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Audia S, Brescia C, Dattilo V, Torchia N, Trapasso F, Amato R. The IL-23R and Its Genetic Variants: A Hitherto Unforeseen Bridge Between the Immune System and Cancer Development. Cancers (Basel) 2024; 17:55. [PMID: 39796684 PMCID: PMC11718844 DOI: 10.3390/cancers17010055] [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: 11/23/2024] [Revised: 12/20/2024] [Accepted: 12/23/2024] [Indexed: 01/13/2025] Open
Abstract
IL-23R (interleukin-23 receptor), found on the surface of several immune cells, plays a key role in the immune system. Indeed, this process is not limited to the inflammatory response but also plays a role in the adaptive immune response. The binding between IL-23R and its specific ligand, the interleukin 23, initiates a number of specific signals by modulating both properties and behavior of immune cells. In particular, it is critical for the regulation of T helper 17 cells (Th17). Th17s are a subset of T cells involved in autoimmune and inflammatory diseases, as well as in cancer. The clinical relevance of IL-23R is underscored by its association with an elevated susceptibility or diminished vulnerability to a spectrum of diseases, including psoriasis, ankylosing spondylitis, and inflammatory bowel disease (IBD). Evidence has emerged that suggests it may also serve to predict both tumor progression and therapeutic responsiveness. It is noteworthy that the IL-23/IL-23R pathway is emerging as a promising therapeutic target. A number of biologic drugs, such as monoclonal antibodies, are currently developing with the aim of blocking this interaction, thus reducing inflammation. This represents a significant advancement in the field of medicine, offering new hope for pursuing more effective and personalized treatments. Recent studies have also investigated the role of such a pathway in autoimmune diseases, and its potential impact on infections as well as in carcinogenesis. The aim of this review is to focus on the role of IL-23R in immune genetics and its potential for modulating the natural history of neoplastic disease.
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Affiliation(s)
- Salvatore Audia
- Immuno-Genetics Lab, Department of Health Science, Medical School, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (C.B.); (N.T.)
| | - Carolina Brescia
- Immuno-Genetics Lab, Department of Health Science, Medical School, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (C.B.); (N.T.)
| | - Vincenzo Dattilo
- Department of Experimental and Clinical Medicine, Medical School, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy;
| | - Naomi Torchia
- Immuno-Genetics Lab, Department of Health Science, Medical School, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (C.B.); (N.T.)
| | - Francesco Trapasso
- Department of Experimental and Clinical Medicine, Medical School, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy;
| | - Rosario Amato
- Immuno-Genetics Lab, Department of Health Science, Medical School, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (S.A.); (C.B.); (N.T.)
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Razali NN, Raja Ali RA, Muhammad Nawawi KN, Yahaya A, Mohd Rathi ND, Mokhtar NM. Roles of phosphatidylinositol-3-kinases signaling pathway in inflammation-related cancer: Impact of rs10889677 variant and buparlisib in colitis-associated cancer. World J Gastroenterol 2023; 29:5543-5556. [PMID: 37970476 PMCID: PMC10642440 DOI: 10.3748/wjg.v29.i40.5543] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 09/05/2023] [Accepted: 10/11/2023] [Indexed: 10/27/2023] Open
Abstract
BACKGROUND Phosphatidylinositol-3-kinases (PI3K) is a well-known route in inflammation-related cancer. Recent discovery on PI3K-related genes revealed a potential variant that links ulcerative colitis (UC) and colorectal cancer (CRC) with colitis-associated cancer (CAC). PI3K/AKT pathway has been recommended as a potential additional therapeutic option for CRC due to its substantial role in modifying cellular processes. Buparlisib is a pan-class I PI3K inhibitor previously shown to reduce tumor growth. AIM To investigate the regulation of rs10889677 and the role of buparlisib in the PI3K signaling pathway in CAC pathogenesis. METHODS Genomic DNA from 32 colonic samples, including CAC (n = 7), UC (n = 10) and CRC (n = 15), was sequenced for the rs10889677 mutation. The mutant and wildtype fragments were amplified and cloned in the pmirGLO vector. The luciferase activity of cloned vectors was assessed after transfection into the HT29 cell line. CAC mice were induced by a mixture of a single azoxymethane injection and three cycles of dextran sulphate sodium, then buparlisib was administered after 14 d. The excised colon was subjected to immunohistochemistry for Ki67 and Cleaved-caspase-3 markers and quantitative real-time polymerase chain reaction analysis for Pdk1 and Sgk2. RESULTS Luciferase activity decreased by 2.07-fold in the rs10889677 mutant, confirming the hypothesis that the variant disrupted miRNA binding sites, which led to an increase in IL23R expression and the activation of the PI3K signaling pathway. Furthermore, CAC-induced mice had a significantly higher disease activity index (P < 0.05). Buparlisib treatment significantly decreased mean weight loss in CAC-induced mice (P < 0.05), reduced the percentage of proliferating cells by 5%, and increased the number of apoptotic cells. The treatment also caused a downward trend of Pdk1 expression and significantly decreased Sgk2 expression. CONCLUSION Our findings suggested that the rs10889677 variant as a critical initiator of the PI3K signaling pathway, and buparlisib had the ability to prevent PI3K-non-AKT activation in the pathophysiology of CAC.
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Affiliation(s)
- Nurul Nadirah Razali
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Kuala Lumpur, Malaysia
| | - Raja Affendi Raja Ali
- School of Medical and Life Sciences, Sunway University, Sunway City 47500, Malaysia
- GUT Research Group, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Kuala Lumpur, Malaysia
- Gastroenterology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Kuala Lumpur, Malaysia
| | - Khairul Najmi Muhammad Nawawi
- GUT Research Group, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Kuala Lumpur, Malaysia
- Gastroenterology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Kuala Lumpur, Malaysia
| | - Azyani Yahaya
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Kuala Lumpur, Malaysia
| | - Norshafila Diana Mohd Rathi
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Kuala Lumpur, Malaysia
| | - Norfilza Mohd Mokhtar
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Kuala Lumpur, Malaysia
- GUT Research Group, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras 56000, Kuala Lumpur, Malaysia
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A functional microRNA binding site variant in IL-23R gene in systemic lupus erythematosus and rheumatoid arthritis: is there any correlation? Mol Biol Rep 2022; 49:11821-11828. [DOI: 10.1007/s11033-022-07922-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 09/05/2022] [Indexed: 11/25/2022]
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Targeted Sequencing of Cytokine-Induced PI3K-Related Genes in Ulcerative Colitis, Colorectal Cancer and Colitis-Associated Cancer. Int J Mol Sci 2022; 23:ijms231911472. [PMID: 36232773 PMCID: PMC9569582 DOI: 10.3390/ijms231911472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/15/2022] [Accepted: 09/20/2022] [Indexed: 11/17/2022] Open
Abstract
Chronic relapsing inflammatory bowel disease is strongly linked to an increased risk of colitis-associated cancer (CAC). One of the well-known inflammatory carcinogenesis pathways, phosphatidylinositol 3-kinase (PI3K), was identified to be a crucial mechanism in long-standing ulcerative colitis (UC). The goal of this study was to identify somatic variants in the cytokine-induced PI3K-related genes in UC, colorectal cancer (CRC) and CAC. Thirty biopsies (n = 8 long-standing UC, n = 11 CRC, n = 8 paired normal colorectal mucosa and n = 3 CAC) were subjected to targeted sequencing on 13 PI3K-related genes using Illumina sequencing and the SureSelectXT Target Enrichment System. The Genome Analysis Toolkit was used to analyze variants, while ANNOVAR was employed to detect annotations. There were 5116 intronic, 355 exonic, 172 untranslated region (UTR) and 59 noncoding intronic variations detected across all samples. Apart from a very small number of frameshifts, the distribution of missense and synonymous variants was almost equal. We discovered changed levels of IL23R, IL12Rß1, IL12Rß2, TYK2, JAK2 and OSMR in more than 50% of the samples. The IL23R variant in the UTR region, rs10889677, was identified to be a possible variant that might potentially connect CAC with UC and CRC. Additional secondary structure prediction using RNAfold revealed that mutant structures were more unstable than wildtype structures. Further functional research on the potential variants is, therefore, highly recommended since it may provide insight on the relationship between inflammation and cancer risk in the cytokine-induced PI3K pathway.
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Cytokine-driven positive feedback loop organizes fibroblast transformation and facilitates gastric cancer progression. Clin Transl Oncol 2022; 24:1354-1364. [PMID: 35303266 DOI: 10.1007/s12094-022-02777-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 01/05/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND Gastric cancer (GC) is a malignancy that belongs to one of the most common leading causes of cancer death. Cancer-associated fibroblasts (CAFs) promote the GC cells' malignant behavior. It is still unknown how GC converts normal fibroblasts (NFs) to CAFs. METHODS GC cells were co-cultured with NFs. Bioinformatics was used to analyze the genes and signaling pathways that were changed in fibroblast. RT-PCR, western blot, and Elisa assays were used to detect the expression of cytokines in fibroblast and condition medium. Western blot and immunofluorescence demonstrated activation of relevant pathways in CAFs-like cells. Transwell, scrape, colony formation, and CCK-8 assays were performed to reveal the feedback effect of CAFs-like cells on GC cells. RESULTS GC promoted the conversion of NFs to CAFs by secreting Interleukin 17A (IL-17). It included both morphological and molecular marker changes. This process was achieved by activating the nuclear factor-κB (NF-κB) pathway. On the other hand, CAFs cells could secrete C-X-C Motif Chemokine Ligand 8 (IL-8, IL-8), which promoted the malignant phenotype of GC cells. In this way, a feedback loop of mutual influence was constructed in the GC and tumor microenvironment (TME). CONCLUSIONS Our research proved a novel model of GC-educated NFs. GC-IL-17-fibroblast-IL-8-GC axis might be a potential pathway of the interaction between GC and TME.
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Alidoust M, Hamzehzadeh L, Khorshid Shamshiri A, Afzaljavan F, Kerachian MA, Fanipakdel A, Aledavood SA, Allahyari A, Bari A, Moosanen Mozaffari H, Goshayeshi L, Pasdar A. Association of SMAD7 genetic markers and haplotypes with colorectal cancer risk. BMC Med Genomics 2022; 15:8. [PMID: 35016683 PMCID: PMC8753827 DOI: 10.1186/s12920-021-01150-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 12/20/2021] [Indexed: 12/11/2022] Open
Abstract
Purpose Colorectal cancer (CRC) is one of the common cancers with a high mortality rate worldwide. In Iran, there has been a trend of increased incidence of colorectal cancer in the last three decades that necessitates the early diagnosis. Genetic factors have an influential role in its etiology along with the conventional risk factors such as age, diet, and lifestyle. Results from GWAS have shown significant associations between SMAD7 gene variants and risk of CRC. This study aimed to assess the association of certain polymorphisms as well as haplotypes of this gene and risk of colorectal cancer.
Methods and materials This study was designed as a case–control association study. After obtaining ethical approval and informed consent, blood samples from 209 patients with colorectal cancer were collected and DNA was extracted. Four variants: rs4939827, rs34007497, rs8085824 and rs8088297 were genotyped using ARMS-PCR method.
Results SMAD7 rs4939827 in the recessive and co-dominant models was associated with colorectal cancer risk [TT/CT + CC: OR = 2.90, 95%CI (1.38–6.09), p = 0.005; CC + TT/CT: OR = 1.66, 95%CI (1.00–2.75), p = 0.01]. Haplotype analysis indicated that some SNP combinations including two for-SNPs haplotypes of T-T-C-C and T-C-C-A were significantly associated with CRC risk. Conclusion Based on the identified association of SMAD7 gene variations and haplotypes with colorectal cancer risk in our population, genetic variations in this gene region may have a role in CRC development. This data may shed light on the genetic predisposition of CRC which involves different pathways including TGF-β. Supplementary Information The online version contains supplementary material available at 10.1186/s12920-021-01150-3.
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Affiliation(s)
- Maryam Alidoust
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Leila Hamzehzadeh
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Asma Khorshid Shamshiri
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fahimeh Afzaljavan
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Amin Kerachian
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Cancer Genetics Research Unit, Reza Radiotherapy and Oncology Center, Mashhad, Iran
| | - Azar Fanipakdel
- Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Abolghasem Allahyari
- Hematology and Oncology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Bari
- Hematology and Oncology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hooman Moosanen Mozaffari
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ladan Goshayeshi
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. .,Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Alireza Pasdar
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. .,Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. .,Division of Applied Medicine, Medical School, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK.
