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Al-Sharabass EA, El-Houseini ME, Effat H, Ibrahim SA, Abdellateif MS. The clinical potential of PDL-1 pathway and some related micro-RNAs as promising diagnostic markers for breast cancer. Mol Med 2025; 31:106. [PMID: 40108523 PMCID: PMC11921724 DOI: 10.1186/s10020-025-01137-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 02/19/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Immune checkpoint pathways play important roles in breast cancer (BC) pathogenesis and therapy. METHODS Expression levels of programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed death-ligand 1 (PD-L1), Forkhead box P3 (FOXP3), miR-155, and miR-195 were assessed in the peripheral blood of 90 BC patients compared to 30 healthy controls using quantitative real-time PCR (qRt-PCR). The plasma level of soluble MHC class I chain related-protein B (MIC-B) protein was assessed using the enzyme linked immunosorbent assay (ELISA) technique. The data were correlated to the clinico-pathological characteristics of the patients. RESULTS There was a significant increase in the expression levels of PDL-1 [17.59 (3.24-123), p < 0.001], CTLA-4 [23.34 (1.3-1267), p = 0.006], PD-1 [10.25 (1-280), p < 0.001], FOXP3 [11.5 (1-234.8), p = 0.001], miR-155 [87.3 (1.5-910), p < 0.001] in BC patients compared to normal controls. The miR-195 was significantly downregulated in BC patients [0.23 (0-0.98, p < 0.001]. The plasma level of MIC-B was significantly increased in the BC patients [0.941 (0.204-6.38) ng/ml], compared to the control group [0.351 (0.211-0.884) ng/mL, p < 0.00]. PDL-1, CTLA-4, PD-1, and FOXP3 achieved a specificity of 100% for distinguishing BC patients, at a sensitivity of 93.3%, 82.2%, 62.2%, and 71.1% respectively. The combined expression of PDL-1 and CTLA-4 scored a 100% sensitivity and 100% specificity for diagnosing BC (p < 0.001). The sensitivity, specificity, and AUC of miR-155 were 88.9%, 96.7%, and 0.934; respectively (p < 0.001). While those of miR-195 were 73.3%, 60%, and 0.716; respectively (p = 0.001). MIC-B expression showed a 77.8% sensitivity, 80% specificity, and 0.811 AUC at a cutoff of 1.17 ng/ml (p < 0.001). Combined expression of miR-155 and miR-195 achieved a sensitivity of 91.1%, a specificity of 96.7%, and AUC of 0.926 (p < 0.001). Multivariate analysis showed that PDL-1 (OR:13.825, p = 0.004), CTLA-4 (OR: 20.958, p = 0.010), PD-1(OR:10.550, p = 0.044), MIC-B (OR: 17.89, p = 0.003), miR-155 (OR: 211.356, P < 0.001), and miR-195(OR:0.006, P < 0.001) were considered as independent risk factors for BC. CONCLUSIONS The PB levels of PDL-1, CTLA-4, PD-1, FOXP3, MIC-B, miR-155, and miR-195 could be used as promising diagnostic markers for BC patients.
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Affiliation(s)
| | - Motawa E El-Houseini
- Medical Biochemistry and Molecular Biology, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Heba Effat
- Medical Biochemistry and Molecular Biology, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | | | - Mona S Abdellateif
- Medical Biochemistry and Molecular Biology, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
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de Matos MDLG, Pinto M, Gonçalves A, Canberk S, Bugalho MJM, Soares P. Insights in biomarkers complexity and routine clinical practice for the diagnosis of thyroid nodules and cancer. PeerJ 2025; 13:e18801. [PMID: 39850836 PMCID: PMC11756370 DOI: 10.7717/peerj.18801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 12/11/2024] [Indexed: 01/25/2025] Open
Abstract
Background The differential diagnosis between benign and malignant thyroid nodules continues to be a major challenge in clinical practice. The rising incidence of thyroid neoplasm and the low incidence of aggressive thyroid carcinoma, urges the exploration of strategies to improve the diagnostic accuracy in a pre-surgical phase, particularly for indeterminate nodules, and to prevent unnecessary surgeries. Only in 2022, the 5th WHO Classification of Endocrine and Neuroendocrine Tumors, and in 2023, the 3rd Bethesda System for Reporting Thyroid Cytopathology and the European Thyroid Association included biomarkers in their guidelines. In this review, we discuss the integration of biomarkers within the routine clinical practice for diagnosis of thyroid nodules and cancer. Methodology The literature search for this review was performed through Pub Med, Science Direct, and Google Scholar. We selected 156 publications with significant contributions to this topic, with the majority (86, or 55.1%) published between January 2019 and March 2024, including some publications from our group during those periods. The inclusion criteria were based on articles published in recognized scientific journals with high contributions to the proposed topic. We excluded articles not emphasizing molecular biomarkers in refine the pre-surgical diagnosis of thyroid nodules. Results We explored genetic biomarkers, considering the division of thyroid neoplasm into BRAF-like tumor and RAS-like tumor. The specificity of BRAF mutation in the diagnosis of papillary thyroid carcinoma (PTC) is nearly 100% but its sensitivity is below 35%. RAS mutations are found in a broad spectrum of thyroid neoplasm, from benign to malignant follicular-patterned tumors, but do not increase the ability to distinguish benign from malignant lesions. The overexpression of miRNAs is correlated with tumor aggressiveness, high tumor node metastasis (TMN) stage, and recurrence, representing a real signature of thyroid cancer, particularly PTC. In addition, associations between the expression levels of selected miRNAs and the presence of specific genetic mutations have been related with aggressiveness and worse prognosis. Conclusions The knowledge of genetic and molecular biomarkers has achieved a high level of complexity, and the difficulties related to its applicability determine that their implementation in clinical practice is not yet a reality. More studies with larger series are needed to optimize their use in routine practice. Additionally, the improvement of new techniques, such as liquid biopsy and/or artificial intelligence, may be the future for a better understanding of molecular biomarkers in thyroid nodular disease.
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Affiliation(s)
- Maria de Lurdes Godinho de Matos
- Department of Endocrinology, Diabetes and Metabolism, Hospital Curry Cabral, Unidade Local de Saúde São José, Centro Clínico Académico de Lisboa, Lisbon, Portugal
| | - Mafalda Pinto
- Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), i3S—Institute for Research & Innovation in Health, Porto, Portugal
| | - Ana Gonçalves
- Department of Pathology, Unidade Local de Saúde São João, Porto, Portugal
| | - Sule Canberk
- Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), i3S—Institute for Research & Innovation in Health, Porto, Portugal
| | - Maria João Martins Bugalho
- Department of Endocrinology, Hospital de Santa Maria, Unidade Local de Saúde Santa Maria; Medical Faculty, University of Lisbon, Lisbon, Portugal
| | - Paula Soares
- Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), i3S—Institute for Research & Innovation in Health, Porto, Portugal
- Medical Faculty, University of Porto, Porto, Portugal
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Condello V, Juhlin CC. MicroRNA regulator gene mutations in thyroid follicular nodular disease and thyroid cancer: does it all come down to timing? Eur Thyroid J 2024; 13:e240298. [PMID: 39601261 PMCID: PMC11737542 DOI: 10.1530/etj-24-0298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 11/04/2024] [Accepted: 11/20/2024] [Indexed: 11/29/2024] Open
Abstract
In recent years, germline mutations in the microRNA (miRNA) processor genes DICER1 and DGCR8 have been coupled to the development of thyroid follicular nodular disease (TFND), thereby casting new light on the etiology of this enigmatic, benign condition in non-iodine-deficient regions. Moreover, DICER1 and DGCR8 mutations have also been reported in rare subsets of follicular cell-derived thyroid carcinomas. Specifically, truncating germline or missense somatic DICER1 mutations have been reported in small subsets of pediatric and adolescent follicular thyroid carcinoma (FTC) and poorly differentiated thyroid carcinoma (PDTC). Similarly, a recurrent somatic mutation of the DGCR8 gene has been observed in highly aggressive FTCs and in some indolent cases of encapsulated follicular variant of papillary thyroid carcinoma. The reason why identical mutations in the same miRNA processor gene can lead to such a myriad of thyroid conditions, ranging from benign TFND to FTCs and PDTCs, remains unclear. This review highlights key features of miRNA regulator gene mutations in thyroid disease and explores their potential roles as drivers or progression events in tumor development.
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Affiliation(s)
- Vincenzo Condello
- Department of Oncology-Pathology,
Karolinska Institutet, Stockholm,
Sweden
| | - C Christofer Juhlin
- Department of Oncology-Pathology,
Karolinska Institutet, Stockholm,
Sweden
- Department of Pathology and
Cancer Diagnostics, Karolinska University Hospital,
Stockholm, Sweden
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Zhang T, Yuan B, Yu S. The Application of microRNAs in Papillary Thyroid Cancer: A Bibliometric and Visualized Analysis. Int J Gen Med 2024; 17:4681-4699. [PMID: 39429957 PMCID: PMC11490214 DOI: 10.2147/ijgm.s487239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 10/02/2024] [Indexed: 10/22/2024] Open
Abstract
Objective Thyroid cancer is the most common malignant endocrine tumor, with papillary thyroid carcinoma (PTC) being the most prevalent type, accounting for 85% of thyroid cancer cases. Here, we conducted a bibliometric analysis of the literature in the field of microRNAs in PTC research to demonstrate current trends and research hotspots, and present a visual map of past and emerging trends. Methods We searched the Web of Scientific Core Collection (WoSCC) database for publications from 1999 to 2023 centered on this field. Next, we employed visualization tools such as VOSviewer, CiteSpace, and Microsoft Excel 2019 to present co-occurrence and co-citation analyses, trends, hotspots, and visual representations of contributions from authors, institutions, journals, and countries/regions. Results The bibliometric analysis encompassed the period from 1999 to 2023, with 994 papers from 54 countries/regions. The country with the most publications and highest total citations was the People's Republic of China, but the United States held the highest average citation rate. Among the top ten productive institutions, the Ohio State University (Ohio State Univ) was the most prominent contributor to this field. The JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM (J Clin Endocrinol Metab) ranked first in terms of citation counts and average citations among the top ten productive journals. In terms of keywords, "circular RNAs", "promotes", and "progression" have become prominent research areas. Conclusion This study elucidates current trends, hotspots, and emerging frontiers in miRNA research within PTC, and provides new insights and guidance for future identification of new PTC biomarkers and clinical trials.
