Abnormal hypermethylation of promoter region downregulates chemokine CXC ligand 14 expression in gastric cancer

Hu,Changyuan; Lin,Feng; Zhu,Guangbao; Xue,Xiangyang; Ding,Yujie; Zhao,Zhiguang; Zhang,Lifang; Shen,Xian

doi:10.3892/ijo.2013.2078

Abnormal hypermethylation of promoter region downregulates chemokine CXC ligand 14 expression in gastric cancer

Authors:
- Changyuan Hu
- Feng Lin
- Guangbao Zhu
- Xiangyang Xue
- Yujie Ding
- Zhiguang Zhao
- Lifang Zhang
- Xian Shen
View Affiliations

Affiliations: Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Ouhai District, Wenzhou, Zhejiang 325035, P.R. China, Department of General Surgery, Taizhou First People's Hospital, Taizhou, Zhejiang 318020, P.R. China, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Wenzhou Medical University, Ouhai District, Wenzhou, Zhejiang 325035, P.R. China, Department of Pathology, The Second Affiliated Hospital of Wenzhou Medical University, Lucheng District, Wenzhou, Zhejiang 325000, P.R. China
Published online on: August 23, 2013 https://doi.org/10.3892/ijo.2013.2078
Pages: 1487-1494

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

CXCL14, a new member of the CXC subfamily of chemokines, is differentially expressed in several types of tumors. The expression of CXCL14 and its clinical significance in gastric cancer are unclear to date. In this study, the expression of CXCL14 was detected by quantitative PCR and immunohistochemistry assay. DNA methylation was analyzed by bisulfite sequencing PCR. Student's t-test and Kruskal-Wallis H test were used to evaluate the differences of the CXCL14 expression between the groups. Kaplan-Meier survival curve and Cox regression model were used to evaluate the clinical significance of CXCL14 expression in gastric cancer. Data indicated that the levels of CXCL14 mRNA declined (P<0.001) in gastric carcinoma tissues compared to the paired normal tissues. Immunohistochemical analysis also showed the decrease of CXCL14 protein in the tumor tissue (P<0.001). Analysis of CpG islands methylation in CXCL14 promoter region and first exon area indicated that the abnormal hypermethylation of promoter region in tumor tissue is one of the mechanisms causing the reduction. When gastric cancer cells were demethylated with 5-Aza-2'-deoxycytidine, CXCL14 expression was restored. Downregulation of CXCL14 was associated with the depth of penetration (P<0.001) and positively correlated with prognosis in stage III/IV (P=0.046). In conclusion, it is possible that CXCL14 is involved in the development and progression of gastric cancer. Hypermethylation in the promoter is one of the reasons that CXCL14 has lower expression in gastric adenocarcinoma tissues. The level of CXCL14 expression may be a valuable adjuvant parameter in predicting the prognosis of gastric cancer patients and, thus, a potential therapeutic target.

