Genome-wide analysis of the effect of esophageal squamous cell carcinoma on human umbilical vein endothelial cells

Jin,Guoguo; Yang,Yi; Liu,Hangfan; Liu,Kangdong; Zhao,Jimin; Chen,Xinhuan; Zhang,Xiaoyan; Zhang,Yanyan; Lu,Jing; Dong,Ziming

doi:10.3892/or.2016.4816

Genome-wide analysis of the effect of esophageal squamous cell carcinoma on human umbilical vein endothelial cells

Authors:
- Guoguo Jin
- Yi Yang
- Hangfan Liu
- Kangdong Liu
- Jimin Zhao
- Xinhuan Chen
- Xiaoyan Zhang
- Yanyan Zhang
- Jing Lu
- Ziming Dong
View Affiliations

Affiliations: Department of Pathophysiology, Basic Medical College, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
Published online on: May 18, 2016 https://doi.org/10.3892/or.2016.4816
Pages: 155-164

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

A large volume of data indicates that controlling tumor-associated angiogenesis is a promising therapy against cancer. However, angiogenesis is a complex process, little is known about the differential gene expression in the process of normal endothelial cell differentiation toward tumor vascular endothelial cells induced by tumor microenvironment. The aim of this study is to investigate the effect of tumor microenvironment simulated by the supernatant of esophageal squamous cancer cells (KYSE70) on normal endothelial cells (HUVECs) at the whole genome level. The gene expression profile was studied through gene ontology and signal pathway analysis. Compared with the normal HUVECs, a total of 3769 differentially expressed genes in induced HUVECs were detected, including 1609 upregulated genes and 2160 downregulated genes. Moreover, the microarray data analysis showed that 11 significant biological processes and 10 significant signaling pathways changed most, which are associated with angiogenesis and cell differentiation. According to the different expression levels in the microarrays and their functions, four differentially expressed genes involved in tumor angiogenesis and cell differentiation (IL6, VEGFA, S1PR1, TYMP) were selected and analyzed by qRT-PCR. The qRT-PCR results were consistent with the microarray data. Furthermore, we simulated the tumor microenvironment by human esophageal carcinoma tissue homogenate to investigate its effect on HUVECs, the qRT-PCR results indicated that the above genes were highly expressed in HUVECs after induction by esophageal carcinoma tissue homogenate. In conclusion, tumor microenvironment impact on normal endothelial cells differentiated toward tumor vascular endothelial cells, and the selected genes, which are associated with tumor angiogenesis, would be anti-angiogenesis targets against esophageal carcinoma.