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Rs-10889677 variant in interleukin-23 receptor may contribute to creating an inflammatory milieu more susceptible to bladder tumourigenesis: report and meta-analysis. Immunogenetics 2021; 73:207-226. [PMID: 33665735 DOI: 10.1007/s00251-021-01205-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 01/20/2021] [Indexed: 12/20/2022]
Abstract
Bladder cancer (BLC) is a recurrent high-risk malignancy typified by an inherent localised chronic inflammation. IL-23-receptor (IL-23R), as a positive regulator in the priming of T helper-17 cells, is regarded a principal coordinator of inflammation-propelled neoplasia. In this article, we indented firstly to scrutinise the influence of rs10889677"A/C" SNP located in IL-23R-gene on BLC development and progression among Egyptians. Findings revealed that the rs10889677"C" allele was significantly associated with the increased BLC risk and its higher frequencies were plainly noticeable in high-grade and invasive tumours when applied the dominant/homozygous/allelic genetic models. Under the same genetic models, elevated serum levels of IL-23R protein in BLC patients were pertinently correlated with the rs10889677"A/C" polymorphism. As a corollary, the frequent up-regulation of IL-23R exerts a subsequent activation of the IL-23/17 inflammatory axis. That is experienced as a drastic increase in IL-23 and IL17 levels under the dominant/homozygous/heterozygous/recessive models. Second, study further described how the rs10889677 variant confers its pro-tumoural influences on IL-23R-bearing immune cells, involving tumour-associated macrophages (TAMs), natural killers (NKs) and CD4+ T-helper cells. When the dominant model was adopted, it was observed that patients bearing the rs10889677 "C" allele had lower counts of IL-23R-positive CD56+NKs and CD4+ T-cells, in tandem with higher levels of IL-23R-positive CD14+ TAMs compared with those with rs10889677 "A" allele. To entrench the idea, we did a meta-analysis on BLC patients from three different ethnicities (Asian, Caucasians and African). We observed that rs10889677"SNP" is significantly correlated with increased risk of BLCs in the overall population using over-dominant model. Consequently, authors suggested that the rs10889677 variant could be directly implicated in developing inflammatory environment more prone to generating malignancy.
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El-Gedamy M, El-Khayat Z, Abol-Enein H, El-Said A, El-Nahrery E. Rs-1884444 G/T variant in IL-23 receptor is likely to modify risk of bladder urothelial carcinoma by regulating IL-23/IL-17 inflammatory pathway. Cytokine 2020; 138:155355. [PMID: 33187815 DOI: 10.1016/j.cyto.2020.155355] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 09/29/2020] [Accepted: 10/19/2020] [Indexed: 12/24/2022]
Abstract
Bladder urothelial carcinoma (BUC) is a chronic relapsing urological malignancy, which poses a serious threat to human life. Non-resolving chronic-inflammation at the neoplastic site is associated consistently with inducing tumor-progression and poor patient outcomes. Interleukin 23 receptor (IL-23R) is a key element in T-helper 17 cell-mediated inflammatory process, that plays a critical role in orchestrating tumor-promoting inflammation. Therefore, we hypothesized that potentially functional genetic variant rs1884444 G/T of IL-23R may modify BUC risk. To validate this hypothesis, our findings demonstrated that the rs1884444 G/T variant was significantly associated with a reduced risk of BUC compared to controls observed under allelic (T vs. G) and dominant (GT + TT vs. GG) models (P < 0.05). In addition, the frequency of the T-allele has dropped to very low values in the case of high-grades and invasive-tumors (P < 0.05). Thus, T-allele has emerged as a reliable genetic marker for good prognosis of BUC. In tumorgenesis, the binding-affinity of the receptor seemed to be distorted by the effect of the non-conservative G/T variation, which in turn caused the IL-23/IL-17 pathway to be disabled. This was recognized by low levels of IL-23 and IL-17 in the serum of patients, under the influence of all the tested genetic models (P < 0.01). Results also indicated that the level of the receptor-bearing immune cells could be altered in response to the G/T protective effect. For example, the median counts of T-helper CD4+ cells and CD56+ natural killers increased significantly in conjunction with the decrease in the median count of CD14+ tumor-associated-macrophages under the dominant model. Nevertheless, the causative link between this subtle polymorphism and the immune-surveillance against BUC needs further in-depth investigation. Overall, we concluded that the rs-1884444 G/T variant is highly-associated with a reduction in the BUC risk, which may occur via deregulation of the IL-23/IL-17 pathway.
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Affiliation(s)
- Mohammed El-Gedamy
- Department of Chemistry (Biochemistry branch), Faculty of Science, Suez University, Suez, Egypt
| | - Zakaria El-Khayat
- Medical Biochemistry Department, National Research Center, Giza, Egypt
| | - Hassan Abol-Enein
- Division of Urology, Urology and Nephrology Center, Mansoura University, Egypt
| | - Afaf El-Said
- Genetics Unit, Children Hospital, Mansoura University, Egypt
| | - Eslam El-Nahrery
- Department of Chemistry (Biochemistry branch), Faculty of Science, Suez University, Suez, Egypt.
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MicroRNA binding site polymorphism in inflammatory genes associated with colorectal cancer: literature review and bioinformatics analysis. Cancer Gene Ther 2020; 27:739-753. [PMID: 32203060 DOI: 10.1038/s41417-020-0172-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 02/21/2020] [Accepted: 03/10/2020] [Indexed: 02/06/2023]
Abstract
Inflammation, among environmental risk factors, is one of the most important contributors to colorectal cancer (CRC) development. In this way, studies revealed that the incidence of CRC in inflammatory bowel disease patients is up to 60% higher than the general population. MicroRNAs (miRNAs), small noncoding RNA molecules, have attracted excessive attention due to their fundamental role in various aspects of cellular biology, such as inflammation by binding to the 3'-untranslated regions (3'-UTR) of pro and anti-inflammatory genes. Based on multiple previous studies, SNPs at 3'-UTR can affect miRNA recognition elements by changing the thermodynamic features and secondary structure. This effect can be categorized, based on the number of changes, into four groups, including break, decrease, create, and enhance. In this paper, we will focus on functional variants in miRNA binding sites in inflammatory genes, which can modulate the risk of CRC by both investigating previous studies, regarding miRSNPs in inflammatory genes associated with CRC and recruiting in silico prediction algorithms to report putative miRSNPs in 176 inflammatory genes. In our analysis, we achieved 110 miRSNPs in 3'-UTR of 67 genes that seem good targets for future researches.
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Liu D, Xing S, Wang W, Huang X, Lin H, Chen Y, Lan K, Chen L, Luo F, Qin S, Liang R, Bai C, Xu J, Liu W. Prognostic value of serum soluble interleukin-23 receptor and related T-helper 17 cell cytokines in non-small cell lung carcinoma. Cancer Sci 2020; 111:1093-1102. [PMID: 32020720 PMCID: PMC7156824 DOI: 10.1111/cas.14343] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 01/10/2020] [Accepted: 01/13/2020] [Indexed: 12/29/2022] Open
Abstract
The signaling of interleukin (IL)‐23 and its receptor (IL‐23R) play a crucial role in the development of cancers. However, the clinical significance of human serum soluble IL‐23R (sIL‐23R) and its relationship with IL‐23 are still not explored in non‐small cell lung cancer (NSCLC). In our study, sIL‐23R was first identified in the serum of NSCLC patients, but not in healthy controls, by proteomics. The IL‐23R mRNA and protein were upregulated in NSCLC cell lines and tissues tested by quantitative PCR, western blot analysis and immunohistochemistry. The levels of sIL‐23R, IL‐23, and IL‐17 in 195 NSCLC patients’ serum were determined by ELISA, and high levels of sIL‐23R were significantly associated with advanced N stage (P = .039), clinical stage (P = .007), and poor 5‐year survival rate. In vitro, sIL‐23R was shown binding to IL‐23 and the balance could affect patients’ N and T stage, overall survival, and downstream cytokine IL‐17 in a potential antagonistic relationship. Although sIL‐23R, IL‐23, and IL‐17 were all associated with poor prognosis, only the sIL‐23R/IL‐23 ratio (hazard ratio, 1.945; 95% confidence interval, 1.147‐3.299; P = .014) was found to be an independent factor for prognosis. Therefore, we identified fragments of soluble cytokine receptor of IL‐23R with affinity ability to its natural ligand IL‐23 in NSCLC patients’ serum. The balance between the 2 antagonists can work as a potential prognostic serum marker.
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Affiliation(s)
- Dan Liu
- Department of Clinical Laboratory, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.,Department of Laboratory Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
| | - Shan Xing
- Department of Clinical Laboratory, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Wan Wang
- Department of Laboratory Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
| | - Xianzhang Huang
- Department of Laboratory Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
| | - Haibiao Lin
- Department of Laboratory Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
| | - Yonghe Chen
- Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Kai Lan
- Department of Laboratory Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
| | - Lin Chen
- Department of Laboratory Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
| | - Fudong Luo
- Department of Laboratory Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
| | - Sheng Qin
- Department of Laboratory Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
| | - Rongliang Liang
- Department of Laboratory Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
| | - Caiying Bai
- Department of Laboratory Science, Guangdong Women and Children Hospital, Guangzhou, China
| | - Jianhua Xu
- Department of Laboratory Science, The ShunDe Hospital of Guangzhou University of Chinese Medicine, Foshan, China
| | - Wanli Liu
- Department of Clinical Laboratory, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Guangzhou, China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
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Guo B, Wu S, Zhu X, Zhang L, Deng J, Li F, Wang Y, Zhang S, Wu R, Lu J, Zhou Y. Micropeptide CIP2A-BP encoded by LINC00665 inhibits triple-negative breast cancer progression. EMBO J 2020; 39:e102190. [PMID: 31755573 PMCID: PMC6939193 DOI: 10.15252/embj.2019102190] [Citation(s) in RCA: 159] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Revised: 10/10/2019] [Accepted: 10/15/2019] [Indexed: 01/22/2023] Open
Abstract
TGF-β signaling pathway plays a key role in breast cancer metastasis. Recent studies suggest that TGF-β regulates tumor progression and invasion not only via transcriptional regulation, but also via translational regulation. Using both bioinformatics and experimental tools, we identified a micropeptide CIP2A-BP encoded by LINC00665, whose translation was downregulated by TGF-β in breast cancer cell lines. Using TNBC cell lines, we showed that TGF-β-activated Smad signaling pathway induced the expression of translation inhibitory protein 4E-BP1, which inhibited eukaryote translation initiation factor elF4E, leading to reduced translation of CIP2A-BP from LINC00665. CIP2A-BP directly binds tumor oncogene CIP2A to replace PP2A's B56γ subunit, thus releasing PP2A activity, which inhibits PI3K/AKT/NFκB pathway, resulting in decreased expression levels of MMP-2, MMP-9, and Snail. Downregulation of CIP2A-BP in TNBC patients was significantly associated with metastasis and poor overall survival. In the MMTV-PyMT model, either introducing CIP2A-BP gene or direct injection of CIP2A-BP micropeptide significantly reduced lung metastases and improved overall survival. In conclusion, we provide evidence that CIP2A-BP is both a prognostic marker and a novel therapeutic target for TNBC.
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Affiliation(s)
- Binbin Guo
- Department of GeneticsMedical College of Soochow UniversitySuzhouChina
| | - Siqi Wu
- Department of GeneticsMedical College of Soochow UniversitySuzhouChina
| | - Xun Zhu
- Department of General SurgeryThe Second Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Liyuan Zhang
- Department of Radiotherapy & OncologyThe Second Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Jieqiong Deng
- Department of GeneticsMedical College of Soochow UniversitySuzhouChina
| | - Fang Li
- Department of GeneticsMedical College of Soochow UniversitySuzhouChina
| | - Yirong Wang
- Department of GeneticsMedical College of Soochow UniversitySuzhouChina
| | - Shenghua Zhang
- Department of GeneticsMedical College of Soochow UniversitySuzhouChina
| | - Rui Wu
- Department of GeneticsMedical College of Soochow UniversitySuzhouChina
| | - Jiachun Lu
- The State Key Lab of Respiratory DiseaseThe First Affiliated HospitalThe School of Public HealthGuangzhou Medical UniversityGuangzhouChina
| | - Yifeng Zhou
- Department of GeneticsMedical College of Soochow UniversitySuzhouChina
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12
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Polymorphisms of genes encoding cytokines predict the risk of high-grade bladder cancer and outcomes of BCG immunotherapy. Cent Eur J Immunol 2020; 45:37-47. [PMID: 32425678 PMCID: PMC7226548 DOI: 10.5114/ceji.2020.94674] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Accepted: 04/23/2019] [Indexed: 12/11/2022] Open
Abstract
Introduction The present study investigated the association of cytokines genes polymorphisms (IL-2, IL-8 and IL-18) and polymorphisms in genes encoding molecules related to the differentiation of Th17 subpopulation (IL-17 and IL-23R) with the risk of bladder cancer (BC) and response to BCG immunotherapy. Material and methods Altogether, 175 BC patients treated with BCG due to high-grade non-muscle invasive tumors and 207 healthy individuals were genotyped for the following polymorphisms: IL-17A-197G>A (rs2275913); IL-17F+7488T>C (rs763780); IL-23Rc.309C>A (rs10889677);IL-23Rc.1142G>A (rs11209026); IL-2-330T>G (rs2069762), IL-8-251A>T (rs4073), and IL-18-137G>C (rs187238) using the TaqMan SNP genotyping assays. Results The IL-23Rc.-309C>A[A] allele was associated with the risk of BC (OR: 1.42, p = 0.03). Moreover, heterozygocities for IL-17A-197G>A[GA] and IL-18-137G>C[GC] increased the risk of BC, as compared to both homozygotes (OR: 1.67, p = 0.01 and OR: 1.84, p = 0.008, respectively). The IL-18-137G>C[GC] heterozygous patients had the highest risk of tumor recurrence and progression, and the worst recurrence-free and progression-free survival. Homozygous IL-17A-197G>A[GG] patients presented the best recurrence-free survival, while IL-17A-197G>A[AA] patients had 1.8-fold higher risk of recurrence. Conclusions The present study highlighted the importance of IL-17, IL-18, and IL-23R gene polymorphisms for BC susceptibility and BCG immunotherapy outcomes. It may help to identify appropriate candidates for early radical treatment.
