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The Search for Cancer Biomarkers: Assessing the Distribution of INDEL Markers in Different Genetic Ancestries. Curr Issues Mol Biol 2022; 44:2275-2286. [PMID: 35678683 PMCID: PMC9164054 DOI: 10.3390/cimb44050154] [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: 04/22/2022] [Revised: 05/10/2022] [Accepted: 05/13/2022] [Indexed: 11/17/2022] Open
Abstract
Cancer is a multifactorial group of diseases, being highly incident and one of the leading causes of death worldwide. In Brazil, there is a great variation in cancer incidence and impact among the different geographic regions, partly due to the genetic heterogeneity of the population in this country, composed mainly by European (EUR), Native American (NAM), African (AFR), and Asian (ASN) ancestries. Among different populations, genetic markers commonly present diverse allelic frequencies, but in admixed populations, such as the Brazilian population, data is still limited, which is an issue that might influence cancer incidence. Therefore, we analyzed the allelic and genotypic distribution of 12 INDEL polymorphisms of interest in populations from the five Brazilian geographic regions and in populations representing EUR, NAM, AFR, and ASN, as well as tissue expression in silico. Genotypes were obtained by multiplex PCR and the statistical analyses were done using R, while data of tissue expression for each marker was extracted from GTEx portal. We highlight that all analyzed markers presented statistical differences in at least one of the population comparisons, and that we found 39 tissues to be differentially expressed depending on the genotype. Here, we point out the differences in genotype distribution and gene expression of potential biomarkers for risk of cancer development and we reinforce the importance of this type of study in populations with different genetic backgrounds.
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Jung SE, Choi JW, Moon H, Oh S, Lim S, Lee S, Kim SW, Hwang KC. Small G protein signaling modulator 3 (SGSM3) knockdown attenuates apoptosis and cardiogenic differentiation in rat mesenchymal stem cells exposed to hypoxia. PLoS One 2020; 15:e0231272. [PMID: 32271805 PMCID: PMC7145021 DOI: 10.1371/journal.pone.0231272] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 03/19/2020] [Indexed: 12/15/2022] Open
Abstract
Connexin 43 (Cx43) may be important in cell death and survival due to cell-to-cell communication-independent mechanisms. In our previous study, we found that small G protein signaling modulator 3 (SGSM3), a partner of Cx43, contributes to myocardial infarction (MI) in rat hearts. Based on these previous results, we hypothesized that SGSM3 could also play a role in bone marrow-derived rat mesenchymal stem cells (MSCs), which differentiate into cardiomyocytes and/or cells with comparable phenotypes under low oxygen conditions. Cx43 and Cx43-related factor expression profiles were compared between normoxic and hypoxic conditions according to exposure time, and Sgsm3 gene knockdown (KD) using siRNA transfection was performed to validate the interaction between SGSM3 and Cx43 and to determine the roles of SGSM3 in rat MSCs. We identified that SGSM3 interacts with Cx43 in MSCs under different oxygen conditions and that Sgsm3 knockdown inhibits apoptosis and cardiomyocyte differentiation under hypoxic stress. SGSM3/Sgsm3 probably has an effect on MSC survival and thus therapeutic potential in diseased hearts, but SGSM3 may worsen the development of MSC-based therapeutic approaches in regenerative medicine. This study was performed to help us better understand the mechanisms involved in the therapeutic efficacy of MSCs, as well as provide data that could be used pharmacologically.
