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1
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Zhang X, Kong W, Gao M, Huang W, Peng C, Huang Z, Xie Z, Guo H. Robust prognostic model based on immune infiltration-related genes and clinical information in ovarian cancer. J Cell Mol Med 2022; 26:3659-3674. [PMID: 35735060 PMCID: PMC9258710 DOI: 10.1111/jcmm.17360] [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: 12/03/2021] [Revised: 03/25/2022] [Accepted: 04/17/2022] [Indexed: 11/30/2022] Open
Abstract
Immune infiltration of ovarian cancer (OV) is a critical factor in determining patient's prognosis. Using data from TCGA and GTEx database combined with WGCNA and ESTIMATE methods, 46 genes related to OV occurrence and immune infiltration were identified. Lasso and multivariate Cox regression were applied to define a prognostic score (IGCI score) based on 3 immune genes and 3 types of clinical information. The IGCI score has been verified by K‐M curves, ROC curves and C‐index on test set. In test set, IGCI score (C‐index = 0.630) is significantly better than AJCC stage (C‐index = 0.541, p < 0.05) and CIN25 (C‐index = 0.571, p < 0.05). In addition, we identified key mutations to analyse prognosis of patients and the process related to immunity. Chi‐squared tests revealed that 6 mutations are significantly (p < 0.05) related to immune infiltration: BRCA1, ZNF462, VWF, RBAK, RB1 and ADGRV1. According to mutation survival analysis, we found 5 key mutations significantly related to patient prognosis (p < 0.05): CSMD3, FLG2, HMCN1, TOP2A and TRRAP. RB1 and CSMD3 mutations had small p‐value (p < 0.1) in both chi‐squared tests and survival analysis. The drug sensitivity analysis of key mutation showed when RB1 mutation occurs, the efficacy of six anti‐tumour drugs has changed significantly (p < 0.05).
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Affiliation(s)
- Xi Zhang
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
| | - Weikaixin Kong
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.,Institute Sanqu Technology (Hangzhou) Co., Ltd., Hangzhou, China
| | - Miaomiao Gao
- Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Weiran Huang
- Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China
| | - Chao Peng
- Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China
| | - Zhuo Huang
- Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China
| | - Zhengwei Xie
- Peking University International Cancer Institute and Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Hongyan Guo
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
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2
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Aziz NS, Yusop N, Ahmad A. Importance of Stem Cell Migration and Angiogenesis Study for Regenerative Cell-based Therapy: A Review. Curr Stem Cell Res Ther 2020; 15:284-299. [DOI: 10.2174/1574888x15666200127145923] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 12/01/2019] [Accepted: 12/11/2019] [Indexed: 12/20/2022]
Abstract
Stem cells play an essential role in maintaining homeostasis, as well as participating in new
tissue regeneration. Over the past 20 years, a great deal of effort has been made to investigate the behaviour
of stem cells to enable their potential use in regenerative medicine. However, a variety of biological
characteristics are known to exist among the different types of stem cells due to variations in
the methodological approach, formulation of cell culture medium, isolation protocol and cellular
niches, as well as species variation. In recent years, cell-based therapy has emerged as one of the advanced
techniques applied in both medical and clinical settings. Cell therapies aim to treat and repair
the injury sites and replace the loss of tissues by stimulating the repair and regeneration process. In
order to enable the use of stem cells in regenerative therapies, further characterisation of cell behaviour,
in terms of their proliferation and differentiation capacity, mainly during the quiescent and inductive
state is regarded as highly necessary. The central focus of regenerative medicine revolves around
the use of human cells, including adult stem cells and induced pluripotent stem cells for cell-based
therapy. The purpose of this review was to examine the existing body of literature on stem cell research
conducted on cellular angiogenesis and migration, to investigate the validity of different strategies and
variations of the cell type used. The information gathered within this review may then be shared with
fellow researchers to assist in future research work, engaging in stem cell homing for cell-based therapy
to enhance wound healing and tissue regeneration process.
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Affiliation(s)
- Nur S. Aziz
- Postgraduate Unit, School of Dentistry, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Norhayati Yusop
- Basic Sciences and Oral Biology Unit, School of Dentistry, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Azlina Ahmad
- Basic Sciences and Oral Biology Unit, School of Dentistry, Universiti Sains Malaysia, Kelantan, Malaysia
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3
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Liu LZ, Zhang Z, Zheng BH, Shi Y, Duan M, Ma LJ, Wang ZC, Dong LQ, Dong PP, Shi JY, Zhang S, Ding ZB, Ke AW, Cao Y, Zhang XM, Xi R, Zhou J, Fan J, Wang XY, Gao Q. CCL15 Recruits Suppressive Monocytes to Facilitate Immune Escape and Disease Progression in Hepatocellular Carcinoma. Hepatology 2019; 69:143-159. [PMID: 30070719 DOI: 10.1002/hep.30134] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 06/05/2018] [Indexed: 12/12/2022]
Abstract
Chemokines play a key role in orchestrating the recruitment and positioning of myeloid cells within the tumor microenvironment. However, the tropism regulation and functions of these cells in hepatocellular carcinoma (HCC) are not completely understood. Herein, by scrutinizing the expression of all chemokines in HCC cell lines and tissues, we found that CCL15 was the most abundantly expressed chemokine in human HCC. Further analyses showed that CCL15 expression was regulated by genetic, epigenetic, and microenvironmental factors, and negatively correlated with patient clinical outcome. In addition to promoting tumor invasion in an autocrine manner, CCL15 specifically recruited CCR1+ cells toward HCC invasive margin, approximately 80% of which were CD14+ monocytes. Clinically, a high density of marginal CCR1+ CD14+ monocytes positively correlated with CCL15 expression and was an independent index for dismal survival. Functionally, these tumor-educated monocytes directly accelerated tumor invasion and metastasis through bursting various pro-tumor factors and activating signal transducer and activator of transcription 1/3, extracellular signal-regulated kinase 1/2, and v-akt murine thymoma viral oncogene homolog signaling in HCC cells. Meanwhile, tumor-derived CCR1+ CD14+ monocytes expressed significantly higher levels of programmed cell death-ligand 1, B7-H3, and T-cell immunoglobulin domain and mucin domain-3 that may lead to immune suppression. Transcriptome sequencing confirmed that tumor-infiltrating CCR1+ CD14+ monocytes were reprogrammed to upregulate immune checkpoints, immune tolerogenic metabolic enzymes (indoleamine and arginase), inflammatory/pro-angiogenic cytokines, matrix remodeling proteases, and inflammatory chemokines. Orthotopic animal models confirmed that CCL15-CCR1 axis forested an inflammatory microenvironment enriched with CCR1+ monocytes and led to increased metastatic potential of HCC cells. Conclusion: A complex tumor-promoting inflammatory microenvironment was shaped by CCL15-CCR1 axis in human HCC. Blockade of CCL15-CCR1 axis in HCC could be an effective anticancer therapy.