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Affiliation(s)
- Tinghua Zhang
- Department of Clinical Laboratory, the Second People’s Hospital of Huaihua City, Huaihua, Hunan, People’s Republic of China
| | - Bo Yuan
- Department of Clinical Laboratory, Southern University of Science and Technology Hospital, Guangdong, Shenzhen, People’s Republic of China
| | - Shaofu Yu
- Department of Clinical Pharmacy, the Second People’s Hospital of Huaihua, Huaihua, Hunan, People’s Republic of China
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Li H, Wu P. Epigenetics in thyroid cancer: a bibliometric analysis. Endocr Connect 2024; 13:e240087. [PMID: 38949925 PMCID: PMC11378139 DOI: 10.1530/ec-24-0087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 07/01/2024] [Indexed: 07/03/2024]
Abstract
Background Epigenetics, which involves regulatory modifications that do not alter the DNA sequence itself, is crucial in the development and progression of thyroid cancer. This study aims to provide a comprehensive analysis of the epigenetic research landscape in thyroid cancer, highlighting current trends, major research areas, and potential future directions. Methods A bibliometric analysis was performed using data from the Web of Science Core Collection (WOSCC) up to 1 November 2023. Analytical tools such as VOSviewer, CiteSpace, and the R package 'bibliometrix' were employed for comprehensive data analysis and visualization. This process identified principal research themes, along with influential authors, institutions, and countries contributing to the field. Results The analysis reveals a marked increase in thyroid cancer epigenetics research over the past two decades. Emergent key themes include the exploration of molecular mechanisms and biomarkers, various subtypes of thyroid cancer, implications for therapeutic interventions, advancements in technologies and methodologies, and the scope of translational research. Research hotspots within these themes highlight intensive areas of study and the potential for significant breakthroughs. Conclusion This study presents an in-depth overview of the current state of epigenetics in thyroid cancer research. It underscores the potential of epigenetic strategies as viable therapeutic options and provides valuable insights for researchers and clinicians in advancing the understanding and treatment of this complex disease. Future research is vital to fully leverage the therapeutic possibilities offered by epigenetics in the management of thyroid cancer.
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Affiliation(s)
- Hui Li
- Department of Thyroid Surgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, Hunan, P. R. China
| | - Peng Wu
- Department of Thyroid Surgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, Hunan, P. R. China
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Armos R, Bojtor B, Papp M, Illyes I, Lengyel B, Kiss A, Szili B, Tobias B, Balla B, Piko H, Illes A, Putz Z, Kiss A, Toth E, Takacs I, Kosa JP, Lakatos P. MicroRNA Profiling in Papillary Thyroid Cancer. Int J Mol Sci 2024; 25:9362. [PMID: 39273308 PMCID: PMC11395536 DOI: 10.3390/ijms25179362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 08/23/2024] [Accepted: 08/28/2024] [Indexed: 09/15/2024] Open
Abstract
Genetic alterations are well known to be related to the pathogenesis and prognosis of papillary thyroid carcinoma (PTC). Some miRNA expression dysregulations have previously been described in the context of cancer development including thyroid carcinoma. In our study, we performed original molecular diagnostics on tissue samples related to our own patients. We aimed to identify all dysregulated miRNAs in potential association with PTC development via sequencing much higher numbers of control-matched PTC tissue samples and analyzing a wider variety of miRNA types than previous studies. We analyzed the expression levels of 2656 different human miRNAs in the context of 236 thyroid tissue samples (118 tumor and control pairs) related to anonymized PTC cases. Also, KEGG pathway enrichment analysis and GO framework analysis were used to establish the links between miRNA dysregulation and certain biological processes, pathways of signaling, molecular functions, and cellular components. A total of 30 significant differential miRNA expressions with at least ±1 log2 fold change were found related to PTC including, e.g., miR-551b, miR-146b, miR-221, miR-222, and miR-375, among others, being highly upregulated, as well as miR-873 and miR-204 being downregulated. In addition, we identified miRNA patterns in vast databases (KEGG and GO) closely similar to that of PTC including, e.g., miRNA patterns of prostate cancer, HTLV infection, HIF-1 signaling, cellular responses to growth factor stimulus and organic substance, and negative regulation of gene expression. We also found 352 potential associations between certain miRNA expressions and states of clinicopathological variables. Our findings-supported by the largest case number of original matched-control PTC-miRNA relation research-suggest a distinct miRNA expression profile in PTC that could contribute to a deeper understanding of the underlying molecular mechanisms promoting the pathogenesis of the disease. Moreover, significant miRNA expression deviations and their signaling pathways in PTC presented in our study may serve as potential biomarkers for PTC diagnosis and prognosis or even therapeutic targets in the future.
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Affiliation(s)
- Richard Armos
- Department of Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083 Budapest, Hungary
- SE HUN-REN-TKI ENDOMOLPAT Research Group, 1085 Budapest, Hungary
| | - Bence Bojtor
- Department of Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083 Budapest, Hungary
| | - Marton Papp
- Centre for Bioinformatics, University of Veterinary Medicine, 1078 Budapest, Hungary
| | - Ildiko Illyes
- Department of Pathology, Forensic and Insurance Medicine, Faculty of Medicine, Semmelweis University, 1091 Budapest, Hungary
| | - Balazs Lengyel
- Department of Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083 Budapest, Hungary
| | - Andras Kiss
- Department of Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083 Budapest, Hungary
| | - Balazs Szili
- Department of Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083 Budapest, Hungary
| | - Balint Tobias
- Department of Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083 Budapest, Hungary
- SE HUN-REN-TKI ENDOMOLPAT Research Group, 1085 Budapest, Hungary
| | - Bernadett Balla
- SE HUN-REN-TKI ENDOMOLPAT Research Group, 1085 Budapest, Hungary
| | - Henriett Piko
- Department of Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083 Budapest, Hungary
| | - Anett Illes
- Department of Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083 Budapest, Hungary
| | - Zsuzsanna Putz
- Department of Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083 Budapest, Hungary
- SE HUN-REN-TKI ENDOMOLPAT Research Group, 1085 Budapest, Hungary
| | - Andras Kiss
- Department of Pathology, Forensic and Insurance Medicine, Faculty of Medicine, Semmelweis University, 1091 Budapest, Hungary
| | - Erika Toth
- Department of Surgical and Molecular Pathology, National Institute of Oncology, 1122 Budapest, Hungary
| | - Istvan Takacs
- Department of Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083 Budapest, Hungary
| | - Janos P Kosa
- Department of Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083 Budapest, Hungary
- SE HUN-REN-TKI ENDOMOLPAT Research Group, 1085 Budapest, Hungary
| | - Peter Lakatos
- Department of Medicine and Oncology, Faculty of Medicine, Semmelweis University, 1083 Budapest, Hungary
- SE HUN-REN-TKI ENDOMOLPAT Research Group, 1085 Budapest, Hungary
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Ferraz C, Cunha GB, de Oliveira MMB, Tenório LR, Cury AN, Padovani RDP, Ward LS. The diagnostic and prognostic role of miR-146b-5p in differentiated thyroid carcinomas. Front Endocrinol (Lausanne) 2024; 15:1390743. [PMID: 39036050 PMCID: PMC11257861 DOI: 10.3389/fendo.2024.1390743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 06/18/2024] [Indexed: 07/23/2024] Open
Abstract
Introduction Samples classified as indeterminate correspond to 10-20% of cytologies obtained by fine needle biopsy of thyroid nodules, preventing an adequate distinction between benign and malignant lesions and leading to diagnostic thyroidectomies that often prove unnecessary, as most cases are benign. Furthermore, although the vast majority of patients with differentiated thyroid cancer (DTC) have such a good prognosis that active surveillance is permitted as an initial therapeutic option, relapses are not rare, and a non-negligible number of patients experience poor outcomes. MicroRNAs (miR) emerge as potential biomarkers capable of helping to define more precise management of patients in all these situations. Methods Aiming to investigate the clinical utility of miR-146b-5p in the diagnostic of thyroid nodules and evaluating its prognostic potential in a realworld setting, we studied 89 thyroid nodule samples, correlating miR-146b-5p expression with clinical tools such as the 8th edition from the American Joint Committee on Cancer (AJCC/UICC) and the American Thyroid Association Guideline Stratification Systems for the rate of recurrence (RR). Results miR-146b-5p expression levels distinguished benign from malignant thyroid FNA samples (p< 0.0001). For indeterminate nodules, overexpression of miR-146b-5p with a cut-off of 0.497 was able to diagnose malignancy with a 90% accuracy; specificity=87.5%; sensitivity=100%. An increased expression of miR-146b-5p was associated with greater RR (p=0.015). A cut-off of 2.21 identified cases with more vascular involvement (p=0.013) and a cut-off of 2.420 was associated with a more advanced TNM stage (p-value=0.047). Discussion We demonstrated that miR-146b5p expression in FNA samples is able to differentiate benign from malignant indeterminate nodules and is associated with an increased risk of recurrence and mortality, suggesting that this single miRNA may be a useful diagnostic and prognostic marker in the personalized management of DTC patients.
