Identification of Bone Metastasis-associated Genes of Gastric Cancer by Genome-wide Transcriptional Profiling

Author(s): Mingzhe Lin*, Xin Li, Haizhou Guo, Faxiang Ji, Linhan Ye, Xuemei Ma, Wen Cheng.

Journal Name: Current Bioinformatics

Volume 14 , Issue 1 , 2019

Submit Manuscript
Submit Proposal

Graphical Abstract:


Abstract:

Background: Gastric cancer is one of the leading causes of cancer-related mortality worldwide. Genome-wide transcriptional profiling has provided valuable insights into the molecular basis underlying processes involved in gastric cancer initiation and progression.

Objective: To understand the pathological and biological mechanisms of gastric cancer metastasis in a genome-wide context.

Method: In this study, we constructed libraries from blood of gastric cancer patients with, and without, bone metastasis. High-throughput sequencing combined with differential expression analysis was used to investigate transcriptional changes.

Results: We identified a total of 425 significantly differentially expressed genes. Protein-protein interaction network analysis suggested that most of these genes are involved in DNA replication, DNA damage response, collagen homeostasis and cell adhesion. Furthermore, our data suggested that NFkappaB and DNA damage response pathways were the key regulators of the bone metastasis associated with gastric cancer. Finally, most of these target genes were involved in pathways such as extracellular matrix organization and extracellular structure organization as revealed by gene set enrichment assay.

Conclusion: Our study provides a comprehensive analysis of the transcriptional alterations involved in gastric cancer bone metastasis, which provides greater insights into the complexity of regulatory changes during tumorigenesis and offers novel diagnostic as well as therapeutic avenues.

Keywords: Gastric cancer, metastasis, transcriptome, RNA-seq, differential expression, genome wide.