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Affiliation(s)
- Seung Eun Jung
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do, Republic of Korea
| | - Jung-Won Choi
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do, Republic of Korea
| | - Hanbyeol Moon
- Department of Integrated Omics for Biomedical Sciences, Graduate School, Yonsei University, Seoul, Republic of Korea
| | - Sena Oh
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do, Republic of Korea
| | - Soyeon Lim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do, Republic of Korea
- International St. Mary’s Hospital, Catholic Kwandong University, Incheon Metropolitan City, Republic of Korea
| | - Seahyoung Lee
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do, Republic of Korea
- International St. Mary’s Hospital, Catholic Kwandong University, Incheon Metropolitan City, Republic of Korea
| | - Sang Woo Kim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do, Republic of Korea
- International St. Mary’s Hospital, Catholic Kwandong University, Incheon Metropolitan City, Republic of Korea
| | - Ki-Chul Hwang
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do, Republic of Korea
- International St. Mary’s Hospital, Catholic Kwandong University, Incheon Metropolitan City, Republic of Korea
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Yu Q, Qian W, Wang J, Wu Y, Zhang J, Chen W. An indel polymorphism in the 3' untranslated region of JAK1 confers risk for hepatocellular carcinoma possibly by regulating JAK1 transcriptional activity in a Chinese population. Oncol Lett 2018; 15:8088-8094. [PMID: 29731916 DOI: 10.3892/ol.2018.8347] [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: 04/01/2017] [Accepted: 12/19/2017] [Indexed: 11/05/2022] Open
Abstract
The purpose of the present study was to assess whether the rs112395617 polymorphism located in the Janus kinase 1 (JAK1) 3' untranslated region (3' UTR) was associated with the risk of hepatocellular carcinoma (HCC), and to explore the potential mechanism of action. Genomic DNA was extracted from peripheral blood of 290 patients with HCC and 320 controls. A polymerase chain reaction-polyacrylamide gel electrophoresis assay was used to genotype the rs112395617 polymorphism. Quantitative (q)PCR was used to detect the genotype-phenotype association between HCC tissues and different genotypes. Vectors containing the insertion (ins)/ins or deletion (del)/del genotype of the rs112395617 polymorphism were constructed, and the luciferase assay was used to detect the JAK1 transcriptional activity affected by the rs112395617 polymorphism. It was identified that, when compared with the ins/ins genotype, the del/del and del/ins genotypes of rs112395617 were significantly associated with a decreased risk of HCC. The qPCR results demonstrated that the JAK1 mRNA expression level with ins/ins and ins/del genotypes was increased by 3.36 and 1.75-fold compared with the del/del genotype in human HCC tissue samples. In addition, the 'AATT' insertion allele of rs112395617 disrupted the binding site for microRNA (miR)-431-5p, thereby increasing JAK1 transcription in vitro. These data suggest that the rs112395617 polymorphism may contribute to HCC susceptibility, in full or at least partially through an effect on JAK1 transcriptional activity by disrupting its binding with miR-431-5p.
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Affiliation(s)
- Qiang Yu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China.,Department of Gastroenterology, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215002, P.R. China
| | - Weifeng Qian
- Department of General Surgery, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215002, P.R. China
| | - Jian Wang
- Department of Medical Oncology, The Fifth People's Hospital of Changshu, Changshu, Jiangsu 215500, P.R. China
| | - Yejiao Wu
- Department of Gastroenterology, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215002, P.R. China
| | - Jinkun Zhang
- Department of Gastroenterology, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215002, P.R. China
| | - Weichang Chen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
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Hashemi M, Bahari G, Bizhani F, Danesh H, Sarhadi S, Ziaee SAM, Basiri A, Narouie B, Taheri M, Ghavami S. Evaluation of 4‐bp insertion/deletion polymorphism within the 3′UTR of SGSM3 in bladder cancer using mismatch PCR‐RFLP method: A preliminary report. J Cell Biochem 2018; 119:6566-6574. [DOI: 10.1002/jcb.26764] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Accepted: 02/02/2018] [Indexed: 12/30/2022]
Affiliation(s)