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Affiliation(s)
- Carolina Ferraz
- Thyroid Diseases Unit - Division of Endocrinology, Department of Medicine, Faculty of Medical Sciences/Irmandade da Santa Casa de Misericórdia de São Paulo, São Paulo, Brazil
| | - Gustavo Bittar Cunha
- Thyroid Diseases Unit - Division of Endocrinology, Department of Medicine, Faculty of Medical Sciences/Irmandade da Santa Casa de Misericórdia de São Paulo, São Paulo, Brazil
| | - Mariana Mazeu Barbosa de Oliveira
- Thyroid Diseases Unit - Division of Endocrinology, Department of Medicine, Faculty of Medical Sciences/Irmandade da Santa Casa de Misericórdia de São Paulo, São Paulo, Brazil
| | - Lucas Ribeiro Tenório
- Division of Head and Neck Surgery, Department of Surgery, Irmandade da Santa Casa de Misericórdia de São Paulo, São Paulo, Brazil
| | - Adriano Namo Cury
- Thyroid Diseases Unit - Division of Endocrinology, Department of Medicine, Faculty of Medical Sciences/Irmandade da Santa Casa de Misericórdia de São Paulo, São Paulo, Brazil
| | - Rosália do Prado Padovani
- Thyroid Diseases Unit - Division of Endocrinology, Department of Medicine, Faculty of Medical Sciences/Irmandade da Santa Casa de Misericórdia de São Paulo, São Paulo, Brazil
| | - Laura Sterian Ward
- Laboratory of Cancer Molecular Genetics, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
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Zhang R, Yu Y, Yang Y, Zhang M, Zhang X, Chang Y, Wang S, Hu L, Li J, Zheng X, Zhao R, Guo Y, Ni X. Therapeutic targeting of TNIK in papillary thyroid carcinoma: a novel approach for tumor growth suppression. Med Oncol 2024; 41:160. [PMID: 38763968 DOI: 10.1007/s12032-024-02380-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Accepted: 04/04/2024] [Indexed: 05/21/2024]
Abstract
Papillary thyroid carcinoma (PTC) is a common endocrine malignancy. The pathology of PTC is far from clear. As a kinase that can be targeted, the role of TNIK in PTC has not been investigated. This study was focused on the effects and molecular mechanisms of TNIK in PTC. Both public datasets and clinical specimens were used to verify TNIK expression. The effects of TNIK were investigated in both cell lines and mice models. Transcriptome analysis was used to explore the underlying mechanism of TNIK. Immunofluorescence, wound healing, and qRT-PCR assays were used to validate the mechanism of TNIK in PTC. The therapeutic effects of TNIK inhibitor NCB-0846 were evaluated by flow cytometry, western blot, and subcutaneous xenografts mice. TNIK expression was upregulated in PTC tissues. TNIK knockdown could suppress cell proliferation and tumor growth in no matter cell models or nude mice. The transcriptome analysis, GO enrichment analysis, and GSEA analysis results indicated TNIK was highly correlated with cytoskeleton, cell motility, and Wnt pathways. The mechanistic studies demonstrated that TNIK regulated cytoskeleton remodeling and promoted cell migration. NCB-0846 significantly inhibited TNIK kinase activity, induced cell apoptosis, and activated apoptosis-related proteins in a dose-dependent manner. In addition, NCB-0846 inhibited tumor growth in tumor-bearing mice. In summary, we proposed a novel regulatory mechanism in which TNIK-mediated cytoskeleton remodeling and cell migration to regulate tumor progression in PTC. TNIK is a therapeutic target in PTC and NCB-0846 would act as a novel targeted drug for PTC therapy.
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Affiliation(s)
- Ruqian Zhang
- Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, MOE Key Laboratory of Major Diseases in Children, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health (NCCH), Beijing, China
| | - Yongbo Yu
- Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, MOE Key Laboratory of Major Diseases in Children, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health (NCCH), Beijing, China
- Biobank for Clinical Data and Samples in Pediatrics, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health (NCCH), Beijing, 100045, China
| | - Yeran Yang
- Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, MOE Key Laboratory of Major Diseases in Children, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health (NCCH), Beijing, China
| | - Meng Zhang
- Department of Pathology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health (NCCH), Beijing, China
| | - Xuan Zhang
- Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, MOE Key Laboratory of Major Diseases in Children, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health (NCCH), Beijing, China
| | - Yan Chang
- Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, MOE Key Laboratory of Major Diseases in Children, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health (NCCH), Beijing, China
| | - Shengcai Wang
- Department of Otolaryngology, Head and Neck Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health (NCCH), Beijing, 100045, People's Republic of China
| | - Linfei Hu
- Department of Thyroid and Neck Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Jiali Li
- Department of Otolaryngology Head and Neck Surgery, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xiangqian Zheng
- Department of Thyroid and Neck Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Ruili Zhao
- Department of Otolaryngology Head and Neck Surgery, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yongli Guo
- Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, MOE Key Laboratory of Major Diseases in Children, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health (NCCH), Beijing, China.
- Biobank for Clinical Data and Samples in Pediatrics, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health (NCCH), Beijing, 100045, China.
| | - Xin Ni
- Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, MOE Key Laboratory of Major Diseases in Children, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health (NCCH), Beijing, China.
- Biobank for Clinical Data and Samples in Pediatrics, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health (NCCH), Beijing, 100045, China.
- Department of Otolaryngology, Head and Neck Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health (NCCH), Beijing, 100045, People's Republic of China.
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Rodrigues L, Da Cruz Paula A, Soares P, Vinagre J. Unraveling the Significance of DGCR8 and miRNAs in Thyroid Carcinoma. Cells 2024; 13:561. [PMID: 38607000 PMCID: PMC11011343 DOI: 10.3390/cells13070561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 03/13/2024] [Accepted: 03/20/2024] [Indexed: 04/13/2024] Open
Abstract
MicroRNAs (miRNAs) act as negative regulators for protein-coding gene expression impacting cell proliferation, differentiation, and survival. These miRNAs are frequently dysregulated in cancer and constitute classes of blood-based biomarkers useful for cancer detection and prognosis definition. In thyroid cancer (TC), the miRNA biogenesis pathway plays a pivotal role in thyroid gland formation, ensuring proper follicle development and hormone production. Several alterations in the miRNA biogenesis genes are reported as a causality for miRNA dysregulation. Mutations in microprocessor component genes are linked to an increased risk of developing TC; in particular, a recurrent mutation affecting DGCR8, the E518K. In this review, we explore these novel findings and resume the current state-of-the-art in miRNAs in thyroid carcinomas.
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Affiliation(s)
- Lia Rodrigues
- Instituto de Investigação e Inovação em Saúde da Universidade do Porto (i3S), Rua Alfredo Allen, 4200-135 Porto, Portugal; (L.R.); (A.D.C.P.); (P.S.)
- Instituto de Patologia e Imunologia Molecular da Universidade do Porto (Ipatimup), Rua Júlio Amaral de Carvalho, 4200-135 Porto, Portugal
- Departamento de Patologia, Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
- Escola Superior de Saúde do Instituto Politécnico do Porto, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal
| | - Arnaud Da Cruz Paula
- Instituto de Investigação e Inovação em Saúde da Universidade do Porto (i3S), Rua Alfredo Allen, 4200-135 Porto, Portugal; (L.R.); (A.D.C.P.); (P.S.)
- Instituto de Patologia e Imunologia Molecular da Universidade do Porto (Ipatimup), Rua Júlio Amaral de Carvalho, 4200-135 Porto, Portugal
| | - Paula Soares
- Instituto de Investigação e Inovação em Saúde da Universidade do Porto (i3S), Rua Alfredo Allen, 4200-135 Porto, Portugal; (L.R.); (A.D.C.P.); (P.S.)
- Instituto de Patologia e Imunologia Molecular da Universidade do Porto (Ipatimup), Rua Júlio Amaral de Carvalho, 4200-135 Porto, Portugal
- Departamento de Patologia, Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
| | - João Vinagre
- Instituto de Investigação e Inovação em Saúde da Universidade do Porto (i3S), Rua Alfredo Allen, 4200-135 Porto, Portugal; (L.R.); (A.D.C.P.); (P.S.)
