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Mocci S, Perra A, Littera R, Pes F, Melis M, Sanna C, Mascia A, Murgia M, Mereu C, Lorrai M, Duś-Ilnicka I, Zedda G, Lai S, Giuressi E, Guarino F, Serra G, Miglianti M, Stradoni R, Vacca M, Zolfino T, Chessa L, Giglio S. Human leukocyte antigen-G in hepatocellular carcinoma driven by chronic viral hepatitis or steatotic liver disease. Sci Rep 2025; 15:13331. [PMID: 40246934 PMCID: PMC12006299 DOI: 10.1038/s41598-025-97406-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 04/04/2025] [Indexed: 04/19/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer globally and the third leading cause of cancer-related mortality, primarily driven by viral infections (HCV, HBV) and steatotic liver diseases (SLD). Despite advances in treatment, early detection and accurate prognosis remain challenging. The Human leukocyte antigen G (HLA-G) molecule is dysregulated in various conditions, including cancers and viral infections. This study aimed to investigate HLA-G's role in viral-related and SLD-driven HCC. We analyzed a cohort of 116 HCC patients and 140 healthy controls to assess HLA-G genetic variants and soluble levels. Results showed significantly higher levels of soluble HLA-G in HCC patients compared to controls (Pc = 0.003). Moreover, overall survival (OS) was significantly lower in patients with the extended HLA-G*01:01:01/UTR-1 haplotype (Log-rank test, p = 0.002), a trend consistent in both HCV and/or HBV-related HCC (p = 0.025) and SLD-related HCC (p = 0.018). Elevated sHLA-G levels were associated with shorter OS across both subgroups (p = 0.034 (HBV/HCV) and p = 0.010 (SLD), respectively). The findings suggest that elevated levels of soluble HLA-G and specific genetic variants are associated with poor prognosis in HCC patients, highlighting the potential of HLA-G as a prognostic biomarker in both viral-related and steatotic liver disease-related HCC.
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Affiliation(s)
- Stefano Mocci
- Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.
- Center for Research University Services (CeSAR), University of Cagliari, Cagliari, Italy.
| | - Andrea Perra
- AART-ODV (Association for the Advancement of Research On Transplantation), Cagliari, Italy
- Oncology and Molecular Pathology Unit, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Roberto Littera
- AART-ODV (Association for the Advancement of Research On Transplantation), Cagliari, Italy
- Medical Genetics, R. Binaghi Hospital, Cagliari, Italy
| | - Francesco Pes
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Maurizio Melis
- AART-ODV (Association for the Advancement of Research On Transplantation), Cagliari, Italy
| | - Celeste Sanna
- Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Alessia Mascia
- Oncology and Molecular Pathology Unit, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Michela Murgia
- Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Caterina Mereu
- Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Michela Lorrai
- Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Irena Duś-Ilnicka
- Department of Oral Pathology, Wrocław Medical University, Wrocław, Poland
| | - Giorgia Zedda
- Oncology and Molecular Pathology Unit, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Sara Lai
- Medical Genetics, R. Binaghi Hospital, Cagliari, Italy
| | | | - Federico Guarino
- Liver Unit, Department of Internal Medicine, University Hospital of Cagliari, Cagliari, Italy
| | - Gianfranco Serra
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Michela Miglianti
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Roberta Stradoni
- Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Monica Vacca
- AART-ODV (Association for the Advancement of Research On Transplantation), Cagliari, Italy
| | | | - Luchino Chessa
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
- Liver Unit, Department of Internal Medicine, University Hospital of Cagliari, Cagliari, Italy
| | - Sabrina Giglio
- Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
- Center for Research University Services (CeSAR), University of Cagliari, Cagliari, Italy
- Medical Genetics, R. Binaghi Hospital, Cagliari, Italy
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Tizaoui K, Ayadi MA, Zemni I, Harrath AH, Rizzo R, Boujelbene N, Zidi I. The 14-bp insertion/deletion as a promising gene polymorphism to understand cancer risk: Evidence from a systematic review and comprehensive meta-analysis. Heliyon 2024; 10:e39740. [PMID: 39605806 PMCID: PMC11599971 DOI: 10.1016/j.heliyon.2024.e39740] [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: 11/08/2023] [Revised: 10/22/2024] [Accepted: 10/22/2024] [Indexed: 11/29/2024] Open
Abstract
Background HLA-G is associated with cancer cell escape. The 3'UTR polymorphism is involved in the regulation of membrane-bound HLA-G and soluble HLA-G proteins. The aim of our study was to assess the association of the HLA-G 14-bp insertion (I)/deletion (D) polymorphism with cancer susceptibility and its interaction with clinicopathological features and environmental factors. Methods A meta-analysis was performed to investigate the association between the HLA-G 14-bp I/D polymorphism and different types of cancers according to the Prisma guidelines. Results Thirty-nine publications that studied the 14-bp I/D polymorphism in cancers met our inclusion criteria. The findings of the meta-analysis showed a significant association between the 14-bp I/D polymorphism and cancer risk under the allelic contrast model D vs. I (OR = 1,112, 95 % CI = 1,009-1,227; P = 0,033) suggesting that the D allele was a risk factor for cancer susceptibility. Stratification by cancer type demonstrated a significant association of the 14-bp I/D polymorphism with breast cancer under the D vs. I contrast allele model (OR = 1,267, 95 % CI = 1,028-1,563; P = 0,027). No significant association was found for digestive, cervical, haematological and thyroid cancers. A comparison of groups stratified by ethnicity showed a significant association for Caucasians under the D vs. I model (OR = 1,147, 95 % CI = 1,002-1,313; P = 0,047); and for mixed ethnicities under the DD + DI vs. II (OR = 1,388, 95 % CI = 1,083-1,780; P = 0,010) and DI vs. II (OR = 1,402, 95 % CI = 1,077-1,824; P = 0,012) models. A comparison of cancer risks associated with the 14-bp I/D polymorphism according to geographic location revealed significant risks for the D allele and DD genotype in North Africa, the Middle East and South America. However, no significant susceptibility to cancer associated with the 14-bp I/D polymorphism was shown for Europe and North Asia. The findings of a meta-analysis of subgroups by disease stage showed a significant association in both early and advanced stages, with the 14-bp deletion variant being a risk factor. Similarly, a significant cancer risk was shown for the 14-bp deletion variant in both low- and high-grade cancers. Finally, the risk associated with the 14-bp I/D polymorphism was higher in cancers with concomitant viral infection with human papillomavirus (HPV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Conclusion The findings of the overall meta-analysis showed a significant association between the HLA-G 14-bp I/D polymorphism and cancer susceptibility. The findings stratified analysis and subgroup comparisons showed that the 14-bp I/D deletion variant was associated with an increased risk of breast cancer. The HLA-G 14-bp I/D polymorphism may interact with individual and clinicopathological factors to alter cancer risk. These promising findings for cancer risk provide the basis for further studies that explore 14bp I/D polymorphism in cancer screening and immunotherapeutic approach.
