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World Journal of Surgical Oncology
Published in: World Journal of Surgical Oncology 1/2018

Open Access 01-12-2018 | Research

Prediction of key genes and pathways involved in trastuzumab-resistant gastric cancer

Authors: Chaoran Yu, Pei Xue, Luyang Zhang, Ruijun Pan, Zhenhao Cai, Zirui He, Jing Sun, Minhua Zheng

Published in: World Journal of Surgical Oncology | Issue 1/2018

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Abstract

Background

Trastuzumab has been prevailingly accepted as a beneficial treatment for gastric cancer (GC) by targeting human epidermal growth factor receptor 2 (HER2)-positive. However, the therapeutic resistance of trastuzumab remains a major obstacle, restricting the therapeutic efficacy. Therefore, identifying potential key genes and pathways is crucial to maximize the overall clinical benefits.

Methods

The gene expression profile GSE77346 was retrieved to identify the differentially expressed genes (DEGs) associated with the trastuzumab resistance in GC. Next, the DEGs were annotated by the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The DEGs-coded protein-protein interaction (PPI) networks and the prognostic values of the 20 hub genes were determined. Correlation of the hub genes were analyzed in The Cancer Genome Atlas. The prognostic values of hub genes were further validated by Kaplan-Meier (KM) plotter.

Results

A total of 849 DEGs were identified, with 374 in upregulation and 475 in downregulation. Epithelium development was the most significantly enriched term in biological processes while membrane-bounded vesicle was in cellular compartments and cell adhesion molecular binding was in molecular functions. Pathways in cancer and ECM-receptor interaction were the most significantly enriched for all DEGs. Among the PPI networks, 20 hub genes were defined, including CD44 molecule (CD44), HER-2, and cadherin 1 (CDH1). Six hub genes were associated with favorable OS while eight were associated with poor OS. Mechanistically, 2′-5′-oligoadenylate synthetase 1, 3 (OAS1, OAS3) and CDH1 featured high degrees and strong correlations with other hub genes.

