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1
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Lu Y, Xing F, Peng S. The effect of CXCL12 on survival outcomes of patients with viral hepatitis-associated hepatocellular carcinoma after hepatectomy. Heliyon 2024; 10:e30782. [PMID: 38756575 PMCID: PMC11096947 DOI: 10.1016/j.heliyon.2024.e30782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 05/05/2024] [Accepted: 05/06/2024] [Indexed: 05/18/2024] Open
Abstract
Background The CXCL12-CXCR4/CXCR7 axis is garnering growing attention. But the comprehension of its function in the progression of HCC remains controversial. The purpose of this study was to investigate the effects of CXCL12 and its receptor on the prognosis of patients with viral hepatitis-associated HCC after hepatectomy. Methods A total of 86 patients had been enrolled who had undergone hepatectomy for HCC and followed up to July 31, 2019, and their clinicopathological and follow-up data were recorded. Tumor and peritumoral tissues were obtained to detect the expression of CXCL12, CXCR4, and CXCR7 using immunohistochemistry. Real-time polymerase chain reaction was utilized to detect hepatitis B or C virus loads, while survival analysis was performed using the Kaplan-Meier method. Furthermore, the Cox proportional hazards regression model was employed to analyze the factors affecting the prognosis. Results The results revealed that the CXCL12, CXCR4, and CXCR7 expression in tumor tissues was lower than in the corresponding non-tumor tissues in 20.93 %, 22.09 %, and 23.26 % of the patients, respectively, and that only CXCL12 was found to be related to the extrahepatic invasion of HCC. The survival analysis and Cox regression showed that only CXCL12 was associated with the postoperative survival of patients with HCC, and that it was an independent prognostic risk factor in the CXCL12-CXCR4/CXCR7 axis. The CXCL12low group represented shorter progression-free survival and lower overall survival rates. However, the subgroup analysis displayed that the survival difference associated with CXCL12 was only manifested in patients with higher expression of CXCR4 or CXCR7 in HCC, as compared to the surrounding tissues. Conclusions Our findings suggest that, when assessing the prognostic significance of CXCL12 in HCC, it is essential to consider the expression level of its receptor. Nevertheless, CXCL12 can potentially serve as a promising prognostic marker for HCC.
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Affiliation(s)
- Yan Lu
- the Department of Hospital Infection Control and Public Health Management, the Seventh Affiliated Hospital, Sun Yat-sen University, No. 628 Zhenyuan Road, Guangming District, Shenzhen, 518107, China
| | - Fei Xing
- the Department of Oncology, the Shengjing Hospital of China Medical University, Shenyang, No. 36 Sanhao Street, Heping District, 110004, China
| | - Songlin Peng
- the Department of General Surgery, the Seventh Affiliated Hospital, Sun Yat-sen University, No. 628 Zhenyuan Road, Guangming District, Shenzhen, 518107, China
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2
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Zhou XH, Li JR, Zheng TH, Chen H, Cai C, Ye SL, Gao B, Xue TC. Portal vein tumor thrombosis in hepatocellular carcinoma: molecular mechanism and therapy. Clin Exp Metastasis 2023; 40:5-32. [PMID: 36318440 DOI: 10.1007/s10585-022-10188-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 10/04/2022] [Indexed: 11/05/2022]
Abstract
Portal vein tumor thrombosis (PVTT), a common complication of advanced hepatocellular carcinoma (HCC), remains the bottleneck of the treatments. Liver cancer cells potentially experienced multi-steps during PVTT process, including cancer cells leave from cancer nest, migrate in extracellular matrix, invade the vascular barrier, and colonize in the portal vein. Accumulated evidences have revealed numerous of molecular mechanisms including genetic and epigenetic regulation, cancer stem cells, immunosuppressive microenvironment, hypoxia, et al. contributed to the PVTT formation. In this review, we discuss state-of-the-art PVTT research on the potential molecular mechanisms and experimental models. In addition, we summarize PVTT-associated clinical trials and current treatments for PVTT and suppose perspectives exploring the molecular mechanisms and improving PVTT-related treatment for the future.
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Affiliation(s)
- Xing-Hao Zhou
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, 200032, China.,Department of Hepatic Oncology, Fudan University, Zhongshan Hospital, Shanghai, 200032, China.,National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China
| | - Jing-Ru Li
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, 200032, China.,Department of Hepatic Oncology, Fudan University, Zhongshan Hospital, Shanghai, 200032, China.,National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China
| | - Tang-Hui Zheng
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China.,Department of Hepatic Oncology, Xiamen Branch, Fudan University, Zhongshan Hospital, Xiamen, 361015, China
| | - Hong Chen
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China.,Department of Hepatic Oncology, Xiamen Branch, Fudan University, Zhongshan Hospital, Xiamen, 361015, China
| | - Chen Cai
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, 200032, China.,Department of Hepatic Oncology, Fudan University, Zhongshan Hospital, Shanghai, 200032, China.,National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China
| | - Sheng-Long Ye
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China.,Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, 200032, China.,Department of Hepatic Oncology, Fudan University, Zhongshan Hospital, Shanghai, 200032, China.,National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China
| | - Bo Gao
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai Medical College, Shanghai, 200032, China.
| | - Tong-Chun Xue
- Liver Cancer Institute, Fudan University, Zhongshan Hospital, 136 Yi Xue Yuan Road, Shanghai, 200032, China. .,Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, 200032, China. .,Department of Hepatic Oncology, Fudan University, Zhongshan Hospital, Shanghai, 200032, China. .,National Clinical Research Center for Interventional Medicine, Fudan University, Shanghai, 200032, China.
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3
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Xin Q, Sun Q, Zhang CS, Zhang Q, Li CJ. Functions and mechanisms of chemokine receptor 7 in tumors of the digestive system. World J Clin Cases 2020; 8:2448-2463. [PMID: 32607322 PMCID: PMC7322425 DOI: 10.12998/wjcc.v8.i12.2448] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 05/12/2020] [Accepted: 06/02/2020] [Indexed: 02/05/2023] Open
Abstract
Chemokine (C-X-C motif) receptor 7 (CXCR7), recently termed ACKR3, belongs to the G protein-coupled cell surface receptor family, binds to stromal cell-derived factor-1 [SDF-1, or chemokine (C-X-C motif) ligand 12] or chemokine (C-X-C motif) ligand 11, and is the most common chemokine receptor expressed in a variety of cancer cells. SDF-1 binds to its receptor chemokine (C-X-C motif) receptor 4 (CXCR4) and regulates cell proliferation, survival, angiogenesis and migration. In recent years, another new receptor for SDF-1, CXCR7, has been discovered, and CXCR7 has also been found to be expressed in a variety of tumor cells and tumor-related vascular endothelial cells. Many studies have shown that CXCR7 can promote the growth and metastasis of a variety of malignant tumor cells. Unlike CXCR4, CXCR7 exhibits a slight modification in the DRYLAIV motif and does not induce intracellular Ca2+ release following ligand binding, which is essential for recruiting and activating G proteins. CXCR7 is generally thought to work in three ways: (1) Recruiting β-arrestin 2; (2) Heterodimerizing with CXCR4; and (3) Acting as a “scavenger” of SDF-1, thus lowering the level of SDF-1 to weaken the activity of CXCR4. In the present review, the expression and role of CXCR7, as well as its prognosis in cancers of the digestive system, were investigated.
