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

Autor: 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
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Zdroj: Molecular Systems Biology, Vol 11, Iss 12, Pp 1-17 (2015)
Druh dokumentu: article
ISSN: 20156308
1744-4292
DOI: 10.15252/msb.20156308
Popis: 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.
Databáze: Directory of Open Access Journals
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