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13
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Mosallaei M, Simonian M, Esmaeilzadeh E, Bagheri H, Miraghajani M, Salehi AR, Mehrzad V, Salehi R. Single nucleotide polymorphism rs10889677 in miRNAs Let-7e and Let-7f binding site of IL23R gene is a strong colorectal cancer determinant: Report and meta-analysis. Cancer Genet 2019; 239:46-53. [PMID: 31546198 DOI: 10.1016/j.cancergen.2019.09.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 08/11/2019] [Accepted: 09/15/2019] [Indexed: 12/13/2022]
Abstract
Single nucleotide polymorphisms (SNPs) in the recognition sites of microRNAs (miRNAs), located at 3' untranslated region (UTR) of mRNAs, interfere with posttranslational gene regulation. Deregulation of genes may contribute to some disease susceptibility including colorectal cancer (CRC). In the present study, in a case-control setup, 167 CRC patients and 161 control subjects were studied for allele and genotype frequency of rs10889677 polymorphism in miRNAs Let-7e and Let-7f binding sites at 3' UTR of IL23R gene using PCR-RFLP assay. Also, related articles were retrieved from MEDLINE, Cochrane review, Google Scholar and Scopus databases for meta-analysis study. According to our results, AA genotype of SNP rs10889677 was significantly correlated with increased risk of CRC (OR = 3.10; 95% CI [1.86-5.18]; P: < 0.001). In a meta-analysis on 10 risk estimates for the CC versus AA genotype, we found an inverse association between CC SNPs and risk of all cancer (OR = 0.59; 95% CI [0.49-0.71]; P < 0.001). In conclusion, our results demonstrate that rs10889677 polymorphism is significantly associated with CRC risk.
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Affiliation(s)
- Meysam Mosallaei
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Miganoosh Simonian
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Emran Esmaeilzadeh
- Neuroscience Research Center, Iran University of Medical Science, Tehran, Iran
| | - Hadi Bagheri
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Maryam Miraghajani
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ahmad Reza Salehi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Valiollah Mehrzad
- Department of Internal Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Rasoul Salehi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran; Gerfa Namayesh Azmayesh (GENAZMA) Science & Research Institute, Isfahan, Iran.
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14
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Li M, Yue C, Jin G, Guo H, Ma H, Wang G, Huang S, Wu F, Zhao X. Rs1884444 variant in
IL23R
gene is associated with a decreased risk in esophageal cancer in Chinese population. Mol Carcinog 2019; 58:1822-1831. [PMID: 31197899 DOI: 10.1002/mc.23069] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 05/15/2019] [Accepted: 05/26/2019] [Indexed: 12/24/2022]
Affiliation(s)
- Miao Li
- Department of Internal Medicine OncologyThe First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi China
- Department of Internal Medicine OncologyThe Fifth People's Hospital of Qinghai Province Xining Qinghai China
| | - Chenli Yue
- Department of Respiratory MedicineShaanxi Provincial Crops Hospital of Chinese People's Armed Police Force Xi'an Shaanxi China
| | - Guoquan Jin
- Department of General SurgeryThe Fifth People's Hospital of Qinghai Province Xining Qinghai China
| | - Hulin Guo
- Department of Internal Medicine OncologyThe Fifth People's Hospital of Qinghai Province Xining Qinghai China
| | - Haizhao Ma
- Medical DepartmentThe Fifth People's Hospital of Qinghai Province Xining Qinghai China
| | - Guanying Wang
- Department of Internal Medicine OncologyThe First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi China
| | - Shangke Huang
- Department of Internal Medicine OncologyThe First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi China
- Department of OncologyThe Affiliated Hospital of Southwest Medical University Luzhou Sichuan China
| | - Fang Wu
- Department of NeonatologyThe First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi China
| | - Xinhan Zhao
- Department of Internal Medicine OncologyThe First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi China
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15
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Jia ZF, Cao DH, Wu YH, Jin MS, Pan YC, Cao XY, Jiang J. Lethal-7-related polymorphisms are associated with susceptibility to and prognosis of gastric cancer. World J Gastroenterol 2019; 25:1012-1023. [PMID: 30833806 PMCID: PMC6397727 DOI: 10.3748/wjg.v25.i8.1012] [Citation(s) in RCA: 7] [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: 12/03/2018] [Revised: 01/18/2019] [Accepted: 01/26/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The lethal-7 (let-7) family members and their targets are involved in the development and progression of tumors. Let-7-related polymorphisms have been reported to be associated with tumorigenesis and prognosis. In gastric cancer, however, the related studies are limited.
AIM To investigate the role of let-7-related microRNA polymorphisms in the tumorigenesis and prognosis of gastric cancer in a Chinese population.
METHODS A total of 898 gastric cancer patients and 992 tumor-free controls were recruited into this study from 2008 to 2013. Gastric cancer patients were followed periodically. Ten single nucleotide polymorphisms (SNPs) in the let-7 gene region or their target mRNAs were genotyped using the MassARRAY system and their associations with the risk for or overall survival of gastric cancer were analyzed.
RESULTS All the ten SNPs were in Hardy-Weinberg equilibrium. The C allele of the rs3811463 polymorphism in the 3’-untranslated region (UTR) of LIN28A was associated with a lower risk of gastric cancer [odds ratio (OR) = 0.74, 95% confidence interval (CI): 0.61-0.88, P = 0.001] after adjustment for age and Helicobacter pylori status. Seven hundred and thirty-five gastric cancer patients who had undergone radical tumorectomy were included in the survival analysis and their 5-year survival rate was 53.9% (95%CI: 50.1%-57.6%). The rs10889677 in the 3’-UTR of IL23R was corresponded to the prognosis of gastric cancer in a dose-response manner, in which the death risk increased by 25% [hazard ratio (HR) = 1.25, 95%CI: 1.04-1.45, P = 0.011] with each increase in the number of C alleles after controlling for other potential clinicopathological parameters.
CONCLUSION The let-7-related polymorphism rs3811463 in LIN28A is associated with the susceptibility to gastric cancer and the let-7-related polymorphism rs10889677 in IL23R is associated with the prognosis of gastric cancer.
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Affiliation(s)
- Zhi-Fang Jia
- Division of Clinical Research, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Dong-Hui Cao
- Division of Clinical Research, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Yan-Hua Wu
- Division of Clinical Research, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Mei-Shan Jin
- Division of Pathology, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Yu-Chen Pan
- Division of Clinical Research, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Xue-Yuan Cao
- Department of Gastrointestinal Surgery, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Jing Jiang
- Division of Clinical Research, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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16
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Kunisato T, Watanabe M, Inoue N, Okada A, Nanba T, Kobayashi W, Inoue Y, Katsumata Y, Omori N, Nobuhara T, Takemura K, Hidaka Y, Iwatani Y. Polymorphisms in Th17-related genes and the pathogenesis of autoimmune thyroid disease. Autoimmunity 2018; 51:360-369. [PMID: 30474404 DOI: 10.1080/08916934.2018.1534963] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The prognosis of autoimmune thyroid disease (AITD) including Graves' disease (GD) and Hashimoto's disease (HD) is difficult to predict. We previously suggested that Th17 cells may be associated with the pathogenesis of AITD. However, the association between gene polymorphisms in Th17-related genes and the prognosis of AITD was not clarified. To clarify this association, we genotyped 12 polymorphisms in 11 Th17-related genes (IL1Ra, IL6R, IL17R, IL21R, IL23R, CCR6, SOCS3, RORC, IL17A, IL17F and IL21) in 142 HD patients including 58 patients with severe HD and 48 patients with mild HD, 170 patients with GD including 81 patients with intractable GD and 49 patients with GD in remission, and 84 healthy volunteers. The frequency of the IL17F rs763780 T allele was higher in patients with severe HD than in patients with mild HD (p = .008). The frequency of the IL17R rs9606615 T allele was higher in patients with HD than in normal subjects (p = .011). The frequencies of the SOCS3 rs4969170 AA genotype, CCR6 rs3093024 AA genotype, and IL21 rs907715 AA genotype were higher in patients with intractable GD than in patients with GD in remission (p = .035, p = .002 and p = .030, respectively). In conclusion, IL17R rs9607715 and IL17F rs763780 polymorphisms are associated with the susceptibility and severity of HD, respectively. IL21 rs907715, SOCS3 rs4969170 and CCR6 rs3093024 polymorphisms are associated with the intractability of GD.
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Affiliation(s)
- Takayuki Kunisato
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Mikio Watanabe
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Naoya Inoue
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka, Japan.,Laboratory for Clinical Investigation, Osaka University Hospital, Osaka, Japan
| | - Azusa Okada
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Takashi Nanba
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Wataru Kobayashi
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yuka Inoue
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yuka Katsumata
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Naoki Omori
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Takayuki Nobuhara
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kazuya Takemura
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yoh Hidaka
- Laboratory for Clinical Investigation, Osaka University Hospital, Osaka, Japan
| | - Yoshinori Iwatani
- Department of Biomedical Informatics, Division of Health Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
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17
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Holder A, Jones G, Soutter F, Palmer DB, Aspinall R, Catchpole B. Polymorphisms in the canine IL7R 3'UTR are associated with thymic output in Labrador retriever dogs and influence post-transcriptional regulation by microRNA 185. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2018; 81:244-251. [PMID: 29247721 DOI: 10.1016/j.dci.2017.12.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 12/08/2017] [Accepted: 12/08/2017] [Indexed: 06/07/2023]
Abstract
Interleukin-7 (IL-7) and its receptor (IL-7R) are essential for T cell development in the thymus, and changes in the IL-7/IL-7R pathway have been implicated in age-associated thymic involution which results in a reduction of naïve T cell output. The aim of this study was to investigate the relationship between IL7 and IL7R genetic variation and thymic output in dogs. No single nucleotide polymorphisms (SNPs) were identified in the canine IL7 gene, but a number were present in the canine IL7R gene. Polymorphisms in the IL7R exon 8 and 3'UTR were found to be associated with signal joint T cell receptor excision circle (sj-TREC) values (a biomarker of thymic output) in young and geriatric Labrador retrievers. Additionally, one of the SNPs in the IL7R 3'UTR (SNP 14 c.1371 + 446 A > C) was found to cause a change in the seed-binding site for microRNA 185 which, a luciferase reporter assay demonstrated, caused changes in post-transcriptional regulation, and therefore might be capable of influencing IL-7R expression. The research findings suggest a genetic link between IL7R genotype and thymic output in dogs, which might impact on immune function as these animals age and provide further evidence of the involvement of IL-7/IL-7R pathway in age-associated thymic involution.
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Affiliation(s)
- Angela Holder
- Department of Pathobiology and Population Sciences, Royal Veterinary College, North Mymms, Hertfordshire, UK
| | - Gareth Jones
- Department of Pathobiology and Population Sciences, Royal Veterinary College, North Mymms, Hertfordshire, UK
| | - Francesca Soutter
- Department of Pathobiology and Population Sciences, Royal Veterinary College, North Mymms, Hertfordshire, UK
| | - Donald B Palmer
- Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK
| | - Richard Aspinall
- Health and Wellbeing Academy, Postgraduate Medical Institute, Anglia Ruskin University, Chelmsford, Essex, UK
| | - Brian Catchpole
- Department of Pathobiology and Population Sciences, Royal Veterinary College, North Mymms, Hertfordshire, UK.
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18
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Deng N, Zhou H, Fan H, Yuan Y. Single nucleotide polymorphisms and cancer susceptibility. Oncotarget 2017; 8:110635-110649. [PMID: 29299175 PMCID: PMC5746410 DOI: 10.18632/oncotarget.22372] [Citation(s) in RCA: 219] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 10/03/2017] [Indexed: 12/12/2022] Open
Abstract
A large number of genes associated with various cancer types contain single nucleotide polymorphisms (SNPs). SNPs are located in gene promoters, exons, introns as well as 5'- and 3'- untranslated regions (UTRs) and affect gene expression by different mechanisms. These mechanisms depend on the role of the genetic elements in which the individual SNPs are located. Moreover, alterations in epigenetic regulation due to gene polymorphisms add to the complexity underlying cancer susceptibility related to SNPs. In this systematic review, we discuss the various genetic and epigenetic mechanisms involved in determining cancer susceptibility related to various SNPs located in different genetic elements. We also discuss the diagnostic potential of these SNPs and the focus for future studies.
