Interleukin‑8 promotes cell migration via CXCR1 and CXCR2 in liver cancer

Bi,Huijuan; Zhang,Yu; Wang,Shanshan; Fang,Wenhao; He,Wenjun; Yin,Lina; Xue,Ying; Cheng,Zhixiang; Yang,Minghui; Shen,Jilu

doi:10.3892/ol.2019.10735

Interleukin‑8 promotes cell migration via CXCR1 and CXCR2 in liver cancer

Authors:
- Huijuan Bi
- Yu Zhang
- Shanshan Wang
- Wenhao Fang
- Wenjun He
- Lina Yin
- Ying Xue
- Zhixiang Cheng
- Minghui Yang
- Jilu Shen
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Affiliations: Department of Clinical Laboratory, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230000, P.R. China
Published online on: August 8, 2019 https://doi.org/10.3892/ol.2019.10735
Pages: 4176-4184
Copyright: © Bi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Liver cancer (LC), which is one of the most common types of cancer worldwide, is notorious for its high morbidity and mortality rates. Interleukin‑8 (IL‑8), an important member of the CXC chemokine family that was originally classified as a potent neutrophil chemoattractant, has been shown to serve an important role in inflammation, tumor growth, invasion and metastasis through interactions with its receptors. However, the expression and functional roles of IL‑8 and its receptors, CXC chemokine receptor (CXCR) 1 and CXCR2 in the progression of liver cancer remain to be fully elucidated. In the present study, it was shown that the mRNA levels of IL‑8, CXCR1 and CXCR2 were increased in peripheral blood mononuclear cells from patients with liver cancer compared with those from patients with cirrhosis or normal controls (P<0.05). Higher levels of CXCR1, CXCR2 and IL‑8 were associated with advanced tumor stage and increased risk of lymph node or distant metastasis. Immunohistochemistry showed that the IL‑8, CXCR1 and CXCR2 proteins were expressed in the cytoplasm of hepatoma cells at higher intensities than those of normal controls (P<0.05). The semi‑quantitative analysis revealed that the relative mean density of hepatic IL‑8, CXCR1 and CXCR2 staining in liver cancer was significantly increased compared with that in normal liver tissues (P<0.05). The analysis revealed that the mRNA expression of IL‑8 was positively associated with that of CXCR1 (r=0.618; P<0.05) and CXCR2 (r=0.569; P<0.05). The mRNA levels of CXCR1 and CXCR2 gradually increased with elevated expression of IL‑8 in liver cancer. Experiments were performed using human Huh‑7 and HepG2 cell lines, incubating cells with IL‑8 and conducting in vitro migration and invasion assays. The results showed that the wound healing activity and migration of Huh‑7 and HepG2 cells were increased by IL‑8. Pretreatment of the cells with anti‑CXCR1 or anti‑CXCR2 (5 µM) for 30 min markedly inhibited IL‑8‑directed cell migration. Taken together, these results indicated that IL‑8 promotes liver cancer cell migration via CXCR1 and CXCR2 and that targeting the CXCR1/2 may be a potential strategy for liver cancer treatment.