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Affiliation(s)
- Long-Zi Liu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Zhao Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Bo-Hao Zheng
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Yang Shi
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Men Duan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Li-Jie Ma
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Zhi-Chao Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Liang-Qing Dong
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Ping-Ping Dong
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jie-Yi Shi
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Shu Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Zhen-Bin Ding
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Ai-Wu Ke
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Ya Cao
- Cancer Research Institute, Xiangya School of Medicine, Central South University, Hunan, China
| | - Xiao-Ming Zhang
- Key Laboratory of Molecular Virology & Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Ruibin Xi
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.,Institute of Biomedical Sciences, Fudan University, Shanghai, China.,State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.,Institute of Biomedical Sciences, Fudan University, Shanghai, China.,State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Xiao-Ying Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Qiang Gao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.,State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
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4
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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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5
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Zhu Y, Gao X, Yang J, Xu D, Zhang Y, Lu M, Zhang Z, Sheng Y, Li J, Yu X, Zheng Y, Dong Q, Qin L. C-C chemokine receptor type 1 mediates osteopontin-promoted metastasis in hepatocellular carcinoma. Cancer Sci 2018; 109:710-723. [PMID: 29285854 PMCID: PMC5834777 DOI: 10.1111/cas.13487] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 12/16/2017] [Accepted: 12/25/2017] [Indexed: 12/19/2022] Open
Abstract
In the hepatocellular carcinoma (HCC) microenvironment, chemokine receptors play a critical role in tumorigenesis and metastasis. Our previous studies have found that osteopontin (OPN) is a promoter for HCC metastasis. However, the role of chemokine receptors in OPN-induced HCC metastasis remains unclear. In this study, we demonstrate that OPN is dramatically elevated in HCC tissues with metastasis and that high expression of OPN correlates with poorer overall survival and higher recurrence rate. OPN upregulates chemokine receptor expression, migration, invasion and pulmonary metastasis in HCC. We find that C-C chemokine receptor type 1 (CCR1) and C-X-C chemokine receptor type 6 (CXCR6) are the most upregulated chemokine receptors induced by OPN. CCR1 knockdown results in reduction of migration, invasion and pulmonary metastasis induced by OPN in vitro and in vivo, whereas CXCR6 knockdown does not reverse OPN-promoted migration and invasion. Moreover, OPN upregulates the expression of CCR1 through activating phosphoinositide 3-kinase (PI3K)/AKT and hypoxia-inducible factor 1α (HIF-1α) in HCC cells. Furthermore, blockade of OPN-CCR1 axis with CCR1 antagonist significantly restrains the promoting effects of OPN on HCC progression and metastasis. In human HCC tissues, OPN expression shows significantly positive correlation with CCR1 expression, and the patients with high levels of both OPN and CCR1 have the most dismal prognosis. Collectively, our results indicate that the OPN-CCR1 axis in HCC is important for accelerating tumor metastasis and that CCR1 is a potential therapeutic target for controlling metastasis in HCC patients with high OPN.
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Affiliation(s)
- Ying Zhu
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
| | - Xiao‐Mei Gao
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
| | - Jing Yang
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
| | - Da Xu
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
| | - Yu Zhang
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
| | - Ming Lu
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
| | - Ze Zhang
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
| | - Yuan‐Yuan Sheng
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
| | - Jian‐Hua Li
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
| | - Xin‐Xin Yu
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
| | - Yan Zheng
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
| | - Qiong‐Zhu Dong
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
| | - Lun‐Xiu Qin
- Department of General SurgeryHuashan HospitalCancer Metastasis InstituteFudan UniversityShanghaiChina
- Institutes of Biomedical SciencesFudan UniversityShanghaiChina
- Institutes of Cancer MetastasisFudan UniversityShanghaiChina
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6
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Huang M, Li G, Pan T, Cheng Y, Ren W, Jia W, Ma J, Xu G. A novel multi-target RNAi adenovirus inhibits hepatoma cell proliferation, migration, and induction of angiogenesis. Oncotarget 2018; 7:57705-57713. [PMID: 27221035 PMCID: PMC5295383 DOI: 10.18632/oncotarget.9531] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Accepted: 05/04/2016] [Indexed: 12/16/2022] Open
Abstract
The pathogenesis of hepatocellular carcinoma (HCC) is a multi-step process involving many genes. Consequently, single gene targeting therapy has limited efficacy, making combination therapy targeting multiple genes a necessity. Based on our previous findings, we constructed a single vector mediating simultaneous expression of multiple short hairpin RNAs (shRNAs) against human vascular endothelial growth factor receptor 2 (VEGFR2), chemokine C-C motif receptor 1 (CCR1), and epithelial cell adhesion molecule (EpCAM), three genes closely related to HCC progression that act through separate pathways. The shRNA vector efficiently downregulated the mRNA and protein of all three molecules in Huh7 hepatoma cells. The vector also inhibited cell proliferation and migration and reduced angiogenesis. Furthermore, this shRNA vector can be recombined into adenovirus, a gene therapy vector, for better in vivo application. It thus offers a potentially effective future gene therapy approach to treating human liver cancer.
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Affiliation(s)
- Mei Huang
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei 230001, China
| | - Guangyao Li
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei 230001, China
| | - Tingting Pan
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei 230001, China
| | - Ya Cheng
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei 230001, China
| | - Weihua Ren
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei 230001, China
| | - Weidong Jia
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei 230001, China.,Department of Hepatic Surgery, Affiliated Provincial Hospital of Anhui Medical University, Hefei 230001, China
| | - Jinliang Ma
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei 230001, China.,Department of Hepatic Surgery, Affiliated Provincial Hospital of Anhui Medical University, Hefei 230001, China
| | - Geliang Xu
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei 230001, China.,Department of Hepatic Surgery, Affiliated Provincial Hospital of Anhui Medical University, Hefei 230001, China
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7
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Li Y, Wu J, Zhang P. CCL15/CCR1 axis is involved in hepatocellular carcinoma cells migration and invasion. Tumour Biol 2015; 37:4501-7. [PMID: 26501423 DOI: 10.1007/s13277-015-4287-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 10/19/2015] [Indexed: 12/14/2022] Open
Abstract
The identification of new biomarkers for the early detection of hepatocellular carcinoma is critical in the development of tumor-targeted therapy, which is possibly advantageous on the prognosis of this disease. Results from our previous study indicated that CCL15 can be a specific proteomic biomarker of hepatocellular carcinoma, which plays an important role in tumorigenesis and tumor invasion. In this study, we found that CCL15 can induce hepatocellular carcinoma cell migration and invasion. Furthermore, CCR1, the receptor of CCL15, was demonstrated to play a critical role in metastatic hepatocellular carcinoma. CCR1 short hairpin RNA significantly inhibited CCL15-induced chemotaxis and invasion of HepG2 cells. Moreover, CCR1 knockdown significantly limited the activity and expression of matrix metalloproteinase-2 (MMP-2) and MMP-9. These findings suggest that CCR1 plays critical roles in hepatocellular carcinoma metastasis, which indicates that CCR1 may be a potential molecular target in hepatocellular carcinoma therapy.
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Affiliation(s)
- Yueguo Li
- Department of Clinical Laboratory, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, People's Republic of China.
