CXCR7 silencing inhibits the migration and invasion of human tumor endothelial cells derived from hepatocellular carcinoma by suppressing STAT3

Wu,Ye; Tian,Lei; Xu,Yongle; Zhang,Minhong; Xiang,Shengqing; Zhao,Jianguo; Wang,Zhenxia

doi:10.3892/mmr.2018.9114

CXCR7 silencing inhibits the migration and invasion of human tumor endothelial cells derived from hepatocellular carcinoma by suppressing STAT3

Authors:
- Ye Wu
- Lei Tian
- Yongle Xu
- Minhong Zhang
- Shengqing Xiang
- Jianguo Zhao
- Zhenxia Wang
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Affiliations: Department of General Surgery, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia 010059, P.R. China, Department of Anesthesia, General Hospital of The PLA Rocket Force, Beijing 100088, P.R. China, Department of Vascular Surgery, General Hospital of PLA, Beijing 100853, P.R. China, Department of Pharmacy, General Hospital of The PLA Rocket Force, Beijing 100088, P.R. China
Published online on: May 31, 2018 https://doi.org/10.3892/mmr.2018.9114
Pages: 1644-1650

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Abstract

C-X-C chemokine receptor type 7 (CXCR7) is reported to be overexpressed in tumor endothelial cells (TECs), which are the primary target cells of antivascular chemotherapy. However, the role of CXCR7 in TECs is not fully understood. In the present study, CXCR7 expression was inhibited in TECs derived from hepatocellular carcinoma (HCC) using short hairpin (sh)RNA plasmids to investigate the role of CXCR7 in the regulation of migration and invasion of TECs as well as its underlying mechanisms. The data showed that the downregulation of CXCR7 significantly inhibited the migration and invasion of TECs. Further study showed that silencing CXCR7 resulted in decreased phosphorylated signal transducer and activator of transcription 3 (STAT3) at Tyr705 and its downstream target genes in TECs, including matrix metalloproteinase‑2 (MMP2) and vascular endothelial growth factor (VEGF). However, restoring STAT3 phosphorylation abolished the CXCR7‑shRNA‑induced decrease in TECs migration and invasion, as well as the downregulation of MMP2 and VEGF in TECs. These findings indicate that CXCR7 may regulate the migration and invasion of TECs derived from HCC via the STAT3 signaling pathway and that CXCR7 could be a potential target for the antivascular therapy of HCC.