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Affiliation(s)
- Kalthoum Tizaoui
- Laboratory of Biomedical Genomics and Oncogenetics, LR16IPT05, Institut Pasteur de Tunis, University of Tunis El Manar, Tunisia
| | - Mohamed Ali Ayadi
- Department of Surgical Oncology, Salah Azaiz Institute, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Ines Zemni
- Department of Surgical Oncology, Salah Azaiz Institute, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Abdel Halim Harrath
- King Saud University, College of Science, Department of Zoology, Riyadh, Saudi Arabia
| | - Roberta Rizzo
- Department of Environmental and Prevention Sciences, University of Ferrara, Ferrara, Italy
| | - Nadia Boujelbene
- Department of Pathology, Salah Azaiz Institute, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Inès Zidi
- Laboratory of Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, University of Tunis El Manar, Tunis, Tunisia
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Mahmud MT, Ahmed F, Rana MJ, Rahman MA, Atta A, Saif-Ur-Rahman KM. Association of HLA gene polymorphisms with Helicobacter pylori related gastric cancer-a systematic review. HLA 2024; 103:e15394. [PMID: 38372631 DOI: 10.1111/tan.15394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 01/28/2024] [Accepted: 02/01/2024] [Indexed: 02/20/2024]
Abstract
The appropriate host cell immune responses for the progression of several diseases, including gastric or stomach cancer (GC), are significantly influenced by HLA polymorphisms. Our objective was to systematically review the evidence linking HLA polymorphisms with the risk of Helicobacter. pylori related GC. We conducted a comprehensive literature search to identify studies published between 2000 and April 2023 on the association of HLA polymorphisms with H. pylori related GC using databases such as Medline through PubMed, Embase, Web of Science (core collection), The Cochrane Library, and Scopus. Two authors independently screened articles, extracted data, and assessed the risk of bias using the Risk of Bias Assessment tool for Non-randomized Studies. From 7872 retrieved studies, 19 met inclusion criteria, encompassing 1656 cases and 16,787 controls across four World Health Organization regions, with Japan contributing the most studies. We explored HLA-A/B/C, HLA-DRB1/DQA1/DQB1, HLA-G, and MICA alleles. Of 29 significant HLA polymorphisms identified, 18 showed a positive association with GC, whereas 11 were negatively associated. HLA-DQB1*06 allele was most frequently associated to susceptibility, as reported in four studies, followed by HLA-DRB1*04 and HLA-DQA1*01, each reported in two studies. Conversely, HLA-G*01, HLA-DQA1*01, HLA-DQA1*05, and HLA-DQB1*03 were identified as protective in two studies each. Additionally, five genotypes and six haplotypes were reported as positive, whereas three genotypes and two haplotypes were negative factors for the disease incidence or mortality. Despite heterogeneity in the study population and types of HLA polymorphisms examined, our analysis indicates certain polymorphisms are associated with H. pylori related GC progression and mortality in specific populations.
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Affiliation(s)
- Md Toslim Mahmud
- Department of Microbiology, Noakhali Science & Technology University, Sonapur, Noakhali, Bangladesh
- Department of Biology, Baylor University, Waco, Texas, USA
| | - Feroz Ahmed
- Department of Biology, University of Texas-Arlington, Arlington, Texas, USA
- Laboratory of Environmental Biology, Division of Environmental Health Sciences, Wadsworth Center, New York State Department of Health, Albany, New York, USA
| | - Md Jowel Rana
- Infectious Diseases Division, icddr,b, Dhaka, Bangladesh
| | - Md Arifur Rahman
- Department of Microbiology, Noakhali Science & Technology University, Sonapur, Noakhali, Bangladesh
| | - Afshan Atta
- Department of Hematopathology, Skims Tertiary Centre Hospital (STCH), Srinagar, India
| | - K M Saif-Ur-Rahman
- College of Medicine, Nursing, and Health Sciences, University of Galway, Galway, Ireland
- Evidence Synthesis Ireland and Cochrane Ireland, University of Galway, Galway, Ireland
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Dhouioui S, Boujelbene N, Ouzari HI, Tizaoui K, Zidi I. Meta-analysis of HLA-G 14bp insertion/deletion polymorphism and soluble HLA-G revealed an association with digestive cancers initiation and prognosis. Heliyon 2022; 8:e09986. [PMID: 35874075 PMCID: PMC9305369 DOI: 10.1016/j.heliyon.2022.e09986] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 05/24/2022] [Accepted: 07/13/2022] [Indexed: 11/27/2022] Open
Abstract
Background/Objective Conflicting results on the association between HLA-G and digestive cancers were reported. We conducted a meta-analysis to further investigate the true relationship between HLA-G and digestive cancers (DC). Methods Following PRISMA guidelines, we performed a meta-analysis including 7 case-control studies on HLA-G 14-bp Insertion/deletion (I/D) polymorphism, and 15 studies on soluble HLA-G (sHLA-G). Odds ratios (OR) and their corresponding 95% confidence intervals (CI) for genetic polymorphisms were calculated. The pooled OR was calculated under three genetic models: allelic, recessive, and dominant models. Concerning sHLA-G meta-analysis, standardized mean differences (SMDs) were calculated. Results The HLA-G 14-bp I/D was not associated with the risk of DC. However, in the subset of HBV/HCV positive hepato-cellular cancer (HCC) patients, we reported a significant association of HLA-G 14-bp I/D with the disease initiation under allelic (D vs. I; OR = 1.698, 95% CI = 1.263-2.282, p = 0.000), dominant (DD + ID vs. II; OR = 2.321, 95% CI = 1.277-4.218, p = 0.006)and recessive (DD vs. DI + II; OR = 1.739, 95% CI = 1.173-2.577, p = 0.006) genetic models. Interestingly, HLA-G 14-bp I/D was not associated with the disease initiation in HBV/HCV negative HCC patients. However, the infection by HBV/HCV seems to be implicated in the HCC development when we compared HBV/HCV positive patients to HBV/HCV negative patients under allelic (D vs. I; OR = 1.429, 95% CI = 1.029-1.983, p = 0.033, and dominant (DD + ID vs.II; OR = 1.981, 95% CI = 1.002-3.916, p = 0.049) genetic models.Overall analysis of DC showed significant increased sHLA-G in patients compared to healthy controls (SMD = 3.341, 95% CI = 2.415-4.267, p = 0.000). In Asian patients with gastric cancer, sHLA-G was significantly increased in grade 3 compared to low grades (SMD = 0.448, 95% CI = 0.109-0.787, p = 0.000). Further analysis showed that sHLA-G was significantly increased in positive DC vascular invasion (SMD = 0.743, 95% CI = 0.385-1.100, p = 0.000). Accordingly, sHLA-G was associated with a poor prognosis for DC. Conclusion The current meta-analysis supports the significant role of HLA-G in DC. The HLA-G 14-bp I/D polymorphism was associated with HCC patients with concomitant HBV/HCV viral infections. Increased sHLA-G indicated a poor prognosis for DC cancer patients.