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Affiliation(s)
- Qi Xin
- Department of Pathology, Tianjin Third Central Hospital, The Third Central Clinical College of Tianjin Medical University, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin 300170, China
- Tianjin Key Laboratory of Brain Science and Neural Engineering, Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300072, China
| | - Quan Sun
- Department of Hepatobiliary Surgery, Tianjin Third Central Hospital, The Third Central Clinical College of Tianjin Medical University, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin 300170, China
| | - Chuan-Shan Zhang
- Department of Pathology, Tianjin Third Central Hospital, The Third Central Clinical College of Tianjin Medical University, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin 300170, China
| | - Qin Zhang
- Department of Pathology, Tianjin Third Central Hospital, The Third Central Clinical College of Tianjin Medical University, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin 300170, China
| | - Chun-Jun Li
- Department of Endocrinology, Health Management Center, Tianjin Union Medical Center, Nankai University Affiliated Hospital, Tianjin 300121, China
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4
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Lokeshwar BL, Kallifatidis G, Hoy JJ. Atypical chemokine receptors in tumor cell growth and metastasis. Adv Cancer Res 2020; 145:1-27. [PMID: 32089162 DOI: 10.1016/bs.acr.2019.12.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Atypical chemokine receptors (ACKRs) are seven-transmembrane cell surface protein receptors expressed in immune cells, normal mesenchymal cells, and several tumor cells. As of this writing, six ACKRs have been characterized by diverse activities. They bind both cysteine-cysteine (CC) type and cysteine-X-cysteine (CXC)-type chemokines, either alone, or together with a ligand bound-functional G-protein coupled (typical) chemokine receptor. The major structural difference between ACKRs and typical chemokine receptors is the substituted DRYLAIV amino acid motif in the second intracellular loop of the ACKR. Due to this substitution, these receptors cannot bind Gαi-type G-proteins responsible for intracellular calcium mobilization and cellular chemotaxis. Although initially characterized as non-signaling transmembrane receptors (decoy receptors) that attenuate ligand-induced signaling by GPCRs, studies of all ACKRs have shown ligand-independent and ligand-dependent transmembrane signaling in both non-tumor and tumor cells. The precise function and mechanism of the differential expression of ACKRs in many tumors are not understood well. The use of antagonists of ACKRs ligands has shown limited antitumor potential; however, depleting ACKR expression resulted in a reduction in experimental tumor growth and metastasis. The ACKRs represent a unique class of transmembrane signaling proteins that regulate growth, survival, and metastatic processes in tumor cells, affecting multiple pathways of tumor growth. Therefore, closer investigations of ACKRs have a high potential for identifying therapeutics which affect the intracellular signaling, preferentially via the ligand-independent mechanism.
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Affiliation(s)
- Bal L Lokeshwar
- Georgia Cancer Center, Augusta University, Augusta, GA, United States; Research Service, Charlie Norwood Veterans Administration Medical Center, Augusta, GA, United States.
| | - Georgios Kallifatidis
- Georgia Cancer Center, Augusta University, Augusta, GA, United States; Research Service, Charlie Norwood Veterans Administration Medical Center, Augusta, GA, United States; Department of Biological Sciences, Augusta University, Augusta, GA, United States
| | - James J Hoy
- LCMB Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States
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5
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Siracusano G, Tagliamonte M, Buonaguro L, Lopalco L. Cell Surface Proteins in Hepatocellular Carcinoma: From Bench to Bedside. Vaccines (Basel) 2020; 8:vaccines8010041. [PMID: 31991677 PMCID: PMC7157713 DOI: 10.3390/vaccines8010041] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 01/16/2020] [Accepted: 01/22/2020] [Indexed: 12/20/2022] Open
Abstract
Cell surface proteins act as the go-between in carrying the information from the extracellular environment to the intracellular signaling proteins. However, these proteins are often deregulated in neoplastic diseases, including hepatocellular carcinoma. This review discusses several recent studies that have investigated the role of cell surface proteins in the occurrence and progression of HCC, highlighting the possibility to use them as biomarkers of the disease and/or targets for vaccines and therapeutics.
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Affiliation(s)
- Gabriel Siracusano
- Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy;
- Correspondence: ; Tel.: +39-022643-4957
| | - Maria Tagliamonte
- Cancer Immunoregulation Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori IRCCS, “Fondazione Pascale”, 80131 Naples, Italy; (M.T.); (L.B.)
| | - Luigi Buonaguro
- Cancer Immunoregulation Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori IRCCS, “Fondazione Pascale”, 80131 Naples, Italy; (M.T.); (L.B.)
| | - Lucia Lopalco
- Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy;
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Ou X, Zhang GT, Tian PK, Chen JS, Lin ZW, Xie Y, Wang AH, Liu XP, Liu JK. Forkhead box P3 gene silencing inhibits the expression of chemokines and chemokine receptors associated with cell growth, migration, and apoptosis in hepatocellular carcinoma cells. Exp Ther Med 2019; 18:1091-1098. [PMID: 31316604 PMCID: PMC6601415 DOI: 10.3892/etm.2019.7658] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Accepted: 05/02/2019] [Indexed: 01/23/2023] Open
Abstract
The aberrant expression of forkhead box P3 (FOXP3) leads to the formation of malignant tumors. FOXP3 expression levels are also elevated in hepatocellular carcinoma (HCC). The aim of the present study was to investigate the effects of FOXP3 silencing on cell proliferation, migration, apoptosis and chemokine/chemokine receptor expression in the MHCC-97H HCC cell line. Three FOXP3 short hairpin (sh)RNA constructs were designed: Sh-FOXP3-1-pGreenPuro, sh-FOXP3-2-pGreenPuro, and sh-FOXP3-3-pGreenPuro. MHCC-97H cells were transfected with shRNA-FOXP3, and the mRNA and protein expression levels of C-X-C motif chemokine (CXC) ligand 12 (CXCL12), CXCL11, CXC receptor 4 (CXCR4) and CXCR7 were measured. Cell Counting Kit-8, terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling and Transwell assays were used to evaluate cell proliferation, apoptosis and migration, respectively. Of the three FOXP3 lentivirus carriers constructed, sh-FOXP3-1 significantly reduced FOXP3 expression levels and was chosen for further experiments. sh-FOXP3-1 inhibited cell proliferation, promoted apoptosis and inhibited cell migration compared with the negative control. The mRNA and protein expression levels of CXCL12, CXCL11, CXCR4 and CXCR7 were decreased significantly in response to FOXP3 silencing. FOXP3 silencing may therefore inhibit cell growth, induce apoptosis and inhibit migration in HCC cells, possibly by impairing the chemokine/chemokine receptor axes.
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Affiliation(s)
- Xi Ou
- Department of Hepatopancreatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Guang-Tao Zhang
- Department of Hepatopancreatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Pei-Kai Tian
- Department of Hepatobiliary Surgery, Shenzhen University General Hospital, Shenzhen, Guangdong 518055, P.R. China
| | - Jing-Sen Chen
- Department of Breast Surgery, Shenzhen Maternity and Child Healthcare Hospital, Shenzhen, Guangdong 518028, P.R. China
| | - Ze-Wei Lin
- Department of Hepatopancreatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Yong Xie
- Department of Hepatopancreatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Ai-Hong Wang
- Department of Hepatopancreatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Xiao-Ping Liu
- Department of Hepatopancreatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - Ji-Kui Liu
- Department of Hepatopancreatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
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7
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Peng WT, Sun WY, Li XR, Sun JC, Du JJ, Wei W. Emerging Roles of G Protein-Coupled Receptors in Hepatocellular Carcinoma. Int J Mol Sci 2018; 19:ijms19051366. [PMID: 29734668 PMCID: PMC5983678 DOI: 10.3390/ijms19051366] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Revised: 04/24/2018] [Accepted: 04/26/2018] [Indexed: 12/13/2022] Open
Abstract
Among a great variety of cell surface receptors, the largest superfamily is G protein-coupled receptors (GPCRs), also known as seven-transmembrane domain receptors. GPCRs can modulate diverse signal-transduction pathways through G protein-dependent or independent pathways which involve β-arrestins, G protein receptor kinases (GRKs), ion channels, or Src kinases under physiological and pathological conditions. Recent studies have revealed the crucial role of GPCRs in the tumorigenesis and the development of cancer metastasis. We will sum up the functions of GPCRs—particularly those coupled to chemokines, prostaglandin, lysophosphatidic acid, endothelin, catecholamine, and angiotensin—in the proliferation, invasion, metastasis, and angiogenesis of hepatoma cells and the development of hepatocellular carcinoma (HCC) in this review. We also highlight the potential avenues of GPCR-based therapeutics for HCC.