- Instituto de Patologia e Imunologia Molecular da Universidade do Porto (Ipatimup), Rua Júlio Amaral de Carvalho, 4200-135 Porto, Portugal
- Departamento de Patologia, Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
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10
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Matos MDL, Pinto M, Alves M, Canberk S, Gonçalves A, Bugalho MJ, Papoila AL, Soares P. Cyto-Histological Profile of MicroRNAs as Diagnostic Biomarkers in Differentiated Thyroid Carcinomas. Genes (Basel) 2024; 15:389. [PMID: 38540448 PMCID: PMC10970297 DOI: 10.3390/genes15030389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 03/17/2024] [Accepted: 03/19/2024] [Indexed: 06/14/2024] Open
Abstract
INTRODUCTION The repertoire of microRNAs (miRNAs) in thyroid carcinomas starts to be elucidated. Among differentiated thyroid carcinomas (DTCs), papillary thyroid carcinoma (PTC) is the most frequent. The assessment of miRNAs expression may contribute to refine the pre-surgical diagnosis in order to obtain a personalized and more effective treatment for patients. AIMS This study aims to evaluate (1) the miRNAs in a series of DTCs, and their association with the presence of selected genetic mutations in order to improve diagnosis and predict the biologic behavior of DTC/PTC. (2) The reliability of molecular tests in Ultrasound-guided Fine Needle Aspiration Cytology (US-FNAC) for a more precise preoperative diagnosis. MATERIAL AND METHODS This series includes 176 samples (98 cytology and 78 histology samples) obtained from 106 patients submitted to surgery, including 13 benign lesions (controls) and 93 DTCs (cases). The microRNA expression was assessed for miR-146b, miR-221, miR-222, and miR-15a through quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). The results were analyzed by the 2-ΔΔCT method, using miR16 as an endogenous control. Regarding PTC diagnosis, the discriminative ability of miRNAs expression was assessed by the area under the Receiver Operating Characteristic Curve (AUC). In PTCs, the association of miRNAs expression, clinicopathological features, and genetic mutations (BRAF, RAS, and TERTp) was evaluated. RESULTS/DISCUSSION All the analyzed miRNAs presented a tendency to be overexpressed in DTCs/PTCs when compared with benign lesions, both in cytology and histology samples. In cytology, miRNAs expression levels were higher in malignant tumors than in benign tumors. In histology, the discriminative abilities regarding PTC diagnosis were as follows: miR-146b (AUC 0.94, 95% CI 0.87-1), miR-221 (AUC 0.79, 95% CI 0.68-0.9), miR-222 (AUC 0.76, 95% CI 0.63-0.89), and miR-15a (AUC 0.85, 95% CI 0.74-0.97). miR-146b showed 89% sensitivity (se) and 87% specificity (sp); miR-221 se = 68.4, sp = 90; miR-222 se = 73, sp = 70; and mi-R15a se = 72, sp = 80. MicroRNAs were associated with worst-prognosis clinicopathological characteristics in PTCs (p < 0.05), particularly for miR-222. Our data reveal a significant association between higher expression levels of miR-146b, miR-221, and miR-222 in the presence of the BRAF mutation (p < 0.001) and miR-146b (p = 0.016) and miR-221 (p = 0.010) with the RAS mutation, suggesting an interplay of these mutations with miRNAs expression. Despite this study having a relatively small sample size, overexpression of miRNAs in cytology may contribute to a more precise preoperative diagnosis. The miRNAs presented a good discriminative ability in PTC diagnosis. The association between the miRNAs expression profile and genetic alterations can be advantageous for an accurate diagnosis of DTCs/PTCs in FNAC.
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Affiliation(s)
- Maria de Lurdes Matos
- Department of Endocrinology, Diabetes and Metabolism, Hospital Curry Cabral, Unidade Saúde Local São José, Centro Clínico e Académico de Lisboa, 1050-166 Lisbon, Portugal
| | - Mafalda Pinto
- Institute for Research & Innovation in Health (i3S), Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), 4200-135 Porto, Portugal; (M.P.); (S.C.)
| | - Marta Alves
- Gabinete de Estatística do Centro de Investigação, Unidade Saúde Local São José, Nova Medical School, Centro de Estatística e Aplicações da Universidade de Lisboa (CEAUL), 1169-166 Lisbon, Portugal; (M.A.); (A.L.P.)
| | - Sule Canberk
- Institute for Research & Innovation in Health (i3S), Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), 4200-135 Porto, Portugal; (M.P.); (S.C.)
| | - Ana Gonçalves
- Department of Pathology, Centro Hospitalar Universitário de São João, 4200-135 Porto, Portugal;
| | - Maria João Bugalho
- Department of Endocrinology, Hospital de Santa Maria, Unidade Saúde Local Santa Maria and Medical Faculty, University of Lisbon, 1069-028 Lisbon, Portugal;
| | - Ana Luísa Papoila
- Gabinete de Estatística do Centro de Investigação, Unidade Saúde Local São José, Nova Medical School, Centro de Estatística e Aplicações da Universidade de Lisboa (CEAUL), 1169-166 Lisbon, Portugal; (M.A.); (A.L.P.)
| | - Paula Soares
- Institute for Research & Innovation in Health (i3S), Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), 4200-135 Porto, Portugal; (M.P.); (S.C.)
- Department of Pathology, Medical Faculty, University of Porto, 4200-135 Porto, Portugal
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11
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Mohammed A, Shaker OG, Khalil MAF, Abu-El-Azayem AK, Samy A, Fathy SA, AbdElguaad MMK, Mahmoud FAM, Erfan R. Circulating miR-206, miR-181b, and miR-21 as promising biomarkers in hypothyroidism and their relationship to related hyperlipidemia and hepatic steatosis. Front Mol Biosci 2024; 11:1307512. [PMID: 38370005 PMCID: PMC10869530 DOI: 10.3389/fmolb.2024.1307512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 01/08/2024] [Indexed: 02/20/2024] Open
Abstract
Background: Thyroid hormones (THs) signaling has profound effects on many physiological processes. The regulation of THs signaling in various tissues involves the action of microRNAs (miRNAs) on thyroid deiodinases and receptors. THs regulate the expression of certain miRNAs and their target messenger RNAs (mRNAs) in various tissues and cells. The modulation of miRNA levels by THs affects their functions in processes such as liver lipid metabolism, skin physiology, and muscle and heart performance. Aim: This research aimed to investigate miR-181b, miR-206, and miR-21 in the serum of patients with subclinical and overt hypothyroidism to determine their possible role in the diagnosis of the disease and their relationship to clinical disorders related to hypothyroidism. Methods: This study included ninety participants, divided evenly into three groups as follows: patients with overt hypothyroidism diagnosed clinically, radiologically, and by investigation, subclinical hypothyroid patients, and healthy volunteers. The patients had a thorough medical history and underwent a clinical examination. Laboratory tests included plasma cholesterol, LDL, HDL, TGs, liver and renal function tests, CBC, fasting insulin, HOMA-IR, HbA1c, TSH, and free T4. The serum levels of miR-21, miR-206, and miR-181b were measured using qRT-PCR. Results: miR-206 and miR-181b levels were higher in the subclinical group, followed by the hypothyroid and control groups. For miR-21, there was a significantly lower mean value in both the hypothyroid and subclinical groups than in the control group, with no difference between the two groups. Both miR-206 and miR-181b showed a significant negative association with albumin and free T4 levels and a significant direct association with GGT, ALT, AST, creatinine, uric acid, TGs, TC, LDL, TSH, thyroid volume, and CAP score. The same correlation pattern was observed for miR-181b, except that it was not significantly correlated with the TGs. For miR-21 levels, there was a significant positive correlation with albumin, free T4 level, and kPa score and a negative correlation with GGT, ALT, AST, creatinine, uric acid, HOMA-IR, HbA1c, TC, LDL, TSH, and CAP score. Cases with F1 kPa score and S2 CAP scores had significantly higher averages for miR-206 and miR-181b, with a p-value of 0.05. Moreover, miR-21 levels were significantly lower in the S2 CAP score group. Conclusion: These miRNAs (miR-206, miR-181b, and miR-21) may be used as diagnostic biomarkers for hypothyroidism. They may be used as therapeutic targets to control dyslipidemia and hepatic steatosis during hypothyroid disease.
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Affiliation(s)
- Asmaa Mohammed
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Olfat G. Shaker
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mahmoud A. F. Khalil
- Department of Microbiology and Immunology, Faculty of Pharmacy, Fayoum University, Fayoum, Egypt
| | - Abeer K. Abu-El-Azayem
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Amira Samy
- Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Shaimaa A. Fathy
- Department of Internal Medicine, Diabetes and Endocrinology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | | | - Fatma A. M. Mahmoud
- Department of Tropical Medicine, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Randa Erfan
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
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12
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Lacoste-Collin L, Decaussin-Petrucci M, Buffet C. [Molecular and other ancillary tests proposed by The Bethesda system for reporting thyroid cytopathology 2023]. Ann Pathol 2024; 44:36-46. [PMID: 37953129 DOI: 10.1016/j.annpat.2023.10.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 10/23/2023] [Indexed: 11/14/2023]
Abstract
For the first time the 2023 version of The Bethesda System for Reporting Thyroid Cytology dedicates a whole chapter (chapter 14) to ancillary studies almost exclusively represented by molecular testing. The latest data reported bring some evidence that molecular testing could help to optimize the diagnostic performance of « indeterminate » categories (AUS and NF). Other studies suggest a promising role to guide the management of suspicious of malignancy and malignant categories. Indeed, the recognition of prognostic and predictive biomarkers analyzed on cytological samples, regardless of how it is collected, has progressed thanks to advances in our knowledge of molecular abnormalities of thyroid tumors. The chapter 14 is presented here highlighting the current and emerging roles of « in-house » and commercialized molecular testing as presented by TSBRTC.
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Affiliation(s)
| | - Myriam Decaussin-Petrucci
- Service d'anatomie pathologique, centre hospitalier Lyon Sud, hospices civils de Lyon, EA 3738, université Lyon 1, Lyon, France
| | - Camille Buffet
- Service des pathologies thyroïdiennes et tumorales endocrines, hôpital Pitié-Salpêtrière, AP-HP, Sorbonne université, GRC n(o) 16, GRC tumeurs thyroïdiennes, 75013 Paris, France; Laboratoire d'Imagerie Biomédicale, CNRS, Inserm, 75006 Paris, France
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13
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Abstract
Background: Very little was known about the molecular pathogenesis of thyroid cancer until the late 1980s. As part of the Centennial celebration of the American Thyroid Association, we review the historical discoveries that contributed to our current understanding of the genetic underpinnings of thyroid cancer. Summary: The pace of discovery was heavily dependent on scientific breakthroughs in nucleic acid sequencing technology, cancer biology, thyroid development, thyroid cell signaling, and growth regulation. Accordingly, we attempt to link the primary observations on thyroid cancer molecular genetics with the methodological and scientific advances that made them possible. Conclusions: The major genetic drivers of the common forms of thyroid cancer are now quite well established and contribute to a significant extent to how we diagnose and treat the disease. However, many challenges remain. Future work will need to unravel the complexity of thyroid cancer ecosystems, which is likely to be a major determinant of their biological behavior and on how they respond to therapy.
