title: Aberrant microRNA expression likely controls RAS oncogene activation during malignant transformation of human prostate epithelial and stem cells by arsenic.
abstract: Inorganic arsenic (iAs), a human carcinogen, potentially targets the prostate. iAs malignantly transforms the RWPE-1 human prostate epithelial line to CAsE-PE cells, and a derivative normal stem cell (SC) line, WPE-stem, to As-Cancer SC (As-CSC) line. MicroRNAs (miRNA) are noncoding but exert negative control on expression by degradation or translational repression of target mRNAs. Aberrant miRNA expression is important in carcinogenesis. A miRNA array of CAsE-PE and As-CSC revealed common altered expression in both for pathways concerning oncogenesis, miRNA biogenesis, cell signaling, proliferation, and tumor metastasis and invasion. The KRAS oncogene is overexpressed in CAsE-PE cells but not by mutation or promoter hypomethylation, and is intensely overexpressed in As-CSC cells. In both transformants, decreased miRNAs targeting KRAS and RAS superfamily members occurred. Reduced miR-134, miR-373, miR-155, miR-138, miR-205, miR-181d, miR-181c, and let-7 in CAsE-PE cells correlated with increased target RAS oncogenes, RAN, RAB27A, RAB22A mRNAs, and KRAS protein. Reduced miR-143, miR-34c-5p, and miR-205 in As-CSC correlated with increased target RAN mRNA, and KRAS, NRAS, and RRAS proteins. The RAS/ERK and PI3K/PTEN/AKT pathways control cell survival, differentiation, and proliferation, and when dysregulated promote a cancer phenotype. iAs transformation increased expression of activated ERK kinase in both transformants and altered components of the PI3K/PTEN/AKT pathway including decreased PTEN and increases in BCL2, BCL-XL, and VEGF in the absence of AKT activation. Thus, dysregulated miRNA expression may be linked to RAS activation in both transformants.
authors.affiliation: Inorganic Toxicology Group, National Toxicology Program Laboratory, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
authors.forename: Ntube N O
authors.initials: NN
authors.lastname: Ngalame
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Tokar
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Person
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xu
authors.forename: Michael P
authors.initials: MP
authors.lastname: Waalkes
mesh_terms: D018053:Arsenites / Q000633:toxicity*; D015153:Blotting, Western; D002274:Carcinogens, Environmental / Q000633:toxicity*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D011905:Genes, ras / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D060888:Real-Time Polymerase Chain Reaction; D017670:Sodium Compounds / Q000633:toxicity*; D018631:ras Proteins / Q000235:genetics
chemical_list: D018053:Arsenites; D002274:Carcinogens, Environmental; C117307:KRAS protein, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D017670:Sodium Compounds; C017947:sodium arsenite; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: KRAS; arsenic; cancer; microRNA; prostate cells; stem/progenitor cells