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Chuma M, Uojima H, Toyoda H, Hiraoka A, Arase Y, Atsukawa M, Itokawa N, Okubo T, Tada T, Numata K, Morimoto M, Sugimori M, Nozaki A, Iwasaki S, Yasuda S, Koshiyama Y, Mishima Y, Tsuruya K, Tokoro C, Miura Y, Hidaka H, Kumada T, Kusano C, Kagawa T, Maeda S. Clinical significance of circulating biomarkers of immune-checkpoint molecules with atezolizumab plus bevacizumab therapy in unresectable hepatocellular carcinoma. Hepatol Int 2024; 18:1472-1485. [PMID: 38963640 DOI: 10.1007/s12072-024-10680-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 04/06/2024] [Indexed: 07/05/2024]
Abstract
BACKGROUND The aims of this study were to identify clinically significant biomarkers of a response to atezolizumab plus bevacizumab (ATZ + BV) therapy and to develop target strategies against unresectable hepatocellular carcinoma (u-HCC). METHOD We first investigated the potential of circulating tumor DNA (ctDNA) to serve as a biomarker for predicting the therapeutic outcome in 24 u-HCC patients treated with ATZ + BV therapy. Next, we analyzed levels of immune-related cytokines in blood samples from 134 u-HCC patients who received ATZ + BV. For this, serum immune-related molecules or cancer-immune cycle-related molecules that have been reported in HCC patient sera, namely CD274, LAG-3, CCL2, 4, 5, CXCL1, 9, 10, 12, 13, CX3CL1, CCR5, IFNγ and IL-6, 8 were measured using enzyme-linked immunosorbent assay. RESULTS More than 1% of variant read frequency (VRF) mutations were found in TP53, APC, PIK3CA and VHL, although with no correlation with treatment response. Among the 15 cytokines evaluated, CXCL9 and LAG-3 levels were significantly different between patients with objective response (OR), stable disease (SD), and progressive disease (PD) following ATZ + BV treatment. Receiver-operating characteristic curve analyses of CXCL9 (cut-off value: 419.1 pg/ml) and LAG-3 (cut-off value: 3736.3 pg/ml) indicated areas of 0.779 and 0.697, respectively, for differentiating PD from non-PD and OR from non-OR. In multivariate analysis of progression-free survival (PFS) and overall survival (OS), high serum CXCL9 (hazard ratio (HR) and 95% confidence interval (CI): 0.412 (0.251-0.677) (p = 0.0005) for PFS and 0.252 (0.125-0.508) (p = 0.0001) for OS), and low serum LAG-3 (HR and 95% CI 0.419 (0.249-0.705) (p = 0.0011) for PFS and 0.294 (0.140-0.617) (p = 0.0012) for OS) were independent positive predictive factors. CONCLUSION Although, as far as we examined, no ctDNA mutations in blood were found to be related to ATZ + BV treatment efficacy, serum CXCL9 and LAG-3 levels, which are related to the cancer-immune cycle, were associated with treatment efficacy and could be predictive markers of the efficacy of ATZ + BV treatment in HCC patients.
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Affiliation(s)
- Makoto Chuma
- Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa, Japan.
| | - Haruki Uojima
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Yoshitake Arase
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Masanori Atsukawa
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Hospital, Tokyo, Japan
| | - Norio Itokawa
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Hospital, Tokyo, Japan
| | - Tomomi Okubo
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan
| | - Toshifumi Tada
- Department of Gastroenterology, Himeji Red Cross Hospital, Himeji, Japan
| | - Kazushi Numata
- Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa, Japan
| | - Manabu Morimoto
- Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center Hospital, Yokohama, Japan
| | - Makoto Sugimori
- Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa, Japan
| | - Akito Nozaki
- Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa, Japan
| | - Shuichiro Iwasaki
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Satoshi Yasuda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Yuichi Koshiyama
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Yusuke Mishima
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Kota Tsuruya
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Chikako Tokoro
- Division of Gastroenterology, Saiseikai Yokohamashi-Nanbu Hospital, Yokohama, Japan
| | - Yuki Miura
- Gastroenterology Division, Hadano Red Cross Hospital, Hadano, Japan
| | - Hisashi Hidaka
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Takashi Kumada
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
- Faculty of Nursing, Gifu Kyoritsu University, Ogaki, Japan
| | - Chika Kusano
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan
| | - Tatehiro Kagawa
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Shin Maeda
- Department of Gastroenterology, Yokohama City University Hospital, Yokohama, Japan
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Huang H, Lan C, Wei Y, Nong J, Liao X, Ye X, Deng G, Peng T, Zhou X. Role of CCR1/5/7 in hepatocellular carcinoma: a study on prognostic evaluation, molecular subtyping, and association with immune infiltration. Aging (Albany NY) 2024; 16:6229-6261. [PMID: 38552222 PMCID: PMC11042939 DOI: 10.18632/aging.205698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 02/02/2024] [Indexed: 04/23/2024]
Abstract
This study aims to assess the prognostic value of the C-C motif chemokine receptor (CCR) gene family in hepatocellular carcinoma (HCC) and its relationship with immune infiltration and molecular subtypes of HCC. The evaluation of the GSE14520 dataset and TCGA database confirmed the prognostic significance of CCR. Building upon the correlation between CCR1, CCR5, and CCR7 and favorable prognosis, we further validated the prognostic importance of CCR1, CCR5, and CCR7 in ICGC database and an independent cohort from Guangxi autonomous region. Then, we constructed a risk prognosis model. Additionally, we observed significant positive correlations between CCR1, CCR5, and CCR7 and the infiltration of B cells, T cells, and macrophages in HCC. Subsequently, we conducted CCK assays, Transwell assays, and colony formation assays to evaluate the molecular biological functions of CCR1, CCR5, and CCR7. These experiments further confirmed that upregulation of CCR1, CCR5, and CCR7 can individually inhibit the proliferation, migration, and stemness of HCC cells. By analyzing the relationship between expression levels and tumor mutation frequency, we discovered that patients with high CCR1 expression were more likely to be classified as non-proliferative HCC. Similar conclusions were observed for CCR5 and CCR7. The association of CCR1, CCR5, and CCR7 with the molecular subtypes of HCC suggests that they may serve as intermediary molecules linking immune status and molecular subtypes in HCC. In summary, CCR1, CCR5, and CCR7 have the potential to serve as prognostic biomarkers for HCC and regulate HCC progression by influencing immune cell infiltration.