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Affiliation(s)
- Sabrine Dhouioui
- Laboratory Microorganisms and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Nadia Boujelbene
- Laboratory Microorganisms and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia
- Department of Pathology, Salah Azaiez Institute, Tunis, Tunisia
| | - Hadda-imene Ouzari
- Laboratory Microorganisms and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Kalthoum Tizaoui
- Laboratory Microorganisms and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Inès Zidi
- Laboratory Microorganisms and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia
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Zhou S, Liu M, Xia Y, Zhang L, Shao L, Wang N, Yu W, Ding N, Zhang K, Liang X. Association of the 3' untranslated region polymorphisms of HLA-G with susceptibility to chronic hepatitis C virus infection in the Chinese population. Hum Immunol 2021; 83:47-52. [PMID: 34556350 DOI: 10.1016/j.humimm.2021.09.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 08/05/2021] [Accepted: 09/01/2021] [Indexed: 02/08/2023]
Abstract
Hepatitis C virus (HCV) infection is a global health problem. Several previous studies have addressed the role of host single-nucleotide polymorphisms (SNPs) in HCV infection. SNPs in the regulatory region of the human leukocyte antigen G (HLA-G) gene play an important role in several diseases. The objective of this study is to determine the association of HLA-G 3'untranslated region (UTR) polymorphisms with the susceptibility to chronic hepatitis C infection in the Chinese population. HLA-G 3' UTR polymorphisms, which include 14-bp Ins/Del (rs371194629), +3003T/C (rs1707), +3010C/G (rs1710), +3027 A/C (rs17179101), +3035C/T (rs17179108), +3142 G/C (rs1063320), +3187 A/G (rs9380142) and + 3196C/G (rs1610696), were analyzed in 246 patients with chronic hepatitis C infection and 294 healthy individuals. The alleles, genotypes, and haplotypes were compared between chronic hepatitis C-infected subjects and controls using chi-square tests and logistic regression models. After a correction of multiple comparisons by the false discovery rate (FDR), the allele frequency of + 3196C, genotype frequencies of + 3187 AA and + 3196CC and frequency of the UTR-3 haplotype were significantly higher in the patients than in the control group (P < 0.05), whereas the frequencies of UTR-1 and UTR-2 haplotypes were significantly lower in the patients than in the control group (P < 0.05). After a correction of multiple comparisons by FDR, UTR-2 and UTR-3 maintained significant associations with chronic hepatitis C. This study indicates that HLA-G 3'UTR polymorphisms are associated with the susceptibility to chronic hepatitis C infection in the Chinese population. HLA-G 3'UTR may play an important role in risk modulation toward HCV infection.
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Affiliation(s)
- Shihang Zhou
- Department of Blood Group, Dalian Blood Center, Dalian, China
| | - Ming Liu
- Department of Cell Biology, Dalian Medical University, Dalian, China
| | - Yuexin Xia
- Department of Blood Group, Dalian Blood Center, Dalian, China
| | - Li Zhang
- Department of Blood Group, Dalian Blood Center, Dalian, China
| | - Linnan Shao
- Department of Blood Group, Dalian Blood Center, Dalian, China
| | - Ni Wang
- Department of Blood Group, Dalian Blood Center, Dalian, China
| | - Weijian Yu
- Department of Blood Group, Dalian Blood Center, Dalian, China
| | - Nan Ding
- Dalian Sixth People's Hospital Affiliated of Dalian Medical University, Dalian, China
| | - Kaili Zhang
- Department of Cell Biology, Dalian Medical University, Dalian, China
| | - Xiaohua Liang
- Department of Blood Group, Dalian Blood Center, Dalian, China.
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Arnaiz-Villena A, Juarez I, Suarez-Trujillo F, López-Nares A, Vaquero C, Palacio-Gruber J, Martin-Villa JM. HLA-G: Function, polymorphisms and pathology. Int J Immunogenet 2021; 48:172-192. [PMID: 33001562 DOI: 10.1111/iji.12513] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 08/04/2020] [Accepted: 08/27/2020] [Indexed: 12/12/2022]
Abstract
HLA-G immune modulatory genes and molecules are presently being studied by a widespread number of research groups. In the present study, we do not aim to be exhaustive since the number of manuscripts published every year is overwhelming. Instead, our aim is pointing out facts about HLA-G function, polymorphism and pathology that have been confirmed by several different researchers, together with exposing aspects that may have been overlooked or not sufficiently remarked in this productive field of study. On the other hand, we question whether performing mainly studies on HLA-G and disease associations is going to give a clear answer in the future, since 40 years of study of classical HLA molecules association with disease has still given no definite answer on this issue.
