miR-21 targets 15-PGDH and promotes cholangiocarcinoma growth.

miRNAs are a group of small, noncoding RNAs that modulate the translation of genes by binding to specific target sites in the target mRNA. This study investigated the biologic function and molecular mechanism of miR-21 in human cholangiocarcinoma. In situ hybridization analysis of human cholangiocarcinoma specimens showed increased miR-21 in cholangiocarcinoma tissue compared with the noncancerous biliary epithelium. Lentiviral transduction of miR-21 enhanced human cholangiocarcinoma cell growth and clonogenic efficiency in vitro, whereas inhibition of miR-21 decreased these parameters. Overexpression of miR-21 also promoted cholangiocarcinoma growth using an in vivo xenograft model system. The NAD(+)-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH/HPGD), a key enzyme that converts the protumorigenic prostaglandin E2 (PGE2) to its biologically inactive metabolite, was identified as a direct target of miR-21 in cholangiocarcinoma cells. In parallel, cyclooxygenase-2 (COX2) overexpression and PGE2 treatment increased miR-21 levels and enhanced miR-21 promoter activity in human cholangiocarcinoma cells. Cholangiocarcinogenesis and tumor progression are regulated by a novel interplay between COX-2/PGE2 and miR-21 signaling, which converges at 15-PGDH.