Identification of genes with universally upregulated or downregulated expressions in colorectal cancer
Kai Song
Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
Search for more papers by this authorWei Su
Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, China
Search for more papers by this authorYanlong Liu
Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
Search for more papers by this authorJiahui Zhang
Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Department of Bioinformatics, Fujian Medical University, Fuzhou, China
Search for more papers by this authorQirui Liang
Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Department of Bioinformatics, Fujian Medical University, Fuzhou, China
Search for more papers by this authorNa Li
Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Department of Bioinformatics, Fujian Medical University, Fuzhou, China
Search for more papers by this authorQingzhou Guan
Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Department of Bioinformatics, Fujian Medical University, Fuzhou, China
Search for more papers by this authorJun He
Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Department of Bioinformatics, Fujian Medical University, Fuzhou, China
Search for more papers by this authorXuefeng Bai
Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
Search for more papers by this authorCorresponding Author
Wenyuan Zhao
Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
Correspondence
Wenyuan Zhao and Zheng Guo, Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, China.
Email: [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Zheng Guo
Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Department of Bioinformatics, Fujian Medical University, Fuzhou, China
Correspondence
Wenyuan Zhao and Zheng Guo, Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, China.
Email: [email protected]; [email protected]
Search for more papers by this authorKai Song
Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
Search for more papers by this authorWei Su
Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, China
Search for more papers by this authorYanlong Liu
Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
Search for more papers by this authorJiahui Zhang
Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Department of Bioinformatics, Fujian Medical University, Fuzhou, China
Search for more papers by this authorQirui Liang
Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Department of Bioinformatics, Fujian Medical University, Fuzhou, China
Search for more papers by this authorNa Li
Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Department of Bioinformatics, Fujian Medical University, Fuzhou, China
Search for more papers by this authorQingzhou Guan
Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Department of Bioinformatics, Fujian Medical University, Fuzhou, China
Search for more papers by this authorJun He
Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Department of Bioinformatics, Fujian Medical University, Fuzhou, China
Search for more papers by this authorXuefeng Bai
Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
Search for more papers by this authorCorresponding Author
Wenyuan Zhao
Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
Correspondence
Wenyuan Zhao and Zheng Guo, Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, China.
Email: [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Zheng Guo
Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Department of Bioinformatics, Fujian Medical University, Fuzhou, China
Correspondence
Wenyuan Zhao and Zheng Guo, Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, China.
Email: [email protected]; [email protected]
Search for more papers by this authorAbstract
Background and Aim
Differentially expressed (DE) genes detected at the population-level through case–control comparison provide no information on the dysregulation frequencies of DE genes in a cancer. In this work, we aimed to identify the genes with universally upregulated or downregulated expressions in colorectal cancer (CRC).
Methods
We firstly clarified that DE genes in an individual cancer tissue should be the disease-relevant genes, which are dysregulated in the cancer tissue in comparison with its own previously normal state. Then, we identified DE genes at the individual level for 2233 CRC samples collected from multiple data sources using the RankComp algorithm.
Results
We found 26 genes that were upregulated or downregulated in almost all the 2233 CRC samples and validated the results using 124 CRC tissues with paired adjacent normal tissues. Especially, we found that two genes (AJUBA and EGFL6), upregulated universally in CRC tissues, were extremely lowly expressed in normal colorectal tissues, which were considered to be oncogenes in CRC oncogenesis and development. Oppositely, we found that one gene (LPAR1), downregulated universally in CRC tissues, was silenced in CRC tissues but highly expressed in normal colorectal tissues, which were considered to be tumor suppressor genes in CRC. Functional evidences revealed that these three genes may induce CRC through deregulating pathways for ribosome biogenesis, cell proliferation, and cell cycle.
Conclusions
In conclusion, the individual-level DE genes analysis can help us find genes dysregulated universally in CRC tissues, which may be important diagnostic biomarkers and therapy targets.
Supporting Information
Filename | Description |
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JGH14529-sup-0001-sf1.tiffTIFF image, 3.4 MB |
Figure S1. The MAplots for each dataset. |
JGH14529-sup-0002-sf2.tifTIFF image, 328.9 KB |
Figure S2. The consistency of DE genes identified by T-test and Limma algorithm. (A) DE genes detected in the dataset of GSE23878. (B) DE genes reproducibly detected in the datasets of GSE23878 and GSE31279. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Kang GH. Four molecular subtypes of colorectal cancer and their precursor lesions. Arch. Pathol. Lab. Med. 2011; 135: 698–703.
- 2Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays applied to the ionizing radiation response. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 5116–5121.
- 3Breitling R, Armengaud P, Amtmann A, Herzyk P. Rank products: a simple, yet powerful, new method to detect differentially regulated genes in replicated microarray experiments. FEBS Lett. 2004; 573: 83–92.