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Affiliation(s)
- James A. Fagin
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Yuri E. Nikiforov
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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14
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Xu GJ, Loberg MA, Gallant JN, Sheng Q, Chen SC, Lehmann BD, Shaddy SM, Tigue ML, Phifer CJ, Wang L, Saab-Chalhoub MW, Dehan LM, Wei Q, Chen R, Li B, Kim CY, Ferguson DC, Netterville JL, Rohde SL, Solórzano CC, Bischoff LA, Baregamian N, Shaver AC, Mehrad M, Ely KA, Byrne DW, Stricker TP, Murphy BA, Choe JH, Kagohara LT, Jaffee EM, Huang EC, Ye F, Lee E, Weiss VL. Molecular signature incorporating the immune microenvironment enhances thyroid cancer outcome prediction. CELL GENOMICS 2023; 3:100409. [PMID: 37868034 PMCID: PMC10589635 DOI: 10.1016/j.xgen.2023.100409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 06/03/2023] [Accepted: 08/23/2023] [Indexed: 10/24/2023]
Abstract
Genomic and transcriptomic analysis has furthered our understanding of many tumors. Yet, thyroid cancer management is largely guided by staging and histology, with few molecular prognostic and treatment biomarkers. Here, we utilize a large cohort of 251 patients with 312 samples from two tertiary medical centers and perform DNA/RNA sequencing, spatial transcriptomics, and multiplex immunofluorescence to identify biomarkers of aggressive thyroid malignancy. We identify high-risk mutations and discover a unique molecular signature of aggressive disease, the Molecular Aggression and Prediction (MAP) score, which provides improved prognostication over high-risk mutations alone. The MAP score is enriched for genes involved in epithelial de-differentiation, cellular division, and the tumor microenvironment. The MAP score also identifies aggressive tumors with lymphocyte-rich stroma that may benefit from immunotherapy. Future clinical profiling of the stromal microenvironment of thyroid cancer could improve prognostication, inform immunotherapy, and support development of novel therapeutics for thyroid cancer and other stroma-rich tumors.
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Affiliation(s)
- George J. Xu
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Matthew A. Loberg
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jean-Nicolas Gallant
- Department of Otolaryngology – Head & Neck Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Quanhu Sheng
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Sheau-Chiann Chen
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Brian D. Lehmann
- Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Sophia M. Shaddy
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, USA
| | - Megan L. Tigue
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Courtney J. Phifer
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Li Wang
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Mario W. Saab-Chalhoub
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Lauren M. Dehan
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Qiang Wei
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Rui Chen
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Bingshan Li
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Christine Y. Kim
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Donna C. Ferguson
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - James L. Netterville
- Department of Otolaryngology – Head & Neck Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Sarah L. Rohde
- Department of Otolaryngology – Head & Neck Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Carmen C. Solórzano
- Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Lindsay A. Bischoff
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Naira Baregamian
- Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Aaron C. Shaver
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Mitra Mehrad
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Kim A. Ely
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Daniel W. Byrne
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Thomas P. Stricker
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Barbara A. Murphy
- Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jennifer H. Choe
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Luciane T. Kagohara
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Convergence Institute, Johns Hopkins University, Baltimore, MD, USA
- Bloomberg-Kimmel Immunotherapy Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Elizabeth M. Jaffee
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Convergence Institute, Johns Hopkins University, Baltimore, MD, USA
- Bloomberg-Kimmel Immunotherapy Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Eric C. Huang
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, USA
| | - Fei Ye
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Ethan Lee
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
- Department of Pharmacology, Vanderbilt University, Nashville, TN, USA
- Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA
| | - Vivian L. Weiss
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Pharmacology, Vanderbilt University, Nashville, TN, USA
- Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA
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15
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Owosho AA, Shasteen AM, Aguirre SE, Summersgill KF. Clinicopathologic Study of Sialadenoma Papilliferum of the Minor Salivary Glands: A Series of 8 New Cases With BRAF V600E Mutation-specific Immunohistochemical Analysis. Int J Surg Pathol 2023; 31:1265-1272. [PMID: 36632022 DOI: 10.1177/10668969221147170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Introduction. Sialadenoma papilliferum (SP) is a rare benign neoplasm that usually arises in the minor salivary glands. Recently, it was demonstrated that SP shares similar molecular genetic alterations (BRAF V600E or HRAS mutations) with its morphologic analog, syringocystadenoma papilliferum. Methods. We sought to perform clinicopathologic and immunophenotypic (BRAF V600E and SOX10) analyses on 8 new cases of SP. Results. The cases were from 4 males and 4 females, with ages ranging from 28 to 81 years (average: 64 years). The common locations were the hard palate (n = 3) and buccal mucosa (n = 3). Histopathologically, 7 cases were classic and 1 case was oncocytic. BRAF V600E immunohistochemistry (IHC) was positive in all classic SP, involving both the exophytic and endophytic components, but negative in the oncocytic SP. SOX10 was positive in the endophytic ductal cells of the evaluated classic SP but was negative in the oncocytic SP. Conclusions. We report 8 new cases of this rare salivary gland neoplasm, using BRAF V600E and SOX10 IHC to further support the following points: (1) the functional role of BRAF V600E mutation, RAS/mitogen-activated protein kinase signaling pathway in the pathogenesis of classic SP of salivary glands by IHC; (2) the analogous relationship between SP, syringocystadenoma papilliferum, and papillary seromucinous adenocarcinoma with sinonasal papilloma-like surface component (PSASP-like surface); (3) endophytic ductal component in classic SP arises from the intercalated ducts and not the excretory ducts; and (4) oncocytic SP is distinct from classic SP.
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Affiliation(s)
- Adepitan A Owosho
- Department of Diagnostic Sciences, College of Dentistry, The University of Tennessee Health Science Center, Memphis, TN, USA
- Department of Otolaryngology - Head & Neck Surgery, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA
| | - Alivia M Shasteen
- Department of Diagnostic Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Sarah E Aguirre
- Department of Diagnostic Sciences, College of Dentistry, The University of Tennessee Health Science Center, Memphis, TN, USA
| | - Kurt F Summersgill
- Department of Diagnostic Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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16
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Khan R, Riaz A, Abbasi SA, Sadaf T, Baig RM, Mansoor Q. Identification of transcriptional level variations in microRNA-221 and microRNA-222 as alternate players in the thyroid cancer tumor microenvironment. Sci Rep 2023; 13:15800. [PMID: 37737255 PMCID: PMC10516937 DOI: 10.1038/s41598-023-42941-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 09/16/2023] [Indexed: 09/23/2023] Open
Abstract
Thyroid cancer (TC) is caused by genetic factors and or their cross talk with lifestyle and environment. An important role of miRNA involvement has been identified in different human diseases alongside the cancer. The growing cloud of miRNA discoveries narrates miRNA-221 and miRNA-222 as key elements of ready arsenal in the cancer micro-niches. The aim of present study was to identify the variations of miRNA-221 and miRNA-222 expression in TC tissues and their likely association with TC. miRNA-221 and miRNA-222 were investigated for their expressional alterations in TC tissue samples and healthy thyroid tissue. Expression of miRNA-221 and -222 was analyzed through real time PCR. The relative gene expression of both the miRNA was quantified and statistically evaluated. miRNA-221 and miRNA-222 were found to be highly over expressed when compared with samples of multinodular goiter (MNG) and normal controls. Interestingly, it was also noted that miRNA-221 and miRNA-222 expression is working in a cluster in thyroid cancer patients. So, it can be concluded that the expressional alterations of miRNA-221 and -222 are playing their potential role in the development of thyroid cancer.
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Affiliation(s)
- Rashida Khan
- Department of Zoology, PMAS-Arid Agriculture University, Rawalpindi, Pakistan
- Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan
| | - Aayesha Riaz
- Department of Zoology, PMAS-Arid Agriculture University, Rawalpindi, Pakistan
| | | | - Tanzeela Sadaf
- Department of Zoology, PMAS-Arid Agriculture University, Rawalpindi, Pakistan
| | - Ruqia Mehmood Baig
- Department of Zoology, PMAS-Arid Agriculture University, Rawalpindi, Pakistan.
| | - Qaisar Mansoor
- Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan.
