title: MicroRNA-145 targets the metalloprotease ADAM17 and is suppressed in renal cell carcinoma patients.
abstract: A disintegrin and metalloproteinase 17 (ADAM17) is a metalloprotease that is overexpressed in many cancer types, including renal cancers. However, the regulatory mechanisms of ADAM17 in cancer development and progression are poorly understood. In the present work, we provide evidence using overexpression and inhibition of microRNA 145 (miR-145) that miR-145 negatively regulates ADAM17 expression. Furthermore, we show that ADAM17 negatively regulates miR-145 through tumor necrosis factor-α, resulting in a reciprocal negative feedback loop. In this study, the expression of ADAM17 and miR-145 correlated negatively in renal cancer tumor tissues and cell lines, suggesting an important regulatory mechanism. Additionally, we showed that the regulation of ADAM17 is partly involved in the effects of miR-145 on proliferation and migration, whereas no involvement in chemosensitivity was observed. Importantly, in the healthy kidney, miR-145 was detected in different cell types including tubular cells, which are considered the origin of renal cancer. In renal cancer cell lines, miR-145 expression was strongly suppressed by methylation. In summary, miR-145 is downregulated in renal cancer patients, which leads to the up-regulation of ADAM17 in renal cancer. Importantly, miR-145 and ADAM17 are regulated in a reciprocal negative feedback loop.
authors: Pharmazentrum Frankfurt/Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit, Goethe University Hospital, Frankfurt am Main, Germany. k.doberstein@dkfz.de
authors: Kai
authors: K
authors: Doberstein
authors: Nico
authors: N
authors: Steinmeyer
authors: Ann-Kathrin
authors: AK
authors: Hartmetz
authors: Wolfgang
authors: W
authors: Eberhardt
authors: Michel
authors: M
authors: Mittelbronn
authors: Patrick N
authors: PN
authors: Harter
authors: Eva
authors: E
authors: Juengel
authors: Roman
authors: R
authors: Blaheta
authors: Josef
authors: J
authors: Pfeilschifter
authors: Paul
authors: P
authors: Gutwein
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000072198:ADAM17 Protein; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human