- Key Laboratory of Cancer Prevention and Therapy, The National "863" Program of Clinical Research Laboratory, Tianjin, 300060, People's Republic of China.
| | - Jing Wu
- Department of Laboratory, Tianjin Third Central Hospital, Tianjin, 300170, People's Republic of China
| | - Peng Zhang
- Department of Clinical Laboratory, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, People's Republic of China
- Key Laboratory of Cancer Prevention and Therapy, The National "863" Program of Clinical Research Laboratory, Tianjin, 300060, People's Republic of China
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8
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The chemokines CCR1 and CCRL2 have a role in colorectal cancer liver metastasis. Tumour Biol 2015; 37:2461-71. [DOI: 10.1007/s13277-015-4089-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Accepted: 09/13/2015] [Indexed: 12/13/2022] Open
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9
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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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10
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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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11
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Control of both myeloid cell infiltration and angiogenesis by CCR1 promotes liver cancer metastasis development in mice. Neoplasia 2014; 15:641-8. [PMID: 23730212 DOI: 10.1593/neo.121866] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2012] [Revised: 03/20/2013] [Accepted: 03/24/2013] [Indexed: 02/04/2023] Open
Abstract
Expression of the CC chemokine receptor 1 (CCR1) by tumor cells has been associated with protumoral activity; however, its role in nontumoral cells during tumor development remains elusive. Here, we investigated the role of CCR1 deletion on stromal and hematopoietic cells in a liver metastasis tumor model. Metastasis development was strongly impaired in CCR1-deficient mice compared to control mice and was associated with reduced liver monocyte infiltration. To decipher the role of myeloid cells, sublethally irradiated mice were reconstituted with CCR1-deficient bone marrow (BM) and showed better survival rates than the control reconstituted mice. These results point toward the involvement of CCR1 myeloid cell infiltration in the promotion of tumor burden. In addition, survival rates were extended in CCR1-deficient mice receiving either control or CCR1-deficient BM, indicating that host CCR1 expression on nonhematopoietic cells also supports tumor growth. Finally, we found defective tumor-induced neoangiogenesis (in vitro and in vivo) in CCR1-deficient mice. Overall, our results indicate that CCR1 expression by both hematopoietic and nonhematopoietic cells favors tumor aggressiveness. We propose CCR1 as a potential therapeutical target for liver metastasis therapy.
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12
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Gao Q, Zhao YJ, Wang XY, Qiu SJ, Shi YH, Sun J, Yi Y, Shi JY, Shi GM, Ding ZB, Xiao YS, Zhao ZH, Zhou J, He XH, Fan J. CXCR6 upregulation contributes to a proinflammatory tumor microenvironment that drives metastasis and poor patient outcomes in hepatocellular carcinoma. Cancer Res 2012; 72:3546-56. [PMID: 22710437 DOI: 10.1158/0008-5472.can-11-4032] [Citation(s) in RCA: 141] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
CXC chemokines and their cognate receptors have been implicated widely in cancer pathogenesis. In this study, we report a critical causal relationship between CXCR6 expression and tumorigenesis in the setting of human hepatocellular carcinoma (HCC). Among the CXC chemokine receptors, only CXCR6 was detected in all the hepatoma cell lines studied. Moreover, in HCC tissue, CXCR6 expression was significantly higher than in noncancerous liver tissues. Reduction of CXCR6 or its ligand CXCL16 in cancer cells reduced cell invasion in vitro and tumor growth, angiogenesis, and metastases in vivo. Importantly, loss of CXCR6 led to reduced Gr-1+ neutrophil infiltration and decreased neoangiogenesis in hepatoma xenografts via inhibition of proinflammatory cytokine production. Clinically, high expression of CXCR6 was an independent predictor of increased recurrence and poor survival in HCCs. Human HCC samples expressing high levels of CXCR6 also contained an increased number of CD66b+ neutrophils and microvessels, and the combination of CXCR6 and neutrophils was a superior predictor of recurrence and survival than either marker used alone. Together, our findings suggest that elevated expression of CXCR6 promotes HCC invasiveness and a protumor inflammatory environment and is associated with poor patient outcome. These results support the concept that inhibition of the CXCR6-CXCL16 pathway may improve prognosis after HCC treatment.
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Affiliation(s)
- Qiang Gao
- Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, PR China
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13
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Xue TC, Chen RX, Han D, Chen J, Xue Q, Gao DM, Sun RX, Tang ZY, Ye SL. Down-regulation of CXCR7 inhibits the growth and lung metastasis of human hepatocellular carcinoma cells with highly metastatic potential. Exp Ther Med 2011; 3:117-123. [PMID: 22969855 DOI: 10.3892/etm.2011.358] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2011] [Accepted: 08/08/2011] [Indexed: 12/13/2022] Open
Abstract
CXCR7, a recently identified chemokine receptor, has been implicated in directing cancer metastasis. In the present study, the potential roles of CXCR7 in the growth and metastasis of hepatocellular carcinoma (HCC) were evaluated. A chemokine receptor gene chip was used to compare the expression of CXCR7 in HCC cell lines with different metastatic potential. Effects of targeting CXCR7 by RNA interference (RNAi) on the proliferation and metastasis of HCCLM3 cells were observed in vitro and in vivo. CXCR7 expression in 116 specimens from patients with or without metastatic HCC was assessed by tissue microarray. As a result, the gene chip showed that expression of CXCR7 was significantly higher in the highly metastatic HCCLM3 cells, which was confirmed by real-time RT-PCR and Western blotting. Chemotaxis assays showed that HCCLM3 cells responded to SDF-1α from 1 to 100 μg/l and lung extractions (1 g/l). Furthermore, down-regulation of CXCR7 in HCCLM3 cells by RNAi inhibited the proliferation and invasion of tumor cells in vitro. Moreover, CXCR7 knockdown significantly reduced the activity of matrix metalloproteinase-2 and matrix metalloproteinase-9. RNAi of CXCR7 in the HCCLM3 cells also decreased the growth of tumors and the number of lung metastases in nude mice. The tissue microarray showed that HCCs with high expression of CXCR7 were prone to metastasize to the lung. These findings suggest that CXCR7 plays critical roles in the growth and metastasis of HCC. RNAi of CXCR7 inhibits the growth and invasion of tumor cells, which indicates that CXCR7 may be a potential molecular target for use in HCC therapy.
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Affiliation(s)
- Tong-Chun Xue
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai
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14
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Likui W, Hong W, Shuwen Z, Yuangang Y, Yan W. The potential of osteopontin as a therapeutic target for human colorectal cancer. J Gastrointest Surg 2011; 15:652-9. [PMID: 21318445 DOI: 10.1007/s11605-011-1445-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2010] [Accepted: 01/28/2011] [Indexed: 01/31/2023]
Abstract
OBJECTIVE Osteopontin (OPN), a phosphorylated glycoprotein, is involved in tumor progression and metastasis. Previously, we have reported that high OPN mRNA expression level possessed clinicopathological or prognostic significance in human colorectal cancer (CRC). The aim of this study is to investigate whether OPN can serve as a novel molecular target for CRC therapy. MATERIAL AND METHODS Western Blot assay was performed to detect the expression of OPN protein in 18 CRC and corresponding nontumor colon tissue samples. RNA interference (RNAi) was employed to knockdown endogenous OPN expression in CRC cell line (LoVo). MTT, colony formation, and tumorigenicity assays were performed to analyze the effect of OPN downregulation on the in vitro and in vivo proliferation of CRC cells. Wound healing and Matrigel invasion assays were performed to analyze the effect of OPN downregulation on migration and invasion of CRC cells. A clonogenic cell survival assay after radiation was performed to analyze the effect of OPN downregulation on the radiosensitivity of CRC cells. RESULTS The relative level of OPN protein expression in CRC tissues was significantly higher than that in corresponding nontumor colon tissues (P < 0.05). We found that RNAi-mediated OPN downregulation could inhibit not only in vitro proliferation but also in vivo tumorigenicity of CRC cells. In addition, OPN downregulation could suppress in vitro invasion capacity and enhance in vitro radiosensitivity of CRC cells, which might be associated with decreased levels of MMP-2 and -9 expression. CONCLUSION RNAi-targeting OPN could inhibit proliferation, invasion and enhance radiosensitivity of human CRC cells. Therefore, OPN could serve as a novel molecular target for gene therapy of CRC.