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Affiliation(s)
- Wen-Ting Peng
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China.
- Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
- Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China.
| | - Wu-Yi Sun
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China.
- Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
- Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China.
| | - Xin-Ran Li
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China.
- Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
- Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China.
| | - Jia-Chang Sun
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China.
- Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
- Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China.
| | - Jia-Jia Du
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China.
- Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
- Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China.
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China.
- Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
- Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China.
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Qian T, Liu Y, Dong Y, Zhang L, Dong Y, Sun Y, Sun D. CXCR7 regulates breast tumor metastasis and angiogenesis in vivo and in vitro. Mol Med Rep 2017; 17:3633-3639. [PMID: 29257351 PMCID: PMC5802168 DOI: 10.3892/mmr.2017.8286] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 03/03/2017] [Indexed: 12/16/2022] Open
Abstract
The chemokine receptor CXCR7 is regarded as a scavenger receptor for CXCL12, and induces numerous key steps in tumor growth and metastasis. However, the exact molecular mechanism of CXCR7 regulation in breast tumor angiogenesis remains unknown. In the present study, the function of CXCR7 in breast tumors was investigated in vitro and in vivo. The breast cancer MDA-MB-231 cell line was used. Pharmacological inhibition of CXCR7 by CCX771 reduced breast tumor invasion, adhesion and metastasis. Furthermore, CXCR7 was essential for the tube formation of HUVECs in vitro, and for blood vessel formation in a Matrigel plug assay in vivo. In addition, vascular endothelial growth factor expression was also decreased in CCX771-treated MDA-MB-231 cells, indicating that CCX771 regulates tumor angiogenesis. The present results indicated that CXCR7 regulated breast cancer metastasis at multiple stages; additional understanding of CXCR7 in tumor environments may develop anti-metastatic therapy.
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Affiliation(s)
- Tingting Qian
- Laboratory Animal Centre, Bengbu Medical College, Bengbu, Anhui 233000, P.R. China
| | - Yancheng Liu
- Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800, P.R. China
| | - Yan Dong
- College of Biology and Food Engineering, Chuzhou University, Chuzhou, Anhui 239000, P.R. China
| | - Lei Zhang
- College of Biology and Food Engineering, Chuzhou University, Chuzhou, Anhui 239000, P.R. China
| | - Yining Dong
- College of Biology and Food Engineering, Chuzhou University, Chuzhou, Anhui 239000, P.R. China
| | - Yanhui Sun
- College of Biology and Food Engineering, Chuzhou University, Chuzhou, Anhui 239000, P.R. China
| | - Dongmei Sun
- School of Life Sciences and Technology, Tongji University, Shanghai 200092, P.R. China
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Xin Q, Zhang N, Yu HB, Zhang Q, Cui YF, Zhang CS, Ma Z, Yang Y, Liu W. CXCR7/CXCL12 axis is involved in lymph node and liver metastasis of gastric carcinoma. World J Gastroenterol 2017; 23:3053-3065. [PMID: 28533662 PMCID: PMC5423042 DOI: 10.3748/wjg.v23.i17.3053] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 01/17/2017] [Accepted: 03/20/2017] [Indexed: 02/07/2023] Open
Abstract
AIM To investigate the role of CXC chemokine receptor (CXCR)-7 and CXCL12 in lymph node and liver metastasis of gastric carcinoma. METHODS In 160 cases of gastric cancer, the expression of CXCR7 and CXCL12 in tumor and matched tumor-adjacent non-cancer tissues, in the lymph nodes around the stomach and in the liver was detected using immunohistochemistry to analyze the relationship between CXCR7/CXCL12 expression and clinicopathological features and to determine whether CXCR7 and CXCL12 constitute a biological axis to promote lymph node and liver metastasis of gastric cancer. Furthermore, the CXCR7 gene was silenced and overexpressed in human gastric cancer SGC-7901 cells, and cell proliferation, migration and invasiveness were measured by the MTT, wound healing and Transwell assays, respectively. RESULTS CXCR7 expression was up-regulated in gastric cancer tissues (P = 0.011). CXCR7/CXCL12 expression was significantly related to high tumor stage and lymph node (r = 0.338, P = 0.000) and liver metastasis (r = 0.629, P = 0.000). The expression of CXCL12 in lymph node and liver metastasis was higher than that in primary gastric cancer tissues (χ2 = 6.669, P = 0.010; χ2 = 25379, P = 0.000), and the expression of CXCL12 in lymph node and liver metastasis of gastric cancer was consistent with the positive expression of CXCR7 in primary gastric cancer (r = 0.338, P = 0.000; r = 0.629, P = 0.000). Overexpression of the CXCR7 gene promoted cell proliferation, migration and invasion. Silencing of the CXCR7 gene suppressed SGC-7901 cell proliferation, migration and invasion. Human gastric cancer cell lines expressed CXCR7 and showed vigorous proliferation and migratory responses to CXCL12. CONCLUSION The CXCR7/CXCL12 axis is involved in lymph node and liver metastasis of gastric cancer. CXCR7 is considered a potential therapeutic target for the treatment of gastric cancer.
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10
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Zhao ZW, Fan XX, Song JJ, Xu M, Chen MJ, Tu JF, Wu FZ, Zhang DK, Liu L, Chen L, Ying XH, Ji JS. ShRNA knock-down of CXCR7 inhibits tumour invasion and metastasis in hepatocellular carcinoma after transcatheter arterial chemoembolization. J Cell Mol Med 2017; 21:1989-1999. [PMID: 28429395 PMCID: PMC5571530 DOI: 10.1111/jcmm.13119] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Accepted: 01/10/2017] [Indexed: 12/23/2022] Open
Abstract
To investigate the effects of lentiviral vector‐mediated shRNA suppressing CXCR7 on tumour invasion and metastasis in hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE). HCCLM3 cell lines were cultured and assigned into the CXCR7‐shRNA, negative control (NC) and blank groups. The qRT‐PCR and Western blotting were applied to detect the mRNA and protein expressions of CXCR7, CXCR4 and MMP‐2 in HCCLM3 cells. Cell proliferation and invasion were evaluated by MTT and Transwell assays. A Buffalo rat model of HCC was established. Fifty model rats were divided into the CXCR7‐shRNA + TACE, CXCR7‐shRNA, TACE, NC and control groups. Immunohistochemistry was performed to detect the expressions of CXCR7, MMP‐2, vascular endothelial growth factor (VEGF) and intratumoral CD31‐positive vessel count in tumour tissues of mice. Compared with the blank and NC groups, the mRNA and protein expressions of CXCR7 and MMP‐2 were decreased in the CXCR7‐shRNA group. The cell proliferation and invasion rates of the CXCR7‐shRNA group were lower than the blank and NC groups. At the 4th week after TACE, tumour weight of the CXCR7‐shRNA + TACE group increased continuously. The CXCR7‐shRNA + TACE group showed longer survival time and smaller tumour sizes than other groups. Compared with other groups, the CXCR7‐shRNA + TACE and CXCR7‐shRNA groups had less number of lung metastatic nodules and lower expressions of CXCR7, MMP‐2, VEGF and CD31‐positive vessel count. CXCR7‐shRNA inhibits tumour invasion and metastasis to improve the efficacy of TACE in HCC by reducing the expressions of CXCR7, MMP‐2 and VEGF.
