Identification of novel biomarkers affecting the metastasis of colorectal cancer through bioinformatics analysis and validation through qRT-PCR

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Abstract

Background

Tumor progression and distant metastasis are the main causes of deaths in colorectal cancer (CRC) patients, and the molecular mechanisms in CRC metastasis have not been completely discovered.

Methods

We identified differentially expressed genes (DEGs) and lncRNAs (DELs) of CRC from The Cancer Genome Atlas (TCGA) database. Then we conducted the weighted gene co-expression network analysis (WGCNA) to investigate co-expression modules related with CRC metastasis. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, DEG-DEL co-expression network and survival analyses of significant modules were also conducted. Finally, the expressions of selected biomarkers were validated in cell lines by quantitative real-time PCR (qRT-PCR).

Results

2032 DEGs and 487 DELs were involved the construction of WGCNA network, and greenyellow, turquoise and brown module were identified to have more significant correlation with CRC metastasis. GO and KEGG pathway analysis of these three modules have proven that the functions of DEGs were closely involved in many important processes in cancer pathogenesis. Through the DEG-DEL co-expression network, 12 DEGs and 2 DELs were considered as hub nodes. Besides, survival analysis showed that 30 DEGs were associated with the overall survival of CRC. Then 10 candidate biomarkers were chosen for validation and the expression of CA2, CHP2, SULT1B1, MOGAT2 and C1orf115 were significantly decreased in CRC cell lines when compared to normal human colonic epithelial cells, which were consistent with the results of differential expression analysis. Especially, low expression of SULT1B1, MOGAT2 and C1orf115 were closely correlated with poorer survival of CRC.

Conclusion

This study identified 5 genes as new biomarkers affecting the metastasis of CRC. Besides, SULT1B1, MOGAT2 and C1orf115 might be implicated in the prognosis of CRC patients.

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Most cited references 27

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Human sulfotransferases and their role in chemical metabolism.

Nancy Martin, Terence McManus, Amanda Barnett … (2006)

Sulfonation is an important reaction in the metabolism of numerous xenobiotics, drugs, and endogenous compounds. A supergene family of enzymes called sulfotransferases (SULTs) catalyze this reaction. In most cases, the addition of a sulfonate moiety to a compound increases its water solubility and decreases its biological activity. However, many of these enzymes are also capable of bioactivating procarcinogens to reactive electrophiles. In humans three SULT families, SULT1, SULT2, and SULT4, have been identified that contain at least thirteen distinct members. SULTs have a wide tissue distribution and act as a major detoxification enzyme system in adult and the developing human fetus. Nine crystal structures of human cytosolic SULTs have now been determined, and together with site-directed mutagenesis experiments and molecular modeling, we are now beginning to understand the factors that govern distinct but overlapping substrate specificities. These studies have also provided insight into the enzyme kinetics and inhibition characteristics of these enzymes. The regulation of human SULTs remains as one of the least explored areas of research in the field, though there have been some recent advances on the molecular transcription mechanism controlling the individual SULT promoters. Interindividual variation in sulfonation capacity may be important in determining an individual's response to xenobiotics, and recent studies have begun to suggest roles for SULT polymorphism in disease susceptibility. This review aims to provide a summary of our present understanding of the function of human cytosolic sulfotransferases.

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Ten hub genes associated with progression and prognosis of pancreatic carcinoma identified by co-expression analysis

Zhou Zhou, Yian Cheng, Yinan Jiang … (2018)

Since the five-year survival rate is less than 5%, pancreatic ductal adenocarcinoma (PDAC) remains the 4th cause of cancer-related death. Although PDAC has been repeatedly researched in recent years, it is still predicted to be the second leading cause of cancer death by year 2030. In our study, the differentially expressed genes in dataset GSE62452 were used to construct a co-expression network by WGCNA. The yellow module related to grade of PDAC was screened. Combined with co-expression network and PPI network, 36 candidates were screened. After survival and regression analysis by using GSE62452 and TCGA dataset, we identified 10 real hub genes (CCNA2, CCNB1, CENPF, DLGAP5, KIF14, KIF23, NEK2, RACGAP1, TPX2 and UBE2C) tightly related to progression of PDAC. According to Oncomine database and The Human Protein Atlas (HPA), we found that all real hub genes were overexpressed in pancreatic carcinoma compared with normal tissues on transcriptional and translational level. ROC curve was plotted and AUC was calculated to distinguish recurrent and non-recurrent PDAC and every AUC of the real hub gene was greater than 0.5. Finally, functional enrichment analysis and gene set enrichment (GSEA) was performed and both of them showed the cell cycle played a vital role in PDAC.