- Mohammad Hashemi
- Department of Clinical BiochemistrySchool of MedicineZahedan University of Medical SciencesZahedanIran
| | - Gholamreza Bahari
- Department of Clinical BiochemistrySchool of MedicineZahedan University of Medical SciencesZahedanIran
| | - Fatemeh Bizhani
- Department of Clinical BiochemistrySchool of MedicineZahedan University of Medical SciencesZahedanIran
| | - Hiva Danesh
- Department of Clinical BiochemistrySchool of MedicineZahedan University of Medical SciencesZahedanIran
| | - Shamim Sarhadi
- Faculty of Advanced Medical SciencesDepartment of Medical BiotechnologyTabriz University of Medical SciencesTabrizIran
| | - Seyed Amir Mohsen Ziaee
- Urology and Nephrology Research Center; Department of UrologyShahid Labbafinejad Medical CenterShahid Beheshti University of Medical SciencesTehranIran
| | - Abbas Basiri
- Urology and Nephrology Research Center; Department of UrologyShahid Labbafinejad Medical CenterShahid Beheshti University of Medical SciencesTehranIran
| | - Behzad Narouie
- Urology and Nephrology Research Center; Department of UrologyShahid Labbafinejad Medical CenterShahid Beheshti University of Medical SciencesTehranIran
| | - Mohsen Taheri
- Department of Genetics, School of MedicineZahedan University of Medical SciencesZahedanIran
| | - Saeid Ghavami
- Department of Human Anatomy and Cell ScienceMax Rady College of MedicineRady Faculty of Health SciencesUniversity of ManitobaWinnipegMBCanada
- Health Policy Research CenterInstitute of HealthShiraz University of Medical SciencesShirazIran
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Zhang H, Sturgis E, Zhu L, Lu Z, Tao Y, Zheng H, Li G. The Modifying Effect of a Functional Variant at the miRNA Binding Site in E2F1 Gene on Recurrence of Oropharyngeal Cancer Patients with Definitive Radiotherapy. Transl Oncol 2018; 11:633-638. [PMID: 29574328 PMCID: PMC6078938 DOI: 10.1016/j.tranon.2018.02.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2017] [Accepted: 02/16/2018] [Indexed: 12/11/2022] Open
Abstract
Human papillomavirus (HPV) activates E2F1-driven transcription via the E7-RB-E2F1 pathway. A polymorphism in the 3' UTR of E2F1 gene may disrupt a binding site for miRNA and may affect its transcription level, thus modifying the susceptibility to radiotherapy and outcomes through this pathway. We evaluated the association of a polymorphism at the 3'UTR miRNA binding site of E2F1 gene (rs3213180) with risk of recurrence of SCCOP in a cohort of 1008 patients. Log-rank test and univariate and multivariable Cox models were used to evaluate the associations. Compared with patients with E2F1-rs3213180 GG homozygous genotype, the patients with E2F1-rs3213180GC+CC variant genotypes had significantly better disease-free survival (log-rank P<.001) and decreased risk of SCCOP recurrence (HR, 0.4, 95% CI, 0.3-0.5) after multivariable adjustment. Furthermore, among patients with HPV16-positive tumors, the patients with E2F1-rs3213180 GC+CC variant genotypes had significantly better disease-free survival rates (log-rank P<.001) and lower recurrence risk than those with E2F1-rs3213180 GG homozygous genotype (HR, 0.2, 95% CI, 0.1-0.4). Our findings suggest that E2F1-rs3213180 polymorphism may modulate the risk of recurrence in SCCOP patients, particularly for patients with HPV16-positive tumors of SCCOP. However, future larger population and functional studies are warranted to validate these results.
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Affiliation(s)
- Hua Zhang
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, USA; Department of Otolaryngology-Head and Neck Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai,China
| | - Erich Sturgis
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, USA; Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Lijun Zhu
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, USA; Department of Oral and Maxillofacial Surgery, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Zhongming Lu
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, USA; Department of Otolaryngology-Head and Neck Surgery, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Ye Tao
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, USA; Department of Otolaryngology-Head and Neck Surgery, the 2nd affiliated hospital of Anhui Medical University, Hefei, China
| | - Hongliang Zheng
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, USA; Department of Otorhinolaryngology-Head and Neck Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.
| | - Guojun Li
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, USA; Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, USA.
