Effect of CXCL12/CXCR4 on increasing the metastatic potential of non‑small cell lung cancer in vitro is inhibited through the downregulation of CXCR4 chemokine receptor expression

Xie,Songping; Zeng,Wenhui; Fan,Guohua; Huang,Jie; Kang,Ganjun; Geng,Qing; Cheng,Bangchang; Wang,Wei; Dong,Ping

doi:10.3892/ol.2014.1837

Effect of CXCL12/CXCR4 on increasing the metastatic potential of non‑small cell lung cancer in vitro is inhibited through the downregulation of CXCR4 chemokine receptor expression

Authors:
- Songping Xie
- Wenhui Zeng
- Guohua Fan
- Jie Huang
- Ganjun Kang
- Qing Geng
- Bangchang Cheng
- Wei Wang
- Ping Dong
View Affiliations

Affiliations: Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
Published online on: January 29, 2014 https://doi.org/10.3892/ol.2014.1837
Pages: 941-947

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

Lung cancer ranks as the most common type of cancer in males worldwide. Although great advances have been achieved in chemotherapy and radiotherapy, the long‑term survival rate of lung cancer patients has not improved significantly. Dissemination of lung cancer in the thoracic cavity and metastatic spread to the liver, bone and brain are characteristic of non‑small cell lung cancer (NSCLC), constituting the primary source of morbidity and mortality in lung cancer. Increasing evidence also indicates that the CXC chemokine receptor 4 (CXCR4)/chemokine CXC motif ligand 12 (CXCL12) chemokine axis is important for the cell invasion and migration of lung cancer. CXCR4 is a G protein‑coupled receptor with a major role in lymphocyte homing. Its ligand, CXCL12, is secreted by target organs and functions as a highly efficient chemotactic factor for T cells, monocytes, pre‑B cells, dendritic cells and myeloid bone marrow‑derived cells. In the current study, recombinant CXCR4‑specific small interfering RNA‑pBSilence1.1 plasmids were constructed and transfected into the A549 NSCLC cell line in vitro. Reverse transcription polymerase chain reaction and western blotting revealed that CXCR4 was downregulated in transfected cells compared with control cells. The results of MTT and Transwell migration assays indicated that the specific downregulation of CXCR4 inhibited cell growth, invasiveness and migration. Thus, siRNA targeting of CXCR4 may effectively inhibit the effect of CXCL12/CXCR4 on increasing the metastatic potential of NSCLC.