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Affiliation(s)
- Zhong-Wei Zhao
- Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Hospital of Zhejiang University, Lishui Central Hospital, Lishui, China
| | - Xiao-Xi Fan
- Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Hospital of Zhejiang University, Lishui Central Hospital, Lishui, China
| | - Jing-Jing Song
- Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Hospital of Zhejiang University, Lishui Central Hospital, Lishui, China
| | - Min Xu
- Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Hospital of Zhejiang University, Lishui Central Hospital, Lishui, China
| | - Min-Jiang Chen
- Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Hospital of Zhejiang University, Lishui Central Hospital, Lishui, China
| | - Jian-Fei Tu
- Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Hospital of Zhejiang University, Lishui Central Hospital, Lishui, China
| | - Fa-Zong Wu
- Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Hospital of Zhejiang University, Lishui Central Hospital, Lishui, China
| | - Deng-Ke Zhang
- Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Hospital of Zhejiang University, Lishui Central Hospital, Lishui, China
| | - Lu Liu
- Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Hospital of Zhejiang University, Lishui Central Hospital, Lishui, China
| | - Li Chen
- Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Hospital of Zhejiang University, Lishui Central Hospital, Lishui, China
| | - Xi-Hui Ying
- Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Hospital of Zhejiang University, Lishui Central Hospital, Lishui, China
| | - Jian-Song Ji
- Department of Radiology, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Hospital of Zhejiang University, Lishui Central Hospital, Lishui, China
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11
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Huang Y, Ye Y, Long P, Zhao S, Zhang L, A Y. Silencing of CXCR4 and CXCR7 expression by RNA interference suppresses human endometrial carcinoma growth in vivo. Am J Transl Res 2017; 9:1896-1904. [PMID: 28469794 PMCID: PMC5411937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 02/09/2017] [Indexed: 06/07/2023]
Abstract
In this paper, the effect of silencing the expression of CXCR4 and CXCR7 by RNAi on the growth of endometrial carcinoma (EC), in vivo, was evaluated. To establish endometrial carcinoma model, thirty nude mice were subcutaneously inoculated with 1 × 107 Ishikawa cells. All tumor-bearing mice were randomly assigned to five groups (six mice in each group) when the tumor xenografts reached 5-7 mm in diameter, and treated with CXCR4-siRNA (5 nmol), CXCR7-siRNA (5 nmol), CXCR4-siRNA (5 nmol) plus CXCR7-siRNA (5 nmol), negative-siRNA (5 nmol) and normal saline, respectively. Following intra-tumor injection, the growth rate of tumor xenografts in the three treatment groups was significantly delayed compared with those in Ne-si and NS group (P<0.05). The results of QRT-PCR and immunohistochemical assessment showed that the expression levels of CXCR4 and CXCR7 could be down regulated by RNA interference. We also observed that treatment with CXCR4-siRNA and CXCR7-siRNA reduced cell proliferation, but there was no significant difference in apoptosis among the five groups. CXCR4 and CXCR7 silencing by RNAi inhibit the growth of human endometrial carcinoma xenografts by inhibiting cancer cell proliferation, in vivo. These results indicate that CXCR4 and CXCR7 could serve as potential alternative targets for gene therapy in endometrial carcinoma.
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Affiliation(s)
- Yu Huang
- The Affiliated Women & Children Hospital of Qingdao UniversityQingdao, Shandong Province, China
- Qingdao Women & Children HospitalQingdao, Shandong Province, China
| | - Yuanying Ye
- The Affiliated Women & Children Hospital of Qingdao UniversityQingdao, Shandong Province, China
- Qingdao Women & Children HospitalQingdao, Shandong Province, China
| | - Ping Long
- The Affiliated Women & Children Hospital of Qingdao UniversityQingdao, Shandong Province, China
- Qingdao Women & Children HospitalQingdao, Shandong Province, China
| | - Shuping Zhao
- The Affiliated Women & Children Hospital of Qingdao UniversityQingdao, Shandong Province, China
- Qingdao Women & Children HospitalQingdao, Shandong Province, China
| | - Lei Zhang
- The Affiliated Women & Children Hospital of Qingdao UniversityQingdao, Shandong Province, China
- Qingdao Women & Children HospitalQingdao, Shandong Province, China
| | - Yanni A
- The Affiliated Women & Children Hospital of Qingdao UniversityQingdao, Shandong Province, China
- Qingdao Women & Children HospitalQingdao, Shandong Province, China
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12
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Zhou SM, Zhang F, Chen XB, Jun CM, Jing X, Wei DX, Xia Y, Zhou YB, Xiao XQ, Jia RQ, Li JT, Sheng W, Zeng Y. miR-100 suppresses the proliferation and tumor growth of esophageal squamous cancer cells via targeting CXCR7. Oncol Rep 2016; 35:3453-9. [PMID: 27035873 DOI: 10.3892/or.2016.4701] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2015] [Accepted: 09/14/2015] [Indexed: 11/06/2022] Open
Abstract
MicroRNAs are highly conserved non-coding RNAs that regulate gene expression at the post-transcriptional level, and play pivotal roles in cancer development and progression. miR-100 has been reported to be significantly downregulated in a variety of cancers, including esophageal cancer. However, the role of miR-100 in human esophageal cancer has not been fully elucidated. We demonstrated that overexpression of miR-100 in esophageal cancer cells markedly inhibited cell proliferation, migration and invasion as well as tumor growth. We subsequently showed that CXCR7 is a direct target gene of miR-100. Our results indicated that miR-100 plays a tumor-suppressor role in esophageal cancer and suggest its potential application for esophageal cancer treatment.
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Affiliation(s)
- Shao-Mei Zhou
- Department of Pharmacology and Biology, College of Life Science and Bioengineering, Beijing University of Technology, Chaoyang, Beijing 100124, P.R. China
| | - Fang Zhang
- Department of Pharmacology and Biology, College of Life Science and Bioengineering, Beijing University of Technology, Chaoyang, Beijing 100124, P.R. China
| | - Xue-Bin Chen
- Department of Pharmacology and Biology, College of Life Science and Bioengineering, Beijing University of Technology, Chaoyang, Beijing 100124, P.R. China
| | - Cao-Ming Jun
- Department of Pharmacology and Biology, College of Life Science and Bioengineering, Beijing University of Technology, Chaoyang, Beijing 100124, P.R. China
| | - Xin Jing
- Department of Pharmacology and Biology, College of Life Science and Bioengineering, Beijing University of Technology, Chaoyang, Beijing 100124, P.R. China
| | - Deng-Xiong Wei
- Department of Pharmacology and Biology, College of Life Science and Bioengineering, Beijing University of Technology, Chaoyang, Beijing 100124, P.R. China
| | - Yang Xia
- Department of Pharmacology and Biology, College of Life Science and Bioengineering, Beijing University of Technology, Chaoyang, Beijing 100124, P.R. China
| | - Yu-Bai Zhou
- Department of Pharmacology and Biology, College of Life Science and Bioengineering, Beijing University of Technology, Chaoyang, Beijing 100124, P.R. China
| | - Xiang-Qian Xiao
- Department of Pharmacology and Biology, College of Life Science and Bioengineering, Beijing University of Technology, Chaoyang, Beijing 100124, P.R. China
| | - Run-Qing Jia
- Department of Pharmacology and Biology, College of Life Science and Bioengineering, Beijing University of Technology, Chaoyang, Beijing 100124, P.R. China
| | - Jing-Tao Li
- Department of Pharmacology and Biology, College of Life Science and Bioengineering, Beijing University of Technology, Chaoyang, Beijing 100124, P.R. China
| | - Wang Sheng
- Department of Pharmacology and Biology, College of Life Science and Bioengineering, Beijing University of Technology, Chaoyang, Beijing 100124, P.R. China
| | - Yi Zeng
- Department of Pharmacology and Biology, College of Life Science and Bioengineering, Beijing University of Technology, Chaoyang, Beijing 100124, P.R. China
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13
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Zhang H, Yang L, Teng X, Liu Z, Liu C, Zhang L, Liu Z. The chemokine receptor CXCR7 is a critical regulator for the tumorigenesis and development of papillary thyroid carcinoma by inducing angiogenesis in vitro and in vivo. Tumour Biol 2015; 37:2415-23. [PMID: 26383519 DOI: 10.1007/s13277-015-4051-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Accepted: 09/02/2015] [Indexed: 01/20/2023] Open
Abstract
Papillary thyroid carcinoma (PTC) is a well-differentiated neoplasm, but it can transfer early to cervical lymph nodes. Accumulating evidences have confirmed the important roles of CXCR7 in tumor cell proliferation, invasion, metastasis, and angiogenesis. Our previous study demonstrated CXCR7 modulated proliferation, apoptosis, and invasion of PTC cells. In this study, we evaluated the effect of expression of CXCR7 in PTC cells on angiogenesis and whether its expression had an influence on the tumor growth of PTC in vivo. We evaluated the effect of CXCR7 on interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) secretion, angiogenesis, and tumor growth by ELISA, endothelial tube formation assay, and a xenograft tumor model in nude mice. Immunohistochemistry was used to assess expression of CD34 in tumor of mice. In vitro and in vivo studies in PTC cells suggested that the alteration of CXCR7 expression was correlated with angiogenesis and tumor growth. Moreover, CXCR7 mediated the expression of IL-8 and VEGF, which might be involved in the regulation of tumor angiogenesis. These findings suggest that CXCR7 affects the growth of PTC cells and participates in the tumorigenesis of PTC, probably through regulating angiogenesis by the proangiogenic VEGF or IL-8.