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MESH Headings
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/mortality
- Humans
- Liver Neoplasms/genetics
- Liver Neoplasms/immunology
- Liver Neoplasms/pathology
- Liver Neoplasms/mortality
- Receptors, CCR1/genetics
- Receptors, CCR1/metabolism
- Receptors, CCR7/genetics
- Receptors, CCR7/metabolism
- Prognosis
- Receptors, CCR5/genetics
- Receptors, CCR5/metabolism
- Biomarkers, Tumor/genetics
- Lymphocytes, Tumor-Infiltrating/immunology
- Female
- Gene Expression Regulation, Neoplastic
- Male
- Cell Line, Tumor
- Cell Movement/genetics
- Cell Proliferation/genetics
- Middle Aged
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Affiliation(s)
- Huasheng Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning 530021, People’s Republic of China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Chenlu Lan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning 530021, People’s Republic of China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Yongguang Wei
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning 530021, People’s Republic of China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Jusen Nong
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning 530021, People’s Republic of China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Xiwen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning 530021, People’s Republic of China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Xinping Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Ganlu Deng
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Department of Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning 530021, People’s Republic of China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Xin Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning 530021, People’s Republic of China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China
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Pessino G, Scotti C, Maggi M, Immuno-Hub Consortium. Hepatocellular Carcinoma: Old and Emerging Therapeutic Targets. Cancers (Basel) 2024; 16:901. [PMID: 38473265 DOI: 10.3390/cancers16050901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 02/16/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
Liver cancer, predominantly hepatocellular carcinoma (HCC), globally ranks sixth in incidence and third in cancer-related deaths. HCC risk factors include non-viral hepatitis, alcohol abuse, environmental exposures, and genetic factors. No specific genetic alterations are unequivocally linked to HCC tumorigenesis. Current standard therapies include surgical options, systemic chemotherapy, and kinase inhibitors, like sorafenib and regorafenib. Immunotherapy, targeting immune checkpoints, represents a promising avenue. FDA-approved checkpoint inhibitors, such as atezolizumab and pembrolizumab, show efficacy, and combination therapies enhance clinical responses. Despite this, the treatment of hepatocellular carcinoma (HCC) remains a challenge, as the complex tumor ecosystem and the immunosuppressive microenvironment associated with it hamper the efficacy of the available therapeutic approaches. This review explores current and advanced approaches to treat HCC, considering both known and new potential targets, especially derived from proteomic analysis, which is today considered as the most promising approach. Exploring novel strategies, this review discusses antibody drug conjugates (ADCs), chimeric antigen receptor T-cell therapy (CAR-T), and engineered antibodies. It then reports a systematic analysis of the main ligand/receptor pairs and molecular pathways reported to be overexpressed in tumor cells, highlighting their potential and limitations. Finally, it discusses TGFβ, one of the most promising targets of the HCC microenvironment.
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Affiliation(s)
- Greta Pessino
- Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Claudia Scotti
- Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Maristella Maggi
- Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Immuno-Hub Consortium
- Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
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Abstract
The human liver is an organ with a diverse array of immunologic functions. Its unique anatomic position that leads to it receiving all the mesenteric venous blood, combined with its unique micro anatomy, allows it to serve as a sentinel for the body's immune system. Hepatocytes, biliary epithelial cells, Kupffer cells, stellate cells, and liver sinusoidal endothelial cells express key molecules that recruit and activate innate and adaptive immunity. Additionally, a diverse array of lymphoid and myeloid immune cells resides within and traffics to the liver in specific circumstances. Derangement of these trafficking mechanisms underlies the pathophysiology of autoimmune liver diseases, nonalcoholic steatohepatitis, and liver transplantation. Here, we review these pathways and interactions along with potential targets that have been identified to be exploited for therapeutic purposes.