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Affiliation(s)
- Na Deng
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China.,Department of Hematology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Heng Zhou
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Hua Fan
- Department of Hematology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China.,National Clinical Research Center for Digestive Diseases, Xi'an 110001, China
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19
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Gomes da Silva IIF, Angelo HD, Rushansky E, Mariano MH, Maia MDMD, de Souza PRE. Interleukin (IL)-23 Receptor, IL-17A and IL-17F Gene Polymorphisms in Brazilian Patients with Rheumatoid Arthritis. Arch Immunol Ther Exp (Warsz) 2017; 65:537-543. [DOI: 10.1007/s00005-017-0473-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 03/14/2017] [Indexed: 12/12/2022]
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20
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Cilião HL, Camargo-Godoy RBO, de Souza MF, Dos Reis MB, Iastrenski L, Alvares Delfino VD, Rogatto SR, de Syllos Cólus IM. Association of UGT2B7, UGT1A9, ABCG2, and IL23R polymorphisms with rejection risk in kidney transplant patients. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2017; 80:661-671. [PMID: 28524801 DOI: 10.1080/15287394.2017.1286922] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Despite advances in testing compatibility between donor and recipient, graft rejection remains a current concern. Single-nucleotide polymorphisms (SNPs) that codify altered enzymes of metabolism, drug transport, and the immune system may contribute to graft rejection in transplant patients. This study examined the association between SNPs present in genes of these processes and occurrence of graft rejection episodes in 246 kidney transplant patients, 35% of which were diagnosed with rejection. Genotype-gene expression associations were also assessed. Peripheral blood samples were used for genotyping of 24 SNPs on the following genes: CYP3A4, CYP3A5, CYP2E1, POR, UGT2B7, UGT1A9, ABCB1, ABCC2, ABCG2, SLCO1B1, TNF, IL2, IRF5, TGFB1, NFKBIA, IL10, IL23R, NFAT, and CCR5 by real-time PCR. The analysis of gene expression was performed by RT-qPCR. The association between graft rejection episodes and polymorphic variants was assessed using odds ratios. Polymorphisms rs7662029 (UGT2B7) and rs6714486 (UGT1A9) were associated with occurrence of graft rejection episodes, rs7662029 (UGT2B7) exhibited a protective effect (1.85-fold), and rs6714486 (UGT1A9) an increased 1.6-fold increased risk of graft rejection. Among drug transporter genes, only rs2231142 (ABCG2) demonstrated an association with a 1.92-fold decrease in the risk of graft rejection. The immunological SNP rs10889677 (IL23R) was associated with a 1.9-fold enhanced risk of graft rejection. Association between genotypes and gene expression was not detected. Therefore, SNPs of UGT2B7, UGT1A9, ABCG2, and IL23R genes may be useful as candidate markers for screening of risk graft rejection in renal transplant patients. These markers may improve medical decisions, avoiding adverse effects.
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Affiliation(s)
- Heloísa Lizotti Cilião
- a Department of General Biology, Center of Biological Sciences , State University of Londrina , Londrina , Paraná , Brazil
| | | | - Marilesia Ferreira de Souza
- a Department of General Biology, Center of Biological Sciences , State University of Londrina , Londrina , Paraná , Brazil
| | | | - Lorena Iastrenski
- a Department of General Biology, Center of Biological Sciences , State University of Londrina , Londrina , Paraná , Brazil
| | | | - Silvia Regina Rogatto
- c Faculty of Medicine , São Paulo State University (UNESP) , Botucatu , São Paulo , Brazil
| | - Ilce Mara de Syllos Cólus
- a Department of General Biology, Center of Biological Sciences , State University of Londrina , Londrina , Paraná , Brazil
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21
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Munde EO, Raballah E, Okeyo WA, Ong'echa JM, Perkins DJ, Ouma C. Haplotype of non-synonymous mutations within IL-23R is associated with susceptibility to severe malaria anemia in a P. falciparum holoendemic transmission area of Kenya. BMC Infect Dis 2017; 17:291. [PMID: 28427357 PMCID: PMC5397818 DOI: 10.1186/s12879-017-2404-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Accepted: 04/13/2017] [Indexed: 12/17/2022] Open
Abstract
Background Improved understanding of the molecular mechanisms involved in pediatric severe malarial anemia (SMA) pathogenesis is a crucial step in the design of novel therapeutics. Identification of host genetic susceptibility factors in immune regulatory genes offers an important tool for deciphering malaria pathogenesis. The IL-23/IL-17 immune pathway is important for both immunity and erythropoiesis via its effects through IL-23 receptors (IL-23R). However, the impact of IL-23R variants on SMA has not been fully elucidated. Methods Since variation within the coding region of IL-23R may influence the pathogenesis of SMA, the association between IL-23R rs1884444 (G/T), rs7530511 (C/T), and SMA (Hb < 6.0 g/dL) was examined in children (n = 369, aged 6–36 months) with P. falciparum malaria in a holoendemic P. falciparum transmission area. Results Logistic regression analysis, controlling for confounding factor of anemia, revealed that individual genotypes of IL-23R rs1884444 (G/T) [GT; OR = 1.34, 95% CI = 0.78–2.31, P = 0.304 and TT; OR = 2.02, 95% CI = 0.53–7.74, P = 0.286] and IL-23R rs7530511 (C/T) [CT; OR = 2.6, 95% CI = 0.59–11.86, P = 0.202 and TT; OR = 1.66, 95% CI = 0.84–3.27, P = 0.142] were not associated with susceptibility to SMA. However, carriage of IL-23R rs1884444T/rs7530511T (TT) haplotype, consisting of both mutant alleles, was associated with increased susceptibility to SMA (OR = 1.12, 95% CI = 1.07–4.19, P = 0.030). Conclusion Results presented here demonstrate that a haplotype of non-synonymous IL-23R variants increase susceptibility to SMA in children of a holoendemic P. falciparum transmission area. Electronic supplementary material The online version of this article (doi:10.1186/s12879-017-2404-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Elly O Munde
- Department of Biomedical Sciences and Technology, School of Public Health and Community Development, Maseno University, Maseno, Kenya.,University of New Mexico/KEMRI Laboratories of Parasitic and Viral Diseases, Centre for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya
| | - Evans Raballah
- University of New Mexico/KEMRI Laboratories of Parasitic and Viral Diseases, Centre for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya.,Department of Medical Laboratory Science, School of Public Health, Biomedical Sciences and Technology, Masinde Muliro University of Science and Technology, Kakamega, Kenya
| | - Winnie A Okeyo
- Department of Biomedical Sciences and Technology, School of Public Health and Community Development, Maseno University, Maseno, Kenya
| | - John M Ong'echa
- University of New Mexico/KEMRI Laboratories of Parasitic and Viral Diseases, Centre for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya.,Centre for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya
| | - Douglas J Perkins
- University of New Mexico/KEMRI Laboratories of Parasitic and Viral Diseases, Centre for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya.,Department of Internal Medicine, Centre for Global Health, Health Sciences Centre, University of New Mexico, Albuquerque, NM, USA
| | - Collins Ouma
- Department of Biomedical Sciences and Technology, School of Public Health and Community Development, Maseno University, Maseno, Kenya. .,Centre for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya. .,Ideal Research Centre, Kisumu, Kenya.
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Joerger M, Finn SP, Cuffe S, Byrne AT, Gray SG. The IL-17-Th1/Th17 pathway: an attractive target for lung cancer therapy? Expert Opin Ther Targets 2016; 20:1339-1356. [PMID: 27353429 DOI: 10.1080/14728222.2016.1206891] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION There is strong pharmaceutical development of agents targeting the IL-17-TH17 pathway for the treatment of psoriasis (Ps) and psoriatic arthritis (PsA). Lung cancer accounts for 28% of all cancer-related deaths worldwide, and roughly 80% of patients with newly-diagnosed non-small cell lung cancer (NSCLC) present with metastatic disease, with a poor prognosis of around 12 months. Therefore, there is a high unmet medical need for the development of new and potent systemic treatments in this deadly disease. The emergence of immunotherapies such as anti-PD-1 or anti-PDL1 as candidate therapies in non-small cell lung cancer (NSCLC) indicates that targeting critical immuno-modulatory cytokines including those within the IL-17-Th1/Th17 axis may have proven benefit in the treatment of lung cancer. Areas covered: In this review we describe the current evidence for aberrant IL-17-Th1/Th17 settings in cancer, particularly with regard to targeting this axis in NSCLC. We further discuss the current agents under pharmaceutical development which could potentially target this axis, and discuss the current limitations and areas of concern regarding the use of these in lung cancer. Expert opinion: Current evidence suggests that moving forward agents targeting the IL-17-Th1/Th17 pathway may have novel new oncoimmunology indications in the treatment paradigm for NSCLC.
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Affiliation(s)
- Markus Joerger
- a Department of Medical Oncology & Hematology , Cantonal Hospital , St. Gallen , Switzerland
| | - Stephen P Finn
- b Department of Histopathology & Morbid Anatomy , Trinity College Dublin , Dublin , Ireland
| | - Sinead Cuffe
- c HOPE Directorate , St James's Hospital , Dublin , Ireland
| | - Annette T Byrne
- d Department of Physiology and Medical Physics & Centre for Systems Medicine , Royal College of Surgeons in Ireland , Dublin , Ireland
| | - Steven G Gray
- e Thoracic Oncology Research Group , IMM, St James's Hospital , Dublin , Ireland.,f Department of Clinical Medicine , Trinity College Dublin , Dublin , Ireland
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23
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Xie S, Wang Y, Liu H, Wang M, Yu H, Qiao Y, Li F, Xie X, Zhang J. Diagnostic significance of circulating multiple miRNAs in breast cancer: a systematic review and meta-analysis. Biomark Med 2016; 10:661-74. [PMID: 27231952 DOI: 10.2217/bmm-2015-0017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Aims: To determine whether circulating multiple miRNAs can be used as novel biomarkers for the diagnosis in breast cancer, we performed a systematic review and meta-analysis. Materials & methods: After searching the databases of PubMed, EMBASE and Web of Science, we used the bivariate meta-analysis model to summarize the diagnostic indices and plot the summary receiver operator characteristic curve. Results: The summary estimates revealed that the pooled sensitivity was 88% (95% CI: 82–93%); specificity was 84% (95% CI: 74–91%); positive likelihood ratio was 4.69 (95% CI: 2.93–7.51); negative likelihood ratio was 0.15 (95% CI: 0.09–0.25); diagnostic odds ratio was 38.21 (95% CI: 13.41–108.85); and the area under the curve was 0.93 (95% CI: 0.90–0.95). Conclusion: These results suggested that circulating multiple miRNAs might serve as novel biomarkers for breast cancer, with a relatively high level of accuracy.
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Affiliation(s)
- Shuduo Xie
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China
- Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang 310016, P.R. China
| | - Yanzhong Wang
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China
- Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang 310016, P.R. China
| | - Huixing Liu
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China
- Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang 310016, P.R. China
| | - Maofeng Wang
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China
- Department of Clinical Laboratory Medicine, Evidence Based Medicine Center, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, P.R. China
| | - Haitao Yu
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China
- Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang 310016, P.R. China
| | - Yingli Qiao
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China
- Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang 310016, P.R. China
| | - Fengying Li
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China
- Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang 310016, P.R. China
| | - Xinyou Xie
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China
- Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang 310016, P.R. China
| | - Jun Zhang
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China
- Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang 310016, P.R. China
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24
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Liu XH, Dai ZM, Kang HF, Lin S, Ma XB, Wang M, Liu K, Dai C, Wang XJ, Dai ZJ. Association of IL-23R Polymorphisms (rs6682925, rs10889677, rs1884444) With Cancer Risk: A PRISMA-Compliant Meta-Analysis. Medicine (Baltimore) 2015; 94:e2361. [PMID: 26717375 PMCID: PMC5291616 DOI: 10.1097/md.0000000000002361] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Although interleukin (IL)-23 receptor (IL-23R) plays an important role in the pathogenesis of multiple cancers, its association with cancer risk is inconsistent across different studies. We therefore conducted a meta-analysis with the aim of resolving the relationship among the 3 common polymorphisms of IL-23R (rs6682925, rs10889677, rs1884444) and cancer risk.Case-control studies evaluating the association between IL-23R polymorphisms (rs6682925, rs10889677, rs1884444) and cancer risk were searched in the PubMed, Web of Science, and CNKI databases.Data were included in the meta-analysis if they were from original studies adopting a case-control design investigating the association between IL-23R polymorphisms and risk of any cancer; all cancer cases must have been confirmed by histology or pathology, and controls selected from noncancer individuals. Case-only studies and review papers were excluded.Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the relationship of IL-23R polymorphisms (rs6682925, rs10889677, rs1884444) with cancer risk. A random-effects model or fixed-effects model was used depending on the heterogeneity of the data.Ultimately, 15 studies, involving 8784 cancer patients and 10,321 cancer-free controls, were included in our meta-analysis. In the overall analysis, the rs10889677 polymorphism was associated with breast cancer (BC) under the allelic, homozygous, dominant, and heterozygous models. Rs1884444 polymorphism was relevant to hepatocellular carcinoma (HCC) under the homozygous, recessive, and allelic models. However, no evidence of a relationship between IL-23R polymorphisms (rs6682925, rs10889677, rs1884444) and cancer risk was found in the overall population.Our meta-analysis provides no evidence supporting a global association of IL-23R polymorphisms (rs6682925, rs10889677, rs1884444) with the risk of cancer. However, rs10889677 may be associated with BC susceptibility and rs1884444 had association with HCC risk. Further large and well-designed studies are warranted to confirm this finding.