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Affiliation(s)
- Antonio Arnaiz-Villena
- Departamento de Inmunología, Facultad de Medicina, Universidad Complutense, Madrid, Spain
| | - Ignacio Juarez
- Departamento de Inmunología, Facultad de Medicina, Universidad Complutense, Madrid, Spain
| | - Fabio Suarez-Trujillo
- Departamento de Inmunología, Facultad de Medicina, Universidad Complutense, Madrid, Spain
| | - Adrián López-Nares
- Departamento de Inmunología, Facultad de Medicina, Universidad Complutense, Madrid, Spain
| | - Christian Vaquero
- Departamento de Inmunología, Facultad de Medicina, Universidad Complutense, Madrid, Spain
| | - Jose Palacio-Gruber
- Departamento de Inmunología, Facultad de Medicina, Universidad Complutense, Madrid, Spain
| | - Jose M Martin-Villa
- Departamento de Inmunología, Facultad de Medicina, Universidad Complutense, Madrid, Spain
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Rodrigues JKF, Crovella S, Celerino da Silva R. The HLA-G 14 bp allele frequency in different populations: A global meta-analysis. Meta Gene 2020. [DOI: 10.1016/j.mgene.2019.100624] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
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The HLA-G 14-bp insertion/deletion polymorphism is associated with chronic hepatitis B in Southern Brazil: A case-control study. Hum Immunol 2020; 81:79-84. [PMID: 31955869 DOI: 10.1016/j.humimm.2020.01.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 12/08/2019] [Accepted: 01/07/2020] [Indexed: 12/14/2022]
Abstract
There is growing evidence that the non-classical HLA-G has a role in the process of the immune response against pathogens, including HBV and HIV. Previous studies demonstrated that a 14-bp insertion/deletion (indel) polymorphism at 3'-untranslated region of HLA-G gene interferes in the mRNA stability and expression. The present study aimed to evaluate the association of the 14-bp indel polymorphism (rs371194629) with HBV infection in chronic hepatitis B (CHB) mono-infected and HBV/HIV co-infected patients from Southern Brazil. A total of 817 individuals were analyzed, including 357 CHB patients, 134 HBV/HIV co-infected patients and 326 healthy controls. The 14-bp indel polymorphism was analyzed by DNA amplification using PCR. Logistic regression models were performed to compute adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs). To control for multiple comparisons, the Bonferroni correction was applied to the p-values. The 14-bp Ins allele was observed in 47.6% of the CHB mono-infected patients and in 41.6% of the controls (aOR = 1.33; 95% CI: 1.05-1.60; p = 0.02; pcorrected = 0.08). The results also showed that the 14-bp Ins/Ins genotype was present in 21.8% of the CHB mono-infected patients and in 12.9% of the controls (aOR = 1.91; 95% CI: 1.21-3.01; p < 0.01; pcorrected = 0.02). There was significant association between the 14-bp indel and CHB monoinfection, but not in HBV/HIV co-infection. In conclusion, the 14-bp indel polymorphism was associated with CHB in this specific population.
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Ouni N, Chaaben AB, Kablouti G, Ayari F, Douik H, Abaza H, Gara S, Elgaaied-Benammar A, Guemira F, Tamouza R. The Impact of HLA-G 3'UTR Polymorphisms in Breast Cancer in a Tunisian Population. Immunol Invest 2019; 48:521-532. [PMID: 30945586 DOI: 10.1080/08820139.2019.1569043] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Human leukocyte antigens G and E (HLA-G and HLA-E) are nonclassical major histocompatibility complex (MHC) class I molecules. These molecules play an important role in immune surveillance by inhibiting natural killer and cytotoxic T cells responsible for immune escape. The expression of HLA-G and HLA-E has been associated with several diseases including tumor. The main objective of the study is to evaluate the impact of three HLA-G 3'UTR potential polymorphisms: +3187 A > G (rs9380142), +3142 G > C (rs1063320), +2960 14-base pair (bp) Insertion/Deletion (Ins/Del) (rs66554220), and the HLA-E*01:01/01:03 A > G (rs1264457) polymorphism in Tunisian breast cancer population. A total of 355 patients and 381 controls were genotyping for HLA-G and HLA-E polymorphisms using a Taq Man assay. +3142 C allele and +3142 C/C genotype were significantly associated with increased risk of breast cancer (p = 0.00002; OR = 1.58; 95% CI = 27-1.97) (49% versus 35%; p = 0.0001; OR = 1.79; 95% CI = 1.32-2.44). In addition, Del allele and the homozygous state for Del/Del genotype confer a risk for breast cancer (52% versus 45%, p = 0.006; OR = 1.33, 95% CI = 1.08-1.64) (28% versus 22%, p = 0.039; OR = 1.43, 95% CI = 0.90-2.25). However, no statistical significant differences were reported for HLA-G + 3187 A > G and HLA-E variations and breast cancer in a Tunisian population. The found results indicate that HLA-G may play an important role in the breast cancer.
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Affiliation(s)
- Nesrine Ouni
- a Clinical Biology Department , Salah Azaiz Institute , Tunis , Tunisia
| | - Arij Ben Chaaben
- a Clinical Biology Department , Salah Azaiz Institute , Tunis , Tunisia
- b Jean Dausset Laboratory and INSERM, U1160 , Saint Louis Hospital , Paris , France
| | - Ghalia Kablouti
- a Clinical Biology Department , Salah Azaiz Institute , Tunis , Tunisia
| | - Fayza Ayari
- a Clinical Biology Department , Salah Azaiz Institute , Tunis , Tunisia
| | - Hayet Douik
- a Clinical Biology Department , Salah Azaiz Institute , Tunis , Tunisia
| | - Hajer Abaza
- a Clinical Biology Department , Salah Azaiz Institute , Tunis , Tunisia
| | - Sonia Gara
- a Clinical Biology Department , Salah Azaiz Institute , Tunis , Tunisia
| | - Amel Elgaaied-Benammar
- c Immunology Department, Faculty of Mathematics, Physics and Natural Sciences , Tunis El Manar University , Tunis , Tunisia
| | - Fethi Guemira
- a Clinical Biology Department , Salah Azaiz Institute , Tunis , Tunisia
| | - Ryad Tamouza
- d INSERM, U955, Translational Psychiatry , Paris-East University , Creteil , France
- e AP-HP, DHU PePSY, Department of Psychiatry , Hôpital Henri Mondor, Université Paris-Est-Creteil , Creteil , France
- f Fondation FondaMental , Creteil , France
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Jiang Y, Lu J, Wu YE, Zhao X, Li L. Genetic variation in the HLA-G 3'UTR 14-bp insertion/deletion and the associated cancer risk: evidence from 25 case-control studies. Biosci Rep 2019; 39:BSR20181991. [PMID: 30962267 PMCID: PMC6509057 DOI: 10.1042/bsr20181991] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 03/29/2019] [Accepted: 04/03/2019] [Indexed: 12/27/2022] Open
Abstract
Human leucocyte antigen-G (HLA-G) plays an important role in the progression of human cancers. A growing number of published studies have investigated the correlation between the HLA-G 3' untranslated region (3'UTR) 14-bp insertion/deletion (Ins/Del) polymorphism and the associated cancer risk in different populations. However, results from previous studies are inconclusive and inconsistent for the different type of cancers. Therefore, we undertook a meta-analysis to assess the effects of the HLA-G 14-bp Ins/Del polymorphism on cancer risk. A systematic literature search was conducted in PubMed, Web of Science, CNKI, VIP, and Wanfang databases to obtain relevant studies up to 28 January 2019. The pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were used. Twenty-five published case-control studies comprising 4981 cases and 6391 controls were included in the current meta-analysis. The results of the overall analysis revealed that the HLA-G 14-bp Ins/Ins genotype and Ins allele were associated with the total cancer risk in the homozygote comparison model (Ins/Ins vs. Del/Del: OR = 0.80, CI = 0.64-1.00; P=0.049) and the allelic comparison model (Ins vs. Del: OR = 0.89, CI = 0.81-0.99; P=0.035), with a protective role. Further subgroup analyses indicated that the HLA-G 14-bp Ins/Del polymorphism was associated with the risk of breast cancer and oesophageal cancer (EC), and significant risk of cancer was also observed in Mixed populations and population-based (PB). The results of our meta-analysis show that the HLA-G 14-bp Ins/Del polymorphism plays an important role in cancer risk, particularly in breast cancer and esophageal cancer in Mixed populations. Additional case-control studies with different types of cancer spanning different ethnicities are needed to extend the present findings.
