TY - JOUR
T1 - A genome-scale screen reveals context-dependent ovarian cancer sensitivity to miRNA overexpression
AU - Shields, Benjamin B.
AU - Pecot, Chad V.
AU - Gao, Hua
AU - McMillan, Elizabeth
AU - Potts, Malia
AU - Nagel, Christa
AU - Purinton, Scott
AU - Wang, Ying
AU - Ivan, Cristina
AU - Kim, Hyun Seok
AU - Borkowski, Robert J.
AU - Khan, Shaheen
AU - Rodriguez-Aguayo, Cristian
AU - Lopez-Berestein, Gabriel
AU - Lea, Jayanthi
AU - Gazdar, Adi
AU - Baggerly, Keith A.
AU - Sood, Anil K.
AU - White, Michael A.
N1 - Funding Information:
This study was supported by grants from the NIH (CA71443, CA129451, P50CA083639, U54CA151668, T32-GM008203), The Robert Welch Foundation (I-1414), and CPRIT (RP110595, RP110763). The authors would like to thank Drs. Hani Gabra, William Hahn, Robert Bast, and John Abrams for their generous donation of cell lines. The data discussed in this publication have been deposited in NCBI''s Gene Expression Omnibus (Edgar et al, 2002) and are accessible through GEO Series accession number GSE67330 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE67330).
Publisher Copyright:
© 2015 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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.
AB - 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.
KW - cancer
KW - cancer genetics
KW - miRNA
KW - microRNA
KW - ovarian cancer
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U2 - 10.15252/msb.20156308
DO - 10.15252/msb.20156308
M3 - Article
C2 - 26655797
AN - SCOPUS:84955463400
SN - 1744-4292
VL - 11
SP - 1
EP - 17
JO - Molecular Systems Biology
JF - Molecular Systems Biology
IS - 12
ER -