Open Access

CXCL1 stimulates migration and invasion in ER‑negative breast cancer cells via activation of the ERK/MMP2/9 signaling axis

  • Authors:
    • Chengcheng Yang
    • Haochen Yu
    • Rui Chen
    • Kai Tao
    • Lei Jian
    • Meixi Peng
    • Xiaotian Li
    • Manran Liu
    • Shengchun Liu
  • View Affiliations

  • Published online on: July 15, 2019     https://doi.org/10.3892/ijo.2019.4840
  • Pages: 684-696
  • Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Chemokine (C‑X‑C motif) ligand 1 (CXCL1), a member of the CXC chemokine family, has been reported to be a critical factor in inflammatory diseases and tumor progression; however, its functions and molecular mechanisms in estrogen receptor α (ER)‑negative breast cancer (BC) remain largely unknown. The present study demonstrated that CXCL1 was upregulated in ER‑negative BC tissues and cell lines compared with ER‑positive tissues and cell lines. Treatment with recombinant human CXCL1 protein promoted ER‑negative BC cell migration and invasion in a dose‑dependent manner, and stimulated the activation of phosphorylated (p)‑ extracellular signal‑regulated kinase (ERK)1/2, but not p‑STAT3 or p‑AKT. Conversely, knockdown of CXCL1 in BC cells attenuated these effects. Additionally, CXCL1 increased the expression of matrix metalloproteinase (MMP)2/9 via the ERK1/2 pathway. Inhibition of MEK1/2 by its antagonist U0126 reversed the effects of CXCL1 on MMP2/9 expression. Furthermore, immunohistochemical analysis revealed a strong positive association between CXCL1 and p‑ERK1/2 expression levels in BC tissues. In conclusion, the present study demonstrated that CXCL1 is highly expressed in ER‑negative BC, and stimulates BC cell migration and invasion via the ERK/MMP2/9 pathway. Therefore, CXCL1 may serve as a potential therapeutic target in ER‑negative BC.

References

1 

Polyak K: Heterogeneity in breast cancer. J Clin Invest. 121:3786–3788. 2011. View Article : Google Scholar : PubMed/NCBI

2 

Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, Karaca G, Troester MA, Tse CK, Edmiston S, et al: Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA. 295:2492–2502. 2006. View Article : Google Scholar : PubMed/NCBI

3 

Litzenburger BC and Brown PH: Advances in Preventive Therapy for Estrogen-Receptor-Negative Breast Cancer. Curr Breast Cancer Rep. 6:96–109. 2014. View Article : Google Scholar : PubMed/NCBI

4 

Barcellos-Hoff MH: Does microenvironment contribute to the etiology of estrogen receptor-negative breast cancer? Clin Cancer Res. 19:541–548. 2013. View Article : Google Scholar : PubMed/NCBI

5 

Chen JQ and Russo J: ERalpha-negative and triple negative breast cancer: Molecular features and potential therapeutic approaches. Biochim Biophys Acta. 1796:162–175. 2009.PubMed/NCBI

6 

Shen K, Rice SD, Gingrich DA, Wang D, Mi Z, Tian C, Ding Z, Brower SL, Ervin PR Jr, Gabrin MJ, et al: Distinct genes related to drug response identified in ER positive and ER negative breast cancer cell lines. PLoS One. 7:e409002012. View Article : Google Scholar : PubMed/NCBI

7 

Bianchini G, Qi Y, Alvarez RH, Iwamoto T, Coutant C, Ibrahim NK, Valero V, Cristofanilli M, Green MC, Radvanyi L, et al: Molecular anatomy of breast cancer stroma and its prognostic value in estrogen receptor-positive and -negative cancers. J Clin Oncol. 28:4316–4323. 2010. View Article : Google Scholar : PubMed/NCBI