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Affiliation(s)
- Hengwei Zhang
- Department of General Surgery, Shengjing Hospital, China Medical University, No. 36 Sanhao Street, Shenyang, 110004, China
| | - Lei Yang
- Department of General Surgery, First Affiliated Hospital, China Medical University, Shenyang, 110001, China
| | - Xuyong Teng
- Department of General Surgery, Shengjing Hospital, China Medical University, No. 36 Sanhao Street, Shenyang, 110004, China
| | - Zhangyi Liu
- Department of General Surgery, Shengjing Hospital, China Medical University, No. 36 Sanhao Street, Shenyang, 110004, China
| | - Chenxi Liu
- Department of General Surgery, Shengjing Hospital, China Medical University, No. 36 Sanhao Street, Shenyang, 110004, China
| | - Lei Zhang
- Department of General Surgery, Shengjing Hospital, China Medical University, No. 36 Sanhao Street, Shenyang, 110004, China
| | - Zhen Liu
- Department of General Surgery, Shengjing Hospital, China Medical University, No. 36 Sanhao Street, Shenyang, 110004, China.
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14
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Stacer AC, Fenner J, Cavnar SP, Xiao A, Zhao S, Chang SL, Salomonnson A, Luker KE, Luker GD. Endothelial CXCR7 regulates breast cancer metastasis. Oncogene 2015; 35:1716-24. [PMID: 26119946 PMCID: PMC4486335 DOI: 10.1038/onc.2015.236] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2014] [Revised: 04/29/2015] [Accepted: 05/01/2015] [Indexed: 02/08/2023]
Abstract
Atypical chemokine receptor CXCR7 (ACKR3) functions as a scavenger receptor for chemokine CXCL12, a molecule that promotes multiple steps in tumor growth and metastasis in breast cancer and multiple other malignancies. While normal vascular endothelium expresses low levels of CXCR7, marked upregulation of CXCR7 occurs in tumor vasculature in breast cancer and other tumors. To investigate effects of endothelial CXCR7 in breast cancer, we conditionally deleted this receptor from vascular endothelium of adult mice, generating CXCR7ΔEND/ΔEND animals. CXCR7ΔEND/ΔEND mice appeared phenotypically normal, although these animals exhibited a modest 35 ± 3% increase in plasma CXCL12 as compared with control. Using two different syngeneic, orthotopic tumor implant models of breast cancer, we discovered that CXCR7ΔEND/ΔEND mice had significantly greater local recurrence of cancer following resection, elevated numbers of circulating tumor cells, and more spontaneous metastases. CXCR7ΔEND/ΔEND mice also showed greater experimental metastases following intracardiac injection of cancer cells. These results establish that endothelial CXCR7 limits breast cancer metastasis at multiple steps in the metastatic cascade, advancing understanding of CXCL12 pathways in tumor environments and informing ongoing drug development targeting CXCR7 in cancer.
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Affiliation(s)
- A C Stacer
- University of Michigan Center for Molecular Imaging, Department of Radiology, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA
| | - J Fenner
- University of Michigan Center for Molecular Imaging, Department of Radiology, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA
| | - S P Cavnar
- Department of Biomedical Engineering, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA
| | - A Xiao
- University of Michigan Center for Molecular Imaging, Department of Radiology, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA
| | - S Zhao
- Department of Radiation Oncology, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA
| | - S L Chang
- Depatment of Chemical Engineering, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA
| | - A Salomonnson
- University of Michigan Center for Molecular Imaging, Department of Radiology, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA
| | - K E Luker
- University of Michigan Center for Molecular Imaging, Department of Radiology, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA
| | - G D Luker
- University of Michigan Center for Molecular Imaging, Department of Radiology, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA.,Department of Biomedical Engineering, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA.,Department of Microbiology and Immunology, University of Michigan Medical School and College of Engineering, Ann Arbor, MI, USA
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15
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Yun HJ, Ryu H, Choi YS, Song IC, Jo DY, Kim S, Lee HJ. C-X-C motif receptor 7 in gastrointestinal cancer. Oncol Lett 2015; 10:1227-1232. [PMID: 26622655 DOI: 10.3892/ol.2015.3407] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 05/22/2015] [Indexed: 02/06/2023] Open
Abstract
Chemokine receptors are key mediators of normal physiology and numerous pathological conditions, including inflammation and cancer. This receptor family is an emerging target for anticancer drug development. C-X-C motif receptor 7 (CXCR7) is an atypical chemokine receptor that was first cloned from a canine cDNA library as an orphan receptor and was initially named receptor dog cDNA 1 (RDC1). Shortly after demonstrating that RDC1 binds with its ligand, stromal cell-derived factor-1α and interferon-inducible T-cell α chemoattractant, RDC1 was officially deorphanized and renamed CXCR7, as the seventh receptor in the CXC class of the chemokine receptor family. Recent accumulating evidence has demonstrated that CXCR7 expression is augmented in the majority of tumor cells compared with their normal counterparts and is involved in cell proliferation, survival, migration, invasion and angiogenesis during the initiation and progression of breast, lung and prostate cancer. In the present review, the expression and role of CXCR7, as well as its clinical relevance in cancer of the gastrointestinal system, were investigated. In addition, the potential of this chemokine receptor as a therapeutic target in the treatment of gastrointestinal cancer was discussed.
