Colon cancer, and cancer in general, is a disease of the genome which invariably is associated with aberrant expression of genes. What is not clearly understood is how these genes are interconnected in the context of an operational network that underlies the cancer phenotype. An understanding of the network connections of cancer-related genes offers the potential to identify critical branch points amendable to therapeutic intervention. The goal of this application is to map cancer gene networks in a well-defined series of colon cancer cell lines from the NCI-60 panel. This will be accomplished by implementing an iterative process involving phenotyping, gene expression profiling, transcription factor binding analysis, and computational modeling of gene interactions. The resulting network model will be tested by perturbing cancer cell lines with molecular probes called short hairpin RNAs (siRNAs) in a process known as RNA interference (RNAi). Genes within the network whose knockdown by RNAi leads to a loss-of-cancer phenotype are hypothesized to regulate the expression of downstream effector genes. This perturbation in cancer cell lines will be examined by a subsequent round of gene expression profiling, transcription factor binding analysis and computational modeling, thereby allowing us to progressively improve our cancer network model. The validity of the revised model will be scrutinized with an ensuing round of RNAi perturbation and loss-of- cancer phenotype screening, and the iterative process is repeated. Lastly, the biological significance of genes in our networks will be cross-validated with expression profiling data of staged human colon cancers (normal colon, adenomas, Dukes'B, C and D stage samples, and liver metastases). Our research objectives are summarized as follows: (1) Construct a map of the invasion gene network, (2) Construct a map of the (anti-)adhesion gene network, and (3) Build probabilistic models of the invasion and (anti-) adhesion gene networks.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA120316-04
Application #
7802088
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Li, Jerry
Project Start
2007-07-18
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$408,698
Indirect Cost
Name
George Washington University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052
House, Carrie D; Wang, Bi-Dar; Ceniccola, Kristin et al. (2015) Voltage-gated Na+ Channel Activity Increases Colon Cancer Transcriptional Activity and Invasion Via Persistent MAPK Signaling. Sci Rep 5:11541
Wang, Bi-Dar; Ceniccola, Kristin; Yang, Qi et al. (2015) Identification and Functional Validation of Reciprocal microRNA-mRNA Pairings in African American Prostate Cancer Disparities. Clin Cancer Res 21:4970-84
Chakrabarti, Lina; Wang, Bi-Dar; Lee, Norman H et al. (2013) A mechanism linking Id2-TGF? crosstalk to reversible adaptive plasticity in neuroblastoma. PLoS One 8:e83521
Posnack, Nikki Gillum; Swift, Luther M; Kay, Matthew W et al. (2012) Phthalate exposure changes the metabolic profile of cardiac muscle cells. Environ Health Perspect 120:1243-51
Li, Y; Jaramillo-Lambert, A N; Yang, Y et al. (2012) And-1 is required for the stability of histone acetyltransferase Gcn5. Oncogene 31:643-52
Henderson, Brian E; Lee, Norman H; Seewaldt, Victoria et al. (2012) The influence of race and ethnicity on the biology of cancer. Nat Rev Cancer 12:648-53
Makhoul, Rami; Schwartz, Arnold M; Williams, Russell et al. (2011) Paranuclear dot-like immunostaining for CD99: presence in colonic adenomas and adenocarcinomas. Am J Surg Pathol 35:1749-50
Posnack, Nikki Gillum; Lee, Norman H; Brown, Ronald et al. (2011) Gene expression profiling of DEHP-treated cardiomyocytes reveals potential causes of phthalate arrhythmogenicity. Toxicology 279:54-64
Formolo, Catherine A; Williams, Russell; Gordish-Dressman, Heather et al. (2011) Secretome signature of invasive glioblastoma multiforme. J Proteome Res 10:3149-59
Ohshiro, Kazufumi; Rayala, Suresh K; Wigerup, Caroline et al. (2010) Acetylation-dependent oncogenic activity of metastasis-associated protein 1 co-regulator. EMBO Rep 11:691-7

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