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Affiliation(s)
- Xing-Han Liu
- From the Department of Oncology (X-HL, H-FK, SL, X-BM, MW, KL, CD, X-JW, Z-JD); and Department of Anesthesia, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China (Z-MD)
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25
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Ni H, Su B, Pan L, Li X, Zhu X, Chen X. Functional variants inPXRare associated with colorectal cancer susceptibility in Chinese populations. Cancer Epidemiol 2015; 39:972-7. [PMID: 26547791 DOI: 10.1016/j.canep.2015.10.029] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Revised: 10/27/2015] [Accepted: 10/27/2015] [Indexed: 12/17/2022]
Abstract
BACKGROUND As an important member of the steroid nuclear receptor family, recent research has suggested that PXR may play important roles in the development of multiple cancers. However, no well-designed studies has been conducted to investigate the associations between genetic polymorphisms of PXR and colorectal cancer (CRC) risk in Chinese populations. MATERIALS AND METHODS We performed a hospital-based case-control analysis to assess two genetic polymorphisms in the 3'-untranslated regions (3'-UTR) via allele-specific MALDI-TOF mass spectrometry assay and evaluated the associations between two polymorphisms and risk of CRC. RESULTS The PXR rs3814058C>T polymorphism was significantly associated with a higher risk of CRC (P<10-3), and the CT/TT variant genotypes had an increased CRC risk (adjusted odds ratio=1.54, 95% confidence interval=1.27-1.83) comparing CC genotype. In stratified analyses, rs3814058CT+TT genotypes was associated with increased risk among alcohol consumers (P=0.002). In vitro experiments indicated that the rs3814058C to rs3814058T transition gained a new binding of the microRNA hsa-miR-129-5p and decreased the PXR expression. CONCLUSIONS Our data suggest that the functional polymorphism rs3814058C>T in 3'-UTR of PXR may be a functional biomarker to predict risk of CRC.
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Affiliation(s)
- Haizhen Ni
- Department of Vascular Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, PR China
| | - Bofeng Su
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, PR China
| | - Lemen Pan
- Department of Vascular Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, PR China
| | - Xueyan Li
- Department of Endoscopic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, PR China
| | - Xixia Zhu
- Operating Room, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, PR China
| | - Xiangjian Chen
- Department of Endoscopic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, PR China.
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26
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Niu YM, Du XY, Lu MY, Xu QL, Luo J, Shen M. Significant association between functional microRNA polymorphisms and head and neck cancer susceptibility: a comprehensive meta-analysis. Sci Rep 2015; 5:12972. [PMID: 26277865 PMCID: PMC4538372 DOI: 10.1038/srep12972] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Accepted: 07/14/2015] [Indexed: 12/16/2022] Open
Abstract
Molecular epidemiological studies have showed a closer association between microRNA polymorphisms with and head and neck cancer (HNC) risk. But the results of these studies were inconsistent. We performed this meta-analysis to clarify the associations between microRNA polymorphisms and HNC risk. Four electronic databases (PubMed, Embase, CNKI, and Wanfang) were searched. Odds ratios (ORs) with 95% confidence interval (CIs) were calculated to assess the association between microRNA-146a rs2910164 G > C, microRNA-196a2 rs11614913 C > T, microRNA-149 rs2292832 C > T, microRNA-499 rs3746444 A > G polymorphisms and HNC risk. Heterogeneity, publication bias and sensitivity analysis were conducted to guarantee the statistical power. Overall, 11 selected articles involving 16100 subjects were included in this meta-analysis. Significantly increased risk between microRNA-146a rs2910164 G > C polymorphism and HNC risk were observed in Caucasian population (GC vs. GG: OR = 1.31, 95%CI = 1.01–1.68; GC + CC vs. GG: OR = 1.26, 95%CI = 1.02–1.57). For microRNA-196a2 rs11614913 C > T, similarly increased risk were also found in Asian population (T vs. C, OR = 1.14, 95%CI = 1.04–1.25; TT vs. CC, OR = 1.33, 95%CI = 1.09–1.61; CT + TT vs. CC OR = 1.32, 95%CI = 0.99–1.76; TT vs. CC + CT, OR = 1.14, 95%CI = 0.99–1.33). In addition, no significant association was detected between microRNA-149 rs2292832 C > T and microRNA-499 rs3746444 A > G polymorphism and HNC risk. This meta-analysis demonstrates that microRNA polymorphisms are associated with HNC development based on ethnicity diversity.
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Affiliation(s)
- Yu-Ming Niu
- 1] Department of Stomatology and Center for Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei University of Medicine, 32 South Renmin Road, Shiyan 442000, China [2] Department of Neurosurgery and Evidence-Based Medicine Center, Taihe Hospital, Hubei University of Medicine, 32 South Renmin Road, Shiyan 442000, China
| | - Xin-Ya Du
- Department of Stomatology, People's Hospital of New District Longhua Shenzhen, 2 East Jianshe Road, Shenzhen 518109, China
| | - Ming-Yi Lu
- Department of Oral and Maxillofacial Surgery, Chung Shan Medical University Hospital, No. 110, Sec. 1, Chien-Kuo N. Rd, Taichung 40201, China
| | - Qiong-Li Xu
- Department of Stomatology and Center for Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei University of Medicine, 32 South Renmin Road, Shiyan 442000, China
| | - Jie Luo
- Department of Neurosurgery and Evidence-Based Medicine Center, Taihe Hospital, Hubei University of Medicine, 32 South Renmin Road, Shiyan 442000, China
| | - Ming Shen
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University; Department of Dental Implant, Affiliated Hospital of Stomatology, Nanjing Medical University, No. 140 Hanzhong Road, Nanjing 210029, China
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27
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Niu L, Li S, Liang H, Li H. The hMLH1 -93G>A Polymorphism and Risk of Ovarian Cancer in the Chinese Population. PLoS One 2015; 10:e0135822. [PMID: 26275295 PMCID: PMC4537278 DOI: 10.1371/journal.pone.0135822] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2015] [Accepted: 07/27/2015] [Indexed: 12/31/2022] Open
Abstract
Background As a mismatch repair (MMR) gene, hMLH1 plays an important role in the maintenance of chromosomal integrity. Several studies have investigated the associations of hMLH1 -93G>A (rs1800734) and Ile219Val (rs1799977) in diverse tumor types with discordant results, but their roles in ovarian cancer in the Chinese population remains to be elucidated. Methods In a case-control analysis, we assessed the association between these two polymorphisms and ovarian cancer risk in 421 ovarian cancer patients and 689 control subjects in the Chinese population using logistic regression. Results We found that the variant hMLH1 genotypes (-93AA and AG) are associated with risk of ovarian cancer (adjusted odds ratio [OR] = 2.02, 95% confidence interval [CI] = 1.42–2.89) compared with the -93GG genotype. The A allele increases the risk of ovarian cancer in a dose-dependent manner (P<10−4). Functional test showed that -93A allele increased hMLH1 promoter transcriptional activity and the luciferase activity. However, no significant difference was found in the genotype frequencies at the Ile219Val site between the cases and controls. Conclusions These findings indicate that the -93G>A polymorphism in hMLH1 may affect ovarian cancer susceptibility in the Chinese population.
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Affiliation(s)
- Leilei Niu
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
| | - Shumin Li
- Department of Gynecology Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Huamao Liang
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
| | - Hua Li
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Department of Gynecology Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China
- * E-mail:
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Abstract
Interleukin (IL-)23 is a central cytokine controlling TH17 development. Overshooting IL-23 signaling contribute to autoimmune diseases. Moreover, GWAS studies have identified several SNPs within the IL-23 receptor, which are associated with autoimmune diseases. IL-23 is a member of the IL-12-type cytokine family and consists of IL-23p19 and p40. Within the IL-12 family, IL-12 and IL-23 share the p40 cytokine subunit and the IL-12Rβ1 as one chain of the receptor complex. For signaling, IL-23 triggers heterodimerization of IL-12Rβ1 and the IL-23R. Subsequently, signal transduction pathways including JAK/STAT, MAPK and PI3K are activated. Most studies have investigated the biological relevance of IL-23 in the development of TH17 cells and autoimmunity, whereas less is known about the molecular context of IL-23 biology. Therefore, we focused on IL-23 receptor complex assembly, signal transduction and functional relevance of IL-23R SNPs in the context of IL-23-inhibitory principles.
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Omrane I, Medimegh I, Baroudi O, Ayari H, Bedhiafi W, Stambouli N, Ferchichi M, Kourda N, Bignon YJ, Uhrhammer N, Mezlini A, Bougatef K, Benammar-Elgaaied A. Involvement of IL17A, IL17F and IL23R Polymorphisms in Colorectal Cancer Therapy. PLoS One 2015; 10:e0128911. [PMID: 26083022 PMCID: PMC4470506 DOI: 10.1371/journal.pone.0128911] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Accepted: 05/03/2015] [Indexed: 12/19/2022] Open
Abstract
IL23/IL17 pathway plays an important role in the development of inflammatory bowel diseases (IBD). In general, the genes encoding the cytokines are genetically polymorphic and polymorphisms in genes IL23R and IL17 have been proved to be associated with its susceptibility to inflammatory diseases as well as cancer including colorectal cancer. Moreover, it has been shown that these interleukins are involved in anti-tumor or pro-tumor effects of various cancers. Previously, we showed that there is a significant association between IL17A, IL17F and IL23R polymorphisms as well as the occurrence of colorectal cancer and the clinical features of the disease. The purpose of the present work is to investigate an association between IL17A, IL17F and IL23R polymorphisms in 102 Tunisian patients with colorectal cancer treatment. The association was analyzed by statistical tools. We found that patients with mutated genotypes of IL17A G197A SNP could be a risk factor for the inefficiency of chemotherapy and radiotherapy. Unlike IL17F variant, patients with wild type genotypes require surgery and adjuvant chemotherapy. On the one hand, we found no evidence that supports a significant association between IL23R polymorphism and the combined genotypes of these three genes and the colorectal cancer treatment. On the other hand, we showed that there is an important interaction between IL17A/IL17F polymorphisms and the stage of the disease as well as its treatment. Finally, patients with IL17F wild type genotype highlighted that there is a valid longer OS without all treatments and with radiotherapy and a neoadjuvant chemotherapy. In contrast, we observed that there are no relationships between IL17A, IL23R and the survival of these patients neither with nor without the treatment. Our results suggest that polymorphisms in IL17A and IL17F genes may be a predictive source of colorectal cancer therapy type. Therefore, IL17F may serve as an independent prognostic factor for overall survival in patients with colorectal cancer.
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Affiliation(s)
- Inés Omrane
- Laboratory of Genetics, Immunology and Human Pathology, Faculty of Sciences of Tunis, University Tunis El Manar, Tunis, Tunisia
- * E-mail:
| | - Imen Medimegh
- Laboratory of Genetics, Immunology and Human Pathology, Faculty of Sciences of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Olfa Baroudi
- Laboratory of Genetics, Immunology and Human Pathology, Faculty of Sciences of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Hager Ayari
- Laboratory of Genetics, Immunology and Human Pathology, Faculty of Sciences of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Walid Bedhiafi
- Laboratory of Genetics, Immunology and Human Pathology, Faculty of Sciences of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Nejla Stambouli
- Laboratory of Genetics, Immunology and Human Pathology, Faculty of Sciences of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Marwa Ferchichi
- Laboratory of Genetics, Immunology and Human Pathology, Faculty of Sciences of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Nadia Kourda
- Laboratory of Anatomy and Cytopathology of the Charles Nicolle Hospital, Tunis, Tunisia
| | - Yves-Jean Bignon
- Laboratory of Diagnostic and Molecular Genetics, Centre Jean Perrin, Clermont Ferrand, France
| | - Nancy Uhrhammer
- Laboratory of Diagnostic and Molecular Genetics, Centre Jean Perrin, Clermont Ferrand, France
| | - Amel Mezlini
- Medical Oncology Department of the Institute Salah Azaiez, Tunis, Tunisia
| | - Karim Bougatef
- Laboratory of Genetics, Immunology and Human Pathology, Faculty of Sciences of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Amel Benammar-Elgaaied
- Laboratory of Genetics, Immunology and Human Pathology, Faculty of Sciences of Tunis, University Tunis El Manar, Tunis, Tunisia
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Yang ZP, Xie YH, Ling DY, Li JR, Jiang J, Fan YH, Zheng JL, Wu WX. SCYL1BP1 has tumor-suppressive functions in human lung squamous carcinoma cells by regulating degradation of MDM2. Asian Pac J Cancer Prev 2015; 15:7467-71. [PMID: 25227860 DOI: 10.7314/apjcp.2014.15.17.7467] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
SCY1-like 1-binding protein 1 (SCYL1BP1) is a newly identified transcriptional activator domain containing protein with many unknown biological functions. Recently emerging evidence has revealed that it is a novel regulator of the p53 pathway, which is very important for the development of human cancer. However, the effects of SCYL1BP1 on human lung squamous carcinoma cell biological behavior remain poorly understood. In this study, we present evidence that SCYL1BP1 can promote the degradation of MDM2 protein and further inhibit the G1/S transition of lung squamous carcinoma cell lines. Functional assays found that reintroduction of SCYL1BP1 into lung squamous carcinoma cell lines significantly inhibited cell proliferation, migration, invasion and tumor formation in nude mice, suggesting strong tumor suppressive function of SCYL1BP1 in lung squamous carcinoma. Taken together, our data suggest that the interaction of SCYL1BP1/MDM2 could accelerate MDM2 degradation, and may function as an important tumor suppressor in lung squamous carcinomas.