- 4Andreassen CN, Alsner J, Overgaard J. Does variability in normal tissue reactions after radiotherapy have a genetic basis—where and how to look for it? Radiother. Oncol.: J. Eur. Soc. Ther. Radiol. Oncol. 2002; 64: 131–140.
- 5Hsiao LL, Dangond F, Yoshida T et al. A compendium of gene expression in normal human tissues. Physiol. Genomics 2001; 7: 97–104.
- 6Linnekamp JF, Wang X, Medema JP, Vermeulen L. Colorectal cancer heterogeneity and targeted therapy: a case for molecular disease subtypes. Cancer Res. 2015; 75: 245–249.
- 7Li J, Han L, Roebuck P et al. TANRIC: an interactive open platform to explore the function of lncRNAs in cancer. Cancer Res. 2015; 75: 3728–3737.
- 8Gross AM, Kreisberg JF, Ideker T. Analysis of matched tumor and normal profiles reveals common transcriptional and epigenetic signals shared across cancer types. PLoS One 2015; 10: e0142618.
- 9Ao L, Yan H, Zheng T et al. Identification of reproducible drug-resistance-related dysregulated genes in small-scale cancer cell line experiments. Sci. Rep. 2015; 5: 11895.
- 10Wang H, Sun Q, Zhao W et al. Individual-level analysis of differential expression of genes and pathways for personalized medicine. Bioinformatics 2015; 31: 62–68.
- 11Guan Q, Chen R, Yan H et al. Differential expression analysis for individual cancer samples based on robust within-sample relative gene expression orderings across multiple profiling platforms. Oncotarget. 2016; 7: 68909–68920.
- 12Barrett T, Wilhite SE, Ledoux P et al. NCBI GEO: archive for functional genomics data sets—update. Nucleic Acids Res. 2013; 41: D991–D995.
- 13 International Cancer Genome C, Hudson TJ, Anderson W et al. International network of cancer genome projects. Nature 2010; 464: 993–998.
- 14Irizarry RA, Hobbs B, Collin F et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 2003; 4: 249–264.
- 15Kauffmann A, Gentleman R, Huber W. arrayQualityMetrics—a bioconductor package for quality assessment of microarray data. Bioinformatics 2009; 25: 415–416.
- 16Leek JT, Scharpf RB, Bravo HC et al. Tackling the widespread and critical impact of batch effects in high-throughput data. Nat. Rev. Genet. 2010; 11: 733–739.
- 17Yu H, Liu BH, Ye ZQ, Li C, Li YX, Li YY. Link-based quantitative methods to identify differentially coexpressed genes and gene pairs. BMC Bioinf. 2011; 12: 315.
- 18Hochberg Y, Benjamini Y. More powerful procedures for multiple significance testing. Stat. Med. 1990; 9: 811–818.
- 19Szklarczyk D, Franceschini A, Wyder S et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015; 43: D447–D452.
- 20Li T, Wernersson R, Hansen RB et al. A scored human protein-protein interaction network to catalyze genomic interpretation. Nat. Methods 2017; 14: 61–64.
- 21Csardi G, Nepusz T. The igraph software package for complex network research. Inter. J. Complex Syst. 2006; 1695: 1–9.
- 22Ashburner M, Ball CA, Blake JA et al. Gene Ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat. Genet. 2000; 25: 25–29.
- 23Wang J, Zhou X, Zhu J et al. GO-function: deriving biologically relevant functions from statistically significant functions. Brief. Bioinform. 2012; 13: 216–227.
- 24Hong G, Zhang W, Li H, Shen X, Guo Z. Separate enrichment analysis of pathways for up- and downregulated genes. J. R. Soc. Interface 2014: 11, 20130950.
- 25Warnecke-Eberz U, Metzger R, Holscher AH, Drebber U, Bollschweiler E. Diagnostic marker signature for esophageal cancer from transcriptome analysis. Tumour Biol.: J. Int. Soc. Oncodev. Biol. Med. 2016; 37: 6349–6358.
- 26Katoh M. Frequent up-regulation of WNT2 in primary gastric cancer and colorectal cancer. Int. J. Oncol. 2001; 19: 1003–1007.
- 27Holcombe RF, Marsh JL, Waterman ML, Lin F, Milovanovic T, Truong T. Expression of Wnt ligands and Frizzled receptors in colonic mucosa and in colon carcinoma. Mol. Pathol.: MP. 2002; 55: 220–226.
- 28Saito S, Liu XF, Kamijo K et al. Deregulation and mislocalization of the cytokinesis regulator ECT2 activate the Rho signaling pathways leading to malignant transformation. J. Biol. Chem. 2004; 279: 7169–7179.