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Affiliation(s)
- Hwan-Jung Yun
- Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University Hospital, Daejeon 301-721, Republic of Korea ; Cancer Research Institute, Chungnam National University School of Medicine, Daejeon 301-747, Republic of Korea
| | - Hyewon Ryu
- Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University Hospital, Daejeon 301-721, Republic of Korea
| | - Yoon Seok Choi
- Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University Hospital, Daejeon 301-721, Republic of Korea
| | - Ik-Chan Song
- Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University Hospital, Daejeon 301-721, Republic of Korea
| | - Deog-Yeon Jo
- Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University Hospital, Daejeon 301-721, Republic of Korea ; Cancer Research Institute, Chungnam National University School of Medicine, Daejeon 301-747, Republic of Korea
| | - Samyong Kim
- Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University Hospital, Daejeon 301-721, Republic of Korea ; Cancer Research Institute, Chungnam National University School of Medicine, Daejeon 301-747, Republic of Korea
| | - Hyo Jin Lee
- Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University Hospital, Daejeon 301-721, Republic of Korea ; Cancer Research Institute, Chungnam National University School of Medicine, Daejeon 301-747, Republic of Korea
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16
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Liang CM, Chen L, Hu H, Ma HY, Gao LL, Qin J, Zhong CP. Chemokines and their receptors play important roles in the development of hepatocellular carcinoma. World J Hepatol 2015; 7:1390-1402. [PMID: 26052384 PMCID: PMC4450202 DOI: 10.4254/wjh.v7.i10.1390] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 11/08/2014] [Accepted: 04/07/2015] [Indexed: 02/06/2023] Open
Abstract
The chemokine system consists of four different subclasses with over 50 chemokines and 19 receptors. Their functions in the immune system have been well elucidated and research during the last decades unveils their new roles in hepatocellular carcinoma (HCC). The chemokines and their receptors in the microenvironment influence the development of HCC by several aspects including: inflammation, effects on immune cells, angiogenesis, and direct effects on HCC cells. Regarding these aspects, pre-clinical research by targeting the chemokine system has yielded promising data, and these findings bring us new clues in the chemokine-based therapies for HCC.
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17
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Xue TC, Zhang L, Ren ZG, Chen RX, Cui JF, Ge NL, Ye SL. Sex-determination gene SRY potentially associates with poor prognosis but not sex bias in hepatocellular carcinoma. Dig Dis Sci 2015; 60:427-35. [PMID: 25274159 DOI: 10.1007/s10620-014-3377-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Accepted: 09/24/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND Gender disparity is well known in hepatocellular carcinoma (HCC). SRY is a critical sex-determination gene involved in embryonic development. AIM The potential relevance of SRY to HCC progression was evaluated. METHODS SRY expression in HCC cell lines and tissues was evaluated. Invasion and wound healing assays were used to evaluate the role of SRY in HCC cell migration. The prognostic value of SRY for HCC patient survival was evaluated. RESULTS SRY was highly expressed in HCC cell lines and tumor tissues. Downregulation of SRY expression decreased migration and invasion potential of HCC cells. High SRY levels correlated with poor HCC patient survival. Additionally, neither spatial position nor expression intensity of SRY was correlated with HCC gender disparity. CONCLUSIONS High levels of SRY expression correlated with cancer progression and poor HCC patient survival. However, high SRY levels are not significantly correlated with HCC sex bias.
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Affiliation(s)
- Tong-Chun Xue
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China,
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18
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Xue TC, Ge NL, Zhang L, Cui JF, Chen RX, You Y, Ye SL, Ren ZG. Goosecoid promotes the metastasis of hepatocellular carcinoma by modulating the epithelial-mesenchymal transition. PLoS One 2014; 9:e109695. [PMID: 25343336 PMCID: PMC4208742 DOI: 10.1371/journal.pone.0109695] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2014] [Accepted: 09/12/2014] [Indexed: 01/30/2023] Open
Abstract
The homeobox gene, goosecoid (GSC), is a transcription factor that participates in cell migration during embryonic development. Because cell migration during development has characteristics similar to cell invasion during metastasis, we evaluated the potential role of GSC in the metastasis of hepatocellular carcinoma (HCC). GSC expression in HCC cell lines and tissues was evaluated, and its effects on the migration potential of HCC cells were determined by GSC knock-down and overexpression methods. In addition, the prognostic role of GSC expression in the metastasis of cancer cells in HCC patients was determined. Our data showed that GSC was highly expressed in several HCC cell lines, particularly in a highly metastatic HCC cell line. Overexpression of GSC promoted cell migration and invasion of HCC cells in vitro. Gain-of-function induced the epithelial-mesenchymal transition but not collective cell migration, whereas loss-of-function induced the reverse change. High-level expression of GSC correlated closely with poor survival and lung metastasis in HCC patients; lung metastases showed more upregulated GSC expression than the primary tumor. We conclude that GSC promotes metastasis of HCC potentially through initiating the epithelial-mesenchymal transition. GSC is also a prognostic factor for poor survival and metastasis of HCC, which suggests its potential as a therapeutic target for metastatic HCC.
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Affiliation(s)
- Tong-Chun Xue
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Ning-Ling Ge
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Lan Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Jie-Feng Cui
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Rong-Xin Chen
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Yang You
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Sheng-Long Ye
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
| | - Zheng-Gang Ren
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, P.R. China
- * E-mail:
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19
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Xue TC, Jia QA, Bu Y, Chen RX, Cui JF, Tang ZY, Ye SL. CXCR7 correlates with the differentiation of hepatocellular carcinoma and suppresses HNF4α expression through the ERK pathway. Oncol Rep 2014; 32:2387-96. [PMID: 25242412 DOI: 10.3892/or.2014.3501] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Accepted: 06/12/2014] [Indexed: 12/28/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignancy with dysregulated differentiation. However, effective differentiation therapy for HCC is lacking. Previous evidence suggests that CXCR7 is associated with the differentiation of embryonic stem cells. Here, we evaluated the potential role of CXCR7 in the differentiation of HCC. In HCC cell lines, the expression of cancer stem cell-related markers was assessed by flow cytometry and confirmed by western blot and immunofluorescence analyses. Dimethyl sulfoxide, oncostatin M and dexamethasone were used to induce the differentiation of HCC. Immunohistochemical assay was performed on a tissue microarray based on 112 HCC cases that received hepatectomy. Ligand activation, inhibition assays and RNA interference were used to analyze the regulation of hepatocyte nuclear factor 4α (HNF4α) by the CXCR7 pathway. Huh7 and HCCLM3 cell lines were screened for differentiation induction based on biomarkers of hepatic cancer stem cells. CXCR7 was found to be closely associated with the differentiation of HCC, and an inverse expression trend between CXCR7 and HNF4α was found upon induced differentiation. Clinically, high CXCR7 expression was negatively correlated with HNF4α expression in patients with relatively well-differentiated HCC. Moreover, high CXCR7 expression was correlated with poor overall survival and accelerated post-resection metastasis in HCC with a low HNF4α level. Mechanistically, CXCR7 signaling inhibited HNF4α through extracellular regulated protein kinase (ERK) activation, which was inhibited by U0126, an inhibitor of MAPK/ERK kinases 1 and 2. Knockdown of CXCR7 further confirmed that CXCR7 signaling can regulate HNF4α expression. Taken together, our findings indicate that CXCR7 participates in the differentiation of HCC by regulating HNF4α. The CXCR7-ERK-HNF4α cascade represents a new target for the differentiation therapy of HCC.