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5
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Singh SK, Mishra MK, Rivers BM, Gordetsky JB, Bae S, Singh R. Biological and Clinical Significance of the CCR5/CCL5 Axis in Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:E883. [PMID: 32260550 PMCID: PMC7226629 DOI: 10.3390/cancers12040883] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 04/01/2020] [Accepted: 04/03/2020] [Indexed: 02/06/2023] Open
Abstract
Despite the improvement in survival for patients with liver cancer (LCa) in recent decades, only one in five patients survive for 5 years after diagnosis. Thus, there is an urgent need to find new treatment options to improve patient survival. For various cancers, including LCa, the chemokine CCL5 (RANTES) facilitates tumor progression and metastasis. Since the function of the CCR5/CCL5 interaction in LCa cell proliferation and migration is poorly understood, the present study was undertaken to investigate the role of the CCR5/CCL5 axis in these processes. Flow cytometry, RT-PCR, Western blot, and immunofluorescence techniques were used to quantify the expression of CCR5 and CCL5 in LCa cells. To determine the biological significance of CCR5 expressed by LCa cell lines, a tissue microarray of LCas stained for CCR5 and CCL5 was analyzed. The results showed higher expression (p < 0.001) of CCR5 and CCL5 in hepatocellular carcinoma (HCC) tissues compared to non-neoplastic liver tissues. Furthermore, to delineate the role of the CCR5/CCL5 interaction in LCa cell proliferation and migration, various LCa cells were treated with maraviroc, a CCR5 antagonist, in the presence of CCL5. These data demonstrated the biological and clinical significance of the CCR5/CCL5 axis in LCa progression. The targeting of this axis is a promising avenue for the treatment of LCa.
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Affiliation(s)
- Santosh K. Singh
- Department of Microbiology, Biochemistry and Immunology, Cancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA;
| | - Manoj K. Mishra
- Department of Biological Sciences, Alabama State University, Montgomery, AL 36101, USA;
| | - Brian M. Rivers
- Cancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA;
| | - Jennifer B. Gordetsky
- Departments of Pathology and Urology, Vanderbilt University Medical Center, Nashville, TN 37232, USA;
| | - Sejong Bae
- Department of Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35205, USA;
| | - Rajesh Singh
- Department of Microbiology, Biochemistry and Immunology, Cancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA;
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Zahran AM, Hetta HF, Rayan A, Eldin AS, Hassan EA, Fakhry H, Soliman A, El-Badawy O. Differential expression of Tim-3, PD-1, and CCR5 on peripheral T and B lymphocytes in hepatitis C virus-related hepatocellular carcinoma and their impact on treatment outcomes. Cancer Immunol Immunother 2020; 69:1253-1263. [PMID: 32170378 DOI: 10.1007/s00262-019-02465-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 12/26/2019] [Indexed: 01/13/2023]
Abstract
BACKGROUND AND OBJECTIVE Activation of the immune checkpoints and expression of chemokines and chemokine receptors have been reported to promote HCC progression. This study aimed to assess the differential expression of Tim-3, PD-1, and CCR5 on peripheral blood lymphocytes from patients with HCV-related HCC and correlate their expression with the treatment outcomes. PATIENTS AND METHODS The study incorporated 40 patients with chronic HCV-related HCC and 40 healthy controls. Patients were radiologically assessed for hepatic focal lesions and portal vein thrombosis. Response to HCC treatment and overall survival (OS) outcomes were determined. The expression of Tim-3, PD-1, and CCR5 among CD19+, CD4+, and CD8+ lymphocytes was assessed by flow cytometry. RESULTS Higher frequencies of CD4+ and CD8+ cells expressing each of Tim-3 and PD-1 and PD-1+CD19+ cells were observed in the HCV-related HCC patients in comparison with controls. The highest expression of Tim-3 and PD-1 was by the CD8+ cells. Strong relations were detected among PD-1+CD19+, PD-1+CD4+ and PD-1+CD8+ cells. Elevated levels of PD-1+ lymphocytes were significantly associated with poor treatment response and shorter OS. CONCLUSION Modulation of the expression of immune checkpoints as Tim-3 and PD-1, and of CCR5 on T cells is somehow related to HCC. CD8+ T cells expressing PD-1 were the most relevant to HCC prognosis (OS and treatment response) and could represent a promising target for immune therapy against HCC. Future studies need to focus on exploring PD-1+ B cells and Tim-3+CD4+ cells, which seem to play a significant role in the pathogenesis of HCC.
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Affiliation(s)
- Asmaa M Zahran
- Clinical Pathology Department, South Egypt Cancer Institute, Assiut, Egypt
| | - Helal F Hetta
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt. .,Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
| | - Amal Rayan
- Clinical Oncology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Abeer Sharaf Eldin
- Department of Gastroenterology and Tropical Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Elham Ahmed Hassan
- Department of Gastroenterology and Tropical Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Hussein Fakhry
- Surgical Oncology Department, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
| | - Ahmed Soliman
- General Surgery Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Omnia El-Badawy
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
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Danilenko NG, Siniauskaya MG, Lukashyk SP, Karpov IA, Davydenko OG. “Double Punch”: Hepatitis C in Patients with Genetic Defects of Iron Metabolism. CYTOL GENET+ 2019. [DOI: 10.3103/s0095452719050062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Wang XZ, Huang XY, Yao JG, Wang C, Xia Q, Long XD. Genetic polymorphisms in ataxin-3 and liver cirrhosis risk related to aflatoxin B1. Oncotarget 2018; 9:27321-27332. [PMID: 29937988 PMCID: PMC6007954 DOI: 10.18632/oncotarget.24535] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Accepted: 11/07/2017] [Indexed: 01/17/2023] Open
Abstract
Background Altered expression of ataxin-3 (AT3) can modify DNA repair capacity and is observed in human diseases. The genetic polymorphisms of this gene in aflatoxin B1 (AFB1)–related liver cirrhosis (LC) have not yet been elucidated. Materials and Methods We conducted a hospital-based case–control study, including 384 patients with LC and 851 controls without any liver diseases, to assess the association between 264 polymorphisms in AT3 and AFB1-related LC risk. Genotype were tested using TaqMan-PCR or sequencing technique. Results We found three differentially distributed SNPs (rs8021276, rs7158733, and rs10146249) via the screening analysis; however, only rs8021276 polymorphism was further identified to modify the risk of LC. Compared with the homozygote of rs8021276 A alleles (rs8021276-AA), the genotypes of rs8021276 G alleles (rs8021276-AG or -GG) increased LC risk (OR: 2.48 and 6.98; 95% CI: 1.84–3.33 and 4.35–11.22, respectively). Significant interactive effects between risk genotypes and AFB1 exposure status were also observed in the joint effects analysis. Additionally, rs8021276 polymorphism was also associated with down-regulation of AT3 mRNA expression and increasing AFB1-DNA adducts in liver tissues with cirrhosis. Conclusions These results suggest AT3 polymorphisms may be risk biomarkers of AFB1-related LC, and rs8021276 is a potential candidate.