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17
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Honardoost M, Maghsoomi Z, Karimi Behnagh A, Hosseinkhan N, Abdolmaleki F, Panahi M, E Khamseh M. MiR-20b Tissue Expression Level Displays the Diagnostic Value in Papillary Thyroid Carcinoma. Med J Islam Repub Iran 2023; 37:101. [PMID: 38021380 PMCID: PMC10657271 DOI: 10.47176/mjiri.37.101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Indexed: 12/01/2023] Open
Abstract
Background Detection of cancer in patients with thyroid nodules requires sensitive and specific diagnostic modalities that are accurate and inexpensive. This study aimed to identify a potential microRNA(miRNA) panel to detect papillary thyroid carcinoma (PTC). Methods Following a comprehensive literature review as well as miRNA target predictor databases, Real-time PCR was used to quantify the expression of candidate miRNAs in 59 tissue specimens from 30 patients with PTC and 29 patients with benign nodules. A receiver operating characteristic (ROC) curve analysis was used to assess the accuracy of miRNA expression levels compared to the pathology report as the gold standard. Based on prediction results, four miRNAs, including miR-9, miR-20b, miR-221, and miR-222, were selected to evaluate their expression level in Iranian thyroid samples. Results A significant difference between the tissue expression level of miR-20b, miR-9, miR-222, and miR-221 was detected in the PTC group compared with non-PTC (P < 0.05). The area under the curves for the included miRs were 1, 0.98, 0.99, 0.98, and 1, respectively. Conclusion Our results confirmed deregulations of miR-20b as well as miR-222, miR-221, and miR-9 in PTC and, therefore, could be used as a helpful miRNA panel to differentiate PTC from benign nodules, which results in the more efficient clinical management of PTC patients.
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Affiliation(s)
- Maryam Honardoost
- Endocrine Research Center, Institute of Endocrinology and Metabolism,
Iran University of Medical Sciences, Tehran, Iran
| | - Zohreh Maghsoomi
- Endocrine Research Center, Institute of Endocrinology and Metabolism,
Iran University of Medical Sciences, Tehran, Iran
| | - Arman Karimi Behnagh
- Endocrine Research Center, Institute of Endocrinology and Metabolism,
Iran University of Medical Sciences, Tehran, Iran
| | - Nazanin Hosseinkhan
- Endocrine Research Center, Institute of Endocrinology and Metabolism,
Iran University of Medical Sciences, Tehran, Iran
| | - Fereshte Abdolmaleki
- Endocrine Research Center, Institute of Endocrinology and Metabolism,
Iran University of Medical Sciences, Tehran, Iran
| | - Mahshid Panahi
- Pathology Department, Faculty of Medicine, Iran University of Medical
Sciences, Tehran, Iran
| | - Mohammad E Khamseh
- Endocrine Research Center, Institute of Endocrinology and Metabolism,
Iran University of Medical Sciences, Tehran, Iran
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18
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Słowińska-Klencka D, Popowicz B, Kulczycka-Wojdala D, Szymańska B, Duda-Szymańska J, Wojtaszek-Nowicka M, Kaczka K, Klencki M. Effective Use of microRNA, BRAF and Sonographic Risk Assessment in Bethesda III Thyroid Nodules Requires a Different Approach to Nodules with Features of Nuclear Atypia and Other Types of Atypia. Cancers (Basel) 2023; 15:4287. [PMID: 37686562 PMCID: PMC10486535 DOI: 10.3390/cancers15174287] [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: 08/06/2023] [Revised: 08/23/2023] [Accepted: 08/25/2023] [Indexed: 09/10/2023] Open
Abstract
The aim of the study was to analyze the diagnostic usefulness of the combined assessment of the ultrasound risk category of the nodule (evaluated with EU-TIRADS system), the presence of BRAF V600E mutation and the expression of selected microRNAs (miR-146b, miR-221 and miR-222) in Bethesda category III thyroid nodules, separately for cases with nuclear atypia (AUS-nuclear) and cases with other types of atypia (AUS-other). We evaluated 161 nodules (66 AUS-nuclear and 95 AUS-other) with known results of postoperative histopathological examination. The rate of cancer and the rate of PTC among cancers were nearly three times higher in the AUS-nuclear than the AUS-other group. For AUS-nuclear nodules, the most effective diagnostic panel included, in addition to repeat FNA, the assessment of BRAF V600E mutation and the expression of miR-146b and miR-222 (sensitivity: 93.5%, specificity: 80.0%). For AUS-other nodules, a two-step procedure was most effective: at the first stage, forgoing surgical treatment in subjects with a benign repeat FNA outcome, and, at the second stage, the assessment of miR-222 expression and the EU-TIRADS category (sensitivity: 92.3%, specificity: 76.8%). The optimal use of molecular methods in the diagnostics of category III thyroid nodules requires a separate approach for nodules with nuclear atypia and nodules with other types of atypia.
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Affiliation(s)
- Dorota Słowińska-Klencka
- Department of Morphometry of Endocrine Glands, Medical University of Lodz, Pomorska 251 St., 92-213 Lodz, Poland; (D.S.-K.); (B.P.)
| | - Bożena Popowicz
- Department of Morphometry of Endocrine Glands, Medical University of Lodz, Pomorska 251 St., 92-213 Lodz, Poland; (D.S.-K.); (B.P.)
| | - Dominika Kulczycka-Wojdala
- Research Laboratory CoreLab, Medical University of Lodz, Mazowiecka 6/8 St., 92-215 Lodz, Poland; (D.K.-W.); (B.S.)
| | - Bożena Szymańska
- Research Laboratory CoreLab, Medical University of Lodz, Mazowiecka 6/8 St., 92-215 Lodz, Poland; (D.K.-W.); (B.S.)
| | - Joanna Duda-Szymańska
- Department of Pathomorphology, Medical University of Lodz, Pomorska 251 St., 92-213 Lodz, Poland;
| | - Martyna Wojtaszek-Nowicka
- Department of Clinical Endocrinology, Medical University of Lodz, Pomorska 251 St., 92-213 Lodz, Poland;
| | - Krzysztof Kaczka
- Department of General and Oncological Surgery, Surgical Clinical Sciences, Medical University of Lodz, Pomorska 251 St., 92-213 Lodz, Poland;
| | - Mariusz Klencki
- Department of Morphometry of Endocrine Glands, Medical University of Lodz, Pomorska 251 St., 92-213 Lodz, Poland; (D.S.-K.); (B.P.)
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19
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Autore F, Ramassone A, Stirparo L, Pagotto S, Fresa A, Innocenti I, Visone R, Laurenti L. Role of microRNAs in Chronic Lymphocytic Leukemia. Int J Mol Sci 2023; 24:12471. [PMID: 37569845 PMCID: PMC10419063 DOI: 10.3390/ijms241512471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 07/29/2023] [Accepted: 07/31/2023] [Indexed: 08/13/2023] Open
Abstract
Chronic Lymphocytic Leukemia (CLL) is the most common form of leukemia in adults, with a highly variable clinical course. Improvement in the knowledge of the molecular pathways behind this disease has led to the development of increasingly specific therapies, such as BCR signaling inhibitors and BCL-2 inhibitors. In this context, the emerging role of microRNAs (miRNAs) in CLL pathophysiology and their possible application in therapy is worth noting. MiRNAs are one of the most important regulatory molecules of gene expression. In CLL, they can act both as oncogenes and tumor suppressor genes, and the deregulation of specific miRNAs has been associated with prognosis, progression, and drug resistance. In this review, we describe the role of the miRNAs that primarily impact the disease, and how these miRNAs could be used as therapeutic tools. Certainly, the use of miRNAs in clinical practice is still limited in CLL. Many issues still need to be solved, particularly regarding their biological and safety profile, even if several studies have suggested their efficacy on the disease, alone or in combination with other drugs.
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Affiliation(s)
- Francesco Autore
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy (A.F.); (I.I.); (L.L.)
| | - Alice Ramassone
- Center for Advanced Studies and Technology (CAST), G. d’Annunzio University, 66100 Chieti, Italy; (A.R.); (S.P.); (R.V.)
| | - Luca Stirparo
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy (A.F.); (I.I.); (L.L.)
| | - Sara Pagotto
- Center for Advanced Studies and Technology (CAST), G. d’Annunzio University, 66100 Chieti, Italy; (A.R.); (S.P.); (R.V.)
- Department of Medical, Oral and Biotechnological Sciences, G. d’Annunzio University, 66100 Chieti, Italy
| | - Alberto Fresa
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy (A.F.); (I.I.); (L.L.)
| | - Idanna Innocenti
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy (A.F.); (I.I.); (L.L.)
| | - Rosa Visone
- Center for Advanced Studies and Technology (CAST), G. d’Annunzio University, 66100 Chieti, Italy; (A.R.); (S.P.); (R.V.)
- Department of Medical, Oral and Biotechnological Sciences, G. d’Annunzio University, 66100 Chieti, Italy
| | - Luca Laurenti
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy (A.F.); (I.I.); (L.L.)
- Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
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20
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Mondin A, Bertazza L, Barollo S, Pedron MC, Manso J, Piva I, Basso D, Merante Boschin I, Iacobone M, Pezzani R, Mian C, Censi S. Validation of miRNAs as diagnostic and prognostic biomarkers, and possible therapeutic targets in medullary thyroid cancers. Front Endocrinol (Lausanne) 2023; 14:1151583. [PMID: 37361540 PMCID: PMC10285659 DOI: 10.3389/fendo.2023.1151583] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 05/29/2023] [Indexed: 06/28/2023] Open
Abstract
Introduction Medullary thyroid cancer (MTC) is a rare type of neuroendocrine tumor that produces a hormone called calcitonin (CT). Thyroidectomy is the preferred treatment for MTC, as chemotherapy has been shown to have limited effectiveness. Targeted therapy approaches are currently being used for patients with advanced, metastatic MTC. Several studies have identified microRNAs, including miR-21, as playing a role in the development of MTC. Programmed cell death 4 (PDCD4) is a tumor suppressor gene that is an important target of miR-21. Our previous research has shown that high levels of miR-21 are associated with low PDCD4 nuclear scores and high CT levels. The aim of this study was to investigate the potential of this pathway as a novel therapeutic target for MTC. Methods We used a specific process to silence miR-21 in two human MTC cell lines. We studied the effect of this anti-miRNA process alone and in combination with cabozantinib and vandetanib, two drugs used in targeted therapy for MTC. We analyzed the effect of miR-21 silencing on cell viability, PDCD4 and CT expression, phosphorylation pathways, cell migration, cell cycle, and apoptosis. Results Silencing miR-21 alone resulted in a reduction of cell viability and an increase in PDCD4 levels at both mRNA and protein levels. It also led to a reduction in CT expression at both mRNA and secretion levels. When combined with cabozantinib and vandetanib, miR-21 silencing did not affect cell cycle or migration but was able to enhance apoptosis. Conclusion Silencing miR-21, although not showing synergistic activity with TKIs (tyrosine kinase inhibitors), represents a potential alternative worth exploring as a therapeutic target for MTC.
