Targeted silencing of CXCL1 by siRNA inhibits tumor growth and apoptosis in hepatocellular carcinoma

Han,Ke-Qi; He,Xue-Qun; Ma,Meng-Yu; Guo,Xiao-Dong; Zhang,Xue-Min; Chen,Jie; Han,Hui; Zhang,Wei-Wei; Zhu,Quan-Gang; Zhao,Wen-Zhao

doi:10.3892/ijo.2015.3203

Targeted silencing of CXCL1 by siRNA inhibits tumor growth and apoptosis in hepatocellular carcinoma

Authors:
- Ke-Qi Han
- Xue-Qun He
- Meng-Yu Ma
- Xiao-Dong Guo
- Xue-Min Zhang
- Jie Chen
- Hui Han
- Wei-Wei Zhang
- Quan-Gang Zhu
- Wen-Zhao Zhao
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Affiliations: Department of Oncology, Shanghai Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P.R. China, Department of Pharmacy, Shanghai Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P.R. China, Department of Surgery, Affiliated Hospital of Henan Science and Technology University, School of Medicine, Luoyang, Henan 471003, P.R. China
Published online on: October 13, 2015 https://doi.org/10.3892/ijo.2015.3203
Pages: 2131-2140

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Abstract

Hepatocellular carcinoma (HCC) is an aggressive malignancy and a major cause of cancer-related mortality worldwide. Our previous study shows that chemokine (C-X-C motif) ligand 1 (CXCL1) was upregulated and CXCR1 was downregulated in tumor tissues as compared to peritumor tissues by chemotaxis assay. As the status of CXCL subgroups and their receptors affect progression of HCC, we evaluated potential mechanisms of CXCL1 associated with anticancer effects in HCC based on our previous study. The effects of targeting CXCL1 by RNA interference (RNAi) on the proliferation and apoptosis of CBRH-7919 cells were observed in vitro and in vivo. Additionally, whether CXCL1 knockdown significantly reduce the activity of STAT3, NF-κB and HIF-1 or not were also estimated. RNAi of CXCL1 in the CBRH-7919 cells decreased the growth of tumors in nude mice by inhibited cells proliferation and induced apoptosis. In conclusion, these findings suggest that CXCL1 plays critical roles in the growth and apoptosis of HCC. RNAi of CXCL1 inhibits the growth and apoptosis of tumor cells, which indicates that CXCL1 may be a potential molecular target for use in HCC therapy.

