دورية أكاديمية
أعرض في EDS

Arsenite malignantly transforms human prostate epithelial cells in vitro by gene amplification of mutated KRAS.

التفاصيل البيبلوغرافية
العنوان: Arsenite malignantly transforms human prostate epithelial cells in vitro by gene amplification of mutated KRAS.
المؤلفون: Merrick BA; Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States of America., Phadke DP; Sciome, LLC, Research Triangle Park, North Carolina, United States of America., Bostrom MA; David H. Murdock Research Institute, Kannapolis, North Carolina, United States of America., Shah RR; Sciome, LLC, Research Triangle Park, North Carolina, United States of America., Wright GM; David H. Murdock Research Institute, Kannapolis, North Carolina, United States of America., Wang X; David H. Murdock Research Institute, Kannapolis, North Carolina, United States of America., Gordon O; David H. Murdock Research Institute, Kannapolis, North Carolina, United States of America., Pelch KE; Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States of America., Auerbach SS; Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States of America., Paules RS; Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States of America., DeVito MJ; Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States of America., Waalkes MP; Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States of America., Tokar EJ; Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States of America.
المصدر: PloS one [PLoS One] 2019 Apr 22; Vol. 14 (4), pp. e0215504. Date of Electronic Publication: 2019 Apr 22 (Print Publication: 2019).
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
أسماء مطبوعة: Original Publication: San Francisco, CA : Public Library of Science
مواضيع طبية MeSH: Mutation*, Arsenites/*poisoning , Cell Transformation, Neoplastic/*drug effects , Epithelial Cells/*drug effects , Gene Amplification/*drug effects , Prostate/*metabolism , Proto-Oncogene Proteins p21(ras)/*genetics, Carcinogens, Environmental/poisoning ; Cell Line ; Cell Transformation, Neoplastic/genetics ; Epithelial Cells/metabolism ; Exons/genetics ; Gene Amplification/genetics ; Gene Expression Profiling ; Gene Regulatory Networks ; Humans ; Male ; Prostate/pathology
مستخلص: Inorganic arsenic is an environmental human carcinogen of several organs including the urinary tract. RWPE-1 cells are immortalized, non-tumorigenic, human prostate epithelia that become malignantly transformed into the CAsE-PE line after continuous in vitro exposure to 5μM arsenite over a period of months. For insight into in vitro arsenite transformation, we performed RNA-seq for differential gene expression and targeted sequencing of KRAS. We report >7,000 differentially expressed transcripts in CAsE-PE cells compared to RWPE-1 cells at >2-fold change, q<0.05 by RNA-seq. Notably, KRAS expression was highly elevated in CAsE-PE cells, with pathway analysis supporting increased cell proliferation, cell motility, survival and cancer pathways. Targeted DNA sequencing of KRAS revealed a mutant specific allelic imbalance, 'MASI', frequently found in primary clinical tumors. We found high expression of a mutated KRAS transcript carrying oncogenic mutations at codons 12 and 59 and many silent mutations, accompanied by lower expression of a wild-type allele. Parallel cultures of RWPE-1 cells retained a wild-type KRAS genotype. Copy number analysis and sequencing showed amplification of the mutant KRAS allele. KRAS is expressed as two splice variants, KRAS4a and KRAS4b, where variant 4b is more prevalent in normal cells compared to greater levels of variant 4a seen in tumor cells. 454 Roche sequencing measured KRAS variants in each cell type. We found KRAS4a as the predominant transcript variant in CAsE-PE cells compared to KRAS4b, the variant expressed primarily in RWPE-1 cells and in normal prostate, early passage, primary epithelial cells. Overall, gene expression data were consistent with KRAS-driven proliferation pathways found in spontaneous tumors and malignantly transformed cell lines. Arsenite is recognized as an important environmental carcinogen, but it is not a direct mutagen. Further investigations into this in vitro transformation model will focus on genomic events that cause arsenite-mediated mutation and overexpression of KRAS in CAsE-PE cells.
Competing Interests: We have the following interests: Dhiral P. Phadke and Ruchir R. Shah are employed by Sciome, LLC. The US government at NIEHS is the sole funder of this research through contracts with Sciome, LLC and DHMRI. Neither Sciome, LLC nor DHMRI derive benefits from the publication of this work and had no role in funding of the work. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.
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معلومات مُعتمدة: HHSN273201100016C United States ES NIEHS NIH HHS; HHSN273201700001C United States ES NIEHS NIH HHS
المشرفين على المادة: 0 (Arsenites)
0 (Carcinogens, Environmental)
0 (KRAS protein, human)
EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
N5509X556J (arsenite)
تواريخ الأحداث: Date Created: 20190423 Date Completed: 20200113 Latest Revision: 20221115
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC6476498
DOI: 10.1371/journal.pone.0215504
PMID: 31009485
قاعدة البيانات: MEDLINE
الوصف
تدمد:1932-6203
DOI:10.1371/journal.pone.0215504