CXCR6 predicts poor prognosis in gastric cancer and promotes tumor metastasis through epithelial-mesenchymal transition

Jin,Jie-Jie; Dai,Fa-Xiang; Long,Zi-Wen; Cai,Hong; Liu,Xiao-Wen; Zhou,Ye; Hong,Qi; Dong,Qiong-Zhu; Wang,Ya-Nong; Huang,Hua

doi:10.3892/or.2017.5598

CXCR6 predicts poor prognosis in gastric cancer and promotes tumor metastasis through epithelial-mesenchymal transition

Authors:
- Jie-Jie Jin
- Fa-Xiang Dai
- Zi-Wen Long
- Hong Cai
- Xiao-Wen Liu
- Ye Zhou
- Qi Hong
- Qiong-Zhu Dong
- Ya-Nong Wang
- Hua Huang
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Affiliations: Gastric Surgery Department, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China, Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China, Institutes of Biomedical Science, Fudan University, Shanghai 200032, P.R. China
Published online on: April 25, 2017 https://doi.org/10.3892/or.2017.5598
Pages: 3279-3286

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Abstract

Chemokines and their receptors have been confirmed to be involved in several types of cancer. However, little is known concerning the role of CXCL16 and its receptor CXCR6 in gastric cancer (GC) progression and metastasis. In the present study, expression of CXCL16 and CXCR6 in GC tumor and peritumoral tissues was detected by immunohistochemistry (IHC) in a cohort of 352 GC patients who underwent gastrectomy, and the correlation between CXCL16/CXCR6 expression and clinicopathological characteristics was further analyzed. To evaluate the function of CXCR6, we overexpressed and knocked down CXCR6 in GC cell lines. Results showed that expression of CXCR6, but not CXCL16, was significantly upregulated in GC tumor tissues, and was significantly correlated with lymph node and distant metastases, and advanced clinical stage in the GC patients. Survival analysis showed that large tumor size (>5 cm), elevated preoperative serum carcinoembryonic antigen (CEA) level, advanced TNM stage and high CXCR6 expression indicated worse overall survival (OS) and disease-free survival (DFS) in GC, and CXCR6 was an independent predictor for both OS and DFS in GC. In vitro experiments showed that CXCR6 overexpression induced cell migration and invasion ability, and promoted epithelial-mesenchymal transition of GC cells by upregulation of mesenchymal markers and inhibition of epithelial markers. In contrast, knockdown of CXCR6 in GC cells resulted in inhibition of cell proliferation, migration and invasion ability, and reversal of epithelial-mesenchymal transition (EMT) phenomenon. Our results demonstrated that CXCR6 is an independent prognostic factor for poor survival in GC patients, and may promote GC metastasis through EMT.