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Affiliation(s)
- You Jiang
- Department of General Surgery, Hefei Second People's Hospital, Anhui Medical University, Hefei 230011, Anhui, China
| | - Jun Lu
- Department of General Surgery, Hefei Second People's Hospital, Anhui Medical University, Hefei 230011, Anhui, China
| | - Yue-E Wu
- Department of Electrocardiogram Diagnosis, The Second Affiliated Hospital, Anhui Medical University, Hefei 230060, Anhui, China
| | - Xin Zhao
- Department of Pathology, The First Affiliated Hospital, Anhui Medical University, Hefei 230022, Anhui, China
| | - Liang Li
- Department of General Surgery, Hefei Second People's Hospital, Anhui Medical University, Hefei 230011, Anhui, China
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11
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Godfrey DI, Le Nours J, Andrews DM, Uldrich AP, Rossjohn J. Unconventional T Cell Targets for Cancer Immunotherapy. Immunity 2018; 48:453-473. [PMID: 29562195 DOI: 10.1016/j.immuni.2018.03.009] [Citation(s) in RCA: 229] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2017] [Revised: 03/01/2018] [Accepted: 03/02/2018] [Indexed: 02/07/2023]
Abstract
Most studies on the immunotherapeutic potential of T cells have focused on CD8 and CD4 T cells that recognize peptide antigens (Ag) presented by polymorphic major histocompatibility complex (MHC) class I and MHC class II molecules, respectively. However, unconventional T cells, which interact with MHC class Ib and MHC-I like molecules, are also implicated in tumor immunity, although their role therein is unclear. These include unconventional T cells targeting MHC class Ib molecules such as HLA-E and its murine ortholog Qa-1b, natural killer T (NKT) cells, mucosal associated invariant T (MAIT) cells, and γδ T cells. Here, we review the current understanding of the roles of these unconventional T cells in tumor immunity and discuss why further studies into the immunotherapeutic potential of these cells is warranted.
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Affiliation(s)
- Dale I Godfrey
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria 3010, Australia.
| | - Jérôme Le Nours
- Infection and Immunity Program and The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia
| | - Daniel M Andrews
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Adam P Uldrich
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria 3010, Australia
| | - Jamie Rossjohn
- Infection and Immunity Program and The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia; Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
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12
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de Almeida BS, Muniz YCN, Prompt AH, Castelli EC, Mendes-Junior CT, Donadi EA. Genetic association between HLA-G 14-bp polymorphism and diseases: A systematic review and meta-analysis. Hum Immunol 2018; 79:724-735. [PMID: 30102938 DOI: 10.1016/j.humimm.2018.08.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 08/09/2018] [Accepted: 08/09/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND HLA-G is an immune checkpoint molecule. Since a differential molecule expression has been reported even for healthy individuals, many studies have focused on polymorphisms at HLA-G regulatory regions, particularly the 3' untranslated region (3'UTR). The presence/absence of a 14-bp sequence was the first polymorphism described and it is the most studied in association between HLA-G and disorders. METHODS In this study, we performed a systematic review and meta-analysis of all association studies published regarding the HLA-G 14-bp. RESULTS We verified association between 14-bp alleles and diseases in the following situations: (1) presence of 14-bp (insertion) conferred susceptibility to preeclampsia (child alleles evaluated) and systemic lupus erythematosus (OR = 1.42; 95%CI = 1.04-1.93; p = 0.026 and OR = 1.13; 95%CI = 1.01-1.27, p = 0.028); (2) 14-bp absence (deletion) was associated with increased risk to breast cancer (OR = 1.23; 95%CI = 1.06-1.43; p = 0.006) and human Cytomegalovirus infection (OR = 2.06; 95%CI = 1.60-2.64; p < 0.0001); and (3) a risk association was observed between the group of reproductive disorders and the 14-bp insertion (OR = 1.12; 95%CI = 1.01-1.24; p = 0.034). CONCLUSIONS Considering that others 14-bp associations were inconclusive and that other variation sites observed at HLA-G 3'UTR exhibit a proven role on post-transcriptional regulation of HLA-G expression, the complete 3'UTR segment should be analyzed in terms of disease susceptibility, instead of a single polymorphism.
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Affiliation(s)
- Bibiana Sgorla de Almeida
- Divisão de Imunologia Clínica, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto (FMRP), Universidade de São Paulo (USP), 14049-900 Ribeirão Preto, SP, Brazil; Laboratório Multiusuário de Estudos em Biologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Brazil.
| | - Yara Costa Netto Muniz
- Departamento de Biologia Celular, Embriologia e Genética, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Brazil.
| | - Alice Heidrich Prompt
- Departamento de Biologia Celular, Embriologia e Genética, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Brazil.
| | - Erick C Castelli
- Departamento de Patologia, Faculdade de Medicina de Botucatu, Unesp - Univ. Estadual Paulista, 18618-970 Botucatu, SP, Brazil.
| | - Celso Teixeira Mendes-Junior
- Faculdade de Filosofia Ciências e Letras de Ribeirão Preto (FFCLRP), Universidade de São Paulo (USP), 14049-900 Ribeirão Preto, SP, Brazil.
| | - Eduardo Antonio Donadi
- Divisão de Imunologia Clínica, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto (FMRP), Universidade de São Paulo (USP), 14049-900 Ribeirão Preto, SP, Brazil.