Conclusions

This bioinformatics analysis identified key genes and pathways for potential targets and survival predictors for trastuzumab treatment in GC.
Appendix
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Literature
1.
2.
Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32.CrossRefPubMed
3.
Ajani JA, Bentrem DJ, Besh S, D’Amico TA, Das P, Denlinger C, Fakih MG, Fuchs CS, Gerdes H, Glasgow RE, Hayman JA. Gastric cancer, version 2.2013. J Natl Compr Cancer Netw. 2013;11(5):531–46.CrossRef
4.
Guggenheim DE, Shah MA. Gastric cancer epidemiology and risk factors. J Surg Oncol. 2013;107(3):230–6.CrossRefPubMed
5.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.CrossRefPubMed
6.
Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2014 (ver. 4). Gastric Cancer. 2017;20(1):1–9.CrossRef
7.
Kang WM, Meng QB, Yu JC, Ma ZQ, Li ZT. Factors associated with early recurrence after curative surgery for gastric cancer. World J Gastroenterol: WJG. 2015;21(19):5934.CrossRefPubMed
8.
Hartgrink HH, Van de Velde CJ, Putter H, Bonenkamp JJ, Klein Kranenbarg E, Songun I, Welvaart K, Van Krieken JH, Meijer S, Plukker JT, Van Elk PJ. Extended lymph node dissection for gastric cancer: who may benefit? Final results of the randomized Dutch gastric cancer group trial. J Clin Oncol. 2004;22(11):2069–77.CrossRefPubMed
9.
Cuschieri A, Weeden S, Fielding J, Bancewicz J, Craven J, Joypaul V, Sydes M. Patient survival after D 1 and D 2 resections for gastric cancer: long-term results of the MRC randomized surgical trial. Br J Cancer. 1999;79(9–10):1522.CrossRefPubMedPubMedCentral
10.
Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224–35.CrossRefPubMed
11.
Satoh T, Lee KH, Rha SY, Sasaki Y, Park SH, Komatsu Y, Yasui H, Kim TY, Yamaguchi K, Fuse N, Yamada Y. Randomized phase II trial of nimotuzumab plus irinotecan versus irinotecan alone as second-line therapy for patients with advanced gastric cancer. Gastric Cancer. 2015;18(4):824–32.CrossRefPubMed
12.
Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, Murphy M, Stewart SJ, Keefe D. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol. 2002;20(5):1215–21.CrossRefPubMed
13.
Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G. 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(9742):687–97.CrossRefPubMed
14.
15.
16.
17.
Piro G, Carbone C, Cataldo I, Di Nicolantonio F, Giacopuzzi S, Aprile G, Simionato F, Boschi F, Zanotto M, Mina MM, Santoro R. An FGFR3 autocrine loop sustains acquired resistance to trastuzumab in gastric cancer patients. Clin Cancer Res. 2016;22(24):6164–75.CrossRefPubMed
18.
Edgar R, Domrachev M, Lash AE. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2002;30(1):207–10.CrossRefPubMedPubMedCentral
19.
Cho JY, et al. Gene expression signature–based prognostic risk score in gastric cancer. Clin Cancer Res. 2011;17(7):1850-57.
20.
Bertotti A, Burbridge MF, Gastaldi S, Galimi F, Torti D, Medico E, Giordano S, Corso S, Rolland-Valognes G, Lockhart BP, Hickman JA. Only a subset of Met-activated pathways are required to sustain oncogene addiction. Sci Signal. 2009;2(100):ra80.CrossRefPubMed
21.
Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat. 2011;128(2):347–56.CrossRefPubMed
22.
Davis S, Meltzer PS. GEOquery: a bridge between the Gene Expression Omnibus (GEO) and BioConductor. Bioinformatics. 2007;23(14):1846–7.CrossRefPubMed
23.
Pathan M, Keerthikumar S, Ang CS, Gangoda L, Quek CY, Williamson NA, Mouradov D, Sieber OM, Simpson RJ, Salim A, Bacic A. FunRich: an open access standalone functional enrichment and interaction network analysis tool. Proteomics. 2015;15(15):2597–601.CrossRefPubMed
24.
Huang DW, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2008;4(1):44.CrossRef
25.
Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA. Gene ontology: tool for the unification of biology. Nat Genet. 2000;25(1):25.CrossRefPubMedPubMedCentral
26.
27.
Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP, Kuhn M. STRING v10: protein–protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2014;43(D1):D447–52.CrossRefPubMedPubMedCentral