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1	Yu SJ: A concise review of updated guidelines regarding the management of hepatocellular carcinoma around the world: 2010–2016. Clin Mol Hepatol. 22:7–17. 2016. View Article : Google Scholar : PubMed/NCBI
2	Omata M, Cheng AL, Kokudo N, Kudo M, Lee JM, Jia J, Tateishi R, Han KH, Chawla YK, Shiina S, et al: Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: A 2017 update. Hepatol Int. 11:317–370. 2017. View Article : Google Scholar : PubMed/NCBI
3	McAllister SS and Weinberg RA: The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat Cell Biol. 16:717–727. 2014. View Article : Google Scholar : PubMed/NCBI
4	Zhang H and Xu X: Mutation-promoting molecular networks of uncontrolled inflammation. Tumour Biol. 39:10104283177013102017. View Article : Google Scholar : PubMed/NCBI
5	Ruffini PA, Morandi P, Cabioglu N, Altundag K and Cristofanilli M: Manipulating the chemokine-chemokine receptor network to treat cancer. Cancer. 109:2392–2404. 2007. View Article : Google Scholar : PubMed/NCBI
6	Karin N: Chemokines and cancer: New immune checkpoints for cancer therapy. Curr Opin Immunol. 51:140–145. 2018. View Article : Google Scholar : PubMed/NCBI
7	Dayer R, Babashah S, Jamshidi S and Sadeghizadeh M: Upregulation of CXC chemokine receptor 4-CXC chemokine ligand 12 axis ininvasive breast carcinoma: A potent biomarker predicting lymph node metastasis. J Cancer Res Ther. 14:345–350. 2018.PubMed/NCBI
8	Mao TL, Fan KF and Liu CL: Targeting the CXCR4/CXCL12 axis in treating epithelial ovarian cancer. Gene Ther. 24:621–629. 2017. View Article : Google Scholar : PubMed/NCBI
9	Bronger H, Karge A, Dreyer T, Zech D, Kraeft S, Avril S, Kiechle M and Schmitt M: Induction of cathepsin B by the CXCR3 chemokines CXCL9 and CXCL10 in human breast cancer cells. Oncol Lett. 13:4224–4230. 2017. View Article : Google Scholar : PubMed/NCBI
10	Hosono M, Koma YI, Takase N, Urakawa N, Higashino N, Suemune K, Kodaira H, Nishio M, Shigeoka M, Kakeji Y and Yokozaki H: CXCL8 derived from tumor-associated macrophages and esophageal squamous cell carcinomas contributes to tumor progression by promoting migration and invasion of cancer cells. Oncotarget. 8:106071–88. 2017. View Article : Google Scholar : PubMed/NCBI
11	Holmes WE, Lee J, Kuang WJ, Rice GC and Wood WI: Structure and functional expression of a human interleukin-8 receptor. Science. 253:1278–1280. 1991. View Article : Google Scholar : PubMed/NCBI
12	Murphy PM and Tiffany HL: Cloning of complementary DNA encoding a functional human interleukin-8 receptor. Science. 253:1280–1283. 1991. View Article : Google Scholar : PubMed/NCBI
13	Bi HJ, Wang J, Huang HS and Liu JH: Influence of IFN on expression of chemokine receptor CXCR1, CXCR2 and their ligand IL-8 in the patients with chronic hepatitis B. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 28:422–425. 2012.(In Chinese). PubMed/NCBI
14	Ha H, Debnath B and Neamati N: Role of the CXCL8-CXCR1/2 axis in cancer and inflammatory diseases. Theranostics. 7:1543–1588. 2017. View Article : Google Scholar : PubMed/NCBI
15	Liu Q, Li A, Tian Y, Wu JD, Liu Y, Li T, Chen Y, Han X and Wu K: The CXCL8-CXCR1/2 pathways in cancer. Cytokine Growth Factor Rev. 31:61–71. 2016. View Article : Google Scholar : PubMed/NCBI
16	Singh S, Sadanandam A, Varney ML, Nannuru KC and Singh RK: Small interfering RNA-mediated CXCR1 or CXCR2 knock-down inhibits melanoma tumor growth and invasion. Int J Cancer. 126:328–336. 2010. View Article : Google Scholar : PubMed/NCBI
17	Zhu H, Gu Y, Xue Y, Yuan M, Cao X and Liu Q: CXCR2⁺ MDSCs promote breast cancer progression by inducing EMT and activated T cell exhaustion. Oncotarget. 8:114554–114567. 2017. View Article : Google Scholar : PubMed/NCBI
18	Franz JM, Portela P, Salim PH, Berger M, Fernando Jobim L, Roesler R, Jobim M and Schwartsmann G: CXCR2 +1208 CT genotype may predict earlier clinical stage at diagnosis in patients with prostate cancer. Cytokine. 97:193–200. 2017. View Article : Google Scholar : PubMed/NCBI
19	Li A, Varney ML and Singh RK: Expression of interleukin 8 and its receptors in human colon carcinoma cells with different metastatic potentials. Clin Cancer Res. 7:3298–3304. 2001.PubMed/NCBI
20	Li Z, Wang Y, Dong S, Ge C, Xiao Y, Li R, Ma X, Xue Y, Zhang Q, Lv J, et al: Association of CXCR1 and 2 expressions with gastric cancer metastasis in ex vivo and tumor cell invasion in vitro. Cytokine. 69:6–13. 2014. View Article : Google Scholar : PubMed/NCBI
21	Yung MM, Tang HW, Cai PC, Leung TH, Ngu SF, Chan KK, Xu D, Yang H, Ngan HY and Chan DW: GRO-α and IL-8 enhance ovarian cancer metastatic potential via the CXCR2-mediated TAK1/NFκB signaling cascade. Theranostics. 8:1270–1285. 2018. View Article : Google Scholar : PubMed/NCBI
22	Ministry of Health of the People's Republic of China, . Standard for diagnosis and treatment of primary hepatocellular carcinoma (2011 edition). Chin J Hepatol. 20:419–426. 2012.(In Chinese).
23	Ren Y, Poon RT, Tsui HT, Chen WH, Li Z, Lau C, Yu WC and Fan ST: Interleukin-8 serum levels in patients with hepatocellular carcinoma: Correlations with clinicopathological features and prognosis. Clin Cancer Res. 9:5996–6001. 2003.PubMed/NCBI
24	Akiba J, Yano H, Ogasawara S, Higaki K and Kojiro M: Expression and function of interleukin-8 in human hepatocellular carcinoma. Int J Oncol. 18:257–264. 2001.PubMed/NCBI
25	Wang J, Han Z and Zhou N: Expression of CXCL8 and its receptors (CXCR1 and CXCR2) in peripheral blood neutrophils of chronic hepatitis B. Chin J Immunol. 375–379. 383:2015.
26	Xue TC, Chen RX, Ye SL, Sun RX, Chen J and Tang ZY: Different expressions of chemokine receptors in human hepatocellular carcinoma cell lines with different metastatic potentials. Zhonghua Gan Zang Bing Za Zhi. 15:261–265. 2007.(In Chinese). PubMed/NCBI
27	Huang W, Chen Z, Zhang L, Tian D, Wang D, Fan D, Wu K and Xia L: Interleukin-8 induces expression of FOXC1 to promote transactivation of CXCR1 and CCL2 in hepatocellular carcinoma cell lines and formation of metastases in mice. Gastroenterology. 149:1053–1067.e14. 2015. View Article : Google Scholar : PubMed/NCBI