View Figures

View References

1	Miura S, Mitsui K, Heishi T, Shukunami C, Sekiguchi K, Kondo J, Sato Y and Hiraki Y: Impairment of VEGF-A-stimulated lamellipodial extensions and motility of vascular endothelial cells by chondromodulin-I, a cartilage-derived angiogenesis inhibitor. Exp Cell Res. 316:775–788. 2010. View Article : Google Scholar
2	Park HJ, Kim MN, Kim JG, Bae YH, Bae MK, Wee HJ, Kim TW, Kim BS, Kim JB, Bae SK, et al: Up-regulation of VEGF expression by NGF that enhances reparative angiogenesis during thymic regeneration in adult rat. Biochim Biophys Acta. 1773:1462–1472. 2007. View Article : Google Scholar : PubMed/NCBI
3	Folkman J: Anti-angiogenesis: New concept for therapy of solid tumors. Ann Surg. 175:409–416. 1972. View Article : Google Scholar : PubMed/NCBI
4	Abajo A, Bitarte N, Zarate R, Boni V, Lopez I, Gonzalez-Huarriz M, Rodriguez J, Bandres E and Garcia-Foncillas J: Identification of colorectal cancer metastasis markers by an angiogenesis-related cytokine-antibody array. World J Gastroenterol. 18:637–645. 2012. View Article : Google Scholar : PubMed/NCBI
5	Liu YR, Guan YY, Luan X, Lu Q, Wang C, Liu HJ, Gao YG, Yang SC, Dong X, Chen HZ, et al: Delta-like ligand 4-targeted nanomedicine for antiangiogenic cancer therapy. Biomaterials. 42:161–171. 2015. View Article : Google Scholar
6	Weis SM and Cheresh DA: Tumor angiogenesis: Molecular pathways and therapeutic targets. Nat Med. 17:1359–1370. 2011. View Article : Google Scholar : PubMed/NCBI
7	Weis SM and Cheresh DA: Pathophysiological consequences of VEGF-induced vascular permeability. Nature. 437:497–504. 2005. View Article : Google Scholar : PubMed/NCBI
8	Lu J, Zhao J, Liu K, Zhao J, Yang H, Huang Y, Qin Z, Bai R, Li P, Ma J, et al: MAPK/ERK1/2 signaling mediates endothelial-like differentiation of immature DCs in the microenvironment of esophageal squamous cell carcinoma. Cell Mol Life Sci. 67:2091–2106. 2010. View Article : Google Scholar : PubMed/NCBI
9	Lu J, Bai R, Qin Z, Zhang Y, Zhang X, Jiang Y, Yang H, Huang Y, Li G, Zhao M, et al: Differentiation of immature DCs into endothelial-like cells in human esophageal carcinoma tissue homogenates. Oncol Rep. 30:739–744. 2013.PubMed/NCBI
10	Hillen F and Griffioen AW: Tumour vascularization: Sprouting angiogenesis and beyond. Cancer Metastasis Rev. 26:489–502. 2007. View Article : Google Scholar : PubMed/NCBI
11	Wang XX, Wang K, Li XZ, Zhai LQ, Qu CX, Zhao Y, Liu ZR, Wang HZ, An QJ, Jing LW, et al: Targeted knockdown of IQGAP1 inhibits the progression of esophageal squamous cell carcinoma in vitro and in vivo. PLoS One. 9:e965012014. View Article : Google Scholar : PubMed/NCBI
12	Bisacchi D, Benelli R, Vanzetto C, Ferrari N, Tosetti F and Albini A: Anti-angiogenesis and angioprevention: Mechanisms, problems and perspectives. Cancer Detect Prev. 27:229–238. 2003. View Article : Google Scholar : PubMed/NCBI
13	Carmeliet P and Jain RK: Molecular mechanisms and clinical applications of angiogenesis. Nature. 473:298–307. 2011. View Article : Google Scholar : PubMed/NCBI
14	Kim BH, Lee Y, Yoo H, Cui M, Lee S, Kim SY, Cho JU, Lee H, Yang BS, Kwon YG, et al: Anti-angiogenic activity of thienopyridine derivative LCB03-0110 by targeting VEGFR-2 and JAK/STAT3 signalling. Exp Dermatol. 24:503–509. 2015. View Article : Google Scholar : PubMed/NCBI
15	Lu J, Bai R, Qin Z, Zhang Y, Zhang X, Jiang Y, Yang H, Huang Y, Li G, Zhao M, et al: Differentiation of immature DCs into endothelial-like cells in human esophageal carcinoma tissue homogenates. Oncol Rep. 30:739–744. 2013.PubMed/NCBI
16	St Croix B, Rago C, Velculescu V, Traverso G, Romans KE, Montgomery E, Lal A, Riggins GJ, Lengauer C, Vogelstein B, et al: Genes expressed in human tumor endothelium. Science. 289:1197–1202. 2000. View Article : Google Scholar : PubMed/NCBI
17	Finley SD and Popel AS: Effect of tumor microenvironment on tumor VEGF during anti-VEGF treatment: Systems biology predictions. J Natl Cancer Inst. 105:802–811. 2013. View Article : Google Scholar : PubMed/NCBI
18	Jiang L, Yin M, Wei X, Liu J, Wang X, Niu C, Kang X, Xu J, Zhou Z, Sun S, et al: Bach1 represses Wnt/β-catenin signaling and angiogenesis. Circ Res. 117:364–375. 2015. View Article : Google Scholar : PubMed/NCBI
19	Severi T, van Malenstein H, Verslype C and van Pelt JF: Tumor initiation and progression in hepatocellular carcinoma: Risk factors, classification, and therapeutic targets. Acta Pharmacol Sin. 31:1409–1420. 2010. View Article : Google Scholar : PubMed/NCBI
20	Gijsbers K, Gouwy M, Struyf S, Wuyts A, Proost P, Opdenakker G, Penninckx F, Ectors N, Geboes K and Van Damme J: GCP-2/CXCL6 synergizes with other endothelial cell-derived chemokines in neutrophil mobilization and is associated with angiogenesis in gastrointestinal tumors. Exp Cell Res. 303:331–342. 2005. View Article : Google Scholar : PubMed/NCBI
21	Lin ZY, Chuang WL and Chuang YH: Amphotericin B up-regulates angiogenic genes in hepatocellular carcinoma cell lines. Eur J Clin Invest. 39:239–245. 2009. View Article : Google Scholar : PubMed/NCBI
22	Zhou Y and Nathans J: Gpr124 controls CNS angiogenesis and blood-brain barrier integrity by promoting ligand-specific canonical wnt signaling. Dev Cell. 31:248–256. 2014. View Article : Google Scholar : PubMed/NCBI
23	Arnon TI, Xu Y, Lo C, Pham T, An J, Coughlin S, Dorn GW and Cyster JG: GRK2-dependent S1PR1 desensitization is required for lymphocytes to overcome their attraction to blood. Science. 333:1898–1903. 2011. View Article : Google Scholar : PubMed/NCBI
24	Jain RK: Molecular regulation of vessel maturation. Nat Med. 9:685–693. 2003. View Article : Google Scholar : PubMed/NCBI
25	Chae SS, Paik JH, Furneaux H and Hla T: Requirement for sphingosine 1-phosphate receptor-1 in tumor angiogenesis demonstrated by in vivo RNA interference. J Clin Invest. 114:1082–1089. 2004. View Article : Google Scholar : PubMed/NCBI
26	Ciaparrone M, Quirino M, Schinzari G, Zannoni G, Corsi DC, Vecchio FM, Cassano A, La Torre G and Barone C: Predictive role of thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase expression in colorectal cancer patients receiving adjuvant 5-fluorouracil. Oncology. 70:366–377. 2006. View Article : Google Scholar : PubMed/NCBI
27	Laudanski P, Charkiewicz R, Kuzmicki M, Szamatowicz J, Świątecka J, Mroczko B and Niklinski J: Profiling of selected angiogenesis-related genes in proliferative eutopic endometrium of women with endometriosis. Eur J Obstet Gynecol Reprod Biol. 172:85–92. 2014. View Article : Google Scholar
28	Mitselou A, Ioachim E, Skoufi U, Tsironis C, Tsimogiannis KE, Skoufi C, Vougiouklakis T and Briasoulis E: Predictive role of thymidine phosphorylase expression in patients with colorectal cancer and its association with angiogenesis-related proteins and extracellular matrix components. In Vivo. 26:1057–1067. 2012.PubMed/NCBI