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Identifying miRNA and gene modules of colon cancer associated with pathological stage by weighted gene co-expression network analysis

Xian-guo Zhou, Xiao-liang Huang, Si-yuan Liang … (2018)

Introduction Colorectal cancer (CRC) is the fourth most common cause of cancer-related mortality worldwide. The tumor, node, metastasis (TNM) stage remains the standard for CRC prognostication. Identification of meaningful microRNA (miRNA) and gene modules or representative biomarkers related to the pathological stage of colon cancer helps to predict prognosis and reveal the mechanisms behind cancer progression. Materials and methods We applied a systems biology approach by combining differential expression analysis and weighted gene co-expression network analysis (WGCNA) to detect the pathological stage-related miRNA and gene modules and construct a miRNA–gene network. The Cancer Genome Atlas (TCGA) colon adenocarcinoma (CAC) RNA-sequencing data and miRNA-sequencing data were subjected to WGCNA analysis, and the GSE29623, GSE35602 and GSE39396 were utilized to validate and characterize the results of WGCNA. Results Two gene modules (Gmagenta and Ggreen) and one miRNA module were associated with the pathological stage. Six hub genes (COL1A2, THBS2, BGN, COL1A1, TAGLN and DACT3) were related to prognosis and validated to be associated with the pathological stage. Five hub miRNAs were identified to be related to prognosis (hsa-miR-125b-5p, hsa-miR-145-5p, hsa-let-7c-5p, hsa-miR-218-5p and hsa-miR-125b-2-3p). A total of 18 hub genes and seven hub miRNAs were predominantly expressed in tumor stroma. Proteoglycans in cancer, focal adhesion, extracellular matrix (ECM)–receptor interaction and so on were common pathways of the three modules. Hsa-let-7c-5p was located at the core of miRNA–gene network. Conclusion These findings help to advance the understanding of tumor stroma in the progression of CAC and provide prognostic biomarkers as well as therapeutic targets.

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Author and article information

Contributors

Mengle Peng:

ORCID: http://orcid.org/0000-0001-8693-6923

pengmengle1990@126.com

Journal

Journal ID (nlm-ta): Cancer Cell Int

Journal ID (iso-abbrev): Cancer Cell Int

Title: Cancer Cell International

Publisher: BioMed Central (London )

ISSN (Electronic): 1475-2867

Publication date (Electronic): 30 March 2020

Publication date PMC-release: 30 March 2020

Publication date Collection: 2020

Volume: 20

Electronic Location Identifier: 105

Affiliations

[1 ]Department of Clinical Laboratory, Henan No. 3 Provincial People’s Hospital, Zhengzhou, 450006 Henan China

[2 ]GRID grid.412633.1, Department of Blood Transfusion, , The First Affiliated Hospital of Zhengzhou University, ; Zhengzhou, 450052 Henan China

[3 ]Department of Basis Medicine, Henan Medical College, Zhengzhou, 451191 Henan China

[4 ]Department of Medical Affair, Henan No. 3 Provincial People’s Hospital, Zhengzhou, 450006 Henan China

[5 ]Department of Clinical Laboratory, Zhecheng People’s Hospital, Shangqiu, 476000 Henan China

[6 ]GRID grid.207374.5, ISNI 0000 0001 2189 3846, Medical College of Zhengzhou University, ; Zhengzhou, 450052 Henan China

[7 ]Department of Anorectal Surgery, Henan No. 3 Provincial People’s Hospital, Zhengzhou, 450006 Henan China

[8 ]GRID grid.477982.7, Henan Province Engineering Laboratory for Clinical Evaluation Technology of Chinese Medicine, , The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, ; Zhengzhou, 450000 China

[9 ]Department of Digestion, Henan No. 3 Provincial People’s Hospital, Zhengzhou, 450006 Henan China

Author information

Mengle Peng http://orcid.org/0000-0001-8693-6923

Article

Publisher ID: 1180

DOI: 10.1186/s12935-020-01180-4

PMC ID: 7106634

SO-VID: 8fc8008e-a882-4e16-a635-8195b9e92419

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 2 January 2020

Date accepted : 17 March 2020

Funding

Funded by: the Scientific and Technological Project of Henan province

Award ID: 2018020578

Award Recipient : Mengle Peng

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: colorectal cancer,metastasis,prognosis,biomarker,wgcna

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: colorectal cancer, metastasis, prognosis, biomarker, wgcna

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Identification of novel biomarkers affecting the metastasis of colorectal cancer through bioinformatics analysis and validation through qRT-PCR

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Abstract

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Karger: Oncology

Most cited references 27

Human sulfotransferases and their role in chemical metabolism.

Ten hub genes associated with progression and prognosis of pancreatic carcinoma identified by co-expression analysis

Identifying miRNA and gene modules of colon cancer associated with pathological stage by weighted gene co-expression network analysis

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Cited by 7

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