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Wang C, Sturgis EM, Chen X, Wei Q, Li G. A functional variant at miRNA-122 binding site in IL-1a 3' UTR predicts risk of recurrence in patients with oropharyngeal cancer. Oncotarget 2018; 7:34472-9. [PMID: 27121322 PMCID: PMC5085169 DOI: 10.18632/oncotarget.8908] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Accepted: 04/07/2016] [Indexed: 12/16/2022] Open
Abstract
IL-1α, an important regulator of immune and inflammation responses, has been implicated in cancer development and prognosis. An insertion (Ins)/deletion (Del) polymorphism (IL-1α rs3783553) in the 3′ UTR of IL-1α may disrupt a binding site for miRNA-122 and may affect its transcription level. Thus, this polymorphism may cause interindividual variation in immune and inflammation responses and thus may lead to different susceptibility to treatment response and prognosis of such patients. We evaluated the association of IL-1α rs3783553 polymorphism with risk of recurrence of squamous cell carcinoma of the oropharynx (SCCOP) in a cohort of 1008 patients. Log-rank test and univariate and multivariable Cox models were used to evaluate associations. Compared with patients with Del/Del homozygous genotype, the patients with Ins/Del+Ins/Ins variant genotypes had worse disease-free survival (log-rank P < 0.0001) and increased risk of SCCOP recurrence (HR, 2.4, 95% CI, 1.7-3.3) after multivariable adjustment. Furthermore, among patients with HPV16-positive tumors, the patients with Ins/Del+Ins/Ins variant genotypes of the IL-1α polymorphism had worse disease-free survival (log-rank P < 0.0001) and much higher recurrence risk than those with Del/Del homozygous genotype of this polymorphism (HR, 16.3, 95% CI, 5.0-52.7). Our findings suggest that IL-1α rs3783553 polymorphism may modulate the risk of SCCOP recurrence in patients, particularly for patients with HPV16-positive tumors. However, larger studies are needed to validate these results.
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Affiliation(s)
- Chengyuan Wang
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.,Department of Otolaryngology-Head and Neck Surgery, China-Japan Friendship Hospital, Beijing 100029, China
| | - Erich M Sturgis
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.,Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Xingming Chen
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.,Department of Otolaryngology-Head and Neck Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Qingyi Wei
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
| | - Guojun Li
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.,Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Marques D, Ferreira-Costa LR, Ferreira-Costa LL, Correa RDS, Borges AMP, Ito FR, Ramos CCDO, Bortolin RH, Luchessi AD, Ribeiro-dos-Santos Â, Santos S, Silbiger VN. Association of insertion-deletions polymorphisms with colorectal cancer risk and clinical features. World J Gastroenterol 2017; 23:6854-6867. [PMID: 29085228 PMCID: PMC5645618 DOI: 10.3748/wjg.v23.i37.6854] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Revised: 06/24/2017] [Accepted: 08/15/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the association between 16 insertion-deletions (INDEL) polymorphisms, colorectal cancer (CRC) risk and clinical features in an admixed population.
METHODS One hundred and forty patients with CRC and 140 cancer-free subjects were examined. Genomic DNA was extracted from peripheral blood samples. Polymorphisms and genomic ancestry distribution were assayed by Multiplex-PCR reaction, separated by capillary electrophoresis on the ABI 3130 Genetic Analyzer instrument and analyzed on GeneMapper ID v3.2. Clinicopathological data were obtained by consulting the patients’ clinical charts, intra-operative documentation, and pathology scoring.
RESULTS Logistic regression analysis showed that polymorphism variations in IL4 gene was associated with increased CRC risk, while TYMS and UCP2 genes were associated with decreased risk. Reference to anatomical localization of tumor Del allele of NFKB1 and CASP8 were associated with more colon related incidents than rectosigmoid. In relation to the INDEL association with tumor node metastasis (TNM) stage risk, the Ins alleles of ACE, HLAG and TP53 (6 bp INDEL) were associated with higher TNM stage. Furthermore, regarding INDEL association with relapse risk, the Ins alleles of ACE, HLAG, and UGT1A1 were associated with early relapse risk, as well as the Del allele of TYMS. Regarding INDEL association with death risk before 10 years, the Ins allele of SGSM3 and UGT1A1 were associated with death risk.
CONCLUSION The INDEL variations in ACE, UCP2, TYMS, IL4, NFKB1, CASP8, TP53, HLAG, UGT1A1, and SGSM3 were associated with CRC risk and clinical features in an admixed population. These data suggest that this cancer panel might be useful as a complementary tool for better clinical management, and more studies need to be conducted to confirm these findings.