8 

Milne RL, Kuchenbaecker KB, Michailidou K, Beesley J, Kar S, Lindström S, Hui S, Lemaçon A, Soucy P, Dennis J, et al: ABCTB Investigators; EMBRACE; GEMO Study Collaborators; HEBON; kConFab/AOCS Investigators; NBSC Collaborators: Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer. Nat Genet. 49:1767–1778. 2017. View Article : Google Scholar : PubMed/NCBI

9 

Silva RL, Lopes AH, Guimarães RM and Cunha TM: CXCL1/CXCR2 signaling in pathological pain: Role in peripheral and central sensitization. Neurobiol Dis. 105:109–116. 2017. View Article : Google Scholar : PubMed/NCBI

10 

Wang D, Yang W, Du J, Devalaraja MN, Liang P, Matsumoto K, Tsubakimoto K, Endo T and Richmond A: MGSA/GRO-mediated melanocyte transformation involves induction of Ras expression. Oncogene. 19:4647–4659. 2000. View Article : Google Scholar : PubMed/NCBI

11 

Balkwill FR: The chemokine system and cancer. J Pathol. 226:148–157. 2012. View Article : Google Scholar

12 

Acharyya S, Oskarsson T, Vanharanta S, Malladi S, Kim J, Morris PG, Manova-Todorova K, Leversha M, Hogg N, Seshan VE, et al: A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell. 150:165–178. 2012. View Article : Google Scholar : PubMed/NCBI

13 

Miyake M, Hori S, Morizawa Y, Tatsumi Y, Nakai Y, Anai S, Torimoto K, Aoki K, Tanaka N, Shimada K, et al: CXCL1-mediated interaction of cancer cells with tumor-associated macrophages and cancer-associated fibroblasts promotes tumor progression in human bladder cancer. Neoplasia. 18:636–646. 2016. View Article : Google Scholar : PubMed/NCBI

14 

Xu J, Zhang C, He Y, Wu H, Wang Z, Song W, Li W, He W, Cai S and Zhan W: Lymphatic endothelial cell-secreted CXCL1 stimulates lymphangiogenesis and metastasis of gastric cancer. Int J Cancer. 130:787–797. 2012. View Article : Google Scholar

15 

Wang Z, Wang Z, Li G, Wu H, Sun K, Chen J, Feng Y, Chen C, Cai S, Xu J, et al: CXCL1 from tumor-associated lymphatic endothelial cells drives gastric cancer cell into lymphatic system via activating integrin β1/FAK/AKT signaling. Cancer Lett. 385:28–38. 2017. View Article : Google Scholar

16 

Kuo PL, Shen KH, Hung SH and Hsu YL: CXCL1/GROα increases cell migration and invasion of prostate cancer by decreasing fibulin-1 expression through NF-κB/HDAC1 epigenetic regulation. Carcinogenesis. 33:2477–2487. 2012. View Article : Google Scholar : PubMed/NCBI

17 

Han KQ, He XQ, Ma MY, Guo XD, Zhang XM, Chen J, Han H, Zhang WW, Zhu QG and Zhao WZ: Targeted silencing of CXCL1 by siRNA inhibits tumor growth and apoptosis in hepatocellular carcinoma. Int J Oncol. 47:2131–2140. 2015. View Article : Google Scholar : PubMed/NCBI

18 

Wang L, Zhang C, Xu J, Wu H, Peng J, Cai S and He Y: CXCL1 gene silencing inhibits HGC803 cell migration and invasion and acts as an independent prognostic factor for poor survival in gastric cancer. Mol Med Rep. 14:4673–4679. 2016. View Article : Google Scholar : PubMed/NCBI

19 

Divella R, Daniele A, Savino E, Palma F, Bellizzi A, Giotta F, Simone G, Lioce M, Quaranta M, Paradiso A, et al: Circulating levels of transforming growth factor-βeta (TGF-β) and chemokine (C-X-C motif) ligand-1 (CXCL1) as predictors of distant seeding of circulating tumor cells in patients with metastatic breast cancer. Anticancer Res. 33:1491–1497. 2013.PubMed/NCBI