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Affiliation(s)
- Wang Likui
- Department of Infection, Beijing Friendship Hospital, Capital Medical University, 95 Yong-An Road, Beijing 100050, People's Republic of China.
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15
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Yang X, Walton W, Cook DN, Hua X, Tilley S, Haskell CA, Horuk R, Blackstock AW, Kirby SL. The chemokine, CCL3, and its receptor, CCR1, mediate thoracic radiation-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 2010; 45:127-35. [PMID: 20870892 DOI: 10.1165/rcmb.2010-0265oc] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Patients receiving thoracic radiation often develop pulmonary injury and fibrosis. Currently, there are no effective measures to prevent or treat these conditions. We tested whether blockade of the chemokine, CC chemokine ligand (CCL) 3, and its receptors, CC chemokine receptor (CCR) 1 and CCR5, can prevent radiation-induced lung inflammation and fibrosis. C57BL/6J mice received thoracic radiation, and the interaction of CCL3 with CCR1 or CCR5 was blocked using genetic techniques, or by pharmacologic intervention. Lung inflammation was assessed by histochemical staining of lung tissue and by flow cytometry. Fibrosis was measured by hydroxyproline assays and collagen staining, and lung function was studied by invasive procedures. Irradiated mice lacking CCL3 or its receptor, CCR1, did not develop the lung inflammation, fibrosis, and decline in lung function seen in irradiated wild-type mice. Pharmacologic treatment of wild-type mice with a small molecule inhibitor of CCR1 also prevented lung inflammation and fibrosis. By contrast, mice lacking CCR5 were not protected from radiation-induced injury and fibrosis. The selective interaction of CCL3 with its receptor, CCR1, is critical for radiation-induced lung inflammation and fibrosis, and these conditions can be largely prevented by a small molecule inhibitor of CCR1.
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Affiliation(s)
- Xuebin Yang
- Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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16
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Khurram SA, Whawell SA, Bingle L, Murdoch C, McCabe BM, Farthing PM. Functional expression of the chemokine receptor XCR1 on oral epithelial cells. J Pathol 2010; 221:153-63. [PMID: 20225245 DOI: 10.1002/path.2695] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Chemokines are chemoattractant cytokines which act on specific receptors and play an important role in leukocyte migration as well as physiological and pathological processes. We investigated the role of the chemokine receptor XCR1 and its ligand lymphotactin (Lptn/XCL1) in the regulation of oral epithelial cell behaviour. In vitro XCR1 mRNA and cell surface protein expression was detected in normal oral keratinocytes and oral squamous cell carcinoma cell lines. Lymphotactin mediated intracellular activation of the ERK1/2 signalling pathway and stimulated migration, invasion, and proliferation of all cells through XCR1. Oral cancer cells showed a greater response to lymphotactin than normal keratinocytes and a direct relationship between receptor expression and migration, invasion, and proliferation was observed. Exposure of normal keratinocytes to lymphotactin resulted in increased adhesion to fibronectin but not collagen and stimulated MMP-2 and MMP-9 but not MMP-7 release, whereas exposure of cancer cells resulted in increased adhesion to both collagen and fibronectin and stimulated production of MMP-2, MMP-9, and MMP-7. We observed XCR1 but not lymphotactin to be expressed by epithelial cells in normal oral mucosa in vivo, whilst both were expressed and up-regulated in inflammatory oral disease and oral cancer including primary and metastatic disease. Lymphotactin mRNA and constitutive intracellular protein were detected in normal keratinocytes and oral cancer cell lines in vitro. These findings show that XCR1 and its ligand, lymphotactin, are expressed by oral epithelial cells and suggest that they play a role in regulating the behaviour of these cells.
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Affiliation(s)
- Syed A Khurram
- Unit of Oral and Maxillofacial Pathology, School of Clinical Dentistry, University of Sheffield, Claremont Crescent, Sheffield, S10 2TA, UK
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Yuan Y, Liu J, Liu Z, He Y, Zhang Z, Jiang C, Qian Q. Chemokine CCL3 facilitates the migration of hepatoma cells by changing the concentration intracellular Ca. Hepatol Res 2010; 40:424-31. [PMID: 20236357 DOI: 10.1111/j.1872-034x.2009.00619.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
AIM Recurrence and metastasis are the major factors associated with the poor prognosis of hepatocellular carcinoma (HCC). It was confirmed that multiple chemokines and their receptors are related to the progression and metastasis of HCC. The aim of this research was to conduct an investigation into whether macrophage inflammatory protein-1alpha/CCL3, and its receptor CCR1 play a role in HCC invasion and metastasis. METHODS We used reverse transcription polymerase chain reaction, immunocytochemistry and flow cytometry to detect CCR1 mRNA and protein expression in the four hepatoma cell lines HepG2, Hep3B, HLE and HLF; and we conducted a microscope cell migration experiment to observe the pseudopodia formation and mobility of the hepatoma cells. The concentration of intracellular calcium was measured by fluorescence microscopy. RESULTS CCR1 mRNA and protein were positively expressed in the four hepatoma cell lines HepG2, Hep3B, HLE and HLF. Following CCL3 stimulation, obvious pseudopodia formation of hepatoma cells was observed using a fluorescence microscope. The cell migration experiment showed that after incubation with CCL3, the number of Hep3B cells which passed through the polycarbonate microporous filter membranes increased to an obvious extent. After CCL3 incubation, the intracellular Ca(2+) level of the Hep3B cells increased to an obvious extent. CONCLUSION Chemokine CCL3 facilitates the migration of hepatoma by changing the concentration intracellular Ca(2+). The CCL3-CCR1 axis may play an important role in HCC invasion and metastasis. It may also be a potential target for HCC therapy or for prevention of the recurrence and metastasis of HCC.
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Affiliation(s)
- Yufeng Yuan
- Division of Hepatobiliary Surgery, Department of Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China
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18
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Dagouassat M, Suffee N, Hlawaty H, Haddad O, Charni F, Laguillier C, Vassy R, Martin L, Schischmanoff PO, Gattegno L, Oudar O, Sutton A, Charnaux N. Monocyte chemoattractant protein-1 (MCP-1)/CCL2 secreted by hepatic myofibroblasts promotes migration and invasion of human hepatoma cells. Int J Cancer 2010; 126:1095-108. [PMID: 19642141 DOI: 10.1002/ijc.24800] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The aim of our study was to investigate whether myofibroblasts and the chemokine monocyte chemoattractant protein-1 (MCP-1)/CCL2 may play a role in hepatocellular carcinoma progression. We observed that hepatic myofibroblast LI90 cells express MCP-1/CCL2 mRNA and secrete this chemokine. Moreover, myofibroblast LI90 cell-conditioned medium (LI90-CM) induces human hepatoma Huh7 cell migration and invasion. These effects are strongly reduced when a MCP-1/CCL2-depleted LI90-CM was used. We showed that MCP-1/CCL2 induces Huh7 cell migration and invasion through its G-protein-coupled receptor CCR2 and, to a lesser extent, through CCR1 only at high MCP-1/CCL2 concentrations. MCP-1/CCL2's chemotactic activities rely on tyrosine phosphorylation of focal adhesion components and depend on matrix metalloproteinase (MMP)-2 and MMP-9. Furthermore, we observed that Huh7 cell migration and invasion induced by the chemokine are strongly inhibited by heparin, by beta-D-xyloside treatment of cells and by anti-syndecan-1 and -4 antibodies. Finally, we developed a 3-dimensional coculture model of myofibroblast LI90 and Huh7 cells and demonstrated that MCP-1/CCL2 and its membrane partners, CCR1 and CCR2, may be involved in the formation of mixed hepatoma-myofibroblast spheroids. In conclusion, our data show that human liver myofibroblasts act on hepatoma cells in a paracrine manner to increase their invasiveness and suggest that myofibroblast-derived MCP-1/CCL2 could be involved in the pathogenesis of hepatocellular carcinoma.
