Loss of atypical chemokine receptor 4 facilitates C‑C motif chemokine ligand 21‑mediated tumor growth and invasion in nasopharyngeal carcinoma

Ju,Yunhe; Sun,Chuanzheng; Wang,Xiaoli

doi:10.3892/etm.2018.7007

Loss of atypical chemokine receptor 4 facilitates C‑C motif chemokine ligand 21‑mediated tumor growth and invasion in nasopharyngeal carcinoma

Authors:
- Yunhe Ju
- Chuanzheng Sun
- Xiaoli Wang
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Affiliations: Department of Radiotherapy, The Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming, Yunnan 650000, P.R. China, Department of Head and Neck Surgery, The Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming, Yunnan 650000, P.R. China
Published online on: November 23, 2018 https://doi.org/10.3892/etm.2018.7007
Pages: 613-620
Copyright: © Ju et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Nasopharyngeal carcinoma (NPC) is a common malignant disease that is prevalent in Asian countries. Atypical chemokine receptor 4 (ACKR4) binds to various chemokines, including C‑C motif chemokine ligand (CCL)19, CCL21, CCL25 and C‑X‑C motif chemokine ligand 13, without inducing downstream signaling transduction. However, the role of ACKR4 in modulating NPC development remains unclear. In the present study, the effects of ACKR4 on NPC growth, invasion and metastasis were investigated, as well as the endogenous mechanisms through which ACKR4 mediates NPC development. The results demonstrated that ACKR4 was downregulated in human NPC tumor tissues, as compared with that in adjacent normal tissue. In a subcutaneous tumor animal model, the knockdown of ACKR4 enhanced NPC invasion and metastasis. Furthermore, CCL21 was accumulated in ACKR4 knockdown tumors. In vitro, the loss of ACKR4 increased CCL21‑mediated SUNE‑1 cell proliferation, epithelial‑mesenchymal transition and invasion. In conclusion, the loss of ACKR4 promoted CCL21‑mediated NPC development; thus, neutralizing CCL21 in NPC with low ACKR4 expression may be a novel treatment strategy.

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1	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
2	Chua ML, Wee JT, Hui EP and Chan AT: Nasopharyngeal carcinoma. Lancet. 387:1012–1024. 2016. View Article : Google Scholar : PubMed/NCBI
3	Blanchard P, Lee A, Marguet S, Leclercq J, Ng WT, Ma J, Chan AT, Huang PY, Benhamou E, Zhu G, et al: Chemotherapy and radiotherapy in nasopharyngeal carcinoma: An update of the MAC-NPC meta-analysis. Lancet Oncol. 16:645–655. 2015. View Article : Google Scholar : PubMed/NCBI
4	Ulvmar MH, Hub E and Rot A: Atypical chemokine receptors. Exp Cell Res. 317:556–568. 2011. View Article : Google Scholar : PubMed/NCBI
5	Massara M, Bonavita O, Mantovani A, Locati M and Bonecchi R: Atypical chemokine receptors in cancer: Friends or foes? J Leukoc Biol. 99:927–933. 2016. View Article : Google Scholar : PubMed/NCBI
6	Feng LY, Ou ZL, Wu FY, Shen ZZ and Shao ZM: Involvement of a novel chemokine decoy receptor CCX-CKR in breast cancer growth, metastasis and patient survival. Clin Cancer Res. 15:2962–2970. 2009. View Article : Google Scholar : PubMed/NCBI
7	Harata-Lee Y, Turvey ME, Brazzatti JA, Gregor CE, Brown MP, Smyth MJ, Comerford I and McColl SR: The atypical chemokine receptor CCX-CKR regulates metastasis of mammary carcinoma via an effect on EMT. Immunol Cell Biol. 92:815–824. 2014. View Article : Google Scholar : PubMed/NCBI
8	Hou T, Liang D, Xu L, Huang X, Huang Y and Zhang Y: Atypical chemokine receptors predict lymph node metastasis and prognosis in patients with cervical squamous cell cancer. Gynecol Oncol. 130:181–187. 2013. View Article : Google Scholar : PubMed/NCBI
9	Zhu Y, Tang W, Liu Y, Wang G, Liang Z and Cui L: CCX-CKR expression in colorectal cancer and patient survival. Int J Biol Markers. 29:e40–e48. 2014. View Article : Google Scholar : PubMed/NCBI
10	Hernandez-Gea V, Toffanin S, Friedman SL and Llovet JM: Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology. 144:512–527. 2013. View Article : Google Scholar : PubMed/NCBI
11	Pang MF, Georgoudaki AM, Lambut L, Johansson J, Tabor V, Hagikura K, Jin Y, Jansson M, Alexander JS, Nelson CM, et al: TGF-β1-induced EMT promotes targeted migration of breast cancer cells through the lymphatic system by the activation of CCR7/CCL21-mediated chemotaxis. Oncogene. 35:748–760. 2016. View Article : Google Scholar : PubMed/NCBI
12	Mo M, Zhou M, Wang L, Qi L, Zhou K, Liu LF, Chen Z and Zu XB: CCL21/CCR7 enhances the proliferation, migration, and invasion of human bladder cancer T24 cells. PLoS One. 10:e01195062015. View Article : Google Scholar : PubMed/NCBI
13	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
14	Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C and Flavell RA: Inflammation-induced cancer: Crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer. 13:759–771. 2013. View Article : Google Scholar : PubMed/NCBI
15	Forster R, Schubel A, Breitfeld D, Kremmer E, Renner-Muller I, Wolf E and Lipp M: CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell. 99:23–33. 1999. View Article : Google Scholar : PubMed/NCBI
16	Shi JY, Yang LX, Wang ZC, Wang LY, Zhou J, Wang XY, Shi GM, Ding ZB, Ke AW, Dai Z, et al: CC chemokine receptor-like 1 functions as a tumour suppressor by impairing CCR7-related chemotaxis in hepatocellular carcinoma. J Pathol. 235:546–558. 2015. View Article : Google Scholar : PubMed/NCBI
17	Xiong Y, Huang F, Li X, Chen Z, Feng D, Jiang H, Chen W and Zhang X: CCL21/CCR7 interaction promotes cellular migration and invasion via modulation of the MEK/ERK1/2 signaling pathway and correlates with lymphatic metastatic spread and poor prognosis in urinary bladder cancer. Int J Oncol. 51:75–90. 2017. View Article : Google Scholar : PubMed/NCBI
18	Irshad S, Flores-Borja F, Lawler K, Monypenny J, Evans R, Male V, Gordon P, Cheung A, Gazinska P, Noor F, et al: RORγt+ Innate lymphoid cells promote lymph node metastasis of breast cancers. Cancer Res. 77:1083–1096. 2017. View Article : Google Scholar : PubMed/NCBI
19	Ma H, Gao L, Li S, Qin J, Chen L, Liu X, Xu P, Wang F, Xiao H, Zhou S, et al: CCR7 enhances TGF-β1-induced epithelial-mesenchymal transition and is associated with lymph node metastasis and poor overall survival in gastric cancer. Oncotarget. 6:24348–24360. 2015. View Article : Google Scholar : PubMed/NCBI