View Figures

View References

1	Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP and Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 350:351–360. 2004. View Article : Google Scholar : PubMed/NCBI
2	Jemal A, Murray T, Ward E, et al: Cancer statistics. CA Cancer J Clin. 55:10–30. 2005.
3	Mehlen P and Puisieux A: Metastasis: a question of life or death. Nat Rev Cancer. 6:449–458. 2006. View Article : Google Scholar : PubMed/NCBI
4	Gangadhar T, Nandi S and Salgia R: The role of chemokine receptor CXCR4 in lung cancer. Cancer Biol Ther. 9:409–416. 2010. View Article : Google Scholar : PubMed/NCBI
5	Vindrieux D, Escobar P and Lazennec G: Emerging roles of chemokines in prostate cancer. Endocr Relat Cancer. 16:663–673. 2009. View Article : Google Scholar : PubMed/NCBI
6	Müller A, Homey B, Soto H, et al: Involvement of chemokine receptors in breast cancer metastasis. Nature. 410:50–56. 2001.PubMed/NCBI
7	Clapham PR and Weiss RA: Immunodeficiency viruses. Spoilt for choice of co-receptors. Nature. 388:230–231. 1997. View Article : Google Scholar : PubMed/NCBI
8	Liang JJ, Zhu S, Bruggeman R, et al: High levels of expression of human stromal cell-derived factor-1 are associated with worse prognosis in patients with stage II pancreatic ductal adenocacinoma. Cancer Epidemiol Biomarkers Prev. 19:2598–2604. 2010. View Article : Google Scholar
9	Castellone MD, Guarino V, De Falco V, et al: Functional expression of the CXCR4 chemokine receptor is induced by RET/PTC oncogenes and is a common event in human papillary thyroid carcinomas. Oncogene. 23:5958–5967. 2004. View Article : Google Scholar
10	Torregrossa L, Giannini R, Borrelli N, et al: CXCR4 expression correlates with the degree of tumor infiltration and BRAF status in papillary thyroid carcinomas. Mod Pathol. 25:46–55. 2012. View Article : Google Scholar : PubMed/NCBI
11	Su L, Zhang J, Xu H, et al: Differential expression of CXCR4 is associated with the metastatic potential of human non-small cell lung cancer cells. Clin Cancer Res. 11:8273–8280. 2005. View Article : Google Scholar
12	Spano JP, Andre F, Morat L, et al: Chemokine receptor CXCR4 and early-stage non-small cell lung cancer: pattern of expression and correlation with outcome. Ann Oncol. 15:613–617. 2004. View Article : Google Scholar : PubMed/NCBI
13	Phillips RJ, Burdick MD, Lutz M, et al: The stromal derived factor-1/CXCL12-CXC chemokine receptor 4 biological axis in non-small cell lung cancer metastases. Am J Respir Crit Care Med. 167:1676–1686. 2003. View Article : Google Scholar
14	Phillips RJ, Mestas J, Gharaee-Kermani M, et al: Epidermal growth factor and hypoxia-induced expression of CXC chemokine receptor 4 on non-small cell lung cancer cells is regulated by the phosphatidylinositol 3-kinase/PTEN/AKT/mammalian target of rapamycin signaling pathway and activation of hypoxia inducible factor-1alpha. J Biol Chem. 280:22473–22481. 2005.
15	Broxmeyer HE, Orschell CM, Clapp DW, et al: Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med. 201:1307–1318. 2005. View Article : Google Scholar : PubMed/NCBI
16	Ok S, Kim SM, Kim C, et al: Emodin inhibits invasion and migration of prostate and lung cancer cells by downregulating the expression of chemokine receptor CXCR4. Immunopharmacol Immunotoxicol. 34:768–778. 2012. View Article : Google Scholar : PubMed/NCBI
17	Xie S, Zeng W, Zuo T, et al: Expression and significance of CXCR4 chemokine receptor in non small cell lung cancer. Chin J Gen Pract. 10:1335–1336. 2012.
18	Huang YC, Hsiao YC, Chen YJ, et al: Stromal cell-derived factor-1 enhances motility and integrin up-regulation through CXCR4, ERK and NF-kappaB-dependent pathway in human lung cancer cells. Biochem Pharmacol. 74:1702–1712. 2007. View Article : Google Scholar : PubMed/NCBI
19	Zheng H, Dai T, Zhou B, et al: SDF-1alpha/CXCR4 decreases endothelial progenitor cells apoptosis under serum deprivation by PI3K/Akt/eNOS pathway. Atherosclerosis. 201:36–42. 2008. View Article : Google Scholar
20	Abedini F, Ismail M, Hosseinkhani H, et al: Effects of CXCR4 siRNA/dextran-spermine nanoparticles on CXCR4 expression and serum LDH levels in a mouse model of colorectal cancer metastasis to the liver. Cancer Manag Res. 3:301–309. 2011.PubMed/NCBI
21	Orimo A, Gupta PB, Sgroi DC, et al: Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 121:335–348. 2005. View Article : Google Scholar
22	Rubie C, Frick VO, Ghadjar P, et al: CXC receptor-4 mRNA silencing abrogates CXCL12-induced migration of colorectal cancer cells. J Transl Med. 9:222011. View Article : Google Scholar : PubMed/NCBI
23	Lee W, Jiang Z, Liu J, Haverty PM, Guan Y, Stinson J, et al: The mutation spectrum revealed by paired genome sequences from a lung cancer patient. Nature. 465:473–477. 2010. View Article : Google Scholar : PubMed/NCBI
24	Wald O, Izhar U, Amir G, et al: Interaction between neoplastic cells and cancer-associated fibroblasts through the CXCL12/CXCR4 axis: role in non-small cell lung cancer tumor proliferation. J Thorac Cardiovasc Surg. 141:1503–1512. 2011. View Article : Google Scholar
25	Sun YX, Wang J, Shelburne CE, et al: Expression of CXCR4 and CXCL12 (SDF-1) in human prostate cancers (PCa) in vivo. J Cell Biochem. 89:462–473. 2003. View Article : Google Scholar : PubMed/NCBI