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Affiliation(s)
- Alberto Mondin
- Endocrinology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Loris Bertazza
- Endocrinology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Susi Barollo
- Endocrinology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Maria Chiara Pedron
- Endocrinology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Jacopo Manso
- Endocrinology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Ilaria Piva
- Endocrinology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Daniela Basso
- Laboratory Medicine, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Isabella Merante Boschin
- Department of Surgical, Oncological and Gastroenterological Sciences (DiSCOG), University of Padua, Padua, Italy
| | - Maurizio Iacobone
- Endocrine Surgery Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Raffaele Pezzani
- Endocrinology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Caterina Mian
- Endocrinology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Simona Censi
- Endocrinology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
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Ruiz-Pozo VA, Cadena-Ullauri S, Guevara-Ramírez P, Paz-Cruz E, Tamayo-Trujillo R, Zambrano AK. Differential microRNA expression for diagnosis and prognosis of papillary thyroid cancer. Front Med (Lausanne) 2023; 10:1139362. [PMID: 37089590 PMCID: PMC10113479 DOI: 10.3389/fmed.2023.1139362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 03/16/2023] [Indexed: 04/08/2023] Open
Abstract
Papillary thyroid cancer accounts for 85% of thyroid cancer. The diagnosis is based on ultrasound methods and tumor biopsies (FNA). In recent years, research has revealed the importance of miRNAs, non-coding RNA molecules that regulate gene expression and are involved in many diseases. The present mini review describes upregulated and downregulated miRNAs expression in papillary thyroid cancer patient samples (tissue, serum, plasma) and the genes regulated by these non-coding molecules. In addition, a bibliographic search was performed to identify the expression of miRNAs that are common in tumor tissue and blood. The miRNAs miR-146b, miR-221-3p, miRNA 222, miR-21, miR-296-5p, and miR-145 are common in both tissue and bloodstream of PTC patient samples. Furthermore, these miRNAs regulate genes involved in biological processes such as cell differentiation, proliferation, migration, invasion, and apoptosis. In conclusion, miRNAs could potentially become valuable biomarkers, which could help in the early diagnosis and prognosis of papillary thyroid cancer.
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22
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Toraih EA, Ruiz E, Ning B, Tortelote GG, Hilliard S, Moroz K, Hu T, Fawzy MS, Kandil E. Chromatin-Accessible miRNA Regulons Driving Thyroid Tumorigenesis and Progression. J Am Coll Surg 2023; 236:732-750. [PMID: 36728308 DOI: 10.1097/xcs.0000000000000541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND Although papillary thyroid cancer can remain indolent, associated lymph node metastases and recurrence rates are approximately 50% and 20%, respectively. Omics-based medicine has led to the discovery of predictive biomarkers that can be used to predict tumor progression and clinical outcomes. We aimed to develop a noninvasive omics-driven blood test to allow accurate risk stratification and help tailor individual patient treatment plans. STUDY DESIGN RNA sequencing (seq) and microRNA analysis of The Cancer Genome Atlas and Gene Expression Omnibus datasets were employed to identify an epigenetic prognostic panel. Integrated bulk assay for transposase-accessible chromatin-seq and RNA-seq experiments confirmed the results. Sixty-two paired tumor and adjacent control thyroid tissues and 67 blood samples (62 papillary thyroid cancer and 5 controls) were analyzed for validation using sequencing and real-time polymerase chain reaction and correlated to clinical outcomes. A liposome-exosome fusion clustered regularly interspaced short palindromic repeats (CRISPR)-fluorescent detection system miRNA assay was developed. A predictive risk nomogram was generated and tested for performance. RESULTS Our miRNA panel (miR-146b-5p and miR-221-3p) from tissue and blood was associated with aggressive features and was located within accessible chromatin regions. The miRNA risk score and prognostic nomogram showed higher accuracy in predicting lymph node metastases (miR-146b: area under the curve [AUC] 0.816, sensitivity 76.9%; miR-221: AUC 0.740, sensitivity 79.5%) and recurrence (miR-146b: AUC 0.921, sensitivity 75.0%; miR-221: AUC 0.756, sensitivity 70.0%; p < 0.001) than staging and American Thyroid Association risk stratification. CRISPR-based miRNA assays showed upregulation in the blood of cancer cohorts. CONCLUSIONS CRISPR-based detection of miR-146b and miR-221 in the blood of thyroid cancer patients is a reliable and noninvasive tool for real-time assessment and prognostication that has great potential to provide a direct impact on the care of these patients.
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Affiliation(s)
- Eman A Toraih
- From the Division of General Endocrine and Oncologic Surgery, Department of Surgery (Toraih, Kandil), Tulane University School of Medicine, New Orleans, LA
- the Medical Genetics Unit, Department of Histology and Cell Biology (Toraih); Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, and Suez Canal University, Ismailia, Egypt
| | - Emmanuelle Ruiz
- the Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA (Ruiz)
| | - Bo Ning
- Department of Biochemistry and Molecular Biology (Ning, Hu), Tulane University School of Medicine, New Orleans, LA
| | - Giovane G Tortelote
- Section of Pediatric Nephrology, Department of Pediatrics (Tortelote, Hilliard), Tulane University School of Medicine, New Orleans, LA
| | - Sylvia Hilliard
- Section of Pediatric Nephrology, Department of Pediatrics (Tortelote, Hilliard), Tulane University School of Medicine, New Orleans, LA
| | - Krzysztof Moroz
- Department of Pathology and Laboratory Medicine (Moroz), Tulane University School of Medicine, New Orleans, LA
| | - Tony Hu
- Department of Biochemistry and Molecular Biology (Ning, Hu), Tulane University School of Medicine, New Orleans, LA
| | - Manal S Fawzy
- the Department of Biochemistry, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia (Fawzy)
| | - Emad Kandil
- From the Division of General Endocrine and Oncologic Surgery, Department of Surgery (Toraih, Kandil), Tulane University School of Medicine, New Orleans, LA
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23
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Significance of miRNAs on the thyroid cancer progression and resistance to treatment with special attention to the role of cross-talk between signaling pathways. Pathol Res Pract 2023; 243:154371. [PMID: 36791561 DOI: 10.1016/j.prp.2023.154371] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 02/06/2023] [Accepted: 02/07/2023] [Indexed: 02/12/2023]
Abstract
Thyroid cancer (TC) is the most prevalent endocrine malignant tumor. It has many types, the Papillary thyroid cancer (PTC)(most common and follicular thyroid carcinoma (FTC). Several risk factors have been associated with TC radiation exposure, autoimmunity, and genetics. Microribonucleic acids (miRNAs) are the most important genetic determinants of TC. They are small chains of nucleic acids that are able to inhibit the expression of several target genes. They could target several genes involved in TC proliferation, angiogenesis, apoptosis, development, and even resistance to therapy. Besides, they could influence the stemness of TC. Moreover, they could regulate several signaling pathways such as WNT/β-catenin, PI3K/AKT/mTOR axis, JAK/STAT, TGF- β, EGFR, and P53. Besides signaling pathways, miRNAs are also involved in the resistance of TC to major treatments such as surgery, thyroid hormone-inhibiting therapy, radioactive iodine, and adjuvant radiation. The stability and sensitivity of several miRNAs might be exploited as an approach for the usage of miRNAs as diagnostic and/or prognostic tools in TC.
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24
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Wang CW, Muzakky H, Lee YC, Lin YJ, Chao TK. Annotation-Free Deep Learning-Based Prediction of Thyroid Molecular Cancer Biomarker BRAF (V600E) from Cytological Slides. Int J Mol Sci 2023; 24:ijms24032521. [PMID: 36768841 PMCID: PMC9916807 DOI: 10.3390/ijms24032521] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/11/2023] [Accepted: 01/20/2023] [Indexed: 01/31/2023] Open
Abstract
Thyroid cancer is the most common endocrine cancer. Papillary thyroid cancer (PTC) is the most prevalent form of malignancy among all thyroid cancers arising from follicular cells. Fine needle aspiration cytology (FNAC) is a non-invasive method regarded as the most cost-effective and accurate diagnostic method of choice in diagnosing PTC. Identification of BRAF (V600E) mutation in thyroid neoplasia may be beneficial because it is specific for malignancy, implies a worse prognosis, and is the target for selective BRAF inhibitors. To the authors' best knowledge, this is the first automated precision oncology framework effectively predict BRAF (V600E) immunostaining result in thyroidectomy specimen directly from Papanicolaou-stained thyroid fine-needle aspiration cytology and ThinPrep cytological slides, which is helpful for novel targeted therapies and prognosis prediction. The proposed deep learning (DL) framework is evaluated on a dataset of 118 whole slide images. The results show that the proposed DL-based technique achieves an accuracy of 87%, a precision of 94%, a sensitivity of 91%, a specificity of 71% and a mean of sensitivity and specificity at 81% and outperformed three state-of-the-art deep learning approaches. This study demonstrates the feasibility of DL-based prediction of critical molecular features in cytological slides, which not only aid in accurate diagnosis but also provide useful information in guiding clinical decision-making in patients with thyroid cancer. With the accumulation of data and the continuous advancement of technology, the performance of DL systems is expected to be improved in the near future. Therefore, we expect that DL can provide a cost-effective and time-effective alternative tool for patients in the era of precision oncology.