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Affiliation(s)
- Xing-Zhizi Wang
- Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
| | - Xiao-Ying Huang
- Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
| | - Jin-Guang Yao
- Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
| | - Chao Wang
- Department of Digestive Medicine, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
| | - Qiang Xia
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Xi-Dai Long
- Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China.,Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.,Guangxi Clinic Research Center of Hepatobiliary Diseases, Baise 533000, China
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9
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Circulating Interferon- λ3, Responsiveness to HBV Vaccination, and HBV/HCV Infections in Haemodialysis Patients. BIOMED RESEARCH INTERNATIONAL 2017; 2017:3713025. [PMID: 29226133 PMCID: PMC5684519 DOI: 10.1155/2017/3713025] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Revised: 08/16/2017] [Accepted: 08/30/2017] [Indexed: 02/07/2023]
Abstract
The IFN-λ3 gene (IFNL3) plays a role in HCV clearance. We investigated circulating IFN-λ3 and IFNL3 SNPs in haemodialysis patients who differed in their response to HBV vaccination and their HBV/HCV infection status. In 201 patients, plasma IFN-λ3 was determined using ELISA. IFNL3 SNPs (rs12979860, rs8099917) were genotyped using HRM analysis. Differences in IFN-λ3 levels were shown between responders and nonresponders to HBV vaccination and between HBsAg-positive patients and those who developed anti-HBs after infection and became HBsAg negative. HBV vaccine responders without HCV resolution revealed lower IFN-λ3 than noninfected responders. HBsAg/HCV RNA-positive subjects showed lower IFN-λ3 than patients positive only for HCV RNA or subjects who resolved both infections. Circulating IFN-λ3 correlated positively with anti-HBs and negatively with positive HCV RNA testing in the adjusted regression analyses. HBV vaccine nonresponders, HBsAg-positive patients, and subjects with replicating HCV composed a group with unfavourable outcomes. Responders to HBV vaccination, subjects who became HBsAg negative, and those who cleared HCV were analysed as having favourable outcomes. The latter showed higher IFN-λ3 but did not differ in distribution of IFNL3 SNPs compared with subjects with unfavourable outcomes. Higher IFN-λ3 concentrations are associated with response to HBV vaccination, self-limited HBV infection, and HCV resolution.
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10
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Santos EUDD, Lima GDCD, Oliveira MDL, Heráclio SDA, Silva HDAD, Crovella S, Maia MDMD, Souza PRED. CCR2 and CCR5 genes polymorphisms in women with cervical lesions from Pernambuco, Northeast Region of Brazil: a case-control study. Mem Inst Oswaldo Cruz 2016; 111:174-80. [PMID: 26982176 PMCID: PMC4804500 DOI: 10.1590/0074-02760150367] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 01/29/2016] [Indexed: 11/22/2022] Open
Abstract
Polymorphisms in chemokine receptors play an important role in the progression of
cervical intraepithelial neoplasia (CIN) to cervical cancer (CC). Our study examined
the association of CCR2-64I (rs1799864) andCCR5-Δ32
(rs333) polymorphisms with susceptibility to develop cervical lesion (CIN and CC) in
a Brazilian population. The genotyping of 139 women with cervical lesions and 151
women without cervical lesions for the CCR2-64I and
CCR5-Δ32 polymorphisms were performed using polymerase chain
reaction-restriction fragment length polymorphism. The individuals carrying
heterozygous or homozygous genotypes (GA+AA) for CCR2-64I
polymorphisms seem to be at lower risk for cervical lesion [odds ratio (OR) = 0.37, p
= 0.0008)]. The same was observed for the A allele (OR = 0.39, p = 0.0002), while no
association was detected (p > 0.05) with CCR5-Δ32 polymorphism.
Regarding the human papillomavirus (HPV) type, patients carrying the
CCR2-64Ipolymorphism were protected against infection by HPV type
16 (OR = 0.35, p = 0.0184). In summary, our study showed a protective effect
ofCCR2-64I rs1799864 polymorphism against the development of
cervical lesions (CIN and CC) and in the susceptibility of HPV 16 infection.