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1	Jemal A, Center MM, DeSantis C and Ward EM: Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev. 19:1893–1907. 2010. View Article : Google Scholar : PubMed/NCBI
2	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
3	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI
4	Schlesinger-Raab A, Mihaljevic AL, Egert S, Emeny R, Jauch KW, Kleeff J, Novotny A, Nüssler NC, Rottmann M, Schepp W, et al: Outcome of gastric cancer in the elderly: A population-based evaluation of the Munich Cancer Registry. Gastric Cancer. 19:713–722. 2016. View Article : Google Scholar : PubMed/NCBI
5	Shen L, Shan YS, Hu HM, Price TJ, Sirohi B, Yeh KH, Yang YH, Sano T, Yang HK, Zhang X, et al: Management of gastric cancer in Asia: Resource-stratified guidelines. Lancet Oncol. 14:e535–e547. 2013. View Article : Google Scholar : PubMed/NCBI
6	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
7	Berx G and van Roy F: Involvement of members of the cadherin superfamily in cancer. Cold Spring Harb Perspect Biol. 1:a0031292009. View Article : Google Scholar : PubMed/NCBI
8	Virchow R: An address on the value of pathological experiments. BMJ. 2:198–203. 1881. View Article : Google Scholar : PubMed/NCBI
9	Luster AD: Chemokines - chemotactic cytokines that mediate inflammation. N Engl J Med. 338:436–445. 1998. View Article : Google Scholar : PubMed/NCBI
10	Verbeke H, Struyf S, Laureys G and Van Damme J: The expression and role of CXC chemokines in colorectal cancer. Cytokine Growth Factor Rev. 22:345–358. 2011. View Article : Google Scholar : PubMed/NCBI
11	Deng L, Chen N, Li Y, Zheng H and Lei Q: CXCR6/CXCL16 functions as a regulator in metastasis and progression of cancer. Biochim Biophys Acta. 1806:42–49. 2010.PubMed/NCBI
12	Gao Q, Zhao YJ, Wang XY, Qiu SJ, Shi YH, Sun J, Yi Y, Shi JY, Shi GM, Ding ZB, et al: CXCR6 upregulation contributes to a proinflammatory tumor microenvironment that drives metastasis and poor patient outcomes in hepatocellular carcinoma. Cancer Res. 72:3546–3556. 2012. View Article : Google Scholar : PubMed/NCBI
13	Kim SS, Ruiz VE, Carroll JD and Moss SF: Helicobacter pylori in the pathogenesis of gastric cancer and gastric lymphoma. Cancer Lett. 305:228–238. 2011. View Article : Google Scholar : PubMed/NCBI
14	Li Y, Fu LX, Zhu WL, Shi H, Chen LJ and Ye B: Blockade of CXCR6 reduces invasive potential of gastric cancer cells through inhibition of AKT signaling. Int J Immunopathol Pharmacol. 28:194–200. 2015. View Article : Google Scholar : PubMed/NCBI
15	Liu X, Long Z, Cai H, Huang H, Shi Y and Wang Y: Analysis of lymph node metastasis correlation with prognosis in patients with T2 gastric cancer. PLoS One. 9:e1051122014. View Article : Google Scholar : PubMed/NCBI
16	Xiao G, Wang X and Wang J, Zu L, Cheng G, Hao M, Sun X, Xue Y, Lu J and Wang J: CXCL16/CXCR6 chemokine signaling mediates breast cancer progression by pERK1/2-dependent mechanisms. Oncotarget. 6:14165–14178. 2015. View Article : Google Scholar : PubMed/NCBI
17	Mir H, Singh R, Kloecker GH, Lillard JW Jr and Singh S: CXCR6 expression in non-small cell lung carcinoma supports metastatic process via modulating metalloproteinases. Oncotarget. 6:9985–9998. 2015. View Article : Google Scholar : PubMed/NCBI
18	Wang J, Lu Y, Wang J, Koch AE, Zhang J and Taichman RS: CXCR6 induces prostate cancer progression by the AKT/mammalian target of rapamycin signaling pathway. Cancer Res. 68:10367–10376. 2008. View Article : Google Scholar : PubMed/NCBI
19	Gooden MJ, Wiersma VR, Boerma A, Leffers N, Boezen HM, ten Hoor KA, Hollema H, Walenkamp AM, Daemen T, Nijman HW, et al: Elevated serum CXCL16 is an independent predictor of poor survival in ovarian cancer and may reflect pro-metastatic ADAM protease activity. Br J Cancer. 110:1535–1544. 2014. View Article : Google Scholar : PubMed/NCBI
20	Held-Feindt J, Rehmke B, Mentlein R, Hattermann K, Knerlich F, Hugo HH, Ludwig A and Mehdorn HM: Overexpression of CXCL16 and its receptor CXCR6/Bonzo promotes growth of human schwannomas. Glia. 56:764–774. 2008. View Article : Google Scholar : PubMed/NCBI
21	Stockinger A, Eger A, Wolf J, Beug H and Foisner R: E-cadherin regulates cell growth by modulating proliferation-dependent beta-catenin transcriptional activity. J Cell Biol. 154:1185–1196. 2001. View Article : Google Scholar : PubMed/NCBI
22	Valdés F, Alvarez AM, Locascio A, Vega S, Herrera B, Fernández M, Benito M, Nieto MA and Fabregat I: The epithelial mesenchymal transition confers resistance to the apoptotic effects of transforming growth factor Beta in fetal rat hepatocytes. Mol Cancer Res. 1:68–78. 2002.PubMed/NCBI
23	Klymkowsky MW and Savagner P: Epithelial-mesenchymal transition: A cancer researcher's conceptual friend and foe. Am J Pathol. 174:1588–1593. 2009. View Article : Google Scholar : PubMed/NCBI
24	Lu M, Marsters S, Ye X, Luis E, Gonzalez L and Ashkenazi A: E-cadherin couples death receptors to the cytoskeleton to regulate apoptosis. Mol Cell. 54:987–998. 2014. View Article : Google Scholar : PubMed/NCBI
25	Uttamsingh S, Bao X, Nguyen KT, Bhanot M, Gong J, Chan JL, Liu F, Chu TT and Wang LH: Synergistic effect between EGF and TGF-beta1 in inducing oncogenic properties of intestinal epithelial cells. Oncogene. 27:2626–2634. 2008. View Article : Google Scholar : PubMed/NCBI
26	Morali OG, Delmas V, Moore R, Jeanney C, Thiery JP and Larue L: IGF-II induces rapid beta-catenin relocation to the nucleus during epithelium to mesenchyme transition. Oncogene. 20:4942–4950. 2001. View Article : Google Scholar : PubMed/NCBI
27	Tanaka T, Bai Z, Srinoulprasert Y, Yang BG, Hayasaka H and Miyasaka M: Chemokines in tumor progression and metastasis. Cancer Sci. 96:317–322. 2005. View Article : Google Scholar : PubMed/NCBI
28	Corso G, Marrelli D and Roviello F: Familial gastric cancer and germline mutations of E-cadherin. Ann Ital Chir. 83:177–182. 2012.PubMed/NCBI
29	Becker KF, Atkinson MJ, Reich U, Becker I, Nekarda H, Siewert JR and Höfler H: E-cadherin gene mutations provide clues to diffuse type gastric carcinomas. Cancer Res. 54:3845–3852. 1994.PubMed/NCBI
30	Corso G, Carvalho J, Marrelli D, Vindigni C, Carvalho B, Seruca R, Roviello F and Oliveira C: Somatic mutations and deletions of the E-cadherin gene predict poor survival of patients with gastric cancer. J Clin Oncol. 31:868–875. 2013. View Article : Google Scholar : PubMed/NCBI
31	Hazan RB, Qiao R, Keren R, Badano I and Suyama K: Cadherin switch in tumor progression. Ann NY Acad Sci. 1014:155–163. 2004. View Article : Google Scholar : PubMed/NCBI