Document Detail


RNA helicase DDX5 regulates microRNA expression and contributes to cytoskeletal reorganization in basal breast cancer cells.
MedLine Citation:
PMID:  22086602     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
RNA helicase DDX5 (also p68) is involved in all aspects of RNA metabolism and serves as a transcriptional coregulator, but its functional role in breast cancer remains elusive. Here, we report an integrative biology study of DDX5 in breast cancer, encompassing quantitative proteomics, global MicroRNA profiling, and detailed biochemical characterization of cell lines and human tissues. We showed that protein expression of DDX5 increased progressively from the luminal to basal breast cancer cell lines, and correlated positively with that of CD44 in the basal subtypes. Through immunohistochemistry analyses of tissue microarrays containing over 200 invasive human ductal carcinomas, we observed that DDX5 was up-regulated in the majority of malignant tissues, and its expression correlated strongly with those of Ki67 and EGFR in the triple-negative tumors. We demonstrated that DDX5 regulated a subset of MicroRNAs including miR-21 and miR-182 in basal breast cancer cells. Knockdown of DDX5 resulted in reorganization of actin cytoskeleton and reduction of cellular proliferation. The effects were accompanied by up-regulation of tumor suppressor PDCD4 (a known miR-21 target); as well as up-regulation of cofilin and profilin, two key proteins involved in actin polymerization and cytoskeleton maintenance, as a consequence of miR-182 down-regulation. Treatment with miR-182 inhibitors resulted in morphologic phenotypes resembling those induced by DDX5 knockdown. Using bioinformatics tools for pathway and network analyses, we confirmed that the network for regulation of actin cytoskeleton was predominantly enriched for the predicted downstream targets of miR-182. Our results reveal a new functional role of DDX5 in breast cancer via the DDX5→miR-182→actin cytoskeleton pathway, and suggest the potential clinical utility of DDX5 and its downstream MicroRNAs in the theranostics of breast cancer.
Authors:
Daojing Wang; Jing Huang; Zhi Hu
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2011-11-15
Journal Detail:
Title:  Molecular & cellular proteomics : MCP     Volume:  11     ISSN:  1535-9484     ISO Abbreviation:  Mol. Cell Proteomics     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-02-07     Completed Date:  2012-06-01     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  101125647     Medline TA:  Mol Cell Proteomics     Country:  United States    
Other Details:
Languages:  eng     Pagination:  M111.011932     Citation Subset:  IM    
Affiliation:
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA. djwang@lbl.gov
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MeSH Terms
Descriptor/Qualifier:
Actins / metabolism*
Blotting, Western
Breast Neoplasms / genetics*,  metabolism,  pathology
Cytoskeleton / physiology*
DEAD-box RNA Helicases / antagonists & inhibitors,  genetics*,  metabolism
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic*
Humans
Immunoenzyme Techniques
MicroRNAs / genetics*,  metabolism
Neoplasm Invasiveness
Neoplasms, Basal Cell / genetics*,  metabolism,  pathology
Oligonucleotide Array Sequence Analysis
Proteome / analysis
RNA, Messenger / genetics
RNA, Small Interfering / genetics
Real-Time Polymerase Chain Reaction
Receptor, Epidermal Growth Factor / genetics,  metabolism
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Tissue Array Analysis
Tumor Cells, Cultured
Tumor Markers, Biological / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
U24 CA126477/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Actins; 0/MicroRNAs; 0/Proteome; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/Tumor Markers, Biological; EC 2.7.10.1/EGFR protein, human; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 3.6.1.-/DEAD-box RNA Helicases; EC 3.6.1.-/Ddx5 protein, human
Comments/Corrections

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