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11
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Sambyal V, Guleria K, Kapahi R, Manjari M, Sudan M, Uppal MS, Singh NR. Association of the -2518 A/G Polymorphism of MCP-1 with Breast Cancer in Punjab, North-West India. Asian Pac J Cancer Prev 2015; 16:7243-8. [DOI: 10.7314/apjcp.2015.16.16.7243] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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12
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Serum levels of chemokines CCL4 and CCL5 in cirrhotic patients indicate the presence of hepatocellular carcinoma. Br J Cancer 2015; 113:756-62. [PMID: 26270232 PMCID: PMC4559820 DOI: 10.1038/bjc.2015.227] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 03/03/2015] [Accepted: 05/13/2015] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Most hepatocellular carcinomas (HCCs) are diagnosed at an advanced stage. The prognostic value of serum tumour markers alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) is limited. The aim of our study is to evaluate the diagnostic value of serum growth factors, apoptotic and inflammatory mediators of cirrhotic patients with and without HCC. METHODS Serum samples were collected from cirrhotic potential liver transplant patients (LTx) with (n=61) and without HCC (n=78) as well as from healthy controls (HCs; n=39). Serum concentrations of CRP, neopterin and IL-6 as markers of inflammation and thrombopoietin (TPO), GCSF, FGF basic and VEGF, HMGB1, CK-18 (M65) and CK18 fragment (M30) and a panel of proinflammatory chemokines (CCL2, CCL3, CCL4, CCL5, CXCL5 and IL-8) were measured. Chi square, Fisher exact, Mann-Whitney U-tests, ROC curve analysis and forward stepwise logistic regression analyses were applied. RESULTS Patients with HCC had higher serum TPO and chemokines (P<0.001 for TPO, CCL4, CCL5 and CXCL5) and lower CCL2 (P=0.008) levels than cirrhotic patients without HCC. Multivariate forward stepwise regression analysis for significant parameters showed that among the studied parameters CCL4 and CCL5 (P=0.001) are diagnostic markers of HCC. Serum levels of TPO and chemokines were lower, whereas M30 was significantly higher in cirrhotic patients than in HCs. CONCLUSIONS High serum levels of inflammatory chemokines such as CCL4 and CCL5 in the serum of cirrhotic patients indicate the presence of HCC.
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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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14
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Zare-Bidaki M, Karimi-Googheri M, Hassanshahi G, Zainodini N, Arababadi MK. The frequency of CCR5 promoter polymorphisms and CCR5 Δ 32 mutation in Iranian populations. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2015; 18:312-6. [PMID: 26019792 PMCID: PMC4439444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Accepted: 03/01/2015] [Indexed: 11/09/2022]
Abstract
Evidence showed that chemokines serve as pro-migratory factors for immune cells. CCL3, CCL4 and CCL5, as the main CC chemokines subfamily members, activate immune cells through binding to CC chemokine receptor 5 or CCR5. Macrophages, NK cells and T lymphocytes express CCR5 and thus, affected CCR5 expression or functions could be associated with altered immune responses. Deletion of 32 base pairs (Δ 32) in the exon 1 of the CCR5 gene, which is known as CCR5 Δ 32 mutation causes down regulation and malfunction of the molecule. Furthermore, it has been evidenced that three polymorphisms in the promoter region of CCR5 modulate its expression. Altered CCR5 expression in microbial infection and immune related diseases have been reported by several researchers but the role of CCR5 promoter polymorphisms and CCR5 Δ 32 mutation in Iranian patients suffering from these diseases are controversial. Due to the fact that Iranian people have different genetic backgrounds compared to other ethnics, hence, CCR5 promoter polymorphisms and CCR5 32 mutation association with the diseases may be different in Iranian patients. Therefore, this review addresses the most recent information regarding the prevalence as well as association of the mutation and polymorphisms in Iranian patients with microbial infection and immune related diseases as along with normal population.
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Affiliation(s)
- Mohammad Zare-Bidaki
- Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Masoud Karimi-Googheri
- Department of Immunology, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | | | - Nahid Zainodini
- Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Mohammad Kazemi Arababadi
- Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran,*Corresponding author: Mohammad Kazemi Arababadi. Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran. Tel: +98-391-5234003-5; Fax: +98-391-5225209;
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15
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Wang Y, Zhang XA, Yang X, Wu ZH, Feng ZC. A MCP-1 promoter polymorphism at G-2518A is associated with spontaneous preterm birth. Mol Genet Genomics 2014; 290:289-96. [PMID: 25234163 DOI: 10.1007/s00438-014-0921-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Accepted: 09/11/2014] [Indexed: 11/28/2022]
Abstract
Monocyte chemoattractant protein-1 (MCP-1) is an important chemokine involved in the pathogenesis of spontaneous preterm birth (SPTB). We examined whether the MCP-1 G-2518A polymorphism is associated with the risk of SPTB in a Chinese population. The MCP-1 G-2518A polymorphism was genotyped in 569 preterm singleton neonates and in 673 term neonates using polymerase chain reaction-restriction fragment length polymorphism analysis. The distribution of the MCP-1 G-2518A genotype and the allele frequencies between the SPTB patients and the controls were not significantly different in the overall sample. However, we found that the AA genotype was associated with significantly increased susceptibility to very SPTB (<32 weeks) [odds ratio (OR) 2.07; 95 % confidence interval (CI), 1.27-3.36; P = 0.005) and extremely SPTB (<28 weeks) (OR 2.74; 95 % CI, 1.10-6.72; P = 0.014) compared with -2518G-positive genotypes (GG + GA genotypes). When extremely preterm neonates and very preterm neonates were combined, the AA genotype was also significantly associated with increased susceptibility to SPTB (OR 2.23; 95 % CI, 1.40-3.54; P < 0.001). The MCP-1 G-2518A polymorphism was not associated with increased susceptibility to SPTB in patients with premature rupture of the membranes (PROM) or in those without PROM. Our findings suggest that the MCP-1 G-2518A polymorphism may plays a role in mediating the susceptibility to SPTB in the Chinese population. Knowledge of genetic factors contributing to the pathogenesis of SPTB may have implications for screening and treatment of this disorder.