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Affiliation(s)
- Zhi-Ping Yang
- Department of Oncology and Pathology, The First Hospital of Jiaxing, Jiaxing, China E-mail :
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31
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Wu XM, Yang HG, Zheng BA, Cao HF, Hu ZM, Wu WD. Functional Genetic Variations at the microRNA Binding-Site in the CD44 Gene Are Associated with Risk of Colorectal Cancer in Chinese Populations. PLoS One 2015; 10:e0127557. [PMID: 26010608 PMCID: PMC4444206 DOI: 10.1371/journal.pone.0127557] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Accepted: 04/16/2015] [Indexed: 11/18/2022] Open
Abstract
CD44 as one of the most putative stem cell markers plays a key role in many cellular processes, including cancer cell growth and migration. Functional single nucleotide polymorphisms (SNPs) of CD44 may modulate its gene functions and thus cancer risk. In the current study, we investigated if polymorphisms in the 3'-untranslated region (UTR) of CD44 are associated with increased susceptibility to colorectal cancer (CRC) by conducting a case-control study of 946 CRC patients and 989 cancer-free controls. Three polymorphisms (rs13347C/T, rs10836347C/T, rs11821102G/A) in the 3'-UTR of CD44 were genotyped. We found that the variant genotypes (CT and TT) of rs13347 (adjusted odds ratio (OR)=1.79, 95% confidence interval (CI)=1.50-2.17) increased an individual's susceptibility to CRC, compared with rs13347CC homozygous genotypes. We also found that CRC patients with the CT/TT genotype had a 1.6-fold increased risk for developing advanced (stage III + IV) CRC. Furthermore, functional assays showed that the C to T base change at rs13347C/T disrupts the binding site for the microRNA hsa-mir-509-3p, thereby increasing CD44 transcriptional activity and expression level. These findings suggest that the rs13347C/T in microRNA binding site may be potential biomarkers for genetic susceptibility to CRC.
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Affiliation(s)
- Xiao-Min Wu
- Department of Anesthesiology, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang Province, People’s Republic of China
| | - Hong-Guo Yang
- Department of General Surgery, Haining Branch of Zhejiang Provincial People’s Hospital, Jiaxing, Zhejiang Province, People’s Republic of China
| | - Bo-An Zheng
- Department of Colo-Rectal Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang Province, People’s Republic of China
| | - Hong-Feng Cao
- Department of Colo-Rectal Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang Province, People’s Republic of China
| | - Zhi-Ming Hu
- Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang Province, People’s Republic of China
| | - Wei-Ding Wu
- Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang Province, People’s Republic of China
- * E-mail:
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32
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Omrane I, Benammar-Elgaaied A. The immune microenvironment of the colorectal tumor: Involvement of immunity genes and microRNAs belonging to the TH17 pathway. Biochim Biophys Acta Rev Cancer 2015; 1856:28-38. [PMID: 25911397 DOI: 10.1016/j.bbcan.2015.04.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 03/16/2015] [Accepted: 04/14/2015] [Indexed: 12/17/2022]
Abstract
Colorectal cancer is a complex and multifactorial disease. Various factors such as genetic, immunological, epigenetic and environmental constitute minor risk factors with their additive effects contributing to the advent of colorectal cancer. In order to evaluate the role of innate and adaptive immunity in the susceptibility, the presentation and the development of colorectal cancer, we considered an immunogenetic approach on polymorphisms in the TLR4 gene and NOD2/CARD15 gene (receptors of innate immunity) as well as in cytokine genes of the TH17 pathway IL17A, IL17F and cytokine receptor IL23R. Then, we evaluated the expression of microRNAs regulated by TLR4 and NOD2/CARD15 or targeting TLR4, IL17 and proinflammatory cytokines (IL-6, TNF) induced by IL17. Through a case-control study, we showed that the polymorphism of IL17A is associated with its susceptibility to colorectal cancer. Considering the tumor location, we found that the mutated alleles of IL17A, IL17F and IL23R are rather associated with colon cancer and not with rectum cancer. This result confirms that the colon and rectum are two different physiological entities. This study shows that TLR4, IL17A/F and IL23R polymorphisms are involved in the presentation of the disease with regard to tumor architecture, histology, and differentiation, advanced stage of the disease and lymph node and metastasis. Overall, these polymorphisms are associated with a poor prognosis of the disease. Furthermore, in order to evaluate the involvement of epigenetic mechanisms in the occurrence of colorectal cancer, we aimed at analyzing the tumor compared to a normal adjacent tissue and the expression of miRNAs (miR21, miR146a, miR135a, miR147b and miR155) that regulate immunity genes especially the cytokines of the TH17 pathway. This research has shown that microRNAs 21, 135a and 146a are associated with colorectal cancer. Indeed, these three miRs are overexpressed in cancer tissue compared to healthy tissue. These results clearly confirm the involvement of epigenetics in colorectal cancer. In other words, this study reveals the importance of immunity and specifically the TH17 pathway in the development and presentation of colorectal cancer. These results suggest that TLR4, IL17A, IL17F and IL23R polymorphisms as well as the expression of microRNAs that regulate inflammation and the TH17 pathway are associated with the evolution and progression of the colorectal tumor that could be considered as biomarkers in colorectal cancer.
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Affiliation(s)
- Inés Omrane
- Laboratoire de Génétique Immunologie et Pathologie Humaine, Faculté des Sciences de Tunis, Université de Tunis EL MANAR, Tunisia.
| | - Amel Benammar-Elgaaied
- Laboratoire de Génétique Immunologie et Pathologie Humaine, Faculté des Sciences de Tunis, Université de Tunis EL MANAR, Tunisia
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Domagala-Kulawik J, Osinska I, Hoser G. Mechanisms of immune response regulation in lung cancer. Transl Lung Cancer Res 2015; 3:15-22. [PMID: 25806277 DOI: 10.3978/j.issn.2218-6751.2013.11.03] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2013] [Accepted: 11/25/2013] [Indexed: 12/12/2022]
Abstract
Lung cancer is a leading cause of cancer deaths. As a solid tumor with low antigenicity and heterogenic phenotype lung cancer evades host immune defense. The cytotoxic anticancer effect is suppressed by a complex mechanism in tumor microenvironment. The population of regulatory T cells (Tregs) plays a crucial role in this inhibition of immune response. Tregs are defined by presence of forkhead box P3 (Foxp3) molecule. The high expression of Foxp3 was found in lung cancer cells and in tumor infiltrating lymphocytes (TIL). Cytotoxic T-lymphocyte antigen 4 (CTLA4) is constitutively expressed on Tregs and suppresses T cell activation. The elevated CTLA4 expression in lymphocytes in patients with lung cancer was found. Recently the antibodies blocking CTLA4 showed some clinical efficacy in patients with lung cancer. Cancer cells and immune cells release many cytokines capable to show suppressive immune effect in cancer microenvironment. The most active are transforming growth factorβ (TGFβ) and IL-10. The pleiotropic function of Th17 population is TGFβ related. The myeloid lineage of suppressor cells in lung cancer is represented by tumor associated macrophages (TAM) with phenotype of M2 macrophages and some regulatory properties with releasing amounts of IL-10 and TGFβ. The myeloid derived suppressor cells (MDSCs) control cytotoxic T cell activity in mechanisms which are highly dependent on the context of tumor environment. The mechanisms of anticancer immune response regulation need further investigation as an important target to new way of treatment.
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Affiliation(s)
- Joanna Domagala-Kulawik
- 1 Department of Internal Diseases, Pneumonology and Allergology, Medical University of Warsaw, Warsaw, Poland ; 2 Department of Pathology, Medical University of Warsaw, Warsaw, Poland ; 3 Laboratory of Flow Cytometry, Medical Center of Postgraduate Education, Warsaw, Poland
| | - Iwona Osinska
- 1 Department of Internal Diseases, Pneumonology and Allergology, Medical University of Warsaw, Warsaw, Poland ; 2 Department of Pathology, Medical University of Warsaw, Warsaw, Poland ; 3 Laboratory of Flow Cytometry, Medical Center of Postgraduate Education, Warsaw, Poland
| | - Grazyna Hoser
- 1 Department of Internal Diseases, Pneumonology and Allergology, Medical University of Warsaw, Warsaw, Poland ; 2 Department of Pathology, Medical University of Warsaw, Warsaw, Poland ; 3 Laboratory of Flow Cytometry, Medical Center of Postgraduate Education, Warsaw, Poland
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Graveel CR, Calderone HM, Westerhuis JJ, Winn ME, Sempere LF. Critical analysis of the potential for microRNA biomarkers in breast cancer management. BREAST CANCER-TARGETS AND THERAPY 2015; 7:59-79. [PMID: 25759599 PMCID: PMC4346363 DOI: 10.2147/bctt.s43799] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Breast cancer is a complex and heterogeneous disease. Signaling by estrogen receptor (ER), progesterone receptor (PR), and/or human EGF-like receptor 2 (HER2) is a main driver in the development and progression of a large majority of breast tumors. Molecular characterization of primary tumors has identified major subtypes that correlate with ER/PR/HER2 status, and also subgroup divisions that indicate other molecular and cellular features of the tumors. While some of these research findings have been incorporated into clinical practice, several challenges remain to improve breast cancer management and patient survival, for which the integration of novel biomarkers into current practice should be beneficial. microRNAs (miRNAs) are a class of short non-coding regulatory RNAs with an etiological contribution to breast carcinogenesis. miRNA-based diagnostic and therapeutic applications are rapidly emerging as novel potential approaches to manage and treat breast cancer. Rapid technological development enables specific and sensitive detection of individual miRNAs or the entire miRNome in tissues, blood, and other biological specimens from breast cancer patients. This review focuses on recent miRNA research and its potential to address unmet clinical needs and challenges. The four sections presented discuss miRNA findings in the context of the following clinical challenges: biomarkers for early detection; prognostic and predictive biomarkers for treatment decisions using targeted therapies against ER and HER2; diagnostic and prognostic biomarkers for subgrouping of triple-negative breast cancer, for which there are currently no targeted therapies; and biomarkers for monitoring and characterization of metastatic breast cancer. The review concludes with a critical analysis of the current state of miRNA breast cancer research and the need for further studies using large patient cohorts under well-controlled conditions before considering the clinical implementation of miRNA biomarkers.
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Affiliation(s)
- Carrie R Graveel
- Breast Cancer Signaling and Therapeutics Team, Program in Molecular Oncology and Pre-clinical Therapeutics, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA
| | - Heather M Calderone
- Laboratory of microRNA Diagnostics and Therapeutics, Program in Skeletal Disease and Tumor Microenvironment, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA
| | - Jennifer J Westerhuis
- Laboratory of microRNA Diagnostics and Therapeutics, Program in Skeletal Disease and Tumor Microenvironment, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA
| | - Mary E Winn
- Bioinformatics and Biostatistics Core, Program for Technologies and Cores, Van Andel Research Institute, Grand Rapids, MI, USA
| | - Lorenzo F Sempere
- Laboratory of microRNA Diagnostics and Therapeutics, Program in Skeletal Disease and Tumor Microenvironment, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA
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Holm A, Bang-Berthelsen CH, Knudsen S, Kornum BR, Modvig S, Jennum P, Gammeltoft S. miRNA profiles in plasma from patients with sleep disorders reveal dysregulation of miRNAs in narcolepsy and other central hypersomnias. Sleep 2014; 37:1525-33. [PMID: 25142559 DOI: 10.5665/sleep.4004] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
STUDY OBJECTIVES MicroRNAs (miRNAs) have been implicated in the pathogenesis of human diseases including neurological disorders. The aim is to address the involvement of miRNAs in the pathophysiology of central hypersomnias including autoimmune narcolepsy with cataplexy and hypocretin deficiency (type 1 narcolepsy), narcolepsy without cataplexy (type 2 narcolepsy), and idiopathic hypersomnia. DESIGN We conducted high-throughput analysis of miRNA in plasma from three groups of patients-with type 1 narcolepsy, type 2 narcolepsy, and idiopathic hypersomnia, respectively-in comparison with healthy controls using quantitative real-time polymerase chain reaction (qPCR) panels. SETTING University hospital based sleep clinic and research laboratories. PATIENTS Twelve patients with type 1 narcolepsy, 12 patients with type 2 narcolepsy, 12 patients with idiopathic hypersomnia, and 12 healthy controls. MEASUREMENTS AND RESULTS By analyzing miRNA in plasma with qPCR we identified 50, 24, and 6 miRNAs that were different in patients with type 1 narcolepsy, type 2 narcolepsy, and idiopathic hypersomnia, respectively, compared with healthy controls. Twenty miRNA candidates who fulfilled the criteria of at least two-fold difference and p-value < 0.05 were selected to validate the miRNA changes in an independent cohort of patients. Four miRNAs differed significantly between type 1 narcolepsy patients and healthy controls. Levels of miR-30c, let-7f, and miR-26a were higher, whereas the level of miR-130a was lower in type 1 narcolepsy than healthy controls. The miRNA differences were not specific for type 1 narcolepsy, since the levels of the four miRNAs were also altered in patients with type 2 narcolepsy and idiopathic hypersomnia compared with healthy controls. CONCLUSION The levels of four miRNAs differed in plasma from patients with type 1 narcolepsy, type 2 narcolepsy and idiopathic hypersomnia suggesting that alterations of miRNAs may be involved in the pathophysiology of central hypersomnias.