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1	McGlynn KA, Petrick JL and London WT: Global epidemiology of hepatocellular carcinoma: An emphasis on demographic and regional variability. Clin Liver Dis. 19:223–238. 2015. View Article : Google Scholar : PubMed/NCBI
2	Zetter BR: Angiogenesis and tumor metastasis. Annu Rev Med. 49:407–424. 1998. View Article : Google Scholar : PubMed/NCBI
3	Folkman J: Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 29 6 Suppl 16:S15–S18. 2002. View Article : Google Scholar
4	Volpert OV, Dameron KM and Bouck N: Sequential development of an angiogenic phenotype by human fibroblasts progressing to tumorigenicity. Oncogene. 14:1495–1502. 1997. View Article : Google Scholar : PubMed/NCBI
5	Liberman J, Sartelet H, Flahaut M, Mühlethaler-Mottet A, Coulon A, Nyalendo C, Vassal G, Joseph JM and Gross N: Involvement of the CXCR7/CXCR4/CXCL12 axis in the malignant progression of human neuroblastoma. PLoS One. 7:e436652012. View Article : Google Scholar : PubMed/NCBI
6	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 : PubMed/NCBI
7	Maishi N, Ohga N, Hida Y, Akiyama K, Kitayama K, Osawa T, Onodera Y, Shinohara N, Nonomura K, Shindoh M and Hida K: CXCR7: a novel tumor endothelial marker in renal cell carcinoma. Pathol Int. 62:309–317. 2012. View Article : Google Scholar : PubMed/NCBI
8	Yamada K, Maishi N, Akiyama K, Alam Towfik M, Ohga N, Kawamoto T, Shindoh M, Takahashi N, Kamiyama T, Hida Y, et al: CXCL12-CXCR7 axis is important for tumor endothelial cell angiogenic property. Int J Cancer. 137:2825–2836. 2015. View Article : Google Scholar : PubMed/NCBI
9	Chen Y, Teng F, Wang G and Nie Z: Overexpression of CXCR7 induces angiogenic capacity of human hepatocellular carcinoma cells via the AKT signaling pathway. Oncol Rep. 36:2275–2281. 2016. View Article : Google Scholar : PubMed/NCBI
10	Hu C, Shen SQ, Cui ZH, Chen ZB and Li W: Effect of microRNA-1 on hepatocellular carcinoma tumor endothelial cells. World J Gastroenterol. 21:5884–5892. 2015. View Article : Google Scholar : PubMed/NCBI
11	Cao Z, Zheng L, Zhao J, Zhuang Q, Hong Z and Lin W: Anti-angiogenic effect of Livistona chinensis seed extract in vitro and in vivo. Oncol Lett. 14:7565–7570. 2017.PubMed/NCBI
12	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
13	Hao M, Zheng J, Hou K and Wang J, Chen X, Lu X, Bo J, Xu C, Shen K and Wang J: Role of chemokine receptor CXCR7 in bladder cancer progression. Biochem Pharmacol. 84:204–214. 2012. View Article : Google Scholar : PubMed/NCBI
14	Li F, Gao L, Jiang Q, Wang Z, Dong B, Yan T and Chen X: Radiation enhances the invasion abilities of pulmonary adenocarcinoma cells via STAT3. Mol Med Rep. 7:1883–1888. 2013. View Article : Google Scholar : PubMed/NCBI
15	Hida K, Maishi N, Torii C and Hida Y: Tumor angiogenesis-characteristics of tumor endothelial cells. Int J Clin Oncol. 21:206–212. 2016. View Article : Google Scholar : PubMed/NCBI
16	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
17	Teicher BA and Fricker SP: CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res. 16:2927–2931. 2010. View Article : Google Scholar : PubMed/NCBI
18	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
19	Wu YC, Tang SJ, Sun GH and Sun KH: CXCR7 mediates TGFβ1-promoted EMT and tumor-initiating features in lung cancer. Oncogene. 35:2123–2132. 2016. View Article : Google Scholar : PubMed/NCBI
20	Yu H, Zhang L and Liu P: CXCR7 signaling induced epithelial-mesenchymal transition by AKT and ERK pathways in epithelial ovarian carcinomas. Tumour Biol. 36:1679–1683. 2015. View Article : Google Scholar : PubMed/NCBI
21	Lin L, Han MM, Wang F, Xu LL, Yu HX and Yang PY: CXCR7 stimulates MAPK signaling to regulate hepatocellular carcinoma progression. Cell Death Dis. 5:e14882014. View Article : Google Scholar : PubMed/NCBI
22	O'Shea JJ, Holland SM and Staudt LM: JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med. 368:161–170. 2013. View Article : Google Scholar : PubMed/NCBI
23	Xuan X, Li S, Lou X, Zheng X, Li Y, Wang F, Gao Y, Zhang H, He H and Zeng Q: Stat3 promotes invasion of esophageal squamous cell carcinoma through up-regulation of MMP2. Mol Biol Rep. 42:907–915. 2015. View Article : Google Scholar : PubMed/NCBI
24	Zhao G, Zhu G, Huang Y, Zheng W, Hua J, Yang S, Zhuang J and Ye J: IL-6 mediates the signal pathway of JAK-STAT3-VEGF-C promoting growth, invasion and lymphangiogenesis in gastric cancer. Oncol Rep. 35:1787–1795. 2016. View Article : Google Scholar : PubMed/NCBI
25	Wang X, Qiu W, Zhang G, Xu S, Gao Q and Yang Z: MicroRNA-204 targets JAK2 in breast cancer and induces cell apoptosis through the STAT3/BCl-2/survivin pathway. Int J Clin Exp Pathol. 8:5017–5025. 2015.PubMed/NCBI