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Affiliation(s)
- Diego Marques
- Laboratório de Bioanálise e Biotecnologia Molecular, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
- Programa de Pós-graduação em Ciências Farmacêutica, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
- Laboratório de Genética Humana e Médica, Universidade Federal do Pará, Belém 66055-080, Pará, Brazil
| | - Layse Raynara Ferreira-Costa
- Laboratório de Bioanálise e Biotecnologia Molecular, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
| | - Lorenna Larissa Ferreira-Costa
- Laboratório de Bioanálise e Biotecnologia Molecular, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
| | - Romualdo da Silva Correa
- Departamento de Cirurgia Oncológica, Liga Norte Riograndense Contra o Câncer, Natal 59040-000, Rio Grande do Norte, Brazil
| | - Aline Maciel Pinheiro Borges
- Departamento de Cirurgia Oncológica, Liga Norte Riograndense Contra o Câncer, Natal 59040-000, Rio Grande do Norte, Brazil
| | - Fernanda Ribeiro Ito
- Departamento de Cirurgia Oncológica, Liga Norte Riograndense Contra o Câncer, Natal 59040-000, Rio Grande do Norte, Brazil
| | - Carlos Cesar de Oliveira Ramos
- Laboratório de Patologia e Citopatologia, Liga Norte Riograndense Contra o Câncer, Natal 59040-000, Rio Grande do Norte, Brazil
| | - Raul Hernandes Bortolin
- Laboratório de Bioanálise e Biotecnologia Molecular, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
- Programa de Pós-graduação em Ciências Farmacêutica, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
| | - André Ducati Luchessi
- Laboratório de Bioanálise e Biotecnologia Molecular, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
- Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
- Programa de Pós-graduação em Ciências Farmacêutica, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
| | - Ândrea Ribeiro-dos-Santos
- Laboratório de Genética Humana e Médica, Universidade Federal do Pará, Belém 66055-080, Pará, Brazil
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém 66073-005, Pará, Brazil
| | - Sidney Santos
- Laboratório de Genética Humana e Médica, Universidade Federal do Pará, Belém 66055-080, Pará, Brazil
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém 66073-005, Pará, Brazil
| | - Vivian Nogueira Silbiger
- Laboratório de Bioanálise e Biotecnologia Molecular, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
- Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
- Programa de Pós-graduação em Ciências Farmacêutica, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
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Transcriptional signature of lymphoblastoid cell lines of BRCA1, BRCA2 and non- BRCA1/2 high risk breast cancer families. Oncotarget 2017; 8:78691-78712. [PMID: 29108258 PMCID: PMC5667991 DOI: 10.18632/oncotarget.20219] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Accepted: 07/17/2017] [Indexed: 12/20/2022] Open
Abstract
Approximately 25% of hereditary breast cancer cases are associated with a strong familial history which can be explained by mutations in BRCA1 or BRCA2 and other lower penetrance genes. The remaining high-risk families could be classified as BRCAX (non-BRCA1/2) families. Gene expression involving alternative splicing represents a well-known mechanism regulating the expression of multiple transcripts, which could be involved in cancer development. Thus using RNA-seq methodology, the analysis of transcriptome was undertaken to potentially reveal transcripts implicated in breast cancer susceptibility and development. RNA was extracted from immortalized lymphoblastoid cell lines of 117 women (affected and unaffected) coming from BRCA1, BRCA2 and BRCAX families. Anova analysis revealed a total of 95 transcripts corresponding to 85 different genes differentially expressed (Bonferroni corrected p-value <0.01) between those groups. Hierarchical clustering allowed distinctive subgrouping of BRCA1/2 subgroups from BRCAX individuals. We found 67 transcripts, which could discriminate BRCAX from BRCA1/BRCA2 individuals while 28 transcripts discriminate affected from unaffected BRCAX individuals. To our knowledge, this represents the first study identifying transcripts differentially expressed in lymphoblastoid cell lines from major classes of mutation-related breast cancer subgroups, namely BRCA1, BRCA2 and BRCAX. Moreover, some transcripts could discriminate affected from unaffected BRCAX individuals, which could represent potential therapeutic targets for breast cancer treatment.