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Affiliation(s)
- Yan Wang
- BaYi Children's Hospital, General Military Hospital of Beijing PLA, 5 Nanmencang Road, Dongcheng District, Beijing, 100700, People's Republic of China
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16
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Common polymorphic effectors of immunity against hepatitis B and C modulate susceptibility to infection and spontaneous clearance in a Moroccan population. INFECTION GENETICS AND EVOLUTION 2014; 26:1-7. [DOI: 10.1016/j.meegid.2014.04.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Revised: 04/14/2014] [Accepted: 04/25/2014] [Indexed: 12/30/2022]
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17
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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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18
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Khorramdelazad H, Mortazavi Y, Momeni M, Arababadi MK, Khandany BK, Moogooei M, Hassanshahi G. Lack of Correlation Between the CCR5-Δ32 Mutation and Acute Myeloid Leukemia in Iranian Patients. Indian J Hematol Blood Transfus 2014; 31:29-31. [PMID: 25548441 DOI: 10.1007/s12288-014-0408-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Accepted: 05/16/2014] [Indexed: 11/24/2022] Open
Abstract
Chemokines and their receptors are crucially important in the pathogenesis of acute myeloblastic leukemia (AML). The CC chemokine receptor 5 (CCR5) is a specific chemokine receptor for CC chemokine ligand 3 (CCL3), CCL4 and CCL5 which all play key roles in identifying cancer properties and localization of leukemia cells. It has been demonstrated that the known mutation in CCR5 gene (CCR5-Δ32) leads to mal-expression of the receptor and affect its function. The aim of this study was to determine the rate of CCR5-Δ32 mutation within Iranian AML patients. In this study, blood samples were obtained from 60 AML patients and 300 healthy controls. The CCR5-Δ32 mutation was evaluated using Gap-PCR technique. Our results showed that CCR5-Δ32 mutation was not found in the patients, while three out of the controls had hetrozygotic form of this mutation. The rest of studied samples had the wild form of the gene. According to these findings, it can probably be concluded that the CCR5-Δ32 is not associated with susceptibility to AML in Iranian patients.
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Affiliation(s)
- Hossein Khorramdelazad
- Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Yousef Mortazavi
- Department of Molecular Medicine, Faculty of Medicine, Zanjan University of Medical Sciences, 4513956111 Zanjan, Iran
| | - Mohammad Momeni
- Department of Immunology, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Mohammad Kazemi Arababadi
- Department of Immunology, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran ; Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | | | - Mozhgan Moogooei
- Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
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19
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Abstract
Hypersensitivity and autoimmunity are the main features of immune system-related diseases such as type 2 diabetes (T2D), multiple sclerosis (MS), and asthma. It has been established that chemokines play key roles in the activation and regulation of immune cell migration which is important in the pathogenesis of the diseases mentioned. CC chemokines receptor 5 or CCR5 is a receptor for RANTES, MIP-1α, and MIP-1β and is expressed by several immune cells including NK cells, T lymphocytes, and macrophages. It plays key roles in the regulation of migration and activation of the immune cells during immune responses against microbe and self-antigens during autoimmunity and hypersensitivity disorders. Therefore, any alteration in the sequence of CCR5 gene or in its expression could be associated with immune system-related diseases. Previous studies revealed that a 32-base pair deletion (Δ 32) in exon 1 of the CCR5 gene led to downregulation of the gene. Previous studies demonstrated that not only CCR5 expression was altered in autoimmune and hypersensitivity disorders, but also that the mutation is associated with the diseases. This review addresses the recent information regarding the association of the CCR5 Δ 32 mutation in immune-related diseases including T2D with and without nephropathy, MS, and asthma. Based on the collected data, it seems that the CCR5 Δ 32 mutation can be considered as a risk factor for MS, but not asthma and T2D with and without nephropathy.
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20
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Khorramdelazad H, Hakimizadeh E, Hassanshahi G, Rezayati M, Sendi H, Arababadi MK. CCR5 Δ 32 mutation is not prevalent in Iranians with chronic HBV infection. J Med Virol 2013; 85:964-8. [DOI: 10.1002/jmv.23510] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/27/2012] [Indexed: 12/24/2022]
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21
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Liarmakopoulos E, Theodoropoulos G, Vaiopoulou A, Rizos S, Aravantinos G, Kouraklis G, Nikiteas N, Gazouli M. Effects of stromal cell-derived factor-1 and survivin gene polymorphisms on gastric cancer risk. Mol Med Rep 2012; 7:887-92. [PMID: 23258739 DOI: 10.3892/mmr.2012.1247] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2012] [Accepted: 11/07/2012] [Indexed: 11/06/2022] Open
Abstract
Stromal-cell derived factor-1 (SDF-1), a CXC chemokine, is important for growth, angiogenesis and metastasis of tumor cells. The SDF1-3'A polymorphism has been investigated in various types of cancer; however, no information is currently available on its role in gastric cancer. Survivin is a member of the inhibitor of apoptosis family of proteins and has a genetic polymorphism (-31G/C) located in the CDE/CHR repressor element of its promoter. In this study, 88 gastric cancer patients and 480 normal healthy control subjects were investigated for the genotype and allelic SDF1-3'A and survivin -31G/C frequencies using polymerase chain reaction‑restriction fragment length polymorphism. The SDF1-3'A genotype frequencies for GG, GA and AA were 44.32, 48.86 and 6.92% in patients and 42.71, 47.71 and 9.58% in healthy subjects, respectively. GA+AA genotype frequency and A allele distribution were not identified as significantly different between gastric cancer cases and controls. The survivin frequencies for GG, GC and CC were 20.45, 50 and 29.54% in patients and 33.96, 45 and 21.04% in healthy subjects, respectively. The C carriers (GC+CC genotype) and the C allele were over-represented among the gastric cancer cases (P=0.013 and P=0.0083, respectively). Overall, no statistically significant association was identified for SDF-1 and survivin gene examined alleles and genotypes and any parameter investigated, (e.g., stage, differentiation status and survival). The survivin promoter -31G/C polymorphism may confer an increased susceptibility to gastric cancer, while the SDF1-3'A polymorphism may not be a candidate genetic variant to select individuals at higher risk of developing gastric cancer.