28.
Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498–504.CrossRefPubMedPubMedCentral
29.
30.
Lánczky A, Nagy Á, Bottai G, Munkácsy G, Szabó A, Santarpia L, Győrffy B. miRpower: a web-tool to validate survival-associated miRNAs utilizing expression data from 2178 breast cancer patients. Breast Cancer Res Treat. 2016;160(3):439–46.CrossRefPubMed
31.
Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45(W1):W98–102.CrossRefPubMedPubMedCentral
32.
Goldman M, Craft B, Zhu J, Haussler D. The UCSC Xena system for cancer genomics data visualization and interpretation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017. Washington, DC., Philadelphia: AACR; 2017. Cancer Res 2017;77(13 Suppl):Abstract nr 2584.
33.
Subramaniam V, Vincent IR, Gilakjan M, Jothy S. Suppression of human colon cancer tumors in nude mice by siRNA CD44 gene therapy. Exp Mol Pathol. 2007;83(3):332–40.CrossRefPubMed
34.
Tan WB, Jiang S, Zhang Y. Quantum-dot based nanoparticles for targeted silencing of HER2/neu gene via RNA interference. Biomaterials. 2007;28(8):1565–71.CrossRefPubMed
35.
Herrero-Mendez A, Almeida A, Fernández E, Maestre C, Moncada S, Bolaños JP. The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C–Cdh1. Nat Cell Biol. 2009;11(6):747.CrossRefPubMed
36.
Zhao J, Feng N, Li Z, Wang P, Qi Z, Liang W, Zhou X, Xu X, Liu B. 2ng P, oligoadenylate synthetase 1 (OAS1) inhibits PRRSV replication in Marc-145 cells. Antivir Res. 2016;132:268–73.CrossRefPubMed
37.
Bin L, Howell MD, Kim BE, Streib JE, Hall CF, Leung DY. Specificity protein 1 is pivotal in the skin’s antiviral response. J Allergy Clin Immunol. 2011;127(2):430–8.CrossRefPubMedPubMedCentral
38.
Lin W, Zhu C, Hong J, Zhao L, Jilg N, Fusco DN, Schaefer EA, Brisac C, Liu X, Peng LF, Xu Q. The spliceosome factor SART1 exerts its anti-HCV action through mRNA splicing. J Hepatol. 2015;62(5):1024–32.CrossRefPubMed
39.
Zheng S, Zhu D, Lian X, Liu W, Cao R, Chen P. Porcine 2ction-oligoadenylate synthetases inhibit Japanese encephalitis virus replication in vitro. J Med Virol. 2016;88(5):760–8.CrossRefPubMed
40.
Chua PK, McCown MF, Rajyaguru S, Kular S, Varma R, Symons J, Chiu SS, Cammack N, Najera I. Modulation of alpha interferon anti-hepatitis C virus activity by ISG15. J Gen Virol. 2009;90(12):2929–39.CrossRefPubMed
41.
Xia Y, Paul BY, Sidis Y, Beppu H, Bloch KD, Schneyer AL, Lin HY. Repulsive guidance molecule RGMa alters utilization of bone morphogenetic protein (BMP) type II receptors by BMP2 and BMP4. J Biol Chem. 2007;282(25):18129–40.CrossRefPubMed
42.
Lin W, Choe WH, Hiasa Y, Kamegaya Y, Blackard JT, Schmidt EV, Chung RT. Hepatitis C virus expression suppresses interferon signaling by degrading STAT1. Gastroenterol. 2005;128(4):1034–41.CrossRef
43.
Ogishima T, Shiina H, Breault JE, Terashima M, Honda S, Enokida H, Urakami S, Tokizane T, Kawakami T, Ribeiro-Filho LA, Fujime M. Promoter CpG hypomethylation and transcription factor EGR1 hyperactivate heparanase expression in bladder cancer. Oncogene. 2005;24(45):6765.CrossRefPubMed
44.
Oridate N, Kim HJ, Xu X, Lotan R. Growth inhibition of head and neck squamous carcinoma cells by small interfering RNAs targeting eIF4E or cyclin D1 alone or combined with cisplatin. Cancer Biol Ther. 2005;4(3):318–23.CrossRefPubMed
45.
Walsh N, O’Donovan N, Kennedy S, Henry M, Meleady P, Clynes M, Dowling P. Identification of pancreatic cancer invasion-related proteins by proteomic analysis. Proteome Sci. 2009;7(1):3.CrossRefPubMedPubMedCentral
46.
Yang L, et al. siRNA-mediated silencing of Wnt5a regulates inflammatory responses in atherosclerosis through the MAPK/NF-kappaB pathways. Int J Mol Med. 2014;34(4):1147–52.
47.
Lefevre G, et al. Roles of stem cell factor/c-Kit and effects of Glivec/STI571 in human uveal melanoma cell tumorigenesis. J Biol Chem. 2004;279(30):31769-79.
48.
Morrow AN, Schmeisser H, Tsuno T, Zoon KC. A novel role for IFN-stimulated gene factor 3II in IFN-γ signaling and induction of antiviral activity in human cells. J Immunol. 2010:1001359.
49.