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Bradshaw G, Sutherland HG, Haupt LM, Griffiths LR. Dysregulated MicroRNA Expression Profiles and Potential Cellular, Circulating and Polymorphic Biomarkers in Non-Hodgkin Lymphoma. Genes (Basel) 2016; 7:genes7120130. [PMID: 27999330 PMCID: PMC5192506 DOI: 10.3390/genes7120130] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Revised: 11/23/2016] [Accepted: 12/05/2016] [Indexed: 02/07/2023] Open
Abstract
A large number of studies have focused on identifying molecular biomarkers, including microRNAs (miRNAs) to aid in the diagnosis and prognosis of the most common subtypes of non-Hodgkin lymphoma (NHL), Diffuse Large B-cell Lymphoma and Follicular Lymphoma. NHL is difficult to diagnose and treat with many cases becoming resistant to chemotherapy, hence the need to identify improved biomarkers to aid in both diagnosis and treatment modalities. This review summarises more recent research on the dysregulated miRNA expression profiles found in NHL, as well as the regulatory role and biomarker potential of cellular and circulating miRNAs found in tissue and serum, respectively. In addition, the emerging field of research focusing on miRNA single nucleotide polymorphisms (miRSNPs) in genes of the miRNA biogenesis pathway, in miRNA genes themselves, and in their target sites may provide new insights on gene expression changes in these genes. These miRSNPs may impact miRNA networks and have been shown to play a role in a host of different cancer types including haematological malignancies. With respect to NHL, a number of SNPs in miRNA-binding sites in target genes have been shown to be associated with overall survival.
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Affiliation(s)
- Gabrielle Bradshaw
- Genomics Research Centre, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, QLD 4059, Australia.
| | - Heidi G Sutherland
- Genomics Research Centre, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, QLD 4059, Australia.
| | - Larisa M Haupt
- Genomics Research Centre, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, QLD 4059, Australia.
| | - Lyn R Griffiths
- Genomics Research Centre, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, QLD 4059, Australia.
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10
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Interaction between p53 codon 72 and MDM2 309T>G polymorphisms and the risk of hepatocellular carcinoma. Tumour Biol 2015; 37:3863-70. [PMID: 26476535 DOI: 10.1007/s13277-015-4222-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 10/12/2015] [Indexed: 12/11/2022] Open
Abstract
The p53 tumor suppressor and its negative regulator, murine double minute 2 (MDM2), play critical roles in carcinogenesis. P53 codon 72 and MDM2 309T>G polymorphisms could influence p53 and MDM2 function, respectively, and might affect cancer susceptibility. We therefore investigated the association between these two SNPs, alone or in combination, and the risk of hepatocellular carcinoma (HCC) in Chinese. In this case-control study, we genotyped p53 codon 72 and MDM2 309T>G polymorphisms in 985 HCC cases and 992 cancer-free age- and sex-matched controls and evaluated their associations with the risk of HCC. Although no significant main effects were found for these two SNPs in the single-locus analysis and stratified analysis by age, sex, smoking, drinking, and hepatitis B virus (HBV) infection, we found that individuals carrying at least one G allele of the MDM2 309T>G polymorphism had statistically significant increased risk of HCC among those with the p53 Pro/Pro genotype (adjusted odds ratio (OR) = 2.23, 95 % confidence interval (95%CI) = 1.20-4.14 for TG genotype; adjusted OR = 2.67, 95%CI = 1.32-5.42 for GG genotype), and the interaction between p53 codon 72 and MDM2 309T>G was significant (P interaction = 0.017). Our findings suggest that the interaction of p53 codon 72 and MDM2 309T>G may play an important role in the etiology of HCC. More studies with well-designed and large sample sizes are required to validate these observations.