20 

Zou A, Lambert D, Yeh H, Yasukawa K, Behbod F, Fan F and Cheng N: Elevated CXCL1 expression in breast cancer stroma predicts poor prognosis and is inversely associated with expression of TGF-β signaling proteins. BMC Cancer. 14:7812014. View Article : Google Scholar

21 

Wang L, Hou Y, Sun Y, Zhao L, Tang X, Hu P, Yang J, Zeng Z, Yang G, Cui X, et al: c-Ski activates cancer-associated fibroblasts to regulate breast cancer cell invasion. Mol Oncol. 7:1116–1128. 2013. View Article : Google Scholar : PubMed/NCBI

22 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-ΔΔC(T) method. Methods. 25:402–408. 2001. View Article : Google Scholar

23 

Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A and Chinnaiyan AM: ONCOMINE: A cancer microarray database and integrated data-mining platform. Neoplasia. 6:1–6. 2004. View Article : Google Scholar : PubMed/NCBI

24 

Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnesn H, Pesich R, Geisler S, et al: Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA. 100:8418–8423. 2003. View Article : Google Scholar : PubMed/NCBI

25 

Desmedt C, Piette F, Loi S, Wang Y, Lallemand F, Haibe-Kains B, Viale G, Delorenzi M, ZhangY d'Assignies MS, et al: Strong time dependence of the 76-gene prognostic signature for node-negative breast cancer patients in the TRANSBIG multicenter independent validation series. Clin Cancer Res. 13:3207–3214. 2007. View Article : Google Scholar : PubMed/NCBI

26 

Zhao J, Ou B, Han D, Wang P, Zong Y, Zhu C, Liu D, Zheng M, Sun J, Feng H, et al: Tumor-derived CXCL5 promotes human colorectal cancer metastasis through activation of the ERK/Elk-1/Snail and AKT/GSK3β/β-catenin pathways. Mol Cancer. 16:702017. View Article : Google Scholar

27 

Fu XT, Dai Z, Song K, Zhang ZJ, Zhou ZJ, Zhou SL, Zhao YM, Xiao YS, Sun QM, Ding ZB, et al: Macrophage-secreted IL-8 induces epithelial-mesenchymal transition in hepatocellular carcinoma cells by activating the JAK2/STAT3/Snail pathway. Int J Oncol. 46:587–596. 2015. View Article : Google Scholar

28 

Li S, Lu J, Chen Y, Xiong N, Li L, Zhang J, Yang H, Wu C, Zeng H and Liu Y: MCP-1-induced ERK/GSK-3β/Snail signaling facilitates the epithelial-mesenchymal transition and promotes the migration of MCF-7 human breast carcinoma cells. Cell Mol Immunol. 14:621–630. 2017. View Article : Google Scholar

29 

Ou B, Zhao J, Guan S, Feng H, Wangpu X, Zhu C, Zong Y, Ma J, Sun J, Shen X, et al: CCR4 promotes metastasis via ERK/NF-κB/MMP13 pathway and acts downstream of TNF-α in colorectal cancer. Oncotarget. 7:47637–47649. 2016. View Article : Google Scholar : PubMed/NCBI

30 

Jabłońska-Trypuć A, Matejczyk M and Rosochacki S: Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J Enzyme Inhib Med Chem. 31(Suppl 1): 177–183. 2016. View Article : Google Scholar

31 

Nishio K, Motozawa K, Omagari D, Gojoubori T, Ikeda T, Asano M and Gionhaku N: Comparison of MMP2 and MMP9 expression levels between primary and metastatic regions of oral squamous cell carcinoma. J Oral Sci. 58:59–65. 2016. View Article : Google Scholar : PubMed/NCBI