View Figures

View References

1.	Kamangar F, Dores GM and Anderson WF: Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 24:2137–2150. 2006. View Article : Google Scholar
2.	Crew KD and Neugut AI: Epidemiology of gastric cancer. World J Gastroenterol. 12:354–362. 2006.
3.	Shellenberger TD, Wang M, Gujrati M, et al: BRAK/CXCL14 is a potent inhibitor of angiogenesis and a chemotactic factor for immature dendritic cells. Cancer Res. 64:8262–8270. 2004. View Article : Google Scholar : PubMed/NCBI
4.	Balkwill F: The significance of cancer cell expression of the chemokine receptor CXCR4. Semin Cancer Biol. 14:171–179. 2004. View Article : Google Scholar : PubMed/NCBI
5.	Zlotnik A, Burkhardt AM and Homey B: Homeostatic chemokine receptors and organ-specific metastasis. Nat Rev Immunol. 11:597–606. 2011. View Article : Google Scholar : PubMed/NCBI
6.	Hromas R, Broxmeyer HE, Kim C, et al: Cloning of BRAK, a novel divergent CXC chemokine preferentially expressed in normal versus malignant cells. Biochem Biophys Res Commun. 255:703–706. 1999. View Article : Google Scholar : PubMed/NCBI
7.	Hara T and Nakayama Y: CXCL14 and insulin action. Vitam Horm. 80:107–123. 2009. View Article : Google Scholar
8.	Sleeman MA, Fraser JK, Murison JG, et al: B cell- and monocyte-activating chemokine (BMAC), a novel non-ELR alpha-chemokine. Int Immunol. 12:677–689. 2000. View Article : Google Scholar : PubMed/NCBI
9.	Frederick MJ, Henderson Y, Xu X, et al: In vivo expression of the novel CXC chemokine BRAK in normal and cancerous human tissue. Am J Pathol. 156:1937–1950. 2000. View Article : Google Scholar : PubMed/NCBI
10.	Meuter S and Moser B: Constitutive expression of CXCL14 in healthy human and murine epithelial tissues. Cytokine. 44:248–255. 2008. View Article : Google Scholar : PubMed/NCBI
11.	Kurth I, Willimann K, Schaerli P, Hunziker T, Clark-Lewis I and Moser B: Monocyte selectivity and tissue localization suggests a role for breast and kidney-expressed chemokine (BRAK) in macrophage development. J Exp Med. 194:855–861. 2001. View Article : Google Scholar : PubMed/NCBI
12.	Maerki C, Meuter S, Liebi M, et al: Potent and broad-spectrum antimicrobial activity of CXCL14 suggests an immediate role in skin infections. J Immunol. 182:507–514. 2009. View Article : Google Scholar : PubMed/NCBI
13.	Shurin GV, Ferris RL, Tourkova IL, et al: Loss of new chemokine CXCL14 in tumor tissue is associated with low infiltration by dendritic cells (DC), while restoration of human CXCL14 expression in tumor cells causes attraction of DC both in vitro and in vivo. J Immunol. 174:5490–5498. 2005. View Article : Google Scholar
14.	Starnes T, Rasila KK, Robertson MJ, et al: The chemokine CXCL14 (BRAK) stimulates activated NK cell migration: implications for the downregulation of CXCL14 in malignancy. Exp Hematol. 34:1101–1105. 2006. View Article : Google Scholar : PubMed/NCBI
15.	Juremalm M and Nilsson G: Chemokine receptor expression by mast cells. Chem Immunol Allergy. 87:130–144. 2005. View Article : Google Scholar : PubMed/NCBI
16.	Tessema M, Klinge DM, Yingling CM, Do K, Van Neste L and Belinsky SA: Re-expression of CXCL14, a common target for epigenetic silencing in lung cancer, induces tumor necrosis. Oncogene. 29:5159–5170. 2010. View Article : Google Scholar : PubMed/NCBI
17.	Balkwill FR: The chemokine system and cancer. J Pathol. 226:148–157. 2012. View Article : Google Scholar
18.	Augsten M, Hagglof C, Olsson E, et al: CXCL14 is an autocrine growth factor for fibroblasts and acts as a multi-modal stimulator of prostate tumor growth. Proc Natl Acad Sci USA. 106:3414–3419. 2009. View Article : Google Scholar
19.	Wente MN, Mayer C, Gaida MM, et al: CXCL14 expression and potential function in pancreatic cancer. Cancer Lett. 259:209–217. 2008. View Article : Google Scholar : PubMed/NCBI
20.	Komori R, Ozawa S, Kato Y, Shinji H, Kimoto S and Hata R: Functional characterization of proximal promoter of gene for human BRAK/CXCL14, a tumor-suppressing chemokine. Biomed Res. 31:123–131. 2010. View Article : Google Scholar : PubMed/NCBI
21.	Park CR, You DJ, Kim DK, et al: CXCL14 enhances proliferation and migration of NCI-H460 human lung cancer cells overexpressing the glycoproteins containing heparan sulfate or sialic acid. J Cell Biochem. 114:1084–1096. 2013. View Article : Google Scholar
22.	Mokhtar NM, Cheng CW, Cook E, Bielby H, Smith SK and Charnock-Jones DS: Progestin regulates chemokine (C-X-C motif) ligand 14 transcript level in human endometrium. Mol Hum Reprod. 16:170–177. 2010. View Article : Google Scholar : PubMed/NCBI
23.	Izukuri K, Suzuki K, Yajima N, et al: Chemokine CXCL14/BRAK transgenic mice suppress growth of carcinoma cell transplants. [corrected]. Transgenic Res. 19:1109–1117. 2010.PubMed/NCBI
24.	Miyamoto C, Maehata Y, Ozawa S, et al: Fasudil suppresses fibrosarcoma growth by stimulating secretion of the chemokine CXCL14/BRAK. J Pharmacol Sci. 120:241–249. 2012. View Article : Google Scholar : PubMed/NCBI
25.	Ikoma T, Ozawa S, Suzuki K, et al: Calcium-calmodulin signaling induced by epithelial cell differentiation upregulates BRAK/CXCL14 expression via the binding of SP1 to the BRAK promoter region. Biochem Biophys Res Commun. 420:217–222. 2012. View Article : Google Scholar
26.	Ozawa S, Kato Y, Ito S, et al: Restoration of BRAK/CXCL14 gene expression by gefitinib is associated with antitumor efficacy of the drug in head and neck squamous cell carcinoma. Cancer Sci. 100:2202–2209. 2009. View Article : Google Scholar : PubMed/NCBI
27.	Pelicano H, Lu W, Zhou Y, et al: Mitochondrial dysfunction and reactive oxygen species imbalance promote breast cancer cell motility through a CXCL14-mediated mechanism. Cancer Res. 69:2375–2383. 2009. View Article : Google Scholar : PubMed/NCBI
28.	Issa JP: CpG island methylator phenotype in cancer. Nat Rev Cancer. 4:988–993. 2004. View Article : Google Scholar : PubMed/NCBI