Toyokawa K, Leite F, Ott TL. Cellular localization and function of the antiviral protein, ovine Mx1 (oMx1): II. The oMx1 protein is a regulator of secretion in an ovine glandular epithelial cell line. Am J Reprod Immunol. 2007;57(1):23–33.CrossRefPubMed
50.
51.
Arimoto KI, Hishiki T, Kiyonari H, Abe T, Cheng C, Yan M, Fan JB, Futakuchi M, Tsuda H, Murakami Y, Suzuki H. Murine Herc6 plays a critical role in protein ISGylation in vivo and has an ISGylation-independent function in seminal vesicles. J Interf Cytokine Res. 2015;35(5):351–8.CrossRef
52.
Bonnevie-Nielsen V, et al. Variation in antiviral 2',5'- oligoadenylate synthetase (2'5'AS) enzyme activity is controlled by a single-nucleotide polymorphism at a splice-acceptor site in the OAS1 gene. Am J Hum Genet. 2005;76(4):623–33.
53.
Bridge AJ, Pebernard S, Ducraux A, Nicoulaz AL, Iggo R. Induction of an interferon response by RNAi vectors in mammalian cells. Nat Genet. 2003;34(3):263.CrossRefPubMed
54.
Barkhash AV, Perelygin AA, Babenko VN, Myasnikova NG, Pilipenko PI, Romaschenko AG, Voevoda AG, Brinton MA. Variability in the 2nko A oligoadenylate synthetase gene cluster is associated with human predisposition to tick-borne encephalitis virus-induced disease. J Infect Dis. 2010;202(12):1813–8.CrossRefPubMed
55.
Chawla-Sarkar M, Lindner DJ, Liu YF, Williams BR, Sen GC, Silverman RH, Borden EC. Apoptosis and interferons: role of interferon-stimulated genes as mediators of apoptosis. Apoptosis. 2003;8(3):237–49.CrossRefPubMed
56.
Wang SS, Gonzalez P, Yu K, Porras C, Li Q, Safaeian M, Rodriguez AC, Sherman ME, Bratti C, Schiffman M, Wacholder S. Common genetic variants and risk for HPV persistence and progression to cervical cancer. PLoS One. 2010;5(1):e8667.CrossRefPubMedPubMedCentral
57.
Boulbes DR, Chauhan GB, Jin Q, Bartholomeusz C, Esteva FJ. CD44 expression contributes to trastuzumab resistance in HER2-positive breast cancer cells. Breast Cancer Res Treat. 2015;151(3):501–13.CrossRefPubMed
58.
Pályi-Krekk Z, Barok M, Isola J, Tammi M, Szöllo J, Nagy P. Hyaluronan-induced masking of ErbB2 and CD44-enhanced trastuzumab internalisation in trastuzumab resistant breast cancer. Eur J Cancer. 2007;43(16):2423–33.CrossRefPubMed
59.
Bao W, Fu HJ, Xie QS, Wang L, Zhang R, Guo ZY, Zhao J, Meng YL, Ren XL, Wang T, Li Q. HER2 interacts with CD44 to up-regulate CXCR4 via epigenetic silencing of microRNA-139 in gastric cancer cells. Gastroenterol. 2011;141(6):2076–87.CrossRef
60.
Barthelemy M. Betweenness centrality in large complex networks. Eur Phys J B. 2004;38(2):163–8.CrossRef
61.
Lastraioli E, Iorio J, Arcangeli A. Ion channel expression as promising cancer biomarker. BBA Biomembranes. 2015;1848(10):2685–702.CrossRefPubMed
62.
63.
Fujimoto M, Inoue T, Kito H, Niwa S, Suzuki T, Muraki K, Ohya S. Transcriptional repression of HER2 by ANO1 Cl− channel inhibition in human breast cancer cells with resistance to trastuzumab. Biochem Biophys Res Commun. 2017;482(1):188–94.CrossRefPubMed
64.
Cai R, Ding X, Zhou K, Shi Y, Ge R, Ren G, Jin Y, Wang Y. Blockade of TRPC6 channels induced G2/M phase arrest and suppressed growth in human gastric cancer cells. Int J Cancer. 2009;125(10):2281–7.CrossRefPubMed
65.
Ding M, et al. Pyrazolo [1,5-a] pyrimidine TRPC6 antagonists for the treatment of gastric cancer. Cancer Lett. 2018;432:47-55.
66.
Huang R, Gu W, Sun B, Gao L. Identification of COL4A1 as a potential gene conferring trastuzumab resistance in gastric cancer based on bioinformatics analysis. Mol Med Rep. 2018;17(5):6387–96.PubMedPubMedCentral
67.
Arteaga CL, Sliwkowski MX, Osborne CK, Perez EA, Puglisi F, Gianni L. Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol. 2012;9(1):16.CrossRef
Metadata
Title
Prediction of key genes and pathways involved in trastuzumab-resistant gastric cancer
Authors
Chaoran Yu
Pei Xue
Luyang Zhang
Ruijun Pan
Zhenhao Cai
Zirui He
Jing Sun
Minhua Zheng
Publication date
01-12-2018
Publisher
BioMed Central
Published in
World Journal of Surgical Oncology / Issue 1/2018
Electronic ISSN: 1477-7819
DOI
https://doi.org/10.1186/s12957-018-1475-6

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