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22
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Single nucleotide polymorphisms and risk of hepatocellular carcinoma in cirrhosis. J Hepatol 2012; 57:663-74. [PMID: 22609306 DOI: 10.1016/j.jhep.2012.02.035] [Citation(s) in RCA: 124] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2012] [Revised: 02/14/2012] [Accepted: 02/15/2012] [Indexed: 12/23/2022]
Abstract
Liver carcinogenesis is a complex and multi-factorial process, in which both environmental and genetic features interfere and contribute to malignant transformation. Patients with cirrhosis are particularly exposed and justify periodical screenings in order to detect the early development of hepatocellular carcinoma (HCC). The risk of HCC is, however, not identical from one patient to another. The identification of host factors that may also play an important role in HCC development may improve our understanding of the implications of the various biological pathways involved in liver carcinogenesis; such progress may as well help refine the selection of patients who could benefit from specific preventative measures or could be given adapted screening policies. Numerous candidate-gene studies have reported associations between single nucleotide polymorphisms (SNPs) and the presence of HCC. Some of these publications unfortunately suffer from major methodological drawbacks because of their case-control, retrospective and monocentric aspect. Prospective cohort studies conducted in large homogeneous populations and comprising a sufficient number of events during follow-up may overcome these pitfalls, but require a long time to be conducted and are still scarce. More recently, the first Genome Wide Association studies (GWAs) have enabled the identification of unsuspected loci that may be involved in various steps implicated in liver tumourigenesis. Taken together, these studies highlight variants that modulate oxidative stress, iron metabolism, inflammatory and immune responses, DNA repair mechanisms or systems involved in cell-cycle regulation as genetic traits susceptible to modify the natural history of cirrhotic patients and partly explain the observed differences in the risk of HCC occurrence. However, large genetic epidemiology studies in the field of cancer diseases have suggested the limited ability of polymorphic traits, alone, to refine individual prognosis. The integration of various panels of genes into clinical scores may in the near future define a "genomic risk prediction" specific to liver cancer developed in cirrhotic patients.
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Kucukgergin C, Isman FK, Cakmakoglu B, Sanli O, Seckin S. Association of Polymorphisms in MCP-1, CCR2, and CCR5 Genes with the Risk and Clinicopathological Characteristics of Prostate Cancer. DNA Cell Biol 2012; 31:1418-24. [DOI: 10.1089/dna.2012.1716] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Affiliation(s)
- Canan Kucukgergin
- Department of Biochemistry, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Ferruh K. Isman
- Clinical Biochemistry Laboratory, Goztepe Teaching and Research Hospital, Istanbul, Turkey
| | - Bedia Cakmakoglu
- Department of Molecular Medicine, Institute for Experimental Medicine Research, Istanbul University, Istanbul, Turkey
| | - Oner Sanli
- Department of Urology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Sule Seckin
- Department of Biochemistry, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
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24
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Meta-analysis of MCP-1 promoter −2518 A/G polymorphism and SLE susceptibility. Mol Biol Rep 2012; 39:8475-82. [DOI: 10.1007/s11033-012-1701-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2012] [Accepted: 06/06/2012] [Indexed: 12/19/2022]
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25
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Polymorphisms of key chemokine genes and survival of non-small cell lung cancer in Chinese. Lung Cancer 2011; 74:164-9. [DOI: 10.1016/j.lungcan.2011.03.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2010] [Revised: 01/09/2011] [Accepted: 03/15/2011] [Indexed: 12/31/2022]
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26
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Smith DA, Harrison A, Morgan P. Multiple Factors Govern the Association between Pharmacology and Toxicity in a Class of Drugs: Toward a Unification of Class Effect Terminology. Chem Res Toxicol 2011; 24:463-74. [DOI: 10.1021/tx100408v] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Affiliation(s)
- Dennis A. Smith
- Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Sandwich, Kent, CT13 9NJ, United Kingdom
| | - Anthony Harrison
- Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Sandwich, Kent, CT13 9NJ, United Kingdom
| | - Paul Morgan
- Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Sandwich, Kent, CT13 9NJ, United Kingdom
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Arababadi MK, Pourfathollah AA, Jafarzadeh A, Hassanshahi G, Mohit M, Hajghani M, Ahmadabadi BN, Kennedy D. Evaluation of CCR5 Expression on NK Cells in Iranian Patients With Occult Hepatitis B Infection. Lab Med 2010. [DOI: 10.1309/lmauisl84q4srsbt] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
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Yeh CB, Tsai HT, Chen YC, Kuo WH, Chen TY, Hsieh YH, Chou MC, Yang SF. Genetic polymorphism of CCR2-64I increased the susceptibility of hepatocellular carcinoma. J Surg Oncol 2010; 102:264-70. [PMID: 20740585 DOI: 10.1002/jso.21623] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND OBJECTIVES The purpose of this study was to investigate genetic impact of monocyte chemoattractant protein-1 (MCP-1) and its receptor chemokine receptor-2 (CCR2) gene polymorphisms on the susceptibility and clinicopathological characteristics of hepatocellular carcinoma (HCC). METHODS A total of 446 subjects, including 344 healthy controls and 102 patients with HCC, were recruited in this study and subjected to PCR-RFLP to estimate the impact of these two polymorphic variants on HCC. RESULTS No relationship between MCP-1 -2518G/A gene polymorphism and HCC risk was found among our recruited HCC patients and healthy controls. However, there was a significantly increased risk (AOR = 1.91; 95% CI = 1.11-3.29) of having HCC among subjects with GA heterozygotes of CCR2 V64I after adjusting for other confoundings. There was no synergistic effect between gene polymorphism and environmental risk factors, including tobacco and alcohol consumptions, as well as clinicopathological parameters of HCC for MCP-1 -2518G/A and CCR2 V64I genes, respectively. CONCLUSIONS CCR2-64I gene polymorphism is an important factor for the susceptibility of HCC but it might not influence the clinical pathological progression of HCC, and the contribution of CCR2-64I gene polymorphism on the susceptibility of HCC could be not through the affection of liver injury-related clinical pathological characteristics.
