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A genome-scale screen reveals context-dependent ovarian cancer sensitivity to miRNA overexpression

Authors
 Benjamin B Shields  ;  Chad V Pecot  ;  Hua Gao  ;  Elizabeth McMillan  ;  Malia Potts  ;  Christa Nagel  ;  Scott Purinton  ;  Ying Wang  ;  Cristina Ivan  ;  Hyun Seok Kim  ;  Robert J Borkowski  ;  Shaheen Khan  ;  Cristian Rodriguez-Aguayo  ;  Gabriel Lopez-Berestein  ;  Jayanthi Lea  ;  Adi Gazdar  ;  Keith A Baggerly  ;  Anil K Sood  ;  Michael A White 
Citation
 MOLECULAR SYSTEMS BIOLOGY, Vol.11(12) : 842, 2015 
Journal Title
 MOLECULAR SYSTEMS BIOLOGY 
Issue Date
2015
MeSH
Animals ; Biomimetic Materials/administration & dosage* ; Biomimetic Materials/pharmacology ; Cell Differentiation/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Down-Regulation ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Genome-Wide Association Study ; Humans ; Mice ; MicroRNAs/genetics* ; Neoplasms, Glandular and Epithelial/drug therapy* ; Neoplasms, Glandular and Epithelial/genetics* ; Ovarian Neoplasms/drug therapy* ; Ovarian Neoplasms/genetics* ; Xenograft Model Antitumor Assays
Keywords
cancer ; cancer genetics ; miRNA ; microRNA ; ovarian cancer
Abstract
Large-scale molecular annotation of epithelial ovarian cancer (EOC) indicates remarkable heterogeneity in the etiology of that disease. This diversity presents a significant obstacle against intervention target discovery. However, inactivation of miRNA biogenesis is commonly associated with advanced disease. Thus, restoration of miRNA activity may represent a common vulnerability among diverse EOC oncogenotypes. To test this, we employed genome-scale, gain-of-function, miRNA mimic toxicity screens in a large, diverse spectrum of EOC cell lines. We found that all cell lines responded to at least some miRNA mimics, but that the nature of the miRNA mimics provoking a response was highly selective within the panel. These selective toxicity profiles were leveraged to define modes of action and molecular response indicators for miRNA mimics with tumor-suppressive characteristics in vivo. A mechanistic principle emerging from this analysis was sensitivity of EOC to miRNA-mediated release of cell fate specification programs, loss of which may be a prerequisite for development of this disease.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Kim, Hyun Seok(김현석) ORCID logo https://orcid.org/0000-0003-4498-8690
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/156946
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