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Identification of candidate biomarkers and therapeutic drugs of colorectal cancer by integrated bioinformatics analysis

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Abstract

Most colorectal cancer (CRC) patients are diagnosed with advanced stages and low prognosis. We aimed to identify potential diagnostic and prognostic biomarkers, as well as active small molecules of CRC. Microarray data (GSE9348, GSE35279, and GSE106582) were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified by the GEO2R platform. Common DEGs were selected for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Cytoscape software was used to construct protein–protein interaction networks and identify hub genes. Hub genes were evaluated by Kaplan–Meier survival analysis in the GEPIA database and validated in two independent microarray data (GSE74602 and GSE83889). Common DEGs were used to select active small molecules by the connectivity map database. A total of 166 DEGs were identified as common DEGs. GO analysis demonstrated that common DEGs were significantly enriched in the apoptotic process, cell proliferation, and cell adhesion. KEGG analysis indicated that the most enriched pathways were the PI3K-Akt signaling pathway and extracellular matrix-receptor interaction. COL1A2, THBS2, TIMP1, and CXCL8 significantly upregulated in colorectal tumor. High expressions of COL1A2, THBS2, and TIMP1 were associated with poor survival, while high expressions of CXCL8 were associated with better survival. We selected 11 small molecules for CRC therapy. In conclusion, we found key dysregulated genes associated with CRC and potential small molecules to reverse them. COL1A2, THBS2, TIMP1, and CXCL8 may act as diagnostic and prognostic biomarkers of CRC.

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Data availability

The datasets analyzed during the current study are available in the Gene Expression Omnibus repository (https://www.ncbi.nlm.nih.gov/geo/), GEPIA repository (https://gepia.cancer-pku.cn/detail.php), and connectivity map database (https://portals.broadinstitute.org/CMap/).

Abbreviations

CRC:

Colorectal cancer

GEO:

Gene Expression Omnibus

DEG:

Differentially expressed genes

GO:

Gene Ontology

KEGG:

Kyoto Encyclopedia of Genes and Genomes

PPI:

Protein–protein interaction

COL1A2:

Collagen type I alpha 2 chain

THBS2:

Thrombospondin 2

CXCL8:

C-X-C motif chemokine ligand 8

TIMP1:

TIMP metallopeptidase inhibitor 1

CMap:

Connectivity map

logFC:

Log fold change

DAVID:

Database for Annotation Visualization and Integrated Discovery

BP:

Biological processes

CC:

Cellular components

MF:

Molecular functions

MCC:

Maximum Correlation Criteria

ECM:

Extracellular matrix

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Funding

This work was supported by the National Natural Science Foundation of China (No. 31371290), the Frontier and Key Technology Innovation Project of Guangdong Province (No.2014B010118003), and the Science and Technology Planning Project of Guangdong Province (No. 2015B010129008).

Author information

Authors and Affiliations

  1. Department of Pharmacy, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Erheng Road of Yuan Village, Guangzhou, 510655, China

    Zhuoling Zheng, Jingwen Xie, Lixiong Xiong, Min Gao, Li Qin, Chunmei Dai, Zhikun Liang, Yiting Wang, Jing Xue, Qinbo Wang & Xiaoyan Li

  2. Network Information Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Erheng Road of Yuan Village, Guangzhou, 510655, China

    Wenhui Wang

  3. National Engineering Research Center of Digital Life, Sun Yat-Sen University, 132 Waihuan Dong Road, University City, Guangzhou, 510006, China

    Wenhui Wang

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  1. Zhuoling Zheng
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Contributions

All authors contributed to the study conception and design. DEG identification and gene functional enrichment analysis were performed by JX and LX. The PPI network construction and hub genes verification were performed by MG, LQ, CD, and ZL. The active small molecules selection was finished by YW, JX, and QW. The first draft of the manuscript was written by ZZ, XL, and WW. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Wenhui Wang or Xiaoyan Li.

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12032_2020_1425_MOESM1_ESM.tif

Supplementary file1 Supplementary Fig. 1 Venn diagram of the common DEGs among GSE9348, GSE35279 and GSE106582. a 78 common upregulated genes. b 88 common downregulated genes (TIF 11085 kb)

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Zheng, Z., Xie, J., Xiong, L. et al. Identification of candidate biomarkers and therapeutic drugs of colorectal cancer by integrated bioinformatics analysis. Med Oncol 37, 104 (2020). https://doi.org/10.1007/s12032-020-01425-2

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