title: miR-192, miR-194, miR-215, miR-200c and miR-141 are downregulated and their common target ACVR2B is strongly expressed in renal childhood neoplasms.
abstract: Micro RNAs (miRNAs) play an important role during renal development and show a tissue-specific enrichment in the kidney. Nephroblastomas, embryonal renal neoplasms of childhood, are considered to develop from nephrogenic rests (NRs) and resemble morphologically and genetically developing kidney. We therefore investigated the role of kidney-enriched miRNAs in the pathogenesis of nephroblastomas. miR-192, miR-215 and miR-194 had a significantly lower expression in nephroblastomas regardless of the subtype compared with mature kidney measured by quantitative real-time-PCR. miR-141 and miR-200c showed a significantly lower expression in blastema-type and mixed-type tumors. In comparison with NRs, a significantly lower expression of miR-192, miR-194 and miR-215 was identified in blastema-type, mixed-type and stroma-type nephroblastomas and of miR-141 and miR-200c in blastema-type tumors. Kidney parenchyma had a significantly higher expression of miR-192, miR-194, miR-215 and miR-200c compared with NRs. In this study, the activin receptor type 2B (ACVR2B), a member of the transforming growth factor (TGF)-β pathway, was identified as single common target gene for miR-192, miR-215, miR-194, miR-141 and miR-200c in silico for the first time. The interaction between all five miRNAs and ACVR2B was also verified by an in vitro assay. Additionally, a distinct protein expression of ACVR2B was detected in 53 of 55 nephroblastomas paralleled by an upregulation of ACVR2B messenger RNA demonstrated in 25 nephroblastomas of all subtypes. A differential regulation of ACVR2B by miRNAs in NRs and nephroblastomas appears to be an important step in the pathogenesis of nephroblastomas implicating for the first time the TGF-β pathway in this process.
authors.affiliation: Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8036 Graz, Austria.
authors.forename: Upeka
authors.initials: U
authors.lastname: Senanayake
authors.forename: Suman
authors.initials: S
authors.lastname: Das
authors.forename: Paul
authors.initials: P
authors.lastname: Vesely
authors.forename: Wael
authors.initials: W
authors.lastname: Alzoughbi
authors.forename: Leopold F
authors.initials: LF
authors.lastname: Fröhlich
authors.forename: Pooja
authors.initials: P
authors.lastname: Chowdhury
authors.forename: Ivo
authors.initials: I
authors.lastname: Leuschner
authors.forename: Gerald
authors.initials: G
authors.lastname: Hoefler
authors.forename: Barbara
authors.initials: B
authors.lastname: Guertl
mesh_terms: D030301:Activin Receptors, Type II / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation; D009396:Wilms Tumor / Q000235:genetics* / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B