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Affiliation(s)
- Maylis Dagouassat
- INSERM U698, Bioingénierie cardiovasculaire, Université Paris 13, Bobigny, France
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19
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Li Q, Wang G, Shan JL, Yang ZX, Wang HZ, Feng J, Zhen JJ, Chen C, Zhang ZM, Xu W, Luo XZ, Wang D. MicroRNA-224 is upregulated in HepG2 cells and involved in cellular migration and invasion. J Gastroenterol Hepatol 2010; 25:164-71. [PMID: 19793168 DOI: 10.1111/j.1440-1746.2009.05971.x] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND AND AIM MicroRNAs are a class of small non-coding RNAs that negatively regulate the expression of their target genes. The aim of the present study was to explore the effects of microRNA on biological behaviors of HepG2 cells and further analyze its characteristics. METHODS We detected different expression profiles of miRNAs in HepG2 and L02 cell lines by microRNA microarray. Northern blot, quantitative real-time polymerase chain reaction, methylthiazolyl tetrazolium, fluorescence-activated cell sorting, scratch wound, transwell migration and Matrigel invasion assays and western blot were carried out to determine whether or not microRNA-224 (miR-224) can influence the biological behaviors of HepG2 cells. RESULTS MiR-224 was significantly upregulated in HepG2 cells. Cell proliferation, migration and invasion, but not cell cycles, were altered after changing the expression of miR-224. Taking invasion and migration as a breakthrough, a close relationship between the expression of miR-224 and its proteins such as PAK4 and MMP9, which were involved in the invasion of tumor, was found. CONCLUSIONS Overexpression of miR-224 was involved in the malignant phenotype of HepG2 cells, and it may be an important factor in regulating the migration and invasion of HepG2 cells.
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Affiliation(s)
- Qiong Li
- Cancer Center, Daping Hospital & Institute of Research Institute of Field Surgery, Third Military Medical University, Chongqing, China
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Gál P, Kravcuková P, Mokrý M, Kluchová D. Chemokines as possible targets in modulation of the secondary damage after acute spinal cord injury: a review. Cell Mol Neurobiol 2009; 29:1025-35. [PMID: 19363652 PMCID: PMC11506275 DOI: 10.1007/s10571-009-9392-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2008] [Accepted: 03/10/2009] [Indexed: 12/23/2022]
Abstract
In spite of many promising experimental studies, an effective treatment dramatically eliminating the secondary damage after spinal cord injury (SCI) is still missing. Since clinical data on the therapeutical effect after methylprednisolone treatment are not conclusive, new therapeutical modalities targeting specific components of secondary spinal cord damage needs to be developed. It is known that immune cells are recruited to injury sites by chemokines, which are small, structurally similar proteins released locally at the site of inflammation. Hence, this review was aimed to summarize possible roles of chemokines in the inflammation following SCI as well as to identify possible new therapeutical targets which can potentially be effective in ameliorating individual components of this inflammatory response. Data concerning inflammation reduction together with techniques improving axonal growth, cell replacement and remyelinization, may be crucial to move a small step forward in an attempt to make paraplegic and quadriplegic patients to walk.
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Affiliation(s)
- Peter Gál
- Institute of Biology and Ecology, Pavol Jozef Safárik University, 041 80 Kosice, Slovak Republic.
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21
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Syndecan-1 and syndecan-4 are involved in RANTES/CCL5-induced migration and invasion of human hepatoma cells. Biochim Biophys Acta Gen Subj 2009; 1790:1314-26. [PMID: 19632304 DOI: 10.1016/j.bbagen.2009.07.015] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2009] [Revised: 07/12/2009] [Accepted: 07/20/2009] [Indexed: 12/16/2022]
Abstract
BACKGROUND We previously demonstrated that the CC-chemokine Regulated upon Activation, Normal T cell Expressed and Secreted (RANTES)/CCL5 exerts pro-tumoral effects on human hepatoma Huh7 cells through its G protein-coupled receptor, CCR1. Glycosaminoglycans play major roles in these biological events. METHODS In the present study, we explored 1/ the signalling pathways underlying RANTES/CCL5-mediated hepatoma cell migration or invasion by the use of specific pharmacological inhibitors, 2/ the role of RANTES/CCL5 oligomerization in these effects by using a dimeric RANTES/CCL5, 3/ the possible involvement of two membrane heparan sulfate proteoglycans, syndecan-1 (SDC-1) and syndecan-4 (SDC-4) in RANTES/CCL5-induced cell chemotaxis and spreading by pre-incubating cells with specific antibodies or by reducing SDC-1 or -4 expression by RNA interference. RESULTS AND CONCLUSION The present data suggest that focal adhesion kinase phosphorylation, phosphoinositide 3-kinase-, mitogen-activated protein kinase- and Rho kinase activations are involved in RANTES/CCL5 pro-tumoral effects on Huh7 cells. Interference with oligomerization of the chemokine reduced RANTES/CCL5-mediated cell chemotaxis. This study also indicates that SDC-1 and -4 may be required for HepG2, Hep3B and Huh7 human hepatoma cell migration, invasion or spreading induced by the chemokine. These results also further demonstrate the involvement of glycosaminoglycans as the glycosaminoglycan-binding deficient RANTES/CCL5 variant, in which arginine 47 was replaced by lysine, was devoid of effect. GENERAL SIGNIFICANCE The modulation of RANTES/CCL5-mediated cellular effects by targeting the chemokine-syndecan interaction could represent a new therapeutic approach for hepatocellular carcinoma.
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Li J, Piao YF, Jiang Z, Chen L, Sun HB. Silencing of signal transducer and activator of transcription 3 expression by RNA interference suppresses growth of human hepatocellular carcinoma in tumor-bearing nude mice. World J Gastroenterol 2009; 15:2602-8. [PMID: 19496189 PMCID: PMC2691490 DOI: 10.3748/wjg.15.2602] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the effect of silencing of signal transducer and activator of transcription 3 (STAT3) expression by RNA interference (RNAi) on growth of human hepatocellular carcinoma (HCC) in tumor-bearing nude mice in vivo.
METHODS: To construct the recombinant plasmid of pSilencer 3.0-H1-STAT3-siRNA-GFP (pSH1-siRNA-STAT3) and establish the tumor-bearing nude mouse model of the HCC cell line SMMC7721, we used intratumoral injection together with electroblotting to transfect the recombinant plasmid pSH1-siRNA-STAT3 into the transplanted tumor. The weight of the nude mice and tumor volumes were recorded. STAT3 gene transcription was detected by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). Level of protein expression and location of STAT3 were determined by Western blotting and immunohistochemical staining. STAT3-related genes such as survivin, c-myc, VEGF, p53 and caspase3 mRNA and protein expression were detected in tumor tissues at the same time. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay was used to detect apoptosis of tumor cells.