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He H, Yin JY, Xu YJ, Li X, Zhang Y, Liu ZG, Zhou F, Zhai M, Li Y, Li XP, Wang Y, Zhou HH, Liu ZQ. Association of ABCB1 Polymorphisms With the Efficacy of Ondansetron in Chemotherapy-induced Nausea and Vomiting. Clin Ther 2014; 36:1242-1252.e2. [DOI: 10.1016/j.clinthera.2014.06.016] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Revised: 06/03/2014] [Accepted: 06/12/2014] [Indexed: 01/08/2023]
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A polymorphism rs12325489C>T in the lincRNA-ENST00000515084 exon was found to modulate breast cancer risk via GWAS-based association analyses. PLoS One 2014; 9:e98251. [PMID: 24879036 PMCID: PMC4039483 DOI: 10.1371/journal.pone.0098251] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2014] [Accepted: 04/30/2014] [Indexed: 12/21/2022] Open
Abstract
Breast cancer, one of the most common malignancies diagnosed among women worldwide, is a complex polygenic disease in the etiology of which genetic factors play an important role. Thus far, a subset of breast cancer genetic susceptibility loci has been addressed among Asian woman through genome-wide association studies (GWASs). In this study, we identified numerous long, intergenic, noncoding RNAs (lincRNAs) enriched in these breast cancer risk-related loci and identified 16 single nucleotide polymorphisms (SNPs) located within the sequences of lincRNA exonic regions. We examined whether these 16 SNPs are associated with breast cancer risk in 2539 cancer patients and 2818 control subjects from eastern, southern, and northern Chinese populations. We found that the C allele of the rs12325489C>T polymorphism in the exonic regions of lincRNA-ENST00000515084 was associated with a significantly increased risk of breast cancer (adjusted odds ratio [OR] = 1.79; 95% confidence interval [CI] = 1.50-2.12), compared with the rs12325489TT genotype. Biochemical analysis demonstrated that the C to T base change at rs12325489C>T disrupts the binding site for miRNA-370, thereby influencing the transcriptional activity of lincRNA-ENST00000515084 in vitro and in vivo, and affecting cell proliferation and tumor growth. Our findings indicate that the rs12325489C>T polymorphism in the lincRNA-ENST00000515084 exon may be a genetic modifier in the development of breast cancer.
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Li Z, Guo Y, Zhou L, Ge Y, Wei L, Li L, Zhou C, Wei J, Yuan Q, Li J, Yang M. Association of a functional RAD52 genetic variant locating in a miRNA binding site with risk of HBV-related hepatocellular carcinoma. Mol Carcinog 2014; 54:853-8. [PMID: 24729511 DOI: 10.1002/mc.22156] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 03/07/2014] [Accepted: 03/19/2014] [Indexed: 12/11/2022]
Abstract
As an important member in homologous recombination repair, RAD52 plays a crucial part in maintaining genomic stability and prevent carcinogenesis. Several cancer susceptibility RAD52 single nucleotide polymorphisms (SNPs) have been identified previously. However, little or nothing has been known about the RAD52 SNPs and their functional significance in hepatitis B viruses (HBV)-related hepatocellular carcinoma (HCC). Therefore, we investigated the association between five RAD52 SNPs (rs1051669, rs10774474, rs11571378, rs7963551, and rs6489769) and HBV-related HCC risk as well as its biological function in vivo. Genotypes were determined in two independent case-control sets from two regions of China. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. The allele-specific regulation on RAD52 expression by the functional genetic variant was examined with normal liver tissues. We found that only the RAD52 rs7963551 SNP was significantly associated with HCC risk, with the odds of having the rs7963551 CC genotype in patients was 0.59 (95% CI = 0.45-0.78, P = 1.5 × 10(-4), HCC cases versus chronic HBV carriers) or 0.65 (95% CI = 0.52-0.81, P = 1.1 × 10(-4), HCC cases versus healthy controls) compared with the AA genotype. In the genotype-phenotype correlation analyses of 44 human liver tissue samples, rs7963551 CC or AC was associated with a statistically significant increase of RAD52 mRNA expression, which are consistent to functional relevance of allelic regulation of RAD52 expression by rs7963551 SNP and miRNA let-7 in cancer cells. Our data demonstrated that RAD52 functional rs7963551 SNP contributes to susceptibility to developing HCC.
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Affiliation(s)
- Ziqiang Li
- Department of Hepatobiliary Surgery, Qianfoshan Hospital, Shandong University, Jinan, Shandong Province, China
| | - Yuan Guo
- Department of Hepatobiliary Surgery, Qianfoshan Hospital, Shandong University, Jinan, Shandong Province, China
| | - Liqing Zhou
- Department of Radiation Oncology, Huaian No. 2 Hospital, Huaian, Jiangsu Province, China
| | - Yunxia Ge
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Lili Wei
- Clinical Laboratory, Shandong Cancer Hospital, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Lichao Li
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Changchun Zhou
- Clinical Laboratory, Shandong Cancer Hospital, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Jinyu Wei
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Qipeng Yuan
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Jie Li
- Department of Hepatobiliary Surgery, Qianfoshan Hospital, Shandong University, Jinan, Shandong Province, China
| | - Ming Yang
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
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Fan QH, Yu R, Huang WX, Cui XX, Luo BH, Zhang LY. The has-miR-526b binding-site rs8506G>a polymorphism in the lincRNA-NR_024015 exon identified by GWASs predispose to non-cardia gastric cancer risk. PLoS One 2014; 9:e90008. [PMID: 24595048 PMCID: PMC3942390 DOI: 10.1371/journal.pone.0090008] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2013] [Accepted: 01/25/2014] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer including the cardia and non-cardia types is the second frequent cause of cancer-related deaths worldwide. A subset of non-cardia gastric cancer genetic susceptibility loci have been addressed among Asian through genome-wide association studies (GWASs). This study was to evaluate the effects of single nucleotide polymorphisms (SNPs) of long intergenic non-coding RNAs (lincRNAs) on non-cardia gastric cancer susceptibility in Chinese populations. We selected long intergenic noncoding RNAs (lincRNAs) located in non-cardia gastric cancer risk-related loci and identified 10 SNPs located within lincRNA exonic regions. We examined whether genetic polymorphisms in lincRNAs exons are associated with non-cardia gastric cancer risk in 438 non-cardia gastric cancer patients and 727 control subjects in Chinese populations using logistic regression. Functional relevance was further examined by biochemical assays. We found that lincRNA-NR_024015 rs8506AA carrier was significantly associated with risk of non-cardia gastric cancer (adjusted odds ratio [OR] = 1.56, 95%CI = 1.03–2.39, compared with the rs8506 AG or GG genotype. Further stratification analysis showed that the risk effect was more pronounced in subgroups of smokers (P = 0.001). Biochemical analysis demonstrated that the G to A base change at rs8506G>A disrupts the binding site for has-miR-526b, thereby influencing the transcriptional activity of lincRNA-NR_024015 and affecting cell proliferation. Our present study established a robust association between the rs8506G>A polymorphism in the lincRNA-NR_024015 exon and the risk of non-cardia gastric cancer.
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Affiliation(s)
- Qiu-Hong Fan
- Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Rong Yu
- Department of Oncology, Suzhou Municipal Hospital, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Wei-Xian Huang
- Department of Gastrointestinal surgery, Wu Jiang first people's hospital, Suzhou, China
| | - Xi-Xi Cui
- Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Bing-Hui Luo
- Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Li-Yuan Zhang
- Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
- * E-mail:
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Ni B, Chen S, Xie H, Ma H. Functional polymorphisms in interleukin-23 receptor and susceptibility to esophageal squamous cell carcinoma in Chinese population. PLoS One 2014; 9:e89111. [PMID: 24586528 PMCID: PMC3938431 DOI: 10.1371/journal.pone.0089111] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2013] [Accepted: 01/19/2014] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND As a key element in the T-helper 17 (Th17) cell-mediated inflammatory process, interleukin-23 receptor (IL-23R) plays a crucial role in the pathogenesis of cancer. Single nucleotide polymorphisms (SNPs) in IL-23R have been frequently studied in several previous case-control cancer studies, but its association with esophageal squamous cell carcinoma (ESCC) in Chinese population has not been investigated. This study examined whether genetic polymorphisms in IL-23R were associated with ESCC susceptibility. METHODS A hospital-based case-control study of 684 ESCC patients and 1064 healthy controls was performed to assess the association between four previous reported IL-23R genotypes (rs6682925, rs6683039, rs1884444 and rs10889677) and ESCC risk. The results revealed that the C allele of the rs10889677A>C polymorphism in the 3'UTR of IL-23R gene was inversely associated with the risk of ESCC. RESULTS The rs10889677AC genotype had significantly decreased cancer risk (odds ratio [OR] = 0.85, 95% confidence interval [CI] = 0.69-1.01) compared to subjects homozygous carriers of rs10889677AA, the risk decreased even further in those carrying rs10889677CC genotype (OR = 0.64, 95% CI = 0.44-0.93). No significant association was found between the other three polymorphisms and the risk of ESCC. CONCLUSION These findings indicated that rs10889677A>C polymorphism in IL-23R may play a protective role in mediating the risk of ESCC.
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Affiliation(s)
- Bin Ni
- Department of Cardiovascular and Thoracic Surgery, The First Affiliated Hospital, Soochow University, SuZhou, China
| | - Shaomu Chen
- Department of Cardiovascular and Thoracic Surgery, The First Affiliated Hospital, Soochow University, SuZhou, China
| | - Hongya Xie
- Department of Cardiovascular and Thoracic Surgery, The First Affiliated Hospital, Soochow University, SuZhou, China
| | - Haitao Ma
- Department of Cardiovascular and Thoracic Surgery, The First Affiliated Hospital, Soochow University, SuZhou, China
- * E-mail:
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Cai L, Fu Y, Zhang Y. APE1 Asp148Glu polymorphism and lung cancer susceptibility. Tumour Biol 2014; 35:5237-44. [DOI: 10.1007/s13277-014-1681-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2013] [Accepted: 01/22/2014] [Indexed: 02/02/2023] Open
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Omrane I, Baroudi O, Bougatef K, Mezlini A, Abidi A, Medimegh I, Stambouli N, Ayari H, Kourda N, Uhrhammer N, Bignon YJ, Benammar Elgaaied A, Marrakchi R. Significant association between IL23R and IL17F polymorphisms and clinical features of colorectal cancer. Immunol Lett 2014; 158:189-94. [PMID: 24440568 DOI: 10.1016/j.imlet.2014.01.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Revised: 01/03/2014] [Accepted: 01/03/2014] [Indexed: 01/09/2023]
Abstract
Th17cells are involved in inflammatory and autoimmune diseases. These cells may be involved in pathological processes mainly producing pro-inflammatory cytokines. Recently, it was shown that the IL23/IL17 pathway plays an important role in the development of inflammatory bowel disease. In general, genes encoding cytokines are genetically polymorphic and polymorphisms in genes IL23R el IL17F were shown associated with susceptibility to Crohn's disease and ulcerative colitis which in their turn are considered as risk factors for developing colorectal cancer (CRC). Our approach is to study IL17F and IL23R polymorphisms as risk factor associated with CRC in the Tunisian population in patients and healthy controls. Interesting, we noted a significant association between IL17F and IL23R polymorphisms and tumor location (p=0.0001 and p=0.049, respectively), tumor histology (p=0.007 and p=0.049, respectively) and tumor architecture (p=0.0000000001 and p=0.07, respectively) in CRC patients. We also showed a significant association of IL17F variant with an increased risk of TNM stage III/IV (p=0.007), showing an increased risk of advanced stage. Finally, we observed a positive link between IL17F polymorphism and CRC patients with lymph nodes (p=0.0000000001) and metastasis (p=0.00000009). However, we found no evidence to support a significant association between IL17F and IL23R polymorphisms and colorectal cancer susceptibility. Our findings suggest that IL17F and IL23R polymorphisms were significantly associated with clinical features variables. The IL17F cytokine appear to be involved in the control of tumor growth and invasion of gastrointestinal tumors. IL17 and IL23 polymorphisms or those of their receptors as important determinants of susceptibility to colorectal cancer are still subject to questioning.
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Affiliation(s)
- Inés Omrane
- Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia.
| | - Olfa Baroudi
- Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia
| | - Karim Bougatef
- Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia
| | - Amel Mezlini
- Gastroenterology Service, Salah Azaiez hospital of Tunis, Tunisia
| | - Ahmed Abidi
- Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia
| | - Imen Medimegh
- Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia
| | - Nejla Stambouli
- Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia
| | - Hager Ayari
- Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia
| | - Nadia Kourda
- Laboratory of Anatomy and Pathology, Charles Nicolle Hospital of Tunis, Tunisia
| | - Nancy Uhrhammer
- Laboratory of Diagnosis and Molecular Genetics, Centre Jean Perrin, Clermont Ferrand, France
| | - Yves Jean Bignon
- Laboratory of Diagnosis and Molecular Genetics, Centre Jean Perrin, Clermont Ferrand, France
| | - Amel Benammar Elgaaied
- Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia
| | - Raja Marrakchi
- Laboratory of Human Genetics Immunology and Pathology, Faculty of Sciences Tunis El Manar, University of Tunis, Tunisia
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Zhou S, Ruan Y, Yu H, Chen Y, Yao Y, Ma Y, Gao Y. Functional IL-23R rs10889677 genetic polymorphism and risk of multiple solid tumors: a meta-analysis. PLoS One 2013; 8:e80627. [PMID: 24278297 PMCID: PMC3835319 DOI: 10.1371/journal.pone.0080627] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Accepted: 10/04/2013] [Indexed: 12/28/2022] Open
Abstract
Interleukin-23 receptor (IL23R) can interact with IL-23 and, thus, is involved in the T-helper 17 (Th17) cell-mediated inflammatory process as well as tumorigenesis. Recently, a functional single nucleotide polymorphism (SNP) rs10889677 has been identified in the 3'-untranslated region of IL-23R. It has been showed that the rs10889677AC SNP could increase the binding affinity of microRNA let-7f and downregulate IL-23R expression. Several case-control studies have examined the association between this SNP and genetic susceptibility of multiple solid tumors. However, the conclusions are conflicting. Therefore, we conducted this meta-analysis to systematically study the role of this functional IL-23R SNP in development of multiple solid tumors. There are a total of 5 studies are eligible (6731 cases and 7296 healthy controls). Either fixed-effect model or random-effect model was used to calculate pooled odds ratios (ORs) and the 95% confidence interval (95% CI). Significant association between this functional rs10889677 genetic variant and risk of multiple solid tumors were observed (CC genotype vs. AA genotype: OR = 0.59, 95% CI = 0.53-0.66, P < 0.001). These findings demonstrated that the IL-23R rs10889677 genetic variant might play an important part during malignant transformation of multiple solid tumors.