32 

Zheng Y, Miu Y, Yang X, Yang X and Zhu M: CCR7 mediates TGF-β1-induced human malignant glioma invasion, migration, and epithelial-mesenchymal transition by activating MMP2/9 through the nuclear factor kappaB signaling pathway. DNA Cell Biol. 36:853–861. 2017. View Article : Google Scholar : PubMed/NCBI

33 

Chen SX, Yin JF, Lin BC, Su HF, Zheng Z, Xie CY and Fei ZH: Upregulated expression of long noncoding RNA SNHG15 promotes cell proliferation and invasion through regulates MMP2/MMP9 in patients with GC. Tumour Biol. 37:6801–6812. 2016. View Article : Google Scholar

34 

Balkwill F: Cancer and the chemokine network. Nat Rev Cancer. 4:540–550. 2004. View Article : Google Scholar : PubMed/NCBI

35 

Mantovani A, Savino B, Locati M, Zammataro L, Allavena P and Bonecchi R: The chemokine system in cancer biology and therapy. Cytokine Growth Factor Rev. 21:27–39. 2010. View Article : Google Scholar

36 

Zhang T, Tseng C, Zhang Y, Sirin O, Corn PG, Li-Ning-Tapia EM, Troncoso P, Davis J, Pettaway C, Ward J, et al: CXCL1 mediates obesity-associated adipose stromal cell trafficking and function in the tumour microenvironment. Nat Commun. 7:116742016. View Article : Google Scholar : PubMed/NCBI

37 

Freund A, Chauveau C, Brouillet JP, Lucas A, Lacroix M, Licznar A, Vignon F and Lazennec G: IL-8 expression and its possible relationship with estrogen-receptor-negative status of breast cancer cells. Oncogene. 22:256–265. 2003. View Article : Google Scholar : PubMed/NCBI

38 

Lian S, Zhai X, Wang X, Zhu H, Zhang S, Wang W, Wang Z and Huang J: Elevated expression of growth-regulated oncogene-alpha in tumor and stromal cells predicts unfavorable prognosis in pancreatic cancer. Medicine (Baltimore). 95:e43282016. View Article : Google Scholar

39 

Han KQ, Han H, He XQ, Wang L, Guo XD, Zhang XM, Chen J, Zhu QG, Nian H, Zhai XF, et al: Chemokine CXCL1 may serve as a potential molecular target for hepatocellular carcinoma. Cancer Med. 5:2861–2871. 2016. View Article : Google Scholar : PubMed/NCBI

40 

Xiang Z, Jiang DP, Xia GG, Wei ZW, Chen W, He Y and Zhang CH: CXCL1 expression is correlated with Snail expression and affects the prognosis of patients with gastric cancer. Oncol Lett. 10:2458–2464. 2015. View Article : Google Scholar : PubMed/NCBI

41 

Cui X, Li Z, Gao J, Gao PJ, Ni YB and Zhu JY: Elevated CXCL1 increases hepatocellular carcinoma aggressiveness and is inhibited by miRNA-200a. Oncotarget. 7:65052–65066. 2016. View Article : Google Scholar : PubMed/NCBI

42 

Zhou J, Yi L, Ouyang Q, Xu L, Cui H and Xu M: Neurotensin signaling regulates stem-like traits of glioblastoma stem cells through activation of IL-8/CXCR1/STAT3 pathway. Cell Signal. 26:2896–2902. 2014. View Article : Google Scholar : PubMed/NCBI

43 

Zhou B, Sun C, Li N, Shan W, Lu H, Guo L, Guo E, Xia M, Weng D, Meng L, et al: Cisplatin-induced CCL5 secretion from CAFs promotes cisplatin-resistance in ovarian cancer via regulation of the STAT3 and PI3K/Akt signaling pathways. Int J Oncol. 48:2087–2097. 2016. View Article : Google Scholar : PubMed/NCBI

44 

Lin HY, Sun SM, Lu XF, Chen PY, Chen CF, Liang WQ and Peng CY: CCR10 activation stimulates the invasion and migration of breast cancer cells through the ERK1/2/MMP-7 signaling pathway. Int Immunopharmacol. 51:124–130. 2017. View Article : Google Scholar : PubMed/NCBI

