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

Overview

Journal J Oncol

Specialty Oncology

Date 2019 Jun 13

PMID 31186640

Citations 21

Authors

Md Nazim Uddin

Mengyuan Li

Xiaosheng Wang

Affiliations

Soon will be listed here.

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 , , , , , and ) and significantly downregulated genes (such as , , , , , and ) 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 , , , , , , and .

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.

Citing Articles

Exploration of crucial stromal risk genes associated with prognostic significance and chemotherapeutic opportunities in invasive ductal breast carcinoma.

Tang G, Wang Z, Geng W, Yu Y, Zhang Y J Genet Eng Biotechnol. 2025; 23(1):100448.

PMID: 40074422 PMC: 11732444. DOI: 10.1016/j.jgeb.2024.100448.

New insight into the CNC-bZIP member, NFE2L3, in human diseases.

Xiong G, Li J, Yao F, Yang F, Xiang Y Front Cell Dev Biol. 2024; 12:1430486.

PMID: 39149514 PMC: 11325725. DOI: 10.3389/fcell.2024.1430486.

Dysregulated Forkhead Box (FOX) Genes Association with Survival Prognosis, Anti-tumor Immunity, and Key Targeting Drugs in Colon Adenocarcinoma.

Xie Q, Wang J, Peng X Arch Iran Med. 2024; 26(9):510-528.

PMID: 38310407 PMC: 10862056. DOI: 10.34172/aim.2023.77.

Single-cell and transcriptomic analyses reveal the influence of diabetes on ovarian cancer.

Zhao Z, Wang Q, Zhao F, Ma J, Sui X, Choe H BMC Genomics. 2024; 25(1):1.

PMID: 38166541 PMC: 10759538. DOI: 10.1186/s12864-023-09893-2.

Cellular and Molecular Mechanisms of the Tumor Stroma in Colorectal Cancer: Insights into Disease Progression and Therapeutic Targets.

Shakhpazyan N, Mikhaleva L, Bedzhanyan A, Gioeva Z, Sadykhov N, Mikhalev A Biomedicines. 2023; 11(9).

PMID: 37760801 PMC: 10525158. DOI: 10.3390/biomedicines11092361.

References

Fujita M, Furukawa Y, Tsunoda T, Tanaka T, Ogawa M, Nakamura Y . Up-regulation of the ectodermal-neural cortex 1 (ENC1) gene, a downstream target of the beta-catenin/T-cell factor complex, in colorectal carcinomas. Cancer Res. 2001; 61(21):7722-6. View

Feilchenfeldt J, Brundler M, Soravia C, Totsch M, Meier C . Peroxisome proliferator-activated receptors (PPARs) and associated transcription factors in colon cancer: reduced expression of PPARgamma-coactivator 1 (PGC-1). Cancer Lett. 2003; 203(1):25-33. DOI: 10.1016/j.canlet.2003.08.024. View

Kumarakulasingham M, Rooney P, Dundas S, Telfer C, Melvin W, Curran S . Cytochrome p450 profile of colorectal cancer: identification of markers of prognosis. Clin Cancer Res. 2005; 11(10):3758-65. DOI: 10.1158/1078-0432.CCR-04-1848. View

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

Johnson W, Li C, Rabinovic A . Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics. 2006; 8(1):118-27. DOI: 10.1093/biostatistics/kxj037. View

Zhang Y, Ba Y, Liu C, Sun G, Ding L, Gao S . PGC-1alpha induces apoptosis in human epithelial ovarian cancer cells through a PPARgamma-dependent pathway. Cell Res. 2007; 17(4):363-73. DOI: 10.1038/cr.2007.11. View

Lu B, Fang Y, Xu J, Wang L, Xu F, Xu E . Analysis of SOX9 expression in colorectal cancer. Am J Clin Pathol. 2008; 130(6):897-904. DOI: 10.1309/AJCPW1W8GJBQGCNI. View

