Dataset Information

Identification of Transcriptional Signatures of Colon Tumor Stroma by a Meta-Analysis.

ABSTRACT: Background:The tumor stroma plays pivotal roles in influencing tumor growth, invasion, and metastasis. Transcriptional signatures of colon tumor stroma (CTS) are significantly associated with prognosis of colon cancer. Thus, identification of the CTS transcriptional features could be useful for colon cancer diagnosis and therapy. Methods:By a meta-analysis of three CTS gene expression profiles datasets, we identified differentially expressed genes (DEGs) between CTS and colon normal stroma. Furthermore, we identified the pathways, upstream regulators, and protein-protein interaction (PPI) network that were significantly associated with the DEGs. Moreover, we analyzed the enrichment levels of immune signatures in CTS. Finally, we identified CTS-associated gene signatures whose expression was significantly associated with prognosis in colon cancer. Results:We identified numerous significantly upregulated genes (such as CTHRC1, NFE2L3, SULF1, SOX9, ENC1, and CCND1) and significantly downregulated genes (such as MYOT, ASPA, KIAA2022, ARHGEF37, BCL-2, and PPARGC1A) in CTS versus colon normal stroma. Furthermore, we identified significantly upregulated pathways in CTS that were mainly involved in cellular development, immune regulation, and metabolism, as well as significantly downregulated pathways in CTS that were mostly metabolism-related. Moreover, we identified upstream TFs (such as SUZ12, NFE2L2, RUNX1, STAT3, and SOX2), kinases (such as MAPK14, CSNK2A1, CDK1, CDK2, and CDK4), and master metabolic transcriptional regulators (MMTRs) (such as HNF1A, NFKB1, ZBTB7A, GATA2, and GATA5) regulating the DEGs. We found that CD8+ T cells were more enriched in CTS than in colon normal stroma. Interestingly, we found that many of the DEGs and their regulators were prognostic markers for colon cancer, including CEBPB, PPARGC1, STAT3, MTOR, BCL2, JAK2, and CDK1. Conclusions:The identification of CTS-specific transcriptional signatures may provide insights into the tumor microenvironment that mediates the development of colon cancer and has potential clinical implications for colon cancer diagnosis and treatment.

SUBMITTER: Uddin MN

PROVIDER: S-EPMC6521457 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Identification of Transcriptional Signatures of Colon Tumor Stroma by a Meta-Analysis.

Uddin Md Nazim MN Li Mengyuan M Wang Xiaosheng X

Journal of oncology 20190502

<h4>Background</h4>The tumor stroma plays pivotal roles in influencing tumor growth, invasion, and metastasis. Transcriptional signatures of colon tumor stroma (CTS) are significantly associated with prognosis of colon cancer. Thus, identification of the CTS transcriptional features could be useful for colon cancer diagnosis and therapy.<h4>Methods</h4>By a meta-analysis of three CTS gene expression profiles datasets, we identified differentially expressed genes (DEGs) between CTS and colon norm ...[more]

PMID: 31186640

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Project description:BackgroundThe expression of carcino-embryonic antigen by colorectal cancer is an example of oncogenic activation of embryonic gene expression. Hypothesizing that oncogenesis-recapitulating-ontogenesis may represent a broad programmatic commitment, we compared gene expression patterns of human colorectal cancers (CRCs) and mouse colon tumor models to those of mouse colon development embryonic days 13.5-18.5.ResultsWe report here that 39 colon tumors from four independent mouse models and 100 human CRCs encompassing all clinical stages shared a striking recapitulation of embryonic colon gene expression. Compared to normal adult colon, all mouse and human tumors over-expressed a large cluster of genes highly enriched for functional association to the control of cell cycle progression, proliferation, and migration, including those encoding MYC, AKT2, PLK1 and SPARC. Mouse tumors positive for nuclear beta-catenin shifted the shared embryonic pattern to that of early development. Human and mouse tumors differed from normal embryonic colon by their loss of expression modules enriched for tumor suppressors (EDNRB, HSPE, KIT and LSP1). Human CRC adenocarcinomas lost an additional suppressor module (IGFBP4, MAP4K1, PDGFRA, STAB1 and WNT4). Many human tumor samples also gained expression of a coordinately regulated module associated with advanced malignancy (ABCC1, FOXO3A, LIF, PIK3R1, PRNP, TNC, TIMP3 and VEGF).ConclusionCross-species, developmental, and multi-model gene expression patterning comparisons provide an integrated and versatile framework for definition of transcriptional programs associated with oncogenesis. This approach also provides a general method for identifying pattern-specific biomarkers and therapeutic targets. This delineation and categorization of developmental and non-developmental activator and suppressor gene modules can thus facilitate the formulation of sophisticated hypotheses to evaluate potential synergistic effects of targeting within- and between-modules for next-generation combinatorial therapeutics and improved mouse models.

Project description:BackgroundColorectal cancer is an important death-related disease in the worldwide. However, specific colon cancer tumor markers currently used for diagnosis and treatment are few. The purpose of this study is to screen the potential colon cancer markers by bioinformatics and verify the results with experiments.MethodsGene expression data were downloaded from two different databases: TCGA database and GEO datasets, which were then analyzed by two different methods (difference analysis and WGCNA method). Venn and PPI analysis obtained the potential core genes, which were then performed the GO enrichment and KEGG pathway analysis. Expressions levels of NKD1 in colon carcinoma tissues were further confirmed by immunohistochemical staining and western blot assays. Moreover, the function was measured by MTT, clone formation, and tumor transplantation experiments. Importantly, co-immunoprecipitation, immunofluorescence, and protein stability assays were further performed to explore the underlying mechanism of NKD1 promoting cell proliferation.ResultsNine potential core genes highly expressed in colon cancer samples were screened out by bioinformatics analysis. NKD1, one of the hub genes, highly expressed in the colon carcinoma tissues could enhance the proliferation of colon cancer cells. Mechanism research demonstrated that NKD1 was essential for the combination between Wnt signalosome (DVL) and β-catenin, and that NKD1 knockout remarkably decreased the β-catenin expression. Immunofluorescence assays further implied that NKD1 knockout significantly inhibited β-catenin nuclear accumulation. Importantly, the stability of β-catenin proteins was maintained by NKD1 in the colon cancer cells.ConclusionWe believe that NKD1 well expressed in the colorectal carcinoma tissues can enhance the proliferation of colon cancer cells. Furthermore, the functions that NKD1 may have in colon cancer cells should be different from that NKD1 has played in the zebrafish. Thus, NKD1 could be a specific colorectal cancer marker.

Dataset Information

Identification of Transcriptional Signatures of Colon Tumor Stroma by a Meta-Analysis.

Publications

Identification of Transcriptional Signatures of Colon Tumor Stroma by a Meta-Analysis.

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