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13
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Wang Z, Zhao L, Liu L, Liu X. Human leucocyte antigen-G 14-bp InDel polymorphism and oral squamous cell carcinoma risk in Chinese Han population: A case-control study. Int J Immunogenet 2018; 45:266-273. [PMID: 30030939 DOI: 10.1111/iji.12390] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Revised: 05/11/2018] [Accepted: 06/07/2018] [Indexed: 12/01/2022]
Abstract
Human leucocyte antigen-G (HLA-G) is a nonclassical HLA class I molecule involved in tumour immune escape. The purpose of this study was to investigate the association between the 14-bp insertion/deletion (InDel) polymorphism in the 3' untranslated region (3'-UTR) of HLA-G gene and oral squamous cell carcinoma (OSCC) risk in Chinese Han population (216 cases and 193 healthy controls), and furthermore, to evaluate serum soluble HLA-G (sHLA-G) levels in the OSCC patients. Our results demonstrated that the Ins allele was significantly less frequent in the OSCC patients than that in the healthy controls (odds ratio [OR] = 0.75; 95% confidence interval [CI]: 0.57-0.99; p = 0.040). Distribution of the 14-bp genotypes in the OSCC patients and the healthy controls revealed that the Ins/Ins genotype was associated with decreased OSCC risk in both the codominant model (Ins/Ins versus Del/Del; OR = 0.57; 95% CI = 0.33-0.99; p = 0.044) and the log-additive model (OR = 0.76; 95% CI: 0.58-0.99; p = 0.044). The serum sHLA-G level was significantly higher in the OSCC patients than those in the healthy controls (p < 0.001). Receiver operating characteristic (ROC) curve revealed the valuable diagnostic value of sHLA-G for OSCC detection, with an area under the ROC curve (AUC) of 0.891 (95% CI: 0.856-0.925, p < 0.001). The OSCC patients with Ins/Ins genotype had lower serum sHLA-G levels than those with Ins/Del and Del/Del genotypes (p = 0.015). Furthermore, serum sHLA-G levels were significantly increased with the increasing TNM stages of the OSCC patients (p = 0.017). Our findings revealed that the HLA-G 14-bp InDel polymorphism might be a genetic risk factor for OSCC susceptibility, and the serum sHLA-G may act as a promising biomarker for noninvasive diagnosis of OSCC.
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Affiliation(s)
- Zengqi Wang
- Department of Clinical Laboratory, Weifang Traditional Chinese Hospital, Weifang, China
| | - Lina Zhao
- Department of Clinical Laboratory, Weifang Traditional Chinese Hospital, Weifang, China
| | - Lina Liu
- Department of Clinical Laboratory, Weifang Traditional Chinese Hospital, Weifang, China
| | - Xueying Liu
- Department of Clinical Laboratory, The Third Hospital of Jinan, Jinan, China
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14
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Zhang Y, Yu S, Han Y, Wang Y, Sun Y. Human leukocyte antigen-G expression and polymorphisms promote cancer development and guide cancer diagnosis/treatment. Oncol Lett 2017; 15:699-709. [PMID: 29399142 PMCID: PMC5772757 DOI: 10.3892/ol.2017.7407] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 06/02/2017] [Indexed: 12/11/2022] Open
Abstract
Human leukocyte antigen-G (HLA-G) is a non-classical HLA molecule, predominantly expressed in cytotrophoblast cells to protect the fetus during pregnancy. Notably, a high frequency of HLA-G expression has been observed in a wide variety of cancer types in previous studies. Furthermore, HLA-G expression in cancer has been considered to be detrimental, since it can protect cancer cells from natural killer cell cytotoxic T lymphocyte-mediated destruction, promote tumor spreading and shorten the survival time of patients by facilitating tumor immune evasion. In addition, HLA-G polymorphisms have been investigated in numerous types of cancer and are considered as risk factors and predictive markers of cancer. This review focuses on HLA-G expression and its polymorphisms in cancer, analyzing the mechanisms of HLA-G in promoting cancer development, and evaluating the potential and value of its clinical application as a diagnostic and prognostic biomarker, or even as a prospective therapeutic target in certain types of tumors.
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Affiliation(s)
- Yanwen Zhang
- Department of Oncology, School of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China.,Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
| | - Shuwen Yu
- Department of Pharmacy, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
| | - Yali Han
- Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
| | - Yunshan Wang
- Medical Research and Laboratory Diagnostic Center, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
| | - Yuping Sun
- Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
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15
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Sun J, Chu H, Ji J, Huo G, Song Q, Zhang X. Long non-coding RNA HOTAIR modulates HLA-G expression by absorbing miR-148a in human cervical cancer. Int J Oncol 2016; 49:943-52. [PMID: 27574106 DOI: 10.3892/ijo.2016.3589] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Accepted: 01/21/2016] [Indexed: 11/05/2022] Open
Abstract
The long non-coding RNA HOX transcript antisense RNA (HOTAIR) has been found overexpressed in many human malignancies and involved in tumor progression and metastasis. However, little is known about the potential biological roles of HOTAIR in tumor escape. In the present study, the expression of HOTAIR was detected in 59 paired cervical cancer tissue samples by real-time PCR and then subjected to correlation analysis with clinical features. The effects of HOTAIR on cervical cancer cells as well as the expression of human leukocyte antigen (HLA)-G were studied by overexpression and RNA interference approaches. Insight into the mechanism of HOTAIR acting as competitive endogenous RNAs (ceRNAs) was gained from bioinformatic analysis and luciferase assays. HOTAIR expression was obviously increased in cervical cancer tissue. HOTAIR upregulation was associated with advanced pathological stage, histology, lymph node invasion and lymphatic metastasis, and also correlated with shorter overall survival of cervical cancer patients. Furthermore, HOTAIR overexpression promoted the proliferation, migration and invasion of cervical cancer cells, while HOTAIR knockdown inhibited cell invasion and cell viability, induced apoptosis and inhibited growth in vitro and in vivo. Moreover, HOTAIR modulated human leucocyte antigen-G (HLA-G) expression by competitively binding miR-148a. Our data suggest that HOTAIR plays an important oncogenic role in cervical cancer and might serve as a marker for cervical cancer prognosis and a potential target for therapeutic intervention.
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Affiliation(s)
- Jinbao Sun
- Department of Gynecological Ward, People's Hospital, Cangzhou, Hebei 061000, P.R. China
| | - Haipeng Chu
- Department of Obstetrics-Gynecology, Daqing LongNan Hospital, Daqing, Heilongjiang 163001, P.R. China
| | - Jianghai Ji
- Department of Gynecological Ward, People's Hospital, Cangzhou, Hebei 061000, P.R. China
| | - Gaoxiang Huo
- Department of Gynecological Ward, People's Hospital, Cangzhou, Hebei 061000, P.R. China
| | - Qinglei Song
- Department of Gynecological Ward, People's Hospital, Cangzhou, Hebei 061000, P.R. China
| | - Xue Zhang
- Department of Gynecological Ward, People's Hospital, Cangzhou, Hebei 061000, P.R. China
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16
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Li T, Huang H, Liao D, Ling H, Su B, Cai M. WITHDRAWN: Lack of association between the HLA-G 3'UTR 14-bp ins/del polymorphism and cancer risk: A meta-analysis of case-control study. Hum Immunol 2015:S0198-8859(15)00564-9. [PMID: 26585360 DOI: 10.1016/j.humimm.2015.11.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2014] [Revised: 08/26/2014] [Accepted: 11/12/2015] [Indexed: 11/22/2022]
Abstract
This article hashas been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.