Slattery M, Lundgreen A, Herrick J, Caan B, Potter J, Wolff R . Associations between genetic variation in RUNX1, RUNX2, RUNX3, MAPK1 and eIF4E and riskof colon and rectal cancer: additional support for a TGF-β-signaling pathway. Carcinogenesis. 2010; 32(3):318-26. PMC: 3047235. DOI: 10.1093/carcin/bgq245. View

Arikan S, Cacina C, Guler E, Culcu S, Tuna G, Yaylim-Eraltan I . The effects of NOS3 Glu298Asp variant on colorectal cancer risk and progression in Turkish population. Mol Biol Rep. 2011; 39(3):3245-9. DOI: 10.1007/s11033-011-1092-8. View

10.

Abba M, Laufs S, Aghajany M, Korn B, Benner A, Allgayer H . Look who's talking: deregulated signaling in colorectal cancer. Cancer Genomics Proteomics. 2012; 9(1):15-25. View

11.

Palma M, Lopez L, Garcia M, de Roja N, Ruiz T, Garcia J . Detection of collagen triple helix repeat containing-1 and nuclear factor (erythroid-derived 2)-like 3 in colorectal cancer. BMC Clin Pathol. 2012; 12:2. PMC: 3293008. DOI: 10.1186/1472-6890-12-2. View

12.

Afratis N, Gialeli C, Nikitovic D, Tsegenidis T, Karousou E, Theocharis A . Glycosaminoglycans: key players in cancer cell biology and treatment. FEBS J. 2012; 279(7):1177-97. DOI: 10.1111/j.1742-4658.2012.08529.x. View

13.

Hanahan D, Coussens L . Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012; 21(3):309-22. DOI: 10.1016/j.ccr.2012.02.022. View

14.

Nishida N, Nagahara M, Sato T, Mimori K, Sudo T, Tanaka F . Microarray analysis of colorectal cancer stromal tissue reveals upregulation of two oncogenic miRNA clusters. Clin Cancer Res. 2012; 18(11):3054-70. DOI: 10.1158/1078-0432.CCR-11-1078. View

15.

Hu X, Sui X, Li L, Huang X, Rong R, Su X . Protocadherin 17 acts as a tumour suppressor inducing tumour cell apoptosis and autophagy, and is frequently methylated in gastric and colorectal cancers. J Pathol. 2012; 229(1):62-73. DOI: 10.1002/path.4093. View

16.

Bertrand F, Angus C, Partis W, Sigounas G . Developmental pathways in colon cancer: crosstalk between WNT, BMP, Hedgehog and Notch. Cell Cycle. 2012; 11(23):4344-51. PMC: 3552917. DOI: 10.4161/cc.22134. View

17.

Bae T, Rho K, Choi J, Horimoto K, Kim W, Kim S . Identification of upstream regulators for prognostic expression signature genes in colorectal cancer. BMC Syst Biol. 2013; 7:86. PMC: 3847874. DOI: 10.1186/1752-0509-7-86. View

18.

Aguirre-Gamboa R, Gomez-Rueda H, Martinez-Ledesma E, Martinez-Torteya A, Chacolla-Huaringa R, Rodriguez-Barrientos A . SurvExpress: an online biomarker validation tool and database for cancer gene expression data using survival analysis. PLoS One. 2013; 8(9):e74250. PMC: 3774754. DOI: 10.1371/journal.pone.0074250. View

19.

Yoshihara K, Shahmoradgoli M, Martinez E, Vegesna R, Kim H, Torres-Garcia W . Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013; 4:2612. PMC: 3826632. DOI: 10.1038/ncomms3612. View

20.

Petrochilos D, Shojaie A, Gennari J, Abernethy N . Using random walks to identify cancer-associated modules in expression data. BioData Min. 2013; 6(1):17. PMC: 4015830. DOI: 10.1186/1756-0381-6-17. View