RESULTS: The weight of the treated nude mice increased, and the tumor volume decreased markedly compared with those of the mock-treated and negative control groups (P < 0.01). The results of RT-PCR and Western blotting showed that mRNA and protein levels of STAT3 declined markedly in the treated group. The change in STAT3-related gene expression in tumor tissues at the mRNA and protein level also varied, the expression of survivin, VEGF and c-myc were obviously reduced, and expression of p53 and caspase3 increased (P < 0.01). Most of the tumor tissue cells in the treated group developed apoptosis that was detected by TUNEL assay.
CONCLUSION: Silencing of STAT3 expression by RNAi significantly inhibits expression of STAT3 mRNA and protein, and suppresses growth of human HCC in tumor-bearing nude mice. The mechanism may be related to down-regulation of survivin, VEGF and c-myc and up-regulation of p53 and caspase3 expression. Accordingly, the STAT3 gene may act as an important and effective target in gene therapy of HCC.
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Martínez-Iglesias O, Garcia-Silva S, Tenbaum SP, Regadera J, Larcher F, Paramio JM, Vennström B, Aranda A. Thyroid hormone receptor beta1 acts as a potent suppressor of tumor invasiveness and metastasis. Cancer Res 2009; 69:501-9. [PMID: 19147563 DOI: 10.1158/0008-5472.can-08-2198] [Citation(s) in RCA: 118] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Loss of thyroid hormone receptors (TR) is a common feature in some tumors, although their role in tumor progression is currently unknown. We show here that expression of TRbeta1 in hepatocarcinoma and breast cancer cells reduces tumor growth, causes partial mesenchymal-to-epithelial cell transition, and has a striking inhibitory effect on invasiveness, extravasation, and metastasis formation in mice. In cultured cells, TRbeta1 abolishes anchorage-independent growth and migration, blocks responses to epidermal growth factor, insulin-like growth factor-I, and transforming growth factor beta, and regulates expression of genes that play a key role in tumorigenicity and metastatic growth. The receptor disrupts the mitogenic action of growth factors by suppressing activation of extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling pathways that are crucial for cell proliferation and invasiveness. Furthermore, increased aggressiveness of skin tumors is found in genetically modified mice lacking TRs, further demonstrating the role of these receptors as inhibitors of tumor progression. These results define a novel role for the thyroid hormone receptor as a metastasis suppressor gene, providing a starting point for the development of novel therapeutic strategies for the treatment of human cancer.
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Affiliation(s)
- Olaia Martínez-Iglesias
- Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Madrid, Spain
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24
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Asirvatham AJ, Magner WJ, Tomasi TB. miRNA regulation of cytokine genes. Cytokine 2009; 45:58-69. [PMID: 19121586 PMCID: PMC3129852 DOI: 10.1016/j.cyto.2008.11.010] [Citation(s) in RCA: 128] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2008] [Revised: 10/23/2008] [Accepted: 11/19/2008] [Indexed: 12/19/2022]
Abstract
In this review we discuss specific examples of regulation of cytokine genes and focus on a new mechanism involving post-transcriptional regulation via miRNAs. The post-transcriptional regulation of cytokine genes via the destabilizing activity of AU-rich elements [AREs] and miRNAs is a pre-requisite for regulating the half-life of many cytokines and achieving the temporal and spatial distributions required for regulation of these genes.
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Affiliation(s)
- Ananthi J. Asirvatham
- Roswell Park Cancer Institute, Laboratory of Molecular Medicine, Department of Immunology, Elm & Carlton Streets, Buffalo, NY 14263, USA
| | - William J. Magner
- Roswell Park Cancer Institute, Laboratory of Molecular Medicine, Department of Immunology, Elm & Carlton Streets, Buffalo, NY 14263, USA
| | - Thomas B. Tomasi
- Roswell Park Cancer Institute, Laboratory of Molecular Medicine, Department of Immunology, Elm & Carlton Streets, Buffalo, NY 14263, USA
- Departments of Medicine and Microbiology & Immunology, State University of New York, School of Medicine and Biomedical Sciences, Buffalo, NY 14214, USA
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Ke AW, Shi GM, Zhou J, Wu FZ, Ding ZB, Hu MY, Xu Y, Song ZJ, Wang ZJ, Wu JC, Bai DS, Li JC, Liu KD, Fan J. Role of overexpression of CD151 and/or c-Met in predicting prognosis of hepatocellular carcinoma. Hepatology 2009; 49:491-503. [PMID: 19065669 DOI: 10.1002/hep.22639] [Citation(s) in RCA: 189] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
UNLABELLED It has been reported that tetraspanin CD151 acts as a promoter of metastasis in several tumors and plays an important role in c-Met/hepatocyte growth factor signaling. However, the role of CD151 alone and coexpression of CD151/c-Met in hepatocellular carcinoma (HCC) remains unclear. We found that expression of CD151 was positively related to metastatic potential of HCC cell lines, and modified cells with CD151(high) showed higher secretion of matrix metalloproteinase 9 and aggressiveness in vitro and higher metastatic ability in vivo. Furthermore, HCC patients with vascular invasion, large tumors, multiple tumors, high tumor-node-metastasis stage, and undifferentiated tumor were prone to have higher CD151 expression. The postoperative 3-, 5-, and 7-year overall survival (OS) of patients in HCCs with CD151(high) were significantly lower than those in the CD151(low) group, and correspondingly cumulative recurrence rates in HCCs with CD151(high) were significantly higher than those in the CD151(low) group. Both CD151 and c-Met were remarkably overexpressed in HCCs, compared with adjacent nontumorous and normal liver tissues. Pearson correlation analysis showed a slight correlation between CD151 and c-Met in HCCs. Importantly, the 5- and 7-year OS rates in CD151(high)/c-Met(high) patients were 50.5% and 37.8%, respectively, significantly lower than those of CD151(low)/c-Met(low) patients (63.9% and 54.6%, respectively). Five- and 7-year cumulative recurrence rates in CD151(high)/c-Met(high) patients were 53.3% and 71.9%, respectively, markedly higher than those of CD151(low)/c-Met(low) patients (39.0% and 52.5%, respectively). Multivariate analysis revealed that CD151 and combination of CD151/c-Met were independent prognostic indicators for OS and cumulative recurrence. CONCLUSION CD151 is positively associated with invasiveness of HCC, and CD151 or combination of CD151/c-Met is a novel marker in predicting the prognosis of HCC and a potential therapeutic target.
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Affiliation(s)
- Ai-Wu Ke
- Experimental Research Center of Zhongshan Hospital, Fudan University, Shanghai, PR China.
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CCR1 knockdown suppresses human non-small cell lung cancer cell invasion. J Cancer Res Clin Oncol 2008; 135:695-701. [PMID: 18972130 DOI: 10.1007/s00432-008-0505-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2008] [Accepted: 10/10/2008] [Indexed: 01/02/2023]
Abstract
PURPOSE CC chemokine receptor 1 (CCR1) plays a critical role in the recruitment of leukocytes to the site of inflammation. Tumor invasion and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. In this study, we aimed to assess the role of CCR1 in non-small cell lung cancer (NSCLC). METHODS CCR1 expression was determined by Western blotting in two human NSCLC clones (95C and 95D) with different metastatic potential. We silenced CCR1 expression through microRNA-mediated RNA interference, and examined the invasiveness and proliferation of CCR1-silenced NSCLC cell through Matrigel assay and MTT assay. Matrix metalloproteinases (MMPs) activity was determined by gelatin zymography. RESULTS We found that expression of CCR1 was correlated with the aggressive phenotype of the NSCLC cells. CCR1 knockdown significantly suppressed the invasiveness of NSCLC cells, but had only a minor effect on cell proliferation. Moreover, we demonstrated that CCR1 knockdown significantly reduced the expression level of matrix metalloproteinase-9. CONCLUSIONS These findings suggest that CCR1 contributes to NSCLC cell migration by stimulating cell invasion, independent of cell proliferation. CCR1 might be a new target for NSCLC therapy.