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Affiliation(s)
- Tong-Chun Xue
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Qing-An Jia
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Yang Bu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Rong-Xin Chen
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Jie-Feng Cui
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Zhao-You Tang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Sheng-Long Ye
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
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20
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Ghanem I, Riveiro ME, Paradis V, Faivre S, de Parga PMV, Raymond E. Insights on the CXCL12-CXCR4 axis in hepatocellular carcinoma carcinogenesis. Am J Transl Res 2014; 6:340-352. [PMID: 25075251 PMCID: PMC4113496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Accepted: 06/11/2014] [Indexed: 06/03/2023]
Abstract
Chemokines, a group of small chemotactic cytokines, and their G-protein-coupled receptors were originally identified for their ability to mediate various pro- and anti-inflammatory responses. Beyond the influence of chemokines and their cognate receptors in several inflammatory diseases, several malignancies have been shown to be dependent of chemokines for progression, tumor growth, cellular migration and invasion, and angiogenesis; those later facilitating the development of distant metastases. In hepatocellular carcinoma (HCC), chemokines were shown to affect leukocyte recruitment, neovascularization and tumor progression. CXCL12 (stromal-derived factor 1 alpha- SDF-1) is the primary ligand for the seven transmembrane G-protein coupled receptor CXCR4. The CXCR4/CXCL12 axis exerts a variety of functions at different steps of HCC tumor progression, using autocrine and/or paracrine mechanisms to sustain tumor cell growth, to induce angiogenesis and to facilitate tumor escape through evasion of immune surveillance. In this review, we have comprehensively described the role of CXCR4/CXCL12 in HCC and also investigated the role of CXCR7, an alternative receptors that also binds CXCL12 with potentially distinct downstream effects. Preclinical data converge to demonstrate that inhibition of the CXCR4/CXCL12 axis may lead to direct inhibition of tumor migration, invasion, and metastases. This pathway is under investigation to identify potential novel treatments in HCC and other cancers. However, one of the major challenges faced in this emerging field targeting the CXCR4/CXCL12 signaling pathway, is the translation of current knowledge into the design and development of effective inhibitors of CXCR4 and/or CXCL12 for cancer therapy.
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Affiliation(s)
- Ismael Ghanem
- Department of Medical Oncology, La Paz University HospitalMadrid, Spain
| | - Maria E Riveiro
- INSERM U728 and Medical Oncology Departments, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot)100 bd du Général Leclerc, 92110 Clichy, France
- Oncology Therapeutic DevelopmentClichy, France
| | - Valerie Paradis
- INSERM U773 and Anatomopathology Departments, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot)100 bd du Général Leclerc, 92110 Clichy, France
| | - Sandrine Faivre
- INSERM U728 and Medical Oncology Departments, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot)100 bd du Général Leclerc, 92110 Clichy, France
| | | | - Eric Raymond
- INSERM U728 and Medical Oncology Departments, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot)100 bd du Général Leclerc, 92110 Clichy, France
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21
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Zhou J, Xiang Y, Yoshimura T, Chen K, Gong W, Huang J, Zhou Y, Yao X, Bian X, Wang JM. The role of chemoattractant receptors in shaping the tumor microenvironment. BIOMED RESEARCH INTERNATIONAL 2014; 2014:751392. [PMID: 25110692 PMCID: PMC4119707 DOI: 10.1155/2014/751392] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Accepted: 06/17/2014] [Indexed: 12/13/2022]
Abstract
Chemoattractant receptors are a family of seven transmembrane G protein coupled receptors (GPCRs) initially found to mediate the chemotaxis and activation of immune cells. During the past decades, the functions of these GPCRs have been discovered to not only regulate leukocyte trafficking and promote immune responses, but also play important roles in homeostasis, development, angiogenesis, and tumor progression. Accumulating evidence indicates that chemoattractant GPCRs and their ligands promote the progression of malignant tumors based on their capacity to orchestrate the infiltration of the tumor microenvironment by immune cells, endothelial cells, fibroblasts, and mesenchymal cells. This facilitates the interaction of tumor cells with host cells, tumor cells with tumor cells, and host cells with host cells to provide a basis for the expansion of established tumors and development of distant metastasis. In addition, many malignant tumors of the nonhematopoietic origin express multiple chemoattractant GPCRs that increase the invasiveness and metastasis of tumor cells. Therefore, GPCRs and their ligands constitute targets for the development of novel antitumor therapeutics.
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Affiliation(s)
- Jiamin Zhou
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
- Endoscopic Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yi Xiang
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
- Department of Pulmonary Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Teizo Yoshimura
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
| | - Keqiang Chen
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
| | - Wanghua Gong
- Basic Research Program, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA
| | - Jian Huang
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Ye Zhou
- Department of Gastric Cancer and Soft Tissue Surgery, Fudan University Cancer Center, Shanghai 200032, China
| | - Xiaohong Yao
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Xiuwu Bian
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Ji Ming Wang
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
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Miyoshi K, Kohashi K, Fushimi F, Yamamoto H, Kishimoto J, Taguchi T, Iwamoto Y, Oda Y. Close correlation between CXCR4 and VEGF expression and frequent CXCR7 expression in rhabdomyosarcoma. Hum Pathol 2014; 45:1900-9. [PMID: 25086956 DOI: 10.1016/j.humpath.2014.05.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Revised: 05/24/2014] [Accepted: 05/30/2014] [Indexed: 12/16/2022]
Abstract
CXC chemokine receptor 4 (CXCR4) expression is reportedly correlated with both vascular endothelial growth factor (VEGF) expression and poor prognosis in a variety of cancers. Its relation to CXC chemokine receptor 7 (CXCR7) is also noted in several malignancies, including rhabdomyosarcoma (RMS) cell lines. However, the correlations between these chemokine receptors and angiogenic factors have not yet been adequately investigated in RMS clinical specimens. By immunohistochemistry, we assessed CXCR4, CXCR7, CC chemokine receptor 6, CC chemokine receptor 7, VEGF expression, microvessel density, and MIB-1 labeling index in 82 formalin-fixed RMS specimens, including 34 primary alveolar RMS and 44 primary embryonal RMS (ERMS). Twenty-six frozen samples were available for investigation by quantitative reverse transcription polymerase chain reaction to detect the messenger RNA expression levels of these molecules. We also evaluated their significance with respect to clinicopathological factors and patient survival rates. Primary RMS showed high expression of CXCR7 (83.1%) regardless of the histologic subtype. High cytoplasmic CXCR4 and high VEGF expression revealed significant correlations in both ERMS and alveolar RMS (P = .0051 and P = .0003, respectively). By univariate analysis of ERMS cases, the tumors with high VEGF expression showed significantly poor prognoses (P = .0017). High VEGF expression also was the independent adverse prognostic factor for ERMS. Because CXCR4, CXCR7, and VEGF are widely expressed in RMS, the combination of these antagonists may provide a potential target for molecular therapy.
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Affiliation(s)
- Kina Miyoshi
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Kenichi Kohashi
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Fumiyoshi Fushimi
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Hidetaka Yamamoto
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Junji Kishimoto
- Department of Research and Development of Next Generation Medicine Faculty of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Tomoaki Taguchi
- Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yukihide Iwamoto
- Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
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Yu Y, Li H, Xue B, Jiang X, Huang K, Ge J, Zhang H, Chen B. SDF-1/CXCR7 axis enhances ovarian cancer cell invasion by MMP-9 expression through p38 MAPK pathway. DNA Cell Biol 2014; 33:543-9. [PMID: 24819308 DOI: 10.1089/dna.2013.2289] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Ovarian cancer is an aggressive gynecological malignancy with high metastatic potential. Recently, the CXC receptor (CXCR7) has been identified as a new receptor for stromal-derived factor-1 (SDF-1), and exerts important roles in cancer development. However, its effect on ovarian cancer and the underlying mechanism remain unknown. In this study, we detected abundant CXCR7 expression in ovarian cancer tissues and cells. Moreover, SDF-1 induced dramatically upregulation of CXCR7 mRNA and protein levels, indicating that the SDF-1/CXCR7 axis existed in ovarian cancer. Further analysis confirmed that SDF-1 enhanced cell adhesion and subsequent invasion, which were significantly attenuated when pretreated with CXCR7 small interference RNA (siRNA), indicating the critical function of SDF-1/CXCR7 in cell invasion. Further mechanistic analysis indicated that SDF-1/CXCR7 enhanced cell invasion by matrix metalloproteinase (MMP)-9, as pretreatment with MMP-9 siRNA significantly abrogated a number of invading cells. Additionally, SDF-1/CXCR7 induced phosphorylation of the p38 MAPK pathway, which was accounted for MMP-9 expression as preconditioning with the p38 MAPK inhibitor SB203580 obviously decreased MMP-9 expression. Together, our data implied that SDF-1/CXCR7 enhanced ovarian cancer cell invasion by MMP-9 expression through the p38 MAPK pathway. Thus, these findings confirmed the critical role of SDF-1/CXCR7 during the pathological processes of ovarian cancer and supported its potential targets for further development of antiovarian cancer therapy.
