Expression and function of CXCL12/CXCR4/CXCR7 in thyroid cancer

Zhu,Xiaoli; Bai,Qianming; Lu,Yongming; Lu,Yiqiong; Zhu,Linlin; Zhou,Xiaoyan; Wu,Lijing

doi:10.3892/ijo.2016.3485

Expression and function of CXCL12/CXCR4/CXCR7 in thyroid cancer

Authors:
- Xiaoli Zhu
- Qianming Bai
- Yongming Lu
- Yiqiong Lu
- Linlin Zhu
- Xiaoyan Zhou
- Lijing Wu
View Affiliations

Affiliations: Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
Published online on: April 12, 2016 https://doi.org/10.3892/ijo.2016.3485
Pages: 2321-2329
Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

The contribution of CXCL12/CXCR4/CXCR7 axis to cancer progression has been increasingly recognized. However, its role in thyroid cancer development remains unclear. The present study aimed to examine the expression and function of CXCL12 and its receptors in thyroid cancer. The expression of CXCL12/CXCR4/CXCR7 in human tissue specimens of papillary, follicular, medullary, and anaplastic thyroid carcinoma, follicular adenoma, Hashimoto's thyroiditis and nodular goiter were examined by immunohistochemistry using a tissue microarray. CXCR4 and CXCR7 were over-expressed in human thyroid cancer cells K1 by transduction of recombinant lentivirus. The effect of overexpression of CXCR4 and CXCR7 on K1 cell proliferation and invasion and the molecular mechanism underlying the effect were investigated. CXCL12 was exclusively expressed in papillary thyroid carcinoma tissue but absent in other types of thyroid malignancies and benign lesions. CXCR7 was widely expressed in the endothelial cells of all types of malignancy but only occasionally detected in benign lesions. CXCR4 was expressed in 62.5% of papillary thyroid carcinoma tissue specimens and in 30-40% of other types of malignancy, and it was either absent or weakly expressed in benign lesions. CXCL12 stimulated the invasion and migration of K1 cells overexpressing CXCR4, but did not affect K1 cells overexpressing CXCR7. K1 cell proliferation was not affected by overexpression of CXCR4 or CXCR7. Overexpression of CXCR4 in K1 cells significantly increased AKT and ERK phosphorylation and markedly induced the expression and activity of matrix metalloproteinase-2 (MMP‑2). Thus, CXCL12 may be an effective diagnostic marker for papillary thyroid carcinoma, and CXCL12/CXCR4/CXCR7 axis may contribute to thyroid cancer development by regulating cancer cell migration and invasion via AKT and ERK signaling and MMP-2 activation.