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Gao YF, Yu L, Wei W, Li JB, Luo QL, Shen JL. Inhibition of hepatitis B virus gene expression and replication by artificial microRNA. World J Gastroenterol 2008; 14:4684-9. [PMID: 18698684 PMCID: PMC2738794 DOI: 10.3748/wjg.14.4684] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the inhibitory effects of hepatitis B virus (HBV) replication and expression by transfecting artificial microRNA (amiRNA) into HepG2.2.15 cells.
METHODS: Three amiRNA-HBV plasmids were constructed and transfected into HepG2.2.15 cells. HBV antigen secretion was detected in the cells with transient and stable transfection by time-resolved fluoroimmunoassays (TRFIA). HBV DNA replication was examined by fluorescence quantitative PCR, and the level of HBV S mRNA was measured by semi-quantitative RT-PCR.
RESULTS: The efficiency of transient transfection of the vectors into 2.2.15 cells was 55%-60%. All the vectors had significant inhibition effects on HBsAg and HBeAg at 72 h and 96 h after transfection (P < 0.01 for all). The secretion of HBsAg and HBeAg into the supernatant was inhibited by 49.8% ± 4.7% and 39.9% ± 6.7%, respectively, at 72 h in amiRNA-HBV-S608 plasmid transfection group. The copy of HBV DNA within culture supernatant was also significantly decreased at 72 h and 96 h after transfection (P < 0.01 for all). In the cells with stable transfection, the secretion of HBsAg and HBeAg into the supernatant was significantly inhibited in all three transfection groups (P < 0.01 for all, vs negative control). The copies of HBV DNA were inhibited by 33.4% ± 3.0%, 60.8% ± 2.3% and 70.1% ± 3.3%, respectively.
CONCLUSION: In HepG2.2.15 cells, HBV replication and expression could be inhibited by artificial microRNA targeting the HBV S coding region. Vector-based artificial microRNA could be a promising therapeutic approach for chronic HBV infection.
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Sugasawa H, Ichikura T, Tsujimoto H, Kinoshita M, Morita D, Ono S, Chochi K, Tsuda H, Seki S, Mochizuki H. Prognostic significance of expression of CCL5/RANTES receptors in patients with gastric cancer. J Surg Oncol 2008; 97:445-50. [PMID: 18297689 DOI: 10.1002/jso.20984] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND OBJECTIVES The clinical significance of CCL5 has been reported in several malignancies. In this study, we examined the prognostic impact of serum CCL5 levels and the expression of CCL5 receptors on tumor cells in patients with gastric cancer. METHODS Serum CCL5 levels in patients with gastric cancer were measured by enzyme-linked immunoabsorbent assay. Immunohistochemical staining of three chemokine receptors, CCR1, CCR3, and CCR5, which are known as CCL5 receptors, was performed in gastric cancer tissue. RESULTS We found that serum CCL5 levels themselves had no impact on survival; however, higher serum CCL5 concentrations were associated with more advanced disease. Eighty-six (41%), 48 (23%), and 60 patients (28%) showed positive expression of CCR1, CCR3, and CCR5, respectively, on gastric cancer cells. Among the patients who underwent curative resection for stages II-IV disease, patients with positive CCR3 expression had significantly lower survival rates compared to those with negative CCR3 expression. Unlike CCR1, positive CCR5 expression was also associated with poorer prognosis. Multivariate analysis revealed that expression of CCR3 and/or CCR5 was an independent prognostic factor. CONCLUSIONS Tumor expression of CCR3 and/or CCR5 (receptors for CCL5) is associated with a lower survival rate in patients with gastric cancer.
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Affiliation(s)
- Hidekazu Sugasawa
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan.
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Shi GM, Xu Y, Fan J, Zhou J, Yang XR, Qiu SJ, Liao Y, Wu WZ, Ji Y, Ke AW, Ding ZB, He YZ, Wu B, Yang GH, Qin WZ, Zhang W, Zhu J, Min ZH, Wu ZQ. Identification of side population cells in human hepatocellular carcinoma cell lines with stepwise metastatic potentials. J Cancer Res Clin Oncol 2008; 134:1155-63. [PMID: 18470535 DOI: 10.1007/s00432-008-0407-1] [Citation(s) in RCA: 126] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2008] [Accepted: 04/23/2008] [Indexed: 12/22/2022]
Abstract
PURPOSE To identify the side population (SP) cells from four hepatocellular carcinoma (HCC) cell lines with stepwise metastatic potentials. METHODS SP cells were sorted from HCCLM3, MHCC97-H, MHCC97-L and Hep3B by flow cytometry, and then analyzed by differentiation study, clonogenic assay, chemoresistance study and tumorigenicity assay in vivo. The expression of ABCG(2) in SP cells was detected by immunocytochemistry, western blotting and real-time quantitative PCR, respectively. RESULTS There was significant difference in SP proportion among HCCLM3, MHCC97-H, MHCC97-L and Hep3B (28.7 +/- 1.6%, 14.5 +/- 0.6%, 4.2 +/- 0.4%, 0.9 +/- 0.1%, respectively, P < 0.01). All the SP cells showed similar characteristics of self-renewal, high clonogenicity, remarkable chemo-resistance and high expression of ABCG(2). As low as 2,000 SP cells could initiate tumors in non-obese diabetic/severe combined immunodeficiency mice successfully. CONCLUSIONS SP cells purified from HCC cell lines harbors cancer stem cell-like properties, and may be related to the metastatic potentials and therapeutic-resistance of HCC.
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Affiliation(s)
- Guo-Ming Shi
- Key Laboratory for Carcinogenesis and Cancer Invasion, Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, the Chinese Ministry of Education, 136 Yi Xue Yuan Road, Shanghai, 200032, People's Republic of China
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Sugasawa H, Ichikura T, Kinoshita M, Ono S, Majima T, Tsujimoto H, Chochi K, Hiroi S, Takayama E, Saitoh D, Seki S, Mochizuki H. Gastric cancer cells exploit CD4+ cell-derived CCL5 for their growth and prevention of CD8+ cell-involved tumor elimination. Int J Cancer 2008; 122:2535-41. [PMID: 18246596 DOI: 10.1002/ijc.23401] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The level of serum CCL5, a C-C chemokine, is reportedly correlated with tumor progression in several cancers. We herein investigated the mechanisms by which CCL5 might contribute to tumor progression in gastric cancer. Serum CCL5 levels significantly correlated with tumor progression and prognosis in patients with gastric cancer. Immunohistochemistry showed that tumor-infiltrating lymphocytes expressed CCL5, while the tumor cells expressed the CCL5 receptors. Fluorescent double staining showed that tumor-infiltrating CD4+ cells rather than CD8+ cells preferentially expressed CCL5. Using gastric cancer cell lines (MKN45, KATO III), we examined CCL5 production by coculturing whole peripheral blood mononuclear cells (PBMCs), CD4+ cells, or CD8+ cells, with tumor cells. CD4+ cells cocultured with tumor cells remarkably enhanced CCL5 production in a direct cell-cell contact manner over other cocultured PBMCs, including CD8+ cells. Gastric cancer cell lines expressed CCL5 receptors and augmented their proliferation in response to CCL5 stimulation. Furthermore, we examined the effect of CCL5-treated cancer cells on the cocultured PBMCs, focusing on the CD4+/CD8+ proportion and apoptosis. Coculture of CCL5-treated gastric cancer cells with PBMCs resulted in a significant decrease in the proportion of CD8+ cells but not CD4+ cells, suggesting Fas-FasL-mediated apoptosis in CD8+ cells. In immunodeficient mice coinjected with KATO III and PBMCs, neutralization of CCL5 significantly suppressed tumor progression, resulting in a favorable outcome. In conclusion, gastric cancer cells might thus induce CD4+ T cells to secrete CCL5 and exploit it for their progression, as well as to aid in the prevention of CD8+ T cell-involved tumor elimination.