[1]
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61: 69-90.
[2]
Ferro A, Peleteiro B, Malvezzi M, et al. Worldwide trends in gastric cancer mortality (1980-2011), with predictions to 2015, and incidence by subtype. Eur J Cancer 2014; 50: 1330-44.
[3]
Brown LM, Devesa SS, Chow WH. Incidence of adenocarcinoma of the esophagus among white Americans by sex, stage, and age. J Natl Cancer Inst 2008; 100: 1184-7.
[4]
Compare D, Rocco A, Nardone G. Risk factors in gastric cancer. Eur Rev Med Pharmacol Sci 2010; 14: 302-8.
[5]
Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010; 376: 687-97.
[6]
Mikami J, Kimura Y, Makari Y, et al. Clinical outcomes and prognostic factors for gastric cancer patients with bone metastasis. World J Surg Oncol 2017; 15: 8.
[7]
Silvestris N, Pantano F, Ibrahim T, et al. Natural history of malignant bone disease in gastric cancer: final results of a multicenter bone metastasis survey. PLoS One 2013; 8: e74402.
[8]
Riihimaki M, Hemminki A, Sundquist K, Sundquist J, Hemminki K. Metastatic spread in patients with gastric cancer. Oncotarget 2016; 7: 52307-16.
[9]
Shimazu K, Fukuda K, Yoshida T, Inoue M, Shibata H. High circulating tumor cell concentrations in a specific subtype of gastric cancer with diffuse bone metastasis at diagnosis. World J Gastroenterol 2016; 22: 6083-8.
[10]
Lee HJ, Nam KT, Park HS, et al. Gene expression profiling of metaplastic lineages identifies CDH17 as a prognostic marker in early stage gastric cancer. Gastroenterology 2010; 139: 213-25.
[11]
Marimuthu A, Jacob HK, Jakharia A, et al. Gene Expression Profiling of Gastric Cancer. J Proteomics Bioinform 2011; 4: 74-82.
[12]
Nam S, Lee J, Goh SH, et al. Differential gene expression pattern in early gastric cancer by an integrative systematic approach. Int J Oncol 2012; 41: 1675-82.
[13]
Zhang Q, Wang H, Ma Y, et al. Overexpression of Nedd9 is a prognostic marker of human gastric cancer. Med Oncol 2014; 31: 33.
[14]
Wu HQ, Wang HY, Sun XW, Liu F, Zhang LW, Tian FJ. Transcriptome profiling of cancers tissue in Chinese gastric patients by high-through sequencing. Int J Clin Exp Pathol 2016; 9: 3537-46.
[15]
Xiao J, Xia SY, Xia J, Xia Q, Wang XR. Transcriptome profiling of biliary atresia from new born infants by deep sequencing. Mol Biol Rep 2014; 12: 8063-9.
[16]
Xie L, Yang ZZ, Li GQ, et al. Genome-Wide Identification of Bone Metastasis-Related MicroRNAs in Lung Adenocarcinoma by High-Throughput Sequencing. PLoS One 2013; 8: e61212.
[17]
Cox MP, Peterson DA, Biggs PJ, Solexa QA. At-a-glance quality assessment of Illumina second-generation sequencing data. BMC Bioinformatics 2010; 11: 485.
[18]
Trapnell C, Pachter L, Salzberg SL. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 2009; 25: 1105-11.
[19]
Langmead B. Aligning short sequencing reads with Bowtie. Curr Protoc Bioinformatics 2010; 32: 1-14.
[20]
Trapnell C, Roberts A, Goff L, et al. Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat Protoc 2012; 7: 562-78.
[21]
Trapnell C, Williams BA, Pertea G, et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol 2010; 28: 511-5.
[22]
Blake JA, Dolan M, Drabkin H, et al. Gene Ontology annotations and resources. Nucleic Acids Res 2013; 41: D530-5.
[23]
Kanehisa M, Araki M, Goto S, et al. KEGG for linking genomes to life and the environment. Nucleic Acids Res 2008; 36: D480-4.
[24]
Huangda W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 2009; 4: 44-57.
[25]
Lopez R, Garrido E, Vazquez G, et al. A subgroup of HOX Abd-B gene is differentially expressed in cervical cancer. Int J Gynecol Cancer 2006; 16: 1289-96.
[26]
Hur H, Lee JY, Yang S, Kim JM, Park AE, Kim MH. HOXC9 Induces Phenotypic Switching between Proliferation and Invasion in Breast Cancer Cells. J Cancer 2016; 7: 768-73.
[27]
Mao L, Ding J, Zha Y, et al. HOXC9 links cell-cycle exit and neuronal differentiation and is a prognostic marker in neuroblastoma. Cancer Res 2011; 71: 4314-24.
[28]
Jin J, Arias EE, Chen J, Harper JW, Walter JC. A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1. Mol Cell 2006; 23: 709-21.
[29]
Scott J, Kuhn P, Anderson AR. Unifying metastasis--integrating intravasation, circulation and end-organ colonization. Nat Rev Cancer 2012; 12: 445-6.
[30]
Chen LT, Oh DY, Ryu MH, et al. Anti-angiogenic Therapy in Patients with Advanced Gastric and Gastroesophageal Junction Cancer: A Systematic Review. Cancer Res Treat 2017; 49: 851-68.
[31]
Niu Y, Wu Y, Huang J, et al. Identification of reference genes for circulating microRNA analysis in colorectal cancer. Sci Rep 2016; 6: 35611.
[32]
Planque C, Choi YH, Guyetant S, Heuze-Vourc’h N, Briollais L, Courty Y. Alternative splicing variant of kallikrein-related peptidase 8 as an independent predictor of unfavorable prognosis in lung cancer. Clin Chem 2010; 56: 987-97.
[33]
Gopal G, Raja UM, Shirley S, Rajalekshmi KR, Rajkumar T. SOSTDC1 down-regulation of expression involves CpG methylation and is a potential prognostic marker in gastric cancer. Cancer Genet 2013; 206: 174-82.
[34]
Liang W, Guan H, He X, et al. Down-regulation of SOSTDC1 promotes thyroid cancer cell proliferation via regulating cyclin A2 and cyclin E2. Oncotarget 2015; 6: 31780-91.
[35]
Tzeng ST, Tsai MH, Chen CL, et al. NDST4 is a novel candidate tumor suppressor gene at chromosome 4q26 and its genetic loss predicts adverse prognosis in colorectal cancer. PLoS One 2016; 8: e67040.


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 14
ISSUE: 1
Year: 2019
Page: [62 - 69]
Pages: 8
DOI: 10.2174/1574893612666171121154017
Price: $58

Article Metrics

PDF: 19
HTML: 2