title: Meta-Analysis of Tumor Stem-Like Breast Cancer Cells Using Gene Set and Network Analysis.
abstract: Generally, cancer stem cells have epithelial-to-mesenchymal-transition characteristics and other aggressive properties that cause metastasis. However, there have been no confident markers for the identification of cancer stem cells and comparative methods examining adherent and sphere cells are widely used to investigate mechanism underlying cancer stem cells, because sphere cells have been known to maintain cancer stem cell characteristics. In this study, we conducted a meta-analysis that combined gene expression profiles from several studies that utilized tumorsphere technology to investigate tumor stem-like breast cancer cells. We used our own gene expression profiles along with the three different gene expression profiles from the Gene Expression Omnibus, which we combined using the ComBat method, and obtained significant gene sets using the gene set analysis of our datasets and the combined dataset. This experiment focused on four gene sets such as cytokine-cytokine receptor interaction that demonstrated significance in both datasets. Our observations demonstrated that among the genes of four significant gene sets, six genes were consistently up-regulated and satisfied the p-value of < 0.05, and our network analysis showed high connectivity in five genes. From these results, we established CXCR4, CXCL1 and HMGCS1, the intersecting genes of the datasets with high connectivity and p-value of < 0.05, as significant genes in the identification of cancer stem cells. Additional experiment using quantitative reverse transcription-polymerase chain reaction showed significant up-regulation in MCF-7 derived sphere cells and confirmed the importance of these three genes. Taken together, using meta-analysis that combines gene set and network analysis, we suggested CXCR4, CXCL1 and HMGCS1 as candidates involved in tumor stem-like breast cancer cells. Distinct from other meta-analysis, by using gene set analysis, we selected possible markers which can explain the biological mechanisms and suggested network analysis as an additional criterion for selecting candidates.
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
authors: Won Jun
authors: WJ
authors: Lee
authors: Department of Biomedical Informatics, Center for Genome Science, National Institute of Health, KCDC, Choongchung-Buk-do, 28159, Republic of Korea.
authors: Sang Cheol
authors: SC
authors: Kim
authors: Department of Biochemistry and Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, 16499, Republic of Korea.
authors: Jung-Ho
authors: JH
authors: Yoon
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
authors: Sang Jun
authors: SJ
authors: Yoon
authors: Department of Statistics, Seoul National University, Seoul, 08826, Republic of Korea.
authors: Johan
authors: J
authors: Lim
authors: Department of Biochemistry and Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, 16499, Republic of Korea.
authors: You-Sun
authors: YS
authors: Kim
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
authors: Sung Won
authors: SW
authors: Kwon
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
authors: Jeong Hill
authors: JH
authors: Park
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D059467:Transcriptome