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Affiliation(s)
- Hidekazu Sugasawa
- Department of Surgery, National Defense Medical College, Tokorozawa, Japan.
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Huang J, Chen K, Gong W, Dunlop NM, Wang JM. G-protein coupled chemoattractant receptors and cancer. FRONT BIOSCI-LANDMRK 2008; 13:3352-63. [PMID: 18508437 DOI: 10.2741/2930] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Chemoattractant receptors are a group of seven transmembrane, G protein coupled receptors (GPCRs). They were initially identified mainly on leukocytes to mediate cell migration in response to pathogen or host-derived chemotactic factors. During the past decade, chemoattractant GPCRs have been discovered not only to mediate leukocyte chemotaxis thus promoting innate and adaptive host immune responses, but also to play essential roles in development, homeostasis, HIV infection, angiogenesis and wound healing. A growing body of evidence further indicates that chemoattractant GPCRs contribute to tumor growth, invasion, angiogenesis/angiostasis and metastasis. The diverse properties of GPCRs in the progression of malignant tumors have attracted intense interest in their potential as novel anti-tumor pharmacological targets.
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Affiliation(s)
- Jian Huang
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA
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Tumor response to combination celecoxib and erlotinib therapy in non-small cell lung cancer is associated with a low baseline matrix metalloproteinase-9 and a decline in serum-soluble E-cadherin. J Thorac Oncol 2008; 3:117-24. [PMID: 18303430 DOI: 10.1097/jto.0b013e3181622bef] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
INTRODUCTION Cyclooxygenase-2 overexpression may mediate resistance to epidermal growth factor receptor tyrosine kinase inhibition through prostaglandin E2-dependent promotion of epithelial to mesenchymal transition (EMT). Suppression of epithelial markers, such as E-cadherin, can lead to resistance to erlotinib. Prostaglandin E2 down-regulates E-cadherin expression by up-regulating transcriptional repressors, including ZEB1 and Snail. Furthermore, E-cadherin can be modulated by matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs), promoting tumor invasion and metastasis. Markers of EMT and tumor invasion were evaluated in patient serum from a phase I clinical trial investigating the combination of celecoxib and erlotinib in non-small cell lung cancer (NSCLC) patients. METHODS Samples from 22 subjects were evaluated. Soluble E-cadherin (sEC) was evaluated by enzyme linked immunosorbent assay in patient serum at baseline, week 4, and week 8 of treatment. Other markers of EMT and angiogenesis were evaluated by enzyme linked immunosorbent assay, including MMP-9, TIMP-1, and CCL15. RESULTS Serum sEC, MMP-9, TIMP-1, and CCL15 levels were determined at baseline and week 8. Patients with a partial response to therapy had a significant decrease in sEC, TIMP-1, and CCL15 at week 8. In patients who responded to the combination therapy, baseline MMP-9 was significantly lower compared with nonresponders (p = 0.006). CONCLUSIONS sEC, MMP-9, TIMP-1, and CCL15 levels correlate with response to combination therapy with erlotinib and celecoxib in patients with NSCLC. A randomized phase II trial is planned comparing erlotinib and celecoxib with erlotinib plus placebo in advanced NSCLC. This study will prospectively assess these and other biomarkers in serum and tumor tissue.
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Hashimoto I, Koizumi K, Tatematsu M, Minami T, Cho S, Takeno N, Nakashima A, Sakurai H, Saito S, Tsukada K, Saiki I. Blocking on the CXCR4/mTOR signalling pathway induces the anti-metastatic properties and autophagic cell death in peritoneal disseminated gastric cancer cells. Eur J Cancer 2008; 44:1022-9. [PMID: 18375114 DOI: 10.1016/j.ejca.2008.02.043] [Citation(s) in RCA: 107] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2007] [Revised: 02/19/2008] [Accepted: 02/20/2008] [Indexed: 12/22/2022]
Abstract
Patients with advanced gastric carcinoma, especially peritoneal dissemination, have a poor prognosis even after any treatment. Chemokines are now known to play an important role in cancer growth and metastasis. We recently reported that the chemokine CXCL12 plays an important role in the development of peritoneal carcinomatosis from gastric carcinoma. In this study, we investigated signalling pathway involved in the peritoneal carcinomatosis induced by chemokine CXCL12. Akt was rapidly and strongly phosphorylated by chemokine CXCL12. CXCL12 also induced the activation of p70S6K (S6K) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1) included in mammalian target of rapamycin (mTOR) pathways which are located downstream of Akt, resulting in enhancements of metastatic properties such as MMP production, cell migration and cell growth in peritoneal disseminated gastric cancer, NUGC4 cells. Furthermore, mTOR inhibitor rapamycin not only drastically inhibited migration and MMP production, but also induced type II programmed cell death, autophagic cell death. In the present study, we have shown for the first time that the mTOR pathway plays a central role in the development of peritoneal carcinomatosis, and blocking this pathway induces autophagic cell death in disseminated gastric cancer. Therefore, blocking on the CXCR4/mTOR signalling pathway may be useful for the future development of a more effective therapeutic strategy for gastric cancer involved in peritoneal dissemination.
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Affiliation(s)
- Isaya Hashimoto
- Department of Surgery II, Faculty of Medicine, University of Toyama, Toyama, Japan
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O'Hayre M, Salanga CL, Handel TM, Allen SJ. Chemokines and cancer: migration, intracellular signalling and intercellular communication in the microenvironment. Biochem J 2008; 409:635-649. [PMID: 18177271 DOI: 10.1042/bj20071493] [Citation(s) in RCA: 210] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
Inappropriate chemokine/receptor expression or regulation is linked to many diseases, especially those characterized by an excessive cellular infiltrate, such as rheumatoid arthritis and other inflammatory disorders. There is now overwhelming evidence that chemokines are also involved in the progression of cancer, where they function in several capacities. First, specific chemokine-receptor pairs are involved in tumour metastasis. This is not surprising, in view of their role as chemoattractants in cell migration. Secondly, chemokines help to shape the tumour microenvironment, often in favour of tumour growth and metastasis, by recruitment of leucocytes and activation of pro-inflammatory mediators. Emerging evidence suggests that chemokine receptor signalling also contributes to survival and proliferation, which may be particularly important for metastasized cells to adapt to foreign environments. However, there is considerable diversity and complexity in the chemokine network, both at the chemokine/receptor level and in the downstream signalling pathways they couple into, which may be key to a better understanding of how and why particular chemokines contribute to cancer growth and metastasis. Further investigation into these areas may identify targets that, if inhibited, could render cancer cells more susceptible to chemotherapy.
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Affiliation(s)
- Morgan O'Hayre
- Skaggs School of Pharmacy and Pharmaceutical Science, University of California San Diego, La Jolla, CA 92093-0684, USA
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