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

Molecular Systems Biology

Benjamin B Shields²  Chad V Pecot⁵  Hua Gao²  Elizabeth McMillan²  Malia Potts²  Christa Nagel¹  Scott Purinton¹  Ying Wang³  Cristina Ivan³  Hyun Seok Kim⁴  Robert J Borkowski²  Shaheen Khan⁶  Cristian Rodriguez-Aguayo⁵  Gabriel Lopez-Berestein⁵  Jayanthi Lea¹  Adi Gazdar⁷  Keith A Baggerly³  Anil K Sood⁵ 

[1] Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, USA;Departments of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA;Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX, USA;Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea;Center for RNA interference and Non-Coding RNA, MD Anderson Cancer Center, Houston, TX, USA;Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA;Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

关键词: cancer;    cancer genetics;    microRNA;    miRNA;    ovarian cancer;   

DOI  :  10.15252/msb.20156308

来源: Wiley

【 摘 要 】

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.

Synopsis

A genomewide miRNA mimic toxicity screen indicates common and selective vulnerabilities of epithelial ovarian cancer cells. Follow-up analyses offer mechanistic insights into the selective sensitivity of ovarian cancer cells to select miRNAs.

• Screening the sensitivity of 16 ovarian cancer cell lines to 400 miRNA mimics reveals miRNAs with broad and selective effects.
• miR-181 and miR-155 are selectively toxic in chemoresistant ovarian cancer cells through dual modulation of TGFβ and AKT signaling.
• miR-517a targets a common vulnerability, primarily via its target ARCN1.
• miR-124 is selectively toxic, mainly by inducing terminal cell differentiation via its target SIX4.

【 授权许可】

CC BY   
© 2015 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.