View Figures

View References

1	Kilfoy BA, Zheng T, Holford TR, Han X, Ward MH, Sjodin A, Zhang Y, Bai Y, Zhu C, Guo GL, et al: International patterns and trends in thyroid cancer incidence, 1973–2002. Cancer Causes Control. 20:525–531. 2009. View Article : Google Scholar :
2	Pellegriti G, Frasca F, Regalbuto C, Squatrito S and Vigneri R: Worldwide increasing incidence of thyroid cancer: Update on epidemiology and risk factors. J Cancer Epidemiol. 2013:9652122013.PubMed/NCBI
3	Yang L, Yuan Y, Sun T, Li H and Wang N: Population-based cancer incidence analysis in Beijing, 2008–2012. Chin J Cancer Res. 27:13–21. 2015.PubMed/NCBI
4	Sun X, Cheng G, Hao M, Zheng J, Zhou X, Zhang J, Taichman RS, Pienta KJ and Wang J: CXCL12/CXCR4/CXCR7 chemokine axis and cancer progression. Cancer Metastasis Rev. 29:709–722. 2010. View Article : Google Scholar : PubMed/NCBI
5	Bleul CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A and Springer TA: A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J Exp Med. 184:1101–1109. 1996. View Article : Google Scholar : PubMed/NCBI
6	Caruz A, Samsom M, Alonso JM, Alcami J, Baleux F, Virelizier JL, Parmentier M and Arenzana-Seisdedos F: Genomic organization and promoter characterization of human CXCR4 gene. FEBS Lett. 426:271–278. 1998. View Article : Google Scholar : PubMed/NCBI
7	Gupta SK and Pillarisetti K: Cutting edge: CXCR4-Lo: molecular cloning and functional expression of a novel human CXCR4 splice variant. J Immunol. 163:2368–2372. 1999.PubMed/NCBI
8	Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, Penfold ME, Sunshine MJ, Littman DR, Kuo CJ, et al: A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med. 203:2201–2213. 2006. View Article : Google Scholar : PubMed/NCBI
9	Balabanian K, Lagane B, Infantino S, Chow KY, Harriague J, Moepps B, Arenzana-Seisdedos F, Thelen M and Bachelerie F: The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem. 280:35760–35766. 2005. View Article : Google Scholar : PubMed/NCBI
10	Lu DY, Tang CH, Yeh WL, Wong KL, Lin CP, Chen YH, Lai CH, Chen YF, Leung YM and Fu WM: SDF-1alpha up-regulates interleukin-6 through CXCR4, PI3K/Akt, ERK, and NF-kappaB-dependent pathway in microglia. Eur J Pharmacol. 613:146–154. 2009. View Article : Google Scholar : PubMed/NCBI
11	Roland J, Murphy BJ, Ahr B, Robert-Hebmann V, Delauzun V, Nye KE, Devaux C and Biard-Piechaczyk M: Role of the intra-cellular domains of CXCR4 in SDF-1-mediated signaling. Blood. 101:399–406. 2003. View Article : Google Scholar
12	Levoye A, Balabanian K, Baleux F, Bachelerie F and Lagane B: CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling. Blood. 113:6085–6093. 2009. View Article : Google Scholar : PubMed/NCBI
13	Sierro F, Biben C, Martínez-Muñoz L, Mellado M, Ransohoff RM, Li M, Woehl B, Leung H, Groom J, Batten M, et al: Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7. Proc Natl Acad Sci USA. 104:14759–14764. 2007. View Article : Google Scholar : PubMed/NCBI
14	Boldajipour B, Mahabaleshwar H, Kardash E, Reichman-Fried M, Blaser H, Minina S, Wilson D, Xu Q and Raz E: Control of chemokine-guided cell migration by ligand sequestration. Cell. 132:463–473. 2008. View Article : Google Scholar : PubMed/NCBI
15	Dambly-Chaudière C, Cubedo N and Ghysen A: Control of cell migration in the development of the posterior lateral line: Antagonistic interactions between the chemokine receptors CXCR4 and CXCR7/RDC1. BMC Dev Biol. 7:232007. View Article : Google Scholar : PubMed/NCBI
16	Wang J, Shiozawa Y, Wang J, Wang Y, Jung Y, Pienta KJ, Mehra R, Loberg R and Taichman RS: The role of CXCR7/ RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. J Biol Chem. 283:4283–4294. 2008. View Article : Google Scholar
17	Sun YX, Schneider A, Jung Y, Wang J, Dai J, Wang J, Cook K, Osman NI, Koh-Paige AJ, Shim H, et al: Skeletal localization and neutralization of the SDF-1(CXCL12)/CXCR4 axis blocks prostate cancer metastasis and growth in osseous sites in vivo. J Bone Miner Res. 20:318–329. 2005. View Article : Google Scholar : PubMed/NCBI
18	Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, et al: Involvement of chemokine receptors in breast cancer metastasis. Nature. 410:50–56. 2001. View Article : Google Scholar : PubMed/NCBI
19	Miao Z, Luker KE, Summers BC, Berahovich R, Bhojani MS, Rehemtulla A, Kleer CG, Essner JJ, Nasevicius A, Luker GD, et al: CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc Natl Acad Sci USA. 104:15735–15740. 2007. View Article : Google Scholar : PubMed/NCBI
20	Chung SY, Park ES, Park SY, Song JY and Ryu HS: CXC motif ligand 12 as a novel diagnostic marker for papillary thyroid carcinoma. Head Neck. 36:1005–1012. 2014. View Article : Google Scholar
21	Jung YY, Park IA, Kim MA, Min HS, Won JK and Ryu HS: Application of chemokine CXC motif ligand 12 as a novel diagnostic marker in preoperative fine-needle aspiration biopsy for papillary thyroid carcinoma. Acta Cytol. 57:447–454. 2013. View Article : Google Scholar : PubMed/NCBI
22	Liu Z, Sun DX, Teng XY, Xu WX, Meng XP and Wang BS: Expression of stromal cell-derived factor 1 and CXCR7 in papillary thyroid carcinoma. Endocr Pathol. 23:247–253. 2012. View Article : Google Scholar : PubMed/NCBI
23	Wagner PL, Moo TA, Arora N, Liu YF, Zarnegar R, Scognamiglio T and Fahey TJ III: The chemokine receptors CXCR4 and CCR7 are associated with tumor size and pathologic indicators of tumor aggressiveness in papillary thyroid carcinoma. Ann Surg Oncol. 15:2833–2841. 2008. View Article : Google Scholar : PubMed/NCBI
24	Lu CL, Guo J, Gu J, Ge D, Hou YY, Lin ZW and Ding JY: CXCR4 heterogeneous expression in esophageal squamous cell cancer and stronger metastatic potential with CXCR4-positive cancer cells. Dis Esophagus. 27:294–302. 2014. View Article : Google Scholar
25	De Falco V, Guarino V, Avilla E, Castellone MD, Salerno P, Salvatore G, Faviana P, Basolo F, Santoro M and Melillo RM: Biological role and potential therapeutic targeting of the chemokine receptor CXCR4 in undifferentiated thyroid cancer. Cancer Res. 67:11821–11829. 2007. View Article : Google Scholar : PubMed/NCBI
26	Hwang JH, Hwang JH, Chung HK, Kim DW, Hwang ES, Suh JM, Kim H, You KH, Kwon OY, Ro HK, et al: CXC chemokine receptor 4 expression and function in human anaplastic thyroid cancer cells. J Clin Endocrinol Metab. 88:408–416. 2003. View Article : Google Scholar : PubMed/NCBI
27	Ghosh MC, Makena PS, Gorantla V, Sinclair SE and Waters CM: CXCR4 regulates migration of lung alveolar epithelial cells through activation of Rac1 and matrix metalloproteinase-2. Am J Physiol Lung Cell Mol Physiol. 302:L846–L856. 2012. View Article : Google Scholar : PubMed/NCBI
28	Ying X, Jing L, Ma S, Li Q, Luo X, Pan Z, Feng Y and Feng P: GSK3β mediates pancreatic cancer cell invasion in vitro via the CXCR4/MMP-2 pathway. Cancer Cell Int. 15:702015. View Article : Google Scholar