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Affiliation(s)
- Shanliang Zhou
- Clinical Laboratory, Cancer Hospital of Shandong Linyi, Shandong Linyi, China
| | - Yueqin Ruan
- Clinical Laboratory, Affiliated Hospital of Binzhou Medical College, Shandong Binzhou, China
| | - Hongchen Yu
- Qingdao Orthopedics and Traumatology Hospital, Shandong Qingdao, China
| | - Yunzhi Chen
- Clinical Laboratory, People's Hospital of Chengwu County, Shandong Heze, China
| | - Yongjun Yao
- Department of Pathology, People’s Hospital of Cangshan County, Shandong Linyi, China
| | - Yanhui Ma
- Qilu Children's Hospital of Shandong University, Jinan, China
- * E-mail: (YM); (YG)
| | - Yan Gao
- Department of Pathology, People’s Hospital of Cangshan County, Shandong Linyi, China
- * E-mail: (YM); (YG)
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Hu XY, Bai XM, Qiao X, Zhu YQ. Copy number variation at 6q13 is associated with lung cancer risk in a Han Chinese population. Exp Lung Res 2013; 39:427-33. [PMID: 24245924 DOI: 10.3109/01902148.2013.822946] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Copy number variations (CNVs), a major source of human genetic polymorphism, have been suggested to have an important role in genetic susceptibility to common diseases such as cancer, immune diseases, and neurological disorders. Lung cancer is a multifactorial tumor closely associated with genetic background. Previous genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that are associated with lung cancer susceptibility. This study examined the CNVR2966.1 at 6q13 and its association with lung cancer susceptibility. The CNVR2966.1 was found to be a 10,379 bp nucleotides deletion/insertion within the uniform boundaries chromosome 6: 74,648,791-74,659,169. The risk of lung cancer observed in 503 cases and 623 controls was significantly associated with copy number of CNVR2966.1, with the odds ratio (OR) being 1.38 [95% confidence interval (CI) = 1.05-1.79; P = .007] for one copy genotype compared with two copies genotype. These results suggest that CNVR2966.1 is associated with lung cancer risk.
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Affiliation(s)
- Xiao-Yun Hu
- 1Department of Respiratory Medicine, The First People's Hospital, Wujiang, Jiangsu, China
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Yao J, Liu L, Yang M. Interleukin-23 receptor genetic variants contribute to susceptibility of multiple cancers. Gene 2013; 533:21-5. [PMID: 24076440 DOI: 10.1016/j.gene.2013.09.054] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Revised: 09/16/2013] [Accepted: 09/17/2013] [Indexed: 01/11/2023]
Abstract
AIM Interleukin-23 (IL-23) and IL-23 receptor (IL23R) play an important role during the T-helper 17 (Th17) cell-mediated inflammatory process as well as pathogenesis of multiple cancers. Several IL-23R single nucleotide polymorphisms (SNPs), especially rs6682925, rs10889677 and rs1884444 polymorphisms, are considered to have significant impacts on susceptibility of multiple cancers. A number of case-control studies have explored the role these genetic polymorphisms in development of carcinogenesis, but the conclusions are inconsistent. Therefore, we conducted this meta-analysis to systematically investigate the associations between the three genetic variants and multiple cancer risk. METHODS A total of ten studies are eligible (12,211 patients and 14,650 controls). Pooled odds ratios (ORs) and the 95% confidence interval (95% CI) were appropriately calculated using either fixed-effect model or random-effect model. RESULTS Significant associations between rs6682925 or rs10889677 polymorphism and cancer risk were found (OR=1.11, 95% CI=1.03-1.21, P=0.007; or OR=0.85, 95% CI=0.71-0.92, P=0.001). However, there was no such association between rs1884444 genotypes and cancer susceptibility (P>0.05). CONCLUSION These findings reveal that the IL-23R rs6682925 and rs10889677 genetic variants play a more important part in pathogenesis of multiple cancers.
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Affiliation(s)
- Jiarui Yao
- Department of Medical Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
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Wu H, Deng J, Zheng J, You Y, Li N, Li W, Wu D, Zhou Y. Functional polymorphisms in the CD44 gene and acute myeloid leukemia cancer risk in a Chinese population. Mol Carcinog 2013; 54:102-10. [PMID: 24038513 DOI: 10.1002/mc.22078] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Revised: 07/17/2013] [Accepted: 07/26/2013] [Indexed: 01/03/2023]
Abstract
CD44 is such one adhesion molecule that mediates interactions between acute myeloid leukemia (AML) cells and stromal. It has been demonstrated that CD4 plays a critical role in AML development. However, studies of functional single nucleotide polymorphisms (SNPs) in CD44 gene have not touched upon AML. This case-control study probed the contribution of functional SNPs in CD44 gene to AML susceptibility in eastern Chinese population. Five representative SNPs of CD44 (rs10836347C>T, rs13347C>T, rs1425802A>G, rs11821102G>A, rs713330T>C) were opted and genotyped in 421 AML patients and 461 healthy subjects and the association with risk of AML was estimated by logistic regression. Moreover, the potential role of rs13347C > T in AML was further explored. Compared with the rs13347CC genotype, CT carriers had a significant increase in AML susceptibility (adjusted odds ratio [OR] = 1.76; 95% confidence interval [CI] = 1.32-2.34), TT carriers had a further increased risk of AML (OR = 2.67; 95% CI = 1.69-4.21). Furthermore, our transient transfection assay and Western blot results demonstrated that the presence of rs13347T allele led to more CD44 expression. Yet, there exists no significant difference in genotype frequencies of the other four sites between cases and controls. Above findings suggest that rs13347C>T in 3'UTR of CD44 may be a genetic modifier for developing AML.
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Affiliation(s)
- Hongchun Wu
- Laboratory of Cancer Molecular Genetics, Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, P.R. China
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Li J, Fu Y, Zhao B, Xiao Y, Chen R. Myeloperoxidase G463A polymorphism and risk of lung cancer. Tumour Biol 2013; 35:821-9. [DOI: 10.1007/s13277-013-1113-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Accepted: 08/13/2013] [Indexed: 10/26/2022] Open
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Wu H, Zheng J, Deng J, Hu M, You Y, Li N, Li W, Lu J, Zhou Y. A genetic polymorphism in lincRNA-uc003opf.1 is associated with susceptibility to esophageal squamous cell carcinoma in Chinese populations. Carcinogenesis 2013; 34:2908-17. [PMID: 23872665 DOI: 10.1093/carcin/bgt252] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The development of esophageal squamous cell carcinoma (ESCC) is a multifactorial process, and associations between genetic variants and ESCC have been identified in genome-wide association studies. The aim of this study was to evaluate the effects of single nucleotide polymorphisms (SNPs) of long intergenic non-coding RNAs (lincRNAs) on ESCC susceptibility in Chinese populations. We scoured exons of lincRNAs located in ESCC susceptibility loci for all probable functional SNPs. These 52 SNPs were opted for and genotyped in 1493 ESCC patients and 1553 cancer-free controls from eastern and southern Chinese populations, and their associations with the risk for ESCC were estimated using logistic regression. Functional relevance was further examined by biochemical assays. Significant differences were found between patients and controls in the genotype frequencies for the rs11752942A>G site in the lincRNA-uc003opf.1 exon. Compared with the rs11752942AA genotype, AG and GG genotypes had a significantly reduced risk of ESCC (adjusted odds ratio = 0.73; 95% confidence interval = 0.63-0.84). Biochemical analysis demonstrated that, when compared with the A allele, the rs11752942G allele could markedly attenuate the level of lincRNA-uc003opf.1 both in vivo and in vitro by binding micro-RNA-149*, thereby affecting cell proliferation and tumor growth. These findings indicated that functional polymorphism rs11752942A>G in lincRNA-uc003opf.1 exon might be a genetic modifier for the development of ESCC.
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Affiliation(s)
- Hongchun Wu
- Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou 215123, China
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Zheng J, Deng J, Xiao M, Yang L, Zhang L, You Y, Hu M, Li N, Wu H, Li W, Lu J, Zhou Y. A sequence polymorphism in miR-608 predicts recurrence after radiotherapy for nasopharyngeal carcinoma. Cancer Res 2013; 73:5151-62. [PMID: 23796562 DOI: 10.1158/0008-5472.can-13-0395] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Nasopharyngeal carcinoma is treated with radiotherapy and other modalities, but there is little information on individual genetic factors to help predict and improve patient outcomes. Single-nucleotide polymorphisms (SNP) in mature microRNA (miRNA) sequences have the potential to exert broad impact as miRNAs target many mRNAs. The aim of this study was to evaluate the effects of SNPs in mature miRNA sequences on clinical outcome in patients with nasopharyngeal carcinoma receiving radiotherapy. In particular, we analyzed associations between seven SNPs and nasopharyngeal carcinoma locoregional recurrence (LRR) in 837 patients from eastern China, validating the findings in an additional 828 patients from southern China. We found that miR-608 rs4919510C > G exhibited a consistent association with LRR in the discovery set [HR, 2.05; 95% confidence interval (CI), 1.35-3.21], the validation set (HR, 2.24; 95% CI, 1.45-3.38), and the combined dataset (HR, 2.08; 95% CI, 1.41-3.26). Biochemical investigations showed that rs4919510C > G affects expression of miR-608 target genes along with nasopharyngeal carcinoma cell growth after irradiation in vivo and in vitro. Notably, X-ray radiation induced more chromatid breaks in lymphocyte cells from rs4919510CC carriers than in those from subjects with other genotypes (P = 0.0024). Our findings reveal rs4919510C > G in miR-608 as a simple marker to predict LRR in patients with radiotherapy-treated nasopharyngeal carcinoma.
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Affiliation(s)
- Jian Zheng
- Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, The Second Affiliated Hospital of Soochow University, Suzhou, China
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Baird AM, Dockry E, Daly A, Stack E, Doherty DG, O'Byrne KJ, Gray SG. IL-23R is Epigenetically Regulated and Modulated by Chemotherapy in Non-Small Cell Lung Cancer. Front Oncol 2013; 3:162. [PMID: 23802098 PMCID: PMC3685824 DOI: 10.3389/fonc.2013.00162] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Accepted: 06/06/2013] [Indexed: 12/11/2022] Open
Abstract
The Interleukin-23 (IL-23)/IL-23R signaling axis is an important inflammatory pathway, involved in the stimulation and regulation of the T helper (Th) 17 lymphocytes, resulting in the production of IL-17. Aside from auto-immunity, this cytokine has also been linked to carcinogenesis and polymorphisms in the IL-23R gene are associated with an increased risk for the development of a number of different cancers. Activation of the IL-23 pathway results in the up-regulation of STAT3 and it is thought that the pathological consequences associated with this are in part due to the production of IL-17. We have previously identified IL-23A as pro-proliferative and epigenetically regulated in non-small cell lung cancer (NSCLC). The current study aims to evaluate IL-23R in greater detail in NSCLC. We demonstrate that IL-23R is expressed and epigenetically regulated in NSCLC through histone post-translation modifications and CpG island methylation. In addition, Gemcitabine treatment, a chemotherapy drug used in the treatment of NSCLC, resulted in the up-regulation of the IL-23R. Furthermore, Apilimod (STA 5326), a small molecule which blocks the expression of IL-23 and IL-12, reduced the proliferative capacity of NSCLC cells, particularly in the adenocarcinoma (A549) sub-type. Apilimod is currently undergoing investigation in a number of clinical trials for the treatment of auto-immune conditions such as Crohn’s disease and Rheumatoid Arthritis. Our results may have implications for treating NSCLC patients with Gemcitabine or epigenetic targeted therapies. However, Apilimod may possibly provide a new treatment avenue for NSCLC patients. Work is currently ongoing to further delineate the IL-23/IL-23R axis in this disease.
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Affiliation(s)
- Anne-Marie Baird
- Department of Clinical Medicine, Trinity College Dublin , Dublin , Ireland ; Thoracic Oncology Research Group, Institute of Molecular Medicine, St. James's Hospital , Dublin , Ireland
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