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.
Highlights
The tumor stroma plays pivotal roles in influencing tumor growth, invasion, and metastasis
We identified 11 significant upstream Transcription Factors (TFs) regulating the differentially expressed genes (DEGs), including SUZ12, NFE2L2, RUNX1, ESR1, STAT3, TCF3, FOSL2, SALL4, AR, SMC3, and SOX2, of which the genes encoding RUNX1 and SALL4 were upregulated in colon tumor stroma (CTS) (Figure 3(a))
We identified 9 (HNF1A, NFKB1, ZBTB7A, ATF6, TEAD4, TFAP2B, JAZF1, FNTB, and EP300) and 12 (PKNOX2, GATA2, MAPK10, TEAD1, TOX, MEF2A, GATA5, ELK1, MAZ, NHLH1, ATF1, and RAD21) master metabolic transcriptional regulators (MMTRs) for the upregulated and the downregulated genes in CTS, respectively (Supplementary Table S7), and built the regulatory networks associated with these MMTRs (Figure 4)
Summary
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. We identified CTS-associated gene signatures whose expression was significantly associated with prognosis in colon cancer. 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. Isella et al demonstrated that the gene signatures of CRC stromal cells (cancer-associated fibroblasts, leukocytes, and endothelial cells) were significantly upregulated in the stem/serrated/mesenchymal transcriptional subtype of CRC which had a poor prognosis [6].
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