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Affiliation(s)
- Yuecheng Yu
- 1 Department of Obstetrics and Gynecology, Xijing Hospital, Fourth Military Medical University , Xi'an, China
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24
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Liu Z, Yang L, Teng X, Zhang H, Guan H. The involvement of CXCR7 in modulating the progression of papillary thyroid carcinoma. J Surg Res 2014; 191:379-88. [PMID: 24814201 DOI: 10.1016/j.jss.2014.04.016] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Revised: 04/03/2014] [Accepted: 04/04/2014] [Indexed: 01/21/2023]
Abstract
BACKGROUND Although papillary thyroid carcinoma (PTC) has favorable prognosis, it is prone to cervical lymph node metastasis. Chemokine receptors play a role in metastasis of tumor cells, and accumulating evidence suggests an important role for the chemokine receptor CXCR7 in cancer development. We previously demonstrated high expression of CXCR7 protein in PTC tissue. In this study, we further evaluated the role of CXCR7 in PTC. METHODS The expression of CXCR7 messenger RNA and protein in 79 cases of PTC and peritumoral tissues was detected by real-time quantitative polymerase chain reaction and Western blot. The association between CXCR7 expression and clinicopathologic characteristics in PTC was analyzed. Stable CXCR7 overexpression and knockdown PTC cells were constructed and used to examine proliferation, cell cycle, apoptosis and invasion of PTC cells by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, propidium iodide staining, 7-amino-actinomycin D staining, and invasion assay. We examined cell cycle regulatory protein levels by Western blot. RESULTS CXCR7 messenger RNA and protein levels were markedly increased in PTC and correlated with tumor progression. CXCR7 could regulate proliferation, cell cycle, apoptosis, invasion, and the expression of cell cycle regulatory proteins involved in the S-G2 phase transition. Knockdown of CXCR7 in PTC cells suppressed cell proliferation and invasion, decreased expression of cyclin A, CDK2 and PCNA, increased expression of p21 and p57, induced S phase arrest, and promoted apoptosis. CONCLUSIONS CXCR7 plays an important role in regulating growth and metastasis ability of PTC cell and provides a potential target for therapeutic interventions in PTC.
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Affiliation(s)
- Zhen Liu
- Department of General Surgery, Affiliated Shengjing Hospital, China Medical University, Shenyang, China.
| | - Lei Yang
- Department of General Surgery, First Affiliated Hospital, China Medical University, Shenyang, China
| | - Xuyong Teng
- Department of General Surgery, Affiliated Shengjing Hospital, China Medical University, Shenyang, China
| | - Hengwei Zhang
- Department of General Surgery, Affiliated Shengjing Hospital, China Medical University, Shenyang, China
| | - Haixia Guan
- Department of Endocrinology, First Affiliated Hospital, China Medical University, Shenyang, China
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25
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Zhao FT, Jia ZS, Yang Q, Song L, Jiang XJ. S100A14 promotes the growth and metastasis of hepatocellular carcinoma. Asian Pac J Cancer Prev 2014; 14:3831-6. [PMID: 23886191 DOI: 10.7314/apjcp.2013.14.6.3831] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND S100A14 has recently been implicated in the progress of several types of cancers. This study aimed to investigate the clinical significance and possible mechanisms of action of S100A14 in the invasion and metastasis of hepatocellular carcinoma (HCC). METHODS S100A14 expression in HCC was detected at mRNA and protein levels and its prognostic significance was assessed. Functional roles of S100A14 in HCC were investigated using MTT, BrdU, wound healing, transwell invasion assay and HCC metastatic mouse model. RESULTS S100A14 was significantly elevated in HCC tissues, correlated with multiple tumor nodes, high Edmondson-Steiner grade and vascular invasion. Multivariate Cox analysis showed that the S100A14 expression level was a significant and independent prognostic factor for overall survival (OS) of HCC patients (hazard ratio=1.98, 95% confidence interval=1.14-3.46, P=0.013). S100A14 promoted cell proliferation, invasion and metastasis of HCC in vitro and in vivo. CONCLUSION These results suggest S100A14 is a novel prognostic marker and therapeutic target for HCC.
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Affiliation(s)
- Fu-Tao Zhao
- Department of Infectious Diseases, Wuhan General Hospital, Guangzhou Military Area Command, Wuhan, China
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26
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Abstract
Chemokines have fundamental roles in regulating immune and inflammatory responses, primarily through their control of leukocyte migration and localization. The biological functions of chemokines are typically mediated by signalling through G protein-coupled chemokine receptors, but chemokines are also bound by a small family of atypical chemokine receptors (ACKRs), the members of which are unified by their inability to initiate classical signalling pathways after ligand binding. These ACKRs are emerging as crucial regulatory components of chemokine networks in a wide range of developmental, physiological and pathological contexts. In this Review, we discuss the biochemical and immunological properties of ACKRs and the potential unifying themes in this family, and we highlight recent studies that identify novel roles for these molecules in development , homeostasis, inflammatory disease, infection and cancer.
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The peculiarities of the SDF-1/CXCL12 system: in some cells, CXCR4 and CXCR7 sing solos, in others, they sing duets. Cell Tissue Res 2013; 355:239-53. [DOI: 10.1007/s00441-013-1747-y] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2013] [Accepted: 10/17/2013] [Indexed: 12/26/2022]
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28
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Xue TC, Chen RX, Ren ZG, Zou JH, Tang ZY, Ye SL. Transmembrane receptor CXCR7 increases the risk of extrahepatic metastasis of relatively well-differentiated hepatocellular carcinoma through upregulation of osteopontin. Oncol Rep 2013; 30:105-10. [PMID: 23636305 DOI: 10.3892/or.2013.2442] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2012] [Accepted: 02/14/2013] [Indexed: 12/29/2022] Open
Abstract
Recurrence and metastasis are the main obstacles to improving the survival of patients with post-resective hepato-cellular carcinoma (HCC). Our previous study suggests a critical role of CXCR7 in the metastasis of HCC. In the present study, the effect of CXCR7 as a risk factor for metastasis of HCC was evaluated. Immunohistochemical assay was performed on tissue microarrays based on HCC with extrahepatic metastases after hepatectomy. Two categories based on staining scores were used to evaluate the risk effect of CXCR7, respectively. The effect of CXCR7 on osteopontin (OPN) was explored by RNA interference. Based on the results, in both categories, highly expressed CXCR7 was a dependent risk factor for extrahepatic metastasis because of the potential association with relatively good cell differentiation. Stratification analyses indicated that CXCR7 was a strong independent risk factor (OR, 3.40; 95% CI, 1.07-18.84; P=0.038 in category 1 and OR, 6.40; 95% CI, 1.64-24.92; P=0.007 in category 2, respectively) in patients with Edmondson grade 1/2. Furthermore, CXCR7 correlated well and positively with expression of OPN (P=0.019 and P<0.001 in two categories, respectively) in HCC cases with Edmondson grade 1/2. Immunocytochemistry and RT-PCR demonstrated downregulation of OPN in a highly metastatic HCC cell line following knockdown of CXCR7. Taken together, these findings suggest that high expression of CXCR7 increases the risk of metastasis in post-resective HCC patients with relatively good differentiated tumors, potentially through upregulation of OPN. This group of patients may acquire a survival benefit from early detection and treatment of recurrence and metastasis.
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Affiliation(s)
- Tong-Chun Xue
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
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