- 29Forbes SA, Beare D, Gunasekaran P et al. COSMIC: exploring the world's knowledge of somatic mutations in human cancer. Nucleic Acids Res. 2015; 43: D805–D811.
- 30Gong X, Wu R, Zhang Y et al. Extracting consistent knowledge from highly inconsistent cancer gene data sources. BMC Bioinf. 2010; 11: 76.
- 31Sekhon RS, Briskine R, Hirsch CN et al. Maize gene atlas developed by RNA sequencing and comparative evaluation of transcriptomes based on RNA sequencing and microarrays. PLoS One 2013; 8: e61005.
- 32Carithers LJ, Moore HM. The genotype-tissue expression (GTEx) project. Biopreserv Biobank. 2015; 13: 307–308.
- 33Yeung G, Mulero JJ, Berntsen RP, Loeb DB, Drmanac R, Ford JE. Cloning of a novel epidermal growth factor repeat containing gene EGFL6: expressed in tumor and fetal tissues. Genomics 1999; 62: 304–307.
- 34Chen X, Stauffer S, Chen Y, Dong J. Ajuba phosphorylation by CDK1 promotes cell proliferation and tumorigenesis. J. Biol. Chem. 2016; 291: 14761–14772.
- 35Liang XH, Zhang GX, Zeng YB et al. LIM protein JUB promotes epithelial-mesenchymal transition in colorectal cancer. Cancer Sci. 2014; 105: 660–666.
- 36Chan JC, Hannan KM, Riddell K et al. AKT promotes rRNA synthesis and cooperates with c-MYC to stimulate ribosome biogenesis in cancer. Sci. Signal. 2011; 4: ra56.
- 37Blagden SP, Willis AE. The biological and therapeutic relevance of mRNA translation in cancer. Nat. Rev. Clin. Oncol. 2011; 8: 280–291.
- 38Moolenaar WH. Bioactive lysophospholipids and their G protein-coupled receptors. Exp. Cell Res. 1999; 253: 230–238.
- 39Mills GB, Moolenaar WH. The emerging role of lysophosphatidic acid in cancer. Nat. Rev. Cancer 2003; 3: 582–591.
- 40Lu C, Bonome T, Li Y et al. Gene alterations identified by expression profiling in tumor-associated endothelial cells from invasive ovarian carcinoma. Cancer Res. 2007; 67: 1757–1768.
- 41Shida D, Kitayama J, Yamaguchi H et al. Lysophosphatidic acid (LPA) enhances the metastatic potential of human colon carcinoma DLD1 cells through LPA1. Cancer Res. 2003; 63: 1706–1711.
- 42Wong SF. Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. Clin. Ther. 2005; 27: 684–694.
- 43Ciardiello F, Caputo R, Borriello G et al. ZD1839 (IRESSA), an EGFR-selective tyrosine kinase inhibitor, enhances taxane activity in bcl-2 overexpressing, multidrug-resistant MCF-7 ADR human breast cancer cells. Int. J. Cancer 2002; 98: 463–469.
- 44Li YH, Tanno M, Itoh T, Yamada H. Role of the monocarboxylic acid transport system in the intestinal absorption of an orally active beta-lactam prodrug: carindacillin as a model. Int. J. Pharm. 1999; 191: 151–159.
- 45Nagai M, Nakamura A, Makino R, Mitamura K. Expression of DNA (5-cytosin)-methyltransferases (DNMTs) in hepatocellular carcinomas. Hepatol. Res.: Off J. Japan Soc. Hepatol 2003; 26: 186–191.
- 46Yakushiji T, Uzawa K, Shibahara T, Noma H, Tanzawa H. Over-expression of DNA methyltransferases and CDKN2A gene methylation status in squamous cell carcinoma of the oral cavity. Int. J. Oncol. 2003; 22: 1201–1207.
- 47Linhart HG, Lin H, Yamada Y et al. Dnmt3b promotes tumorigenesis in vivo by gene-specific de novo methylation and transcriptional silencing. Genes Dev. 2007; 21: 3110–3122.
- 48Coulthard S, Hogarth L. The thiopurines: an update. Invest. New Drugs 2005; 23: 523–532.
- 49Jeanmougin M, de Reynies A, Marisa L, Paccard C, Nuel G, Guedj M. Should we abandon the t-test in the analysis of gene expression microarray data: a comparison of variance modeling strategies. PLoS One 2010; 5: e12336.
- 50Zhang M, Yao C, Guo Z et al. Apparently low reproducibility of true differential expression discoveries in microarray studies. Bioinformatics 2008; 24: 2057–2063.