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Zhang Y, Sturgis EM, Sun Y, Sun C, Wei Q, Huang Z, Li G. A functional variant at miRNA-122 binding site in IL-1α 3' UTR predicts risk and HPV-positive tumours of oropharyngeal cancer. Eur J Cancer 2015; 51:1415-23. [PMID: 25981582 PMCID: PMC4768464 DOI: 10.1016/j.ejca.2015.04.016] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Revised: 04/17/2015] [Accepted: 04/19/2015] [Indexed: 12/19/2022]
Abstract
BACKGROUND Genetic polymorphisms in the 3' untranslated regions (3' UTRs) targeted by miRNAs alter the strength of miRNA binding in a manner that affects the behaviour of individual miRNAs. An insertion (Ins)/deletion (Del) polymorphism (rs3783553) in the 3' UTR of IL-1α may disrupt a binding site for miRNA-122. IL-1α plays an important role in inflammation, immunity and defense against infection. Thus, we hypothesised that the rs3783553 polymorphism affects individual susceptibility to human papillomavirus (HPV)-associated oral squamous cell carcinoma (OSCC). METHODS We genotyped the rs3783553 polymorphism; and determined HPV16 L1 serology, tumour HPV16 DNA and serum IL-1α expression. Univariate/multivariable logistic regression models were used to calculate associations. RESULTS We found that HPV16 L1 seropositivity alone was associated with an increased risk of OSCC (Odds ratio (OR), 3.1; 95% confidence interval (CI), 2.1-4.6), and the risk of HPV16-associated OSCC was modified by the rs3783553 polymorphism. Patients with both HPV16 L1 seropositivity and Del/Del genotype for the rs3783553 had the highest risk of OSCC when using patients with HPV16 L1 seronegativity and Ins/Del+Ins/Ins genotypes as a comparison group. Notably, that effect modification was particularly pronounced in several subgroups (e.g. SCCOP, never-smokers and never-drinkers). The patients with Del/Del genotype were approximately 3.0 times more likely to have HPV16-positive squamous cell carcinoma of the oropharynx (SCCOP) tumours compared to those patients with Ins/Del+Ins/Ins genotypes. Additionally, functional relevance of this variant was characterised to explore the genotype-phenotype correlation. CONCLUSION These results suggest that IL-1α 3' UTR rs3783553 polymorphism may be functional and influence susceptibility to HPV16-associated OSCC, particularly for SCCOP. Validation of our findings is warranted.
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Affiliation(s)
- Yang Zhang
- Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Key Laboratory of Otolaryngology Head and Neck Surgery, Ministry of Education, Beijing Institute of Otolaryngology, Beijing 100730, China; Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Erich M Sturgis
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Yan Sun
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Otorhinolaryngology and Head and Neck Surgery, Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Chuanzheng Sun
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Head and Neck Surgery, The Tumor Hospital of Yunnan Province, Kunming 650118, China
| | - Qingyi Wei
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
| | - Zhigang Huang
- Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Key Laboratory of Otolaryngology Head and Neck Surgery, Ministry of Education, Beijing Institute of Otolaryngology, Beijing 100730, China; Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
| | - Guojun Li
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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Cipollini M, Landi S, Gemignani F. MicroRNA binding site polymorphisms as biomarkers in cancer management and research. Pharmgenomics Pers Med 2014; 7:173-91. [PMID: 25114582 PMCID: PMC4126202 DOI: 10.2147/pgpm.s61693] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
MicroRNAs (miRNAs) are important regulators of eukaryotic gene expression. They have been implicated in a broad range of biological processes, and miRNA-related genetic alterations probably underlie several human diseases. Single nucleotide polymorphisms of transcripts may modulate the posttranscriptional regulation of gene expression by miRNAs and explain interindividual variability in cancer risk and in chemotherapy response. On the basis of recent association studies published in the literature, the present review mainly summarizes the potential role of miRNAs as molecular biomarkers for disease susceptibility, diagnosis, prognosis, and drug-response prediction in tumors. Many clues suggest a role for polymorphisms within the 3' untranslated regions of KRAS rs61764370, SET8 rs16917496, and MDM4 rs4245739 as SNPs in miRNA binding sites highly promising in the biology of human cancer. However, more studies are needed to better characterize the composite spectrum of genetic determinants for future use of markers in risk prediction and clinical management of diseases, heading toward personalized medicine.
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Affiliation(s)
| | - Stefano Landi
- Department of Biology, University of Pisa, Pisa, Italy
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