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Affiliation(s)
- Tao Li
- Department of Chemotherapy, People's Hospital of Gaozhou, Gaozhou, Guangdong, China.
| | - Haohai Huang
- School of Pharmacy, Guangdong Medical College, Dongguan, Guangdong, China
| | - Dan Liao
- Sino-American Cancer Research Institute, Guangdong Medical College, Dongguan, Guangdong, China
| | - Huahuang Ling
- Department of Chemotherapy, People's Hospital of Gaozhou, Gaozhou, Guangdong, China
| | - Bingguang Su
- Department of Chemotherapy, People's Hospital of Gaozhou, Gaozhou, Guangdong, China
| | - Maode Cai
- Department of Chemotherapy, People's Hospital of Gaozhou, Gaozhou, Guangdong, China
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17
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Silva HPV, Ururahy MAG, Souza KSC, Loureiro MB, Oliveira YMC, Oliveira GHM, Luchessi AD, Carvalho KTC, Freitas JCOC, Donadi EA, Hirata RDC, Almeida MG, Arrais RF, Hirata MH, Rezende AA. The association between the HLA-G 14-bp insertion/deletion polymorphism and type 1 diabetes. Genes Immun 2015; 17:13-8. [DOI: 10.1038/gene.2015.45] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Revised: 08/07/2015] [Accepted: 09/08/2015] [Indexed: 11/09/2022]
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18
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Dias FC, Castelli EC, Collares CVA, Moreau P, Donadi EA. The Role of HLA-G Molecule and HLA-G Gene Polymorphisms in Tumors, Viral Hepatitis, and Parasitic Diseases. Front Immunol 2015; 6:9. [PMID: 25699038 PMCID: PMC4313582 DOI: 10.3389/fimmu.2015.00009] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Accepted: 01/07/2015] [Indexed: 12/11/2022] Open
Abstract
Considering that the non-classical HLA-G molecule has well-recognized tolerogenic properties, HLA-G expression is expected to be deleterious when present in tumor cells and in cells chronically infected by viruses, whereas HLA-G expression is expected to be advantageous in autoimmune disorders. The expression of HLA-G on tissue or peripheral blood cells, the levels of soluble HLA-G and polymorphic sites along the gene have been studied in several disorders. In this study, we revised the role of the molecule and polymorphic sites along the HLA-G gene in tumors, viral hepatitis, and parasitic disorders. Overall, several lines of evidence clearly show that the induction of HLA-G expression in tumors has been associated with worse disease outcome and disease spread. In addition, the few studies conducted on hepatitis and parasitic disorders indicate that HLA-G may contribute to disease pathogenesis. Few isolated polymorphic sites, primarily located at the coding or 3′ untranslated HLA-G region, have been evaluated in these disorders, and a complete HLA-G typing together with the study of gene regulatory elements may further help on the understanding of the influence of the genetic background on disease susceptibility.
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Affiliation(s)
- Fabrício C Dias
- Division of Clinical Immunology, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo , Ribeirão Preto , Brazil
| | - Erick C Castelli
- Department of Pathology, School of Medicine of Botucatu, Universidade Estadual Paulista , Botucatu , Brazil
| | - Cristhianna V A Collares
- Division of Clinical Immunology, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo , Ribeirão Preto , Brazil
| | - Philippe Moreau
- Research Division in Hematology and Immunology, Institute of Emerging Diseases and Innovative Therapies, Saint-Louis Hospital, CEA , Paris , France
| | - Eduardo A Donadi
- Division of Clinical Immunology, Department of Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo , Ribeirão Preto , Brazil
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19
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Genetic polymorphism in HLA-G 3′UTR 14-bp ins/del and risk of cancer: a meta-analysis of case–control study. Mol Genet Genomics 2015; 290:1235-45. [DOI: 10.1007/s00438-014-0985-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Accepted: 12/30/2014] [Indexed: 10/24/2022]
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20
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21
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Zhang X, Li S, Zhang Y, Lu Y, Wang J, Xu J, Li X, Qin X. Meta-analysis of the relationship between 14bp insertion/deletion polymorphism of HLA-G gene and susceptibility to systemic lupus erythematosus. Hum Immunol 2014; 75:1171-6. [DOI: 10.1016/j.humimm.2014.10.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Revised: 10/09/2014] [Accepted: 10/09/2014] [Indexed: 10/24/2022]
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22
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Gimenes F, Teixeira JJV, de Abreu ALP, Souza RP, Pereira MW, da Silva VRS, Bôer CG, Maria-Engler SS, Bonini MG, Borelli SD, Consolaro MEL. Human leukocyte antigen (HLA)-G and cervical cancer immunoediting: a candidate molecule for therapeutic intervention and prognostic biomarker? Biochim Biophys Acta Rev Cancer 2014; 1846:576-89. [PMID: 25453366 DOI: 10.1016/j.bbcan.2014.10.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2014] [Revised: 10/14/2014] [Accepted: 10/14/2014] [Indexed: 02/06/2023]
Abstract
While persistent infection with oncogenic types of human Papillomavirus (HPV) is required for cervical epithelial cell transformation and cervical carcinogenesis, HPV infection alone is not sufficient to induce tumorigenesis. Only a minor fraction of HPV infections produce high-grade lesions and cervical cancer, suggesting complex host-virus interactions. Based on its pronounced immunoinhibitory properties, human leukocyte antigen (HLA)-G has been proposed as a possible prognostic biomarker and therapeutic target relevant in a wide variety of cancers and viral infections, but to date remains underexplored in cervical cancer. Given the possible influence of HLA-G on the clinical course of HPV infection, cervical lesions and cancer progression, a better understanding of HLA-G involvement in cervical carcinogenesis might contribute to two aspects of fundamental importance: 1. Characterization of a novel diagnostic/prognostic biomarker to identify cervical cancer and to monitor disease stage, critical for patient screening; 2. Identification of HLA-G-driven immune mechanisms involved in lesion development and cancer progression, leading to the development of strategies for modulating HLA-G expression for treatment purposes. Thus, this systematic review explores the potential involvement of HLA-G protein expression and polymorphisms in cervical carcinogenesis.
