Computational Reconstruction of NFκB Pathway Interaction Mechanisms during Prostate Cancer
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Computational Reconstruction of NFκB Pathway Interaction Mechanisms during Prostate Cancer. / Börnigen, Daniela; Tyekucheva, Svitlana; Wang, Xiaodong; Rider, Jennifer R; Lee, Gwo-Shu; Mucci, Lorelei A; Sweeney, Christopher; Huttenhower, Curtis.
in: PLOS COMPUT BIOL, Jahrgang 12, Nr. 4, 04.2016, S. e1004820.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Computational Reconstruction of NFκB Pathway Interaction Mechanisms during Prostate Cancer
AU - Börnigen, Daniela
AU - Tyekucheva, Svitlana
AU - Wang, Xiaodong
AU - Rider, Jennifer R
AU - Lee, Gwo-Shu
AU - Mucci, Lorelei A
AU - Sweeney, Christopher
AU - Huttenhower, Curtis
PY - 2016/4
Y1 - 2016/4
N2 - Molecular research in cancer is one of the largest areas of bioinformatic investigation, but it remains a challenge to understand biomolecular mechanisms in cancer-related pathways from high-throughput genomic data. This includes the Nuclear-factor-kappa-B (NFκB) pathway, which is central to the inflammatory response and cell proliferation in prostate cancer development and progression. Despite close scrutiny and a deep understanding of many of its members' biomolecular activities, the current list of pathway members and a systems-level understanding of their interactions remains incomplete. Here, we provide the first steps toward computational reconstruction of interaction mechanisms of the NFκB pathway in prostate cancer. We identified novel roles for ATF3, CXCL2, DUSP5, JUNB, NEDD9, SELE, TRIB1, and ZFP36 in this pathway, in addition to new mechanistic interactions between these genes and 10 known NFκB pathway members. A newly predicted interaction between NEDD9 and ZFP36 in particular was validated by co-immunoprecipitation, as was NEDD9's potential biological role in prostate cancer cell growth regulation. We combined 651 gene expression datasets with 1.4M gene product interactions to predict the inclusion of 40 additional genes in the pathway. Molecular mechanisms of interaction among pathway members were inferred using recent advances in Bayesian data integration to simultaneously provide information specific to biological contexts and individual biomolecular activities, resulting in a total of 112 interactions in the fully reconstructed NFκB pathway: 13 (11%) previously known, 29 (26%) supported by existing literature, and 70 (63%) novel. This method is generalizable to other tissue types, cancers, and organisms, and this new information about the NFκB pathway will allow us to further understand prostate cancer and to develop more effective prevention and treatment strategies.
AB - Molecular research in cancer is one of the largest areas of bioinformatic investigation, but it remains a challenge to understand biomolecular mechanisms in cancer-related pathways from high-throughput genomic data. This includes the Nuclear-factor-kappa-B (NFκB) pathway, which is central to the inflammatory response and cell proliferation in prostate cancer development and progression. Despite close scrutiny and a deep understanding of many of its members' biomolecular activities, the current list of pathway members and a systems-level understanding of their interactions remains incomplete. Here, we provide the first steps toward computational reconstruction of interaction mechanisms of the NFκB pathway in prostate cancer. We identified novel roles for ATF3, CXCL2, DUSP5, JUNB, NEDD9, SELE, TRIB1, and ZFP36 in this pathway, in addition to new mechanistic interactions between these genes and 10 known NFκB pathway members. A newly predicted interaction between NEDD9 and ZFP36 in particular was validated by co-immunoprecipitation, as was NEDD9's potential biological role in prostate cancer cell growth regulation. We combined 651 gene expression datasets with 1.4M gene product interactions to predict the inclusion of 40 additional genes in the pathway. Molecular mechanisms of interaction among pathway members were inferred using recent advances in Bayesian data integration to simultaneously provide information specific to biological contexts and individual biomolecular activities, resulting in a total of 112 interactions in the fully reconstructed NFκB pathway: 13 (11%) previously known, 29 (26%) supported by existing literature, and 70 (63%) novel. This method is generalizable to other tissue types, cancers, and organisms, and this new information about the NFκB pathway will allow us to further understand prostate cancer and to develop more effective prevention and treatment strategies.
KW - Adaptor Proteins, Signal Transducing
KW - Bayes Theorem
KW - Cell Line, Tumor
KW - Cell Proliferation
KW - Computational Biology
KW - Databases, Genetic
KW - Gene Expression Profiling
KW - Gene Knockdown Techniques
KW - Gene Ontology
KW - Gene Regulatory Networks
KW - Humans
KW - Immunoprecipitation
KW - Male
KW - Models, Biological
KW - NF-kappa B
KW - Phosphoproteins
KW - Prostatic Neoplasms
KW - Signal Transduction
KW - Tristetraprolin
KW - Journal Article
KW - Research Support, N.I.H., Extramural
KW - Research Support, U.S. Gov't, Non-P.H.S.
KW - Validation Studies
U2 - 10.1371/journal.pcbi.1004820
DO - 10.1371/journal.pcbi.1004820
M3 - SCORING: Journal article
C2 - 27078000
VL - 12
SP - e1004820
JO - PLOS COMPUT BIOL
JF - PLOS COMPUT BIOL
SN - 1553-734X
IS - 4
ER -