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Affiliation(s)
- Chao-Bin Yeh
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC
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29
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CCL2 −2518 A/G single nucleotide polymorphism as a risk factor for breast cancer. Mol Biol Rep 2010; 38:1263-7. [DOI: 10.1007/s11033-010-0225-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2010] [Accepted: 06/11/2010] [Indexed: 01/16/2023]
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Abstract
Chemokines play a paramount role in tumor progression. In hepatocellular carcinoma (HCC) progression, chemokines and their receptors play an intricate role. Currently, chemokines and their receptors such as the CXCL12-CXCR4 axis, CX3CL1-CX3CR1 axis and the CCL20-CCR6 axis have received much research attention. Although a large number of studies show that these axes are strongly associated with HCC, the exact mechanism by which these axes promote the growth and progression of HCC remains unknown. In this paper, several chemokines and their receptor interactions in HCC progression, growth and metastasis and immune response to HCC are reviewed.
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Arababadi MK, Pourfathollah AA, Jafarzadeh A, Hassanshahi G, Mohit M, Hajghani M, Shamsizadeh A. Peripheral Blood CD8+T Cells CCR5 Expression and Its Δ32 Mutation in Iranian Patients with Occult Hepatitis B Infections. Lab Med 2010. [DOI: 10.1309/lmvukwrox0ebqr01] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
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32
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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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Chang CC, Chen SC, Hsieh YH, Chen YC, Chen TY, Chu YH, Ma HJ, Chou MC, Tsai HT, Yang SF. Stromal cell-derived factor-1 but not its receptor, CXCR4, gene variants increase susceptibility and pathological development of hepatocellular carcinoma. Clin Chem Lab Med 2009; 47:412-8. [PMID: 19327121 DOI: 10.1515/cclm.2009.092] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most frequent malignant neoplasms worldwide. Genetic polymorphism has been reported as a predictive factor related to a higher risk for HCC. Because the stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4, have been reported to play important roles in tumor cell proliferation, angiogenesis, and metastasis of HCC, the aim of this study was to estimate the relationship between SDF-1 and CXCR4 gene variants to HCC risk and clinicopathological status. METHODS Polymerase chain reaction-restriction fragment length polymorphism was used to measure SDF-1 (rs1801157) and CXCR4 (rs2228014) gene polymorphisms in 311 healthy controls and 102 patients with HCC. RESULTS Compared to controls, individuals with at least one A allele had a higher risk of 1.57-fold (95% CI: 1.00-2.47) to induce HCC and had a risk of 2.81-fold (95% CI: 1.04-7.58) to develop a status of stage III or stage IV disease, after being adjusted for other confounders. However, there was no significant association between CXCR4 gene polymorphism and either HCC risk or pathological status. Additionally, both gene polymorphisms were not associated with the serum expression of liver-related clinical pathological markers. CONCLUSIONS SDF-1-3'A gene polymorphism could be considered as a factor related to an increased susceptibility to the risk and pathological development of HCC.
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Affiliation(s)
- Chi-Chung Chang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
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Abstract
A surge in interest in the chemokine–chemokine receptor network is probably related to the expanding roles that chemokines have now been identified to play in human biology, particularly immunity. Specific tissue microenvironments express distinct chemokines and both hematopoietic and nonhematopoietic cells have receptor expression profiles that permit the coordinated trafficking and organization of cells within these specific tissues. Since the chemokine network plays critical roles in both the function of the immune system and the progression of cancer, it is an attractive target for therapeutic manipulation. This review will focus on chemokine and chemokine receptor network-related therapeutic interventions that utilize host–tumor interactions particularly involving the immune system.
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Affiliation(s)
- Trina J Stewart
- Cancer Immunology Research Program, The Peter MacCallum Cancer Centre, Level 2 Smorgon Family Building, St Andrews Place, East Melbourne, Victoria, 3002, Australia
| | - Mark J Smyth
- Cancer Immunology Research Program, The Peter MacCallum Cancer Centre, Level 2 Smorgon Family Building, St Andrews Place, East Melbourne, Victoria, 3002, Australia
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