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Affiliation(s)
- Fabrícia Gimenes
- Laboratory of Clinical Cytology, Department of Clinical Analysis and Biomedicine, State University of Maringá, 87020900 Paraná, Brazil
| | - Jorge Juarez Vieira Teixeira
- Laboratory of Clinical Cytology, Department of Clinical Analysis and Biomedicine, State University of Maringá, 87020900 Paraná, Brazil
| | - André Luelsdorf Pimenta de Abreu
- Laboratory of Clinical Cytology, Department of Clinical Analysis and Biomedicine, State University of Maringá, 87020900 Paraná, Brazil
| | - Raquel Pantarotto Souza
- Laboratory of Clinical Cytology, Department of Clinical Analysis and Biomedicine, State University of Maringá, 87020900 Paraná, Brazil
| | - Monalisa Wolski Pereira
- Laboratory of Clinical Cytology, Department of Clinical Analysis and Biomedicine, State University of Maringá, 87020900 Paraná, Brazil
| | - Vânia Ramos Sela da Silva
- Laboratory of Clinical Cytology, Department of Clinical Analysis and Biomedicine, State University of Maringá, 87020900 Paraná, Brazil
| | - Cinthia Gandolfi Bôer
- Laboratory of Clinical Cytology, Department of Clinical Analysis and Biomedicine, State University of Maringá, 87020900 Paraná, Brazil
| | - Silvya Stuchi Maria-Engler
- Clinical Chemistry and Toxicology Department, School of Pharmaceutical Sciences, University of São Paulo, 05508000 São Paulo, Brazil
| | - Marcelo Gialluisi Bonini
- College of Medicine, Departments of Medicine, Pharmacology and Pathology, University of Illinois at Chicago, 60612 Chicago, IL, USA
| | - Sueli Donizete Borelli
- Laboratory of Immunogenetics, Department of Basic Health Sciences, State University of Maringá, 87020900 Paraná, Brazil
| | - Márcia Edilaine Lopes Consolaro
- Laboratory of Clinical Cytology, Department of Clinical Analysis and Biomedicine, State University of Maringá, 87020900 Paraná, Brazil.
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Catamo E, Zupin L, Crovella S, Celsi F, Segat L. Non-classical MHC-I human leukocyte antigen (HLA-G) in hepatotropic viral infections and in hepatocellular carcinoma. Hum Immunol 2014; 75:1225-31. [PMID: 25318079 DOI: 10.1016/j.humimm.2014.09.019] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Revised: 09/27/2014] [Accepted: 09/27/2014] [Indexed: 01/05/2023]
Abstract
The human leukocyte antigen (HLA)-G is a "nonclassical" major histocompatibility complex (MHC) class Ib gene, located at chromosome 6, in the 6p21.3 region. The HLA-G presents immunomodulatory functions essential in pregnancy for the tolerance of the semi-allogenic fetus, but an abnormal expression of HLA-G has been observed in numerous pathological conditions, such as tumors, autoimmune diseases and viral infections. In recent years, numerous studies have assessed the clinical relevance of HLA-G expression in different types of cancer: in general, a higher HLA-G expression correlates with a lower survival rate or a shorter disease-free survival. Altered expression of HLA-G has been found in both HCV and HBV infection, and some genetic polymorphisms have been associated with altered susceptibility/disease development for these infections, however, whether the biologic role of HLA-G in HCV and HBV infection is beneficial or hazardous, it is not completely clear. In the context of hepatocellular carcinoma, HLA-G has shown a potential diagnostic role, moreover a prognostic value in HCC patients has been also attributed to HLA-G molecules. We revise here the role of HLA-G in hepatotropic HBV/HCV infections and in hepatocellular carcinoma (HCC).
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Affiliation(s)
- Eulalia Catamo
- Medical Science Department, University of Trieste, Italy
| | - Luisa Zupin
- Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy
| | - Sergio Crovella
- Medical Science Department, University of Trieste, Italy; Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy
| | - Fulvio Celsi
- Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy
| | - Ludovica Segat
- Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy.
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Ge YZ, Ge Q, Li MH, Shi GM, Xu X, Xu LW, Xu Z, Lu TZ, Wu R, Zhou LH, Wu JP, Liang K, Dou QL, Zhu JG, Li WC, Jia RP. Association between human leukocyte antigen-G 14-bp insertion/deletion polymorphism and cancer risk: A meta-analysis and systematic review. Hum Immunol 2014; 75:827-32. [DOI: 10.1016/j.humimm.2014.06.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2014] [Revised: 06/03/2014] [Accepted: 06/03/2014] [Indexed: 11/27/2022]
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Garziera M, Toffoli G. Inhibition of host immune response in colorectal cancer: Human leukocyte antigen-G and beyond. World J Gastroenterol 2014; 20:3778-3794. [PMID: 24744572 PMCID: PMC3983436 DOI: 10.3748/wjg.v20.i14.3778] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Revised: 01/22/2014] [Accepted: 02/27/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most diffuse cancers worldwide and is still a clinical burden. Increasing evidences associate CRC clinical outcome to immune contexture represented by adaptive immune cells. Their type, density and location are summarized in the Immune Score that has been shown to improve prognostic prediction of CRC patients. The non-classical MHC class I human leukocyte antigen-G (HLA-G), is a crucial tumor-driven immune escape molecule involved in immune tolerance. HLA-G and soluble counterparts are able to exert inhibitory functions by direct interactions with inhibitory receptors present on both innate cells such as natural killer cells, and adaptive immune cells as cytotoxic T and B lymphocytes. HLA-G may play a prominent role in CRC strategies to avoid host immunosurveillance. This review highlights the current knowledge on HLA-G contribution in CRC, in related inflammatory diseases and in other type of cancers and disorders. HLA-G genetic setting (specific haplotypes, genotypes and alleles frequencies) and association with circulating/soluble profiles was highlighted. HLA G prognostic and predictive value in CRC was investigated in order to define a novel prognostic immune biomarker in CRC.
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Bortolotti D, Gentili V, Rotola A, Di Luca D, Rizzo R. Implication of HLA-G 3′ untranslated region polymorphisms in human papillomavirus infection. ACTA ACUST UNITED AC 2014; 83:113-8. [DOI: 10.1111/tan.12281] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2013] [Revised: 11/29/2013] [Accepted: 12/02/2013] [Indexed: 11/30/2022]
Affiliation(s)
- D. Bortolotti
- Department of Medical Sciences, Section of Microbiology and Medical Genetics; University of Ferrara; Ferrara Italy
| | - V. Gentili
- Department of Medical Sciences, Section of Microbiology and Medical Genetics; University of Ferrara; Ferrara Italy
| | - A. Rotola
- Department of Medical Sciences, Section of Microbiology and Medical Genetics; University of Ferrara; Ferrara Italy
| | - D. Di Luca
- Department of Medical Sciences, Section of Microbiology and Medical Genetics; University of Ferrara; Ferrara Italy
| | - R. Rizzo
- Department of Medical Sciences, Section of Microbiology and Medical Genetics; University of Ferrara; Ferrara Italy
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