpression greatly reduced 15‐PGDH protein level. Since miR26a/b locate in intron region of gene family CTDSP, their expression is intensely correlated and regulated by transcription factor C‐myc. We found significant consistency between C‐myc expression and CTDSPL, CTDSP1 gene or miR26a/b levels. Tumor growth assays, in vitro and in vivo, showed Fat‐1 undermined tumor growth while miR26a/b had a reverse effect. This phenomenon could be attributed to that those two factors regulate the 15‐PGDH expression and further affect the PGE2 production. Taken together, our data provide important mechanistic insights and therapeutic implications for utilizing omega‐3 PUFAs for the treatment of human cholangiocarcinoma.Grant Funding Source: NIH/NCI