TY - JOUR
T1 - In silico pathway analysis in cervical carcinoma reveals potential new targets for treatment
AU - Papadimitriou, Konstantinos
AU - Giallombardo, Marco
AU - Trinh, Xuan Bich
AU - Altintas, Sevilay
AU - Papadimitriou, Kostas
AU - Van Berckelaer, Christophe
AU - Van Dam, Pieter-Jan H.H.
AU - Giallombardo, Marco
AU - Van Dam, Peter A.
AU - Van Laere, Steven
AU - Rolfo, Christian
AU - Huizing, Manon
AU - Tjalma, Wiebren A.A.
AU - Rolfo, Christian Diego
PY - 2016
Y1 - 2016
N2 - An in silico pathway analysis was performed in order to improve current knowledge on the molecular drivers of cervical cancer and detect potential targets for treatment. Three publicly available Affymetrix gene expression data-sets (GSE5787, GSE7803, GSE9750) were retrieved, vouching for a total of 9 cervical cancer cell lines (CCCLs), 39 normal cervical samples, 7 CIN3 samples and 111 cervical cancer samples (CCSs). Predication analysis of microarrays was performed in the Affymetrix sets to identify cervical cancer biomarkers. To select cancer cell-specific genes the CCSs were compared to the CCCLs. Validated genes were submitted to a gene set enrichment analysis (GSEA) and Expression2Kinases (E2K). In the CCSs a total of 1,547 probe sets were identified that were overexpressed (FDR < 0.1). Comparing to CCCLs 560 probe sets (481 unique genes) had a cancer cell-specific expression profile, and 315 of these genes (65%) were validated. GSEA identified 5 cancer hallmarks enriched in CCSs (P < 0.01 and FDR < 0.25) showing that deregulation of the cell cycle is a major component of cervical cancer biology. E2K identified a protein-protein interaction (PPI) network of 162 nodes (including 20 drugable kinases) and 1626 edges. This PPI-network consists of 5 signaling modules associated with MYC signaling (Module 1), cell cycle deregulation (Module 2), TGFβ-signaling (Module 3), MAPK signaling (Module 4) and chromatin modeling (Module 5). Potential targets for treatment which could be identified were CDK1, CDK2, ABL1, ATM, AKT1, MAPK1, MAPK3 among others. The present study identified important driver pathways in cervical carcinogenesis which should be assessed for their potential therapeutic drugability.
AB - An in silico pathway analysis was performed in order to improve current knowledge on the molecular drivers of cervical cancer and detect potential targets for treatment. Three publicly available Affymetrix gene expression data-sets (GSE5787, GSE7803, GSE9750) were retrieved, vouching for a total of 9 cervical cancer cell lines (CCCLs), 39 normal cervical samples, 7 CIN3 samples and 111 cervical cancer samples (CCSs). Predication analysis of microarrays was performed in the Affymetrix sets to identify cervical cancer biomarkers. To select cancer cell-specific genes the CCSs were compared to the CCCLs. Validated genes were submitted to a gene set enrichment analysis (GSEA) and Expression2Kinases (E2K). In the CCSs a total of 1,547 probe sets were identified that were overexpressed (FDR < 0.1). Comparing to CCCLs 560 probe sets (481 unique genes) had a cancer cell-specific expression profile, and 315 of these genes (65%) were validated. GSEA identified 5 cancer hallmarks enriched in CCSs (P < 0.01 and FDR < 0.25) showing that deregulation of the cell cycle is a major component of cervical cancer biology. E2K identified a protein-protein interaction (PPI) network of 162 nodes (including 20 drugable kinases) and 1626 edges. This PPI-network consists of 5 signaling modules associated with MYC signaling (Module 1), cell cycle deregulation (Module 2), TGFβ-signaling (Module 3), MAPK signaling (Module 4) and chromatin modeling (Module 5). Potential targets for treatment which could be identified were CDK1, CDK2, ABL1, ATM, AKT1, MAPK1, MAPK3 among others. The present study identified important driver pathways in cervical carcinogenesis which should be assessed for their potential therapeutic drugability.
KW - Cancer; Cervical carcinoma; In silico pathway analysis; Treatment targets; Amino Acid Sequence; Biomarkers
KW - Neoplastic; Oncology
KW - Tumor; Cell Cycle; Cell Line
KW - Tumor; Chromatin Assembly and Disassembly; Computational Biology; Computer Simulation; Female; Gene Expression Profiling; HeLa Cells; Humans; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Oligonucleotide Array Sequence Analysis; Proto-On
KW - Cancer; Cervical carcinoma; In silico pathway analysis; Treatment targets; Amino Acid Sequence; Biomarkers
KW - Neoplastic; Oncology
KW - Tumor; Cell Cycle; Cell Line
KW - Tumor; Chromatin Assembly and Disassembly; Computational Biology; Computer Simulation; Female; Gene Expression Profiling; HeLa Cells; Humans; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Oligonucleotide Array Sequence Analysis; Proto-On
UR - http://hdl.handle.net/10447/295330
UR - http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=download&path%5B%5D=6667&path%5B%5D=18623
M3 - Article
VL - 7
SP - 2780
EP - 2795
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
ER -