45 

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

46 

Miyake M, Goodison S, Urquidi V, Gomes Giacoia E and Rosser CJ: Expression of CXCL1 in human endothelial cells induces angiogenesis through the CXCR2 receptor and the ERK1/2 and EGF pathways. Lab Invest. 93:768–778. 2013. View Article : Google Scholar : PubMed/NCBI

47 

Al-Alwan LA, Chang Y, Rousseau S, Martin JG, Eidelman DH and Hamid Q: CXCL1 inhibits airway smooth muscle cell migration through the decoy receptor Duffy antigen receptor for chemokines. J Immunol. 193:1416–1426. 2014. View Article : Google Scholar : PubMed/NCBI

48 

Filipovic R and Zecevic N: The effect of CXCL1 on human fetal oligodendrocyte progenitor cells. Glia. 56:1–15. 2008. View Article : Google Scholar

49 

Alaseem A, Alhazzani K, Dondapati P, Alobid S, Bishayee A and Rathinavelu A: Matrix Metalloproteinases: A challenging paradigm of cancer management. Semin Cancer Biol. 56:100–115. 2019. View Article : Google Scholar

50 

Zeng L, Qian J, Zhu F, Wu F, Zhao H and Zhu H: The prognostic values of matrix metalloproteinases in ovarian cancer. J Int Med Res. May 17–2019.Epub ahead of print. View Article : Google Scholar

51 

Ren F, Tang R, Zhang X, Madushi WM, Luo D, Dang Y, Li Z, Wei K and Chen G: Overexpression of MMP family members functions as prognostic biomarker for breast cancer patients: A systematic review and meta-snalysis. PLoS One. 10:e01355442015. View Article : Google Scholar

52 

Bai L, Lin G, Sun L, Liu Y, Huang X, Cao C, Guo Y and Xie C: Upregulation of SIRT6 predicts poor prognosis and promotes metastasis of non-small cell lung cancer via the ERK1/2/MMP9 pathway. Oncotarget. 7:40377–40386. 2016. View Article : Google Scholar : PubMed/NCBI

53 

Wang Y, Wu N, Pang B, Tong D, Sun D, Sun H, Zhang C, Sun W, Meng X, Bai J, et al: TRIB1 promotes colorectal cancer cell migration and invasion through activation MMP-2 via FAK/Src and ERK pathways. Oncotarget. 8:47931–47942. 2017.PubMed/NCBI

54 

Robbins P, Pinder S, de Klerk N, Dawkins H, Harvey J, Sterrett G, Ellis I and Elston C: Histological grading of breast carcinomas: A study of interobserver agreement. Hum Pathol. 26:873–879. 1995. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
APA
Yang, C., Yu, H., Chen, R., Tao, K., Jian, L., Peng, M. ... Liu, S. (2019). CXCL1 stimulates migration and invasion in ER‑negative breast cancer cells via activation of the ERK/MMP2/9 signaling axis. International Journal of Oncology, 55, 684-696. https://doi.org/10.3892/ijo.2019.4840
MLA
Yang, C., Yu, H., Chen, R., Tao, K., Jian, L., Peng, M., Li, X., Liu, M., Liu, S."CXCL1 stimulates migration and invasion in ER‑negative breast cancer cells via activation of the ERK/MMP2/9 signaling axis". International Journal of Oncology 55.3 (2019): 684-696.
Chicago
Yang, C., Yu, H., Chen, R., Tao, K., Jian, L., Peng, M., Li, X., Liu, M., Liu, S."CXCL1 stimulates migration and invasion in ER‑negative breast cancer cells via activation of the ERK/MMP2/9 signaling axis". International Journal of Oncology 55, no. 3 (2019): 684-696. https://doi.org/10.3892/ijo.2019.4840