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1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI
2	Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 127:2893–2917. 2010. View Article : Google Scholar
3	Li G, Chang H, Zhai YP and Xu W: Targeted silencing of inhibitor of apoptosis proteins by siRNA: A potential anti-cancer strategy for hepatocellular carcinoma. Asian Pac J Cancer Prev. 14:4943–4952. 2013. View Article : Google Scholar
4	Shi YH, Ding WX, Zhou J, He JY, Xu Y, Gambotto AA, Rabinowich H, Fan J and Yin XM: Expression of X-linked inhibitor-of-apoptosis protein in hepatocellular carcinoma promotes metastasis and tumor recurrence. Hepatology. 48:497–507. 2008. View Article : Google Scholar : PubMed/NCBI
5	Zhang L, Zhao Z, Feng Z, Yin N, Liu G and Shan B: RNA interference-mediated silencing of Stat5 induces apoptosis and growth suppression of hepatocellular carcinoma cells. Neoplasma. 59:302–309. 2012. View Article : Google Scholar : PubMed/NCBI
6	Strieter RM, Burdick MD, Mestas J, Gomperts B, Keane MP and Belperio JA: Cancer CXC chemokine networks and tumour angiogenesis. Eur J Cancer. 42:768–78. 2006. View Article : Google Scholar : PubMed/NCBI
7	Han KQ, He XQ, Ma MY, Guo XD, Zhang XM, Chen J, Han H, Zhang WW, Zhu QG, Nian H, et al: Inflammatory microenvironment and expression of chemokines in hepatocellular carcinoma. World J Gastroenterol. 21:4864–4874. 2015. View Article : Google Scholar : PubMed/NCBI
8	Ghanem I, Riveiro ME, Paradis V, Faivre S, de Parga PM and Raymond E: Insights on the CXCL12-CXCR4 axis in hepatocellular carcinoma carcinogenesis. Am J Transl Res. 6:340–352. 2014.PubMed/NCBI
9	An H, Xu L, Zhu Y, Lv T, Liu W, Liu Y, Liu H, Chen L, Xu J and Lin Z: High CXC chemokine receptor 4 expression is an adverse prognostic factor in patients with clear-cell renal cell carcinoma. Br J Cancer. 110:2261–2268. 2014. View Article : Google Scholar : PubMed/NCBI
10	Rentoft M, Coates PJ, Loljung L, Wilms T, Laurell G and Nylander K: Expression of CXCL10 is associated with response to radiotherapy and overall survival in squamous cell carcinoma of the tongue. Tumour Biol. 35:4191–4198. 2014. View Article : Google Scholar : PubMed/NCBI
11	Verbeke H, Struyf S, Laureys G and Van Damme J: The expression and role of CXC chemokines in colorectal cancer. Cytokine Growth Factor Rev. 22:345–358. 2011. View Article : Google Scholar : PubMed/NCBI
12	Miyake M, Lawton A, Goodison S, Urquidi V and Rosser CJ: Chemokine (C-X-C motif) ligand 1 (CXCL1) protein expression is increased in high-grade prostate cancer. Pathol Res Pract. 210:74–75. 2014. View Article : Google Scholar
13	Dhawan P and Richmond A: Role of CXCL1 in tumorigenesis of melanoma. J Leukoc Biol. 72:9–18. 2002.PubMed/NCBI
14	Miyake M, Lawton A, Goodison S, Urquidi V, Gomes-Giacoia E, Zhang G, Ross S, Kim J and Rosser CJ: Chemokine (C-X-C) ligand 1 (CXCL1) protein expression is increased in aggressive bladder cancers. BMC Cancer. 13:3222013. View Article : Google Scholar : PubMed/NCBI
15	Liu Z, Yang L, Xu J, Zhang X and Wang B: Enhanced expression and clinical significance of chemokine receptor CXCR2 in hepatocellular carcinoma. J Surg Res. 166:241–246. 2011. View Article : Google Scholar
16	Grivennikov SI, Greten FR and Karin M: Immunity, inflammation, and cancer. Cell. 140:883–899. 2010. View Article : Google Scholar : PubMed/NCBI
17	Yu H, Pardoll D and Jove R: STATs in cancer inflammation and immunity: A leading role for STAT3. Nat Rev Cancer. 9:798–809. 2009. View Article : Google Scholar : PubMed/NCBI
18	Wani N, Nasser MW, Ahirwar DK, Zhao H, Miao Z, Shilo K and Ganju RK: C-X-C motif chemokine 12/C-X-C chemokine receptor type 7 signaling regulates breast cancer growth and metastasis by modulating the tumor microenvironment. Breast Cancer Res. 16:R542014. View Article : Google Scholar : PubMed/NCBI
