title: Polycyclic aromatic hydrocarbon (PAH)-mediated upregulation of hepatic microRNA-181 family promotes cancer cell migration by targeting MAPK phosphatase-5, regulating the activation of p38 MAPK.
abstract: Growing evidence indicates that changes in microRNA (miRNA) expression in cancer induced by chemical carcinogens play an important role in cancer development and progression by regulating related genes. However, the mechanisms underlying miRNA involvement in hepatocarcinogenesis induced by polycyclic aromatic hydrocarbons (PAHs) remain unclear. Thus, the identification of aberrant miRNA expression during PAH-induced cancer cell migration will lead to a better understanding of the substantial role of miRNAs in cancer progression. In the present study, miRNA expression profiling showed significant upregulation of miR-181a, -181b, and -181d in human hepatocellular carcinoma cells (HepG2 line) exposed to benzo[a]anthracene (BA) and benzo[k]fluoranthene (BF). MAPK phosphatase-5 (MKP-5), a validated miR-181 target that deactivates MAPKs, was markedly suppressed while phosphorylation of p38 MAPK was increased after BA and BF exposure. The migration of HepG2 cells, observed using the scratch wound-healing assay, also increased in a dose-dependent manner. Depletion of miR-181 family members by miRNA inhibitors enhanced the expression of MKP-5 and suppressed the phosphorylation of p38 MAPK. Furthermore, the depletion of the miR-181 family inhibited cancer cell migration. Based on these results, we conclude that the miR-181 family plays a critical role in PAH-induced hepatocarcinogenesis by targeting MKP-5, resulting in the regulation of p38 MAPK activation.
authors.affiliation: Center for Integrated Risk Research, Cellular and Molecular Toxicology Laboratory, Korea Institute of Science and Technology (KIST), Republic of Korea; School of Life Sciences and Biotechnology, Korea University, Anam-Dong, Seoungbuk-Gu, Seoul 136-701, Republic of Korea.
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Song
authors.forename: Yong-Keun
authors.initials: YK
authors.lastname: Park
authors.forename: Jae-Chun
authors.initials: JC
authors.lastname: Ryu
mesh_terms: D001551:Benz(a)Anthracenes / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D054637:Dual-Specificity Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005449:Fluorenes / Q000633:toxicity*; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D001551:Benz(a)Anthracenes; D002273:Carcinogens; D005449:Fluorenes; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; C030935:benz(a)anthracene; D048051:p38 Mitogen-Activated Protein Kinases; C120407:DUSP10 protein, human; D054639:Mitogen-Activated Protein Kinase Phosphatases; D054637:Dual-Specificity Phosphatases; C022921:benzo(k)fluoranthene
keywords: Hepatocellular carcinoma (HCC); MAPK phosphatase (MKP); MicroRNA (miRNA); Migration; Polycyclic aromatic hydrocarbons (PAHs); p38 MAPK