19	Boissière-Michot F, Lazennec G, Frugier H, Jarlier M, Roca L, Duffour J, Du Paty E, Laune D, Blanchard F, Le Pessot F, et al: Characterization of an adaptive immune response in microsatellite-instable colorectal cancer. OncoImmunology. 3:e292562014. View Article : Google Scholar : PubMed/NCBI
20	Bandapalli OR, Ehrmann F, Ehemann V, Gaida M, Macher-Goeppinger S, Wente M, Schirmacher P and Brand K: Down-regulation of CXCL1 inhibits tumor growth in colorectal liver metastasis. Cytokine. 57:46–53. 2012. View Article : Google Scholar
21	Wang JG, Strong JA, Xie W, Yang RH, Coyle DE, Wick DM, Dorsey ED and Zhang JM: The chemokine CXCL1/growth related oncogene increases sodium currents and neuronal excitability in small diameter sensory neurons. Mol Pain. 4:382008. View Article : Google Scholar : PubMed/NCBI
22	Benelli R, Stigliani S, Minghelli S, Carlone S and Ferrari N: Impact of CXCL1 overexpression on growth and invasion of prostate cancer cell. Prostate. 73:941–951. 2013. View Article : Google Scholar : PubMed/NCBI
23	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
24	Killian PH, Kronski E, Michalik KM, Barbieri O, Astigiano S, Sommerhoff CP, Pfeffer U, Nerlich AG and Bachmeier BE: Curcumin inhibits prostate cancer metastasis in vivo by targeting the inflammatory cytokines CXCL1 and -2. Carcinogenesis. 33:2507–2519. 2012. View Article : Google Scholar : PubMed/NCBI
25	Pecot CV, Rupaimoole R, Yang D, Akbani R, Ivan C, Lu C, Wu S, Han HD, Shah MY, Rodriguez-Aguayo C, et al: Tumour angiogenesis regulation by the miR-200 family. Nat Commun. 4:24272013. View Article : Google Scholar : PubMed/NCBI
26	Jung JJ, Noh S, Jeung HC, Jung M, Kim TS, Noh SH, Roh JK, Chung HC and Rha SY: Chemokine growth-regulated oncogene 1 as a putative biomarker for gastric cancer progression. Cancer Sci. 101:2200–2206. 2010. View Article : Google Scholar : PubMed/NCBI
27	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-beta (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
28	Kavandi L, Collier MA, Nguyen H and Syed V: Progesterone and calcitriol attenuate inflammatory cytokines CXCL1 and CXCL2 in ovarian and endometrial cancer cells. J Cell Biochem. 113:3143–3152. 2012. View Article : Google Scholar : PubMed/NCBI
29	Yu H and Jove R: The STATs of cancer - new molecular targets come of age. Nat Rev Cancer. 4:97–105. 2004. View Article : Google Scholar : PubMed/NCBI
30	Liang Y, Zheng T, Song R, Wang J, Yin D, Wang L, Liu H, Tian L, Fang X, Meng X, et al: Hypoxia-mediated sorafenib resistance can be overcome by EF24 through Von Hippel-Lindau tumor suppressor-dependent HIF-1α inhibition in hepatocellular carcinoma. Hepatology. 57:1847–1857. 2013. View Article : Google Scholar : PubMed/NCBI
31	Novell A, Martinez-Alonso M, Mira M, Tarragona J, Salud A and Matias-Guiu X: Prognostic value of c-FLIPL/s, HIF-1α, and NF-κβ in stage II and III rectal cancer. Virchows Arch. 464:645–654. 2014. View Article : Google Scholar : PubMed/NCBI
32	Chen SP, Yang Q, Wang CJ, Zhang LJ, Fang Y, Lei FY, Wu S, Song LB, Guo X and Guo L: Transducin β-like 1 X-linked receptor 1 suppresses cisplatin sensitivity in nasopharyngeal carcinoma via activation of NF-κB pathway. Mol Cancer. 13:1952014. View Article : Google Scholar
33	Byrne AJ, Jones CP, Gowers K, Rankin SM and Lloyd CM: Lung macrophages contribute to house dust mite driven airway remodeling via HIF-1α. PLoS One. 8:e692462013. View Article : Google Scholar
34	Wang J, Yu F, Jia X, Iwanowycz S, Wang Y, Huang S, Ai W and Fan D: MicroRNA-155 deficiency enhances the recruitment and functions of myeloid-derived suppressor cells in tumor microenvironment and promotes solid tumor growth. Int J Cancer. 136:E602–E613. 2014. View Article : Google Scholar : PubMed/NCBI