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Affiliation(s)
- Ching-Wei Wang
- Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei 106335, Taiwan
- Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei 106335, Taiwan
| | - Hikam Muzakky
- Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei 106335, Taiwan
| | - Yu-Ching Lee
- Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei 106335, Taiwan
| | - Yi-Jia Lin
- Department of Pathology, Tri-Service General Hospital, Taipei 106335, Taiwan
- Institute of Pathology and Parasitology, National Defense Medical Center, Taipei 106335, Taiwan
| | - Tai-Kuang Chao
- Department of Pathology, Tri-Service General Hospital, Taipei 106335, Taiwan
- Institute of Pathology and Parasitology, National Defense Medical Center, Taipei 106335, Taiwan
- Correspondence:
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25
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Alves LF, Geraldo MV. MiR-495-3p regulates cell migration and invasion in papillary thyroid carcinoma. Front Oncol 2023; 13:1039654. [PMID: 36776296 PMCID: PMC9911110 DOI: 10.3389/fonc.2023.1039654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 01/10/2023] [Indexed: 01/27/2023] Open
Abstract
Background Papillary thyroid carcinoma (PTC) is the most prevalent histotype of thyroid cancer and the presence of BRAFV600E mutation in these tumors is related to the malignancy and prognosis of the disease. In recent years attention has been focused on the role of microRNAs in the biology of PTC cells, especially in their role in the modulation of pathways related to tumorigenesis. DLK1-DIO3-derived miRNAs have been shown to play important roles in tumor context and are globally downregulated in PTC. Methods Based on a previous in silico target prediction and gene enrichment analysis, we identified miR-495-3p as the candidate with the highest tumor suppressor potential role in PTC among DLK1-DIO3-derived miRNAs. We used bioinformatics and an in vitro model of miR-495-3p overexpression to further understand the influence of this molecule on the tumorigenic processes of PTC. Results Overexpression of miR-495-3p impaired cell migration and invasion of PTC cells harboring the BRAFV600E mutation and affected the expression of targets predicted in the bioinformatic analysis, such as TGFB2, EREG and CCND1. Conclusion Overall, our results indicate that the loss of miR-495-3p expression during PTC development might play an important role in its progression.
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Affiliation(s)
| | - Murilo Vieira Geraldo
- Department of Structural and Functional Biology, University of Campinas (UNICAMP), São Paulo, Brazil
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26
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Weng D, He L, Chen X, Lin H, Ji D, Lu S, Ao L, Wang S. Integrated analysis of transcription factor-mRNA-miRNA regulatory network related to immune characteristics in medullary thyroid carcinoma. Front Immunol 2023; 13:1055412. [PMID: 36713370 PMCID: PMC9877459 DOI: 10.3389/fimmu.2022.1055412] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 12/30/2022] [Indexed: 01/15/2023] Open
Abstract
Background Medullary thyroid carcinoma (MTC), a thyroid C cell-derived malignancy, is poorly differentiated and more aggressive than papillary, follicular and oncocytic types of thyroid cancer. The current therapeutic options are limited, with a third of population suffering resistance. The differential gene expression pattern among thyroid cancer subtypes remains unclear. This study intended to explore the exclusive gene profile of MTC and construct a comprehensive regulatory network via integrated analysis, to uncover the potential key biomarkers. Methods Multiple datasets of thyroid and other neuroendocrine tumors were obtained from GEO and TCGA databases. Differentially expressed genes (DEGs) specific in MTC were identified to construct a transcription factor (TF)-mRNA-miRNA network. The impact of the TF-mRNA-miRNA network on tumor immune characteristics and patient survival was further explored by single-sample GSEA (ssGSEA) and ESTIMATE algorithms, as well as univariate combined with multivariate analyses. RT-qPCR, cell viability and apoptosis assays were performed for in vitro validation. Results We identified 81 genes upregulated and 22 downregulated in MTC but not in other types of thyroid tumor compared to the normal thyroid tissue. According to the L1000CDS2 database, potential targeting drugs were found to reverse the expressions of DEGs, with panobinostat (S1030) validated effective for tumor repression in MTC by in vitro experiments. The 103 DEGs exclusively seen in MTC were involved in signal release, muscle contraction, pathways of neurodegeneration diseases, neurotransmitter activity and related amino acid metabolism, and cAMP pathway. Based on the identified 15 hub genes, a TF-mRNA-miRNA linear network, as well as REST-cored coherent feed-forward loop networks, namely REST-KIF5C-miR-223 and REST-CDK5R2-miR-130a were constructed via online prediction and validation by public datasets and our cohort. Hub-gene, TF and miRNA scores in the TF-mRNA-miRNA network were related to immune score, immune cell infiltration and immunotherapeutic molecules in MTC as well as in neuroendocrine tumor of lung and neuroblastoma. Additionally, a high hub-gene score or a low miRNA score indicated good prognoses of neuroendocrine tumors. Conclusion The present study uncovers underlying molecular mechanisms and potential immunotherapy-related targets for the pathogenesis and drug discovery of MTC.
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Affiliation(s)
- Danfeng Weng
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Long He
- Department of Pain, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Xiangna Chen
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Huangfeng Lin
- Department of Orthopedics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Daihan Ji
- Department of Bioinformatics, Fujian Key Laboratory of Medical Bioinformatics, School of Medical Technology and Engineering, Fujian Medical University, Fuzhou, China
| | - Shuting Lu
- Department of Bioinformatics, Fujian Key Laboratory of Medical Bioinformatics, School of Medical Technology and Engineering, Fujian Medical University, Fuzhou, China
| | - Lu Ao
- Department of Bioinformatics, Fujian Key Laboratory of Medical Bioinformatics, School of Medical Technology and Engineering, Fujian Medical University, Fuzhou, China,*Correspondence: Shenglin Wang, ; Lu Ao,
| | - Shenglin Wang
- Department of Orthopedics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China,Department of Bioinformatics, Fujian Key Laboratory of Medical Bioinformatics, School of Medical Technology and Engineering, Fujian Medical University, Fuzhou, China,*Correspondence: Shenglin Wang, ; Lu Ao,
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Stojanović S, Dobrijević Z, Šelemetjev S, Đorić I, Janković Miljuš J, Živaljević V, Išić Denčić T. MiR-203a-3p, miR-204-3p, miR-222-3p as useful diagnostic and prognostic tool for thyroid neoplasia spectrum. Endocrine 2023; 79:98-112. [PMID: 36103016 DOI: 10.1007/s12020-022-03185-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 08/28/2022] [Indexed: 01/11/2023]
Abstract
PURPOSE The challenge in the diagnosis and treatment of thyroid carcinoma is to correctly classify neoplasias with overlapping features and to identify the high-risk patients among those with a less aggressive form, in order to personalize the treatment of thyroid carcinoma patients accordingly. METHODS MiR-203a-3p, miR-204-3p, and miR-222-3p levels were determined in 99 cases of thyroid neoplasias (77 papillary thyroid carcinomas (PTC) of diverse variants, 12 follicular thyroid adenomas (FTA) and 10 nodular goiters (NG)) along with 99 adjacent non-malignant thyroid tissues using quantitative RT-PCR. The results were evaluated in comparison with the clinicopathological features of the patients and available TCGA data. RESULTS Down-regulated miR-203a-3p indicates the presence of thyroid tumor (PTC or FTA) with high sensitivity (75%) and specificity (73%), while its up-regulation indicates NG. If miR-203a-3p is down-regulated, up-regulated miR-204-3p with high sensitivity (83.3%) and specificity (74.4%) indicates FTA presence, while up-regulated miR-222-3p, with high sensitivity (76.6%) and specificity (75.0%), points to PTC. The expression of miR-204-3p and miR-222-3p depends on the PTC subtype (P < 0.05). While the deregulated expression of tested miRs is associated with a long-range of unfavorable clinicopathological parameters of PTC, only abundant expression of miR-222-3p may be used as an independent predictive factor for the presence of extrathyroid invasion and advanced pTNM stage of PTC (P < 0.05). CONCLUSION Successive evaluation of miR-203a-3p, miR-204-3p, and miR-222-3p expression can help in the differential diagnosis of thyroid neoplasias. A high relative value of miR-222-3p expression is an independent predictive factor for the presence of extrathyroid invasion and advanced pTNM stage of PTC. The panel consisting of miR-203a-3p, miR-204-3p, and miR-222-3p could be used as a diagnostic and prognostic tool for personalizing the treatment of thyroid cancer patients.
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Affiliation(s)
- Stefana Stojanović
- Department for Endocrinology and Radioimmunology, Institute for the Application of Nuclear Energy (INEP), University of Belgrade, Banatska 31b, 11080, Belgrade, Serbia
| | - Zorana Dobrijević
- Department for Metabolism, Institute for the Application of Nuclear Energy (INEP), University of Belgrade, Banatska 31b, 11080, Belgrade, Serbia
| | - Sonja Šelemetjev
- Department for Endocrinology and Radioimmunology, Institute for the Application of Nuclear Energy (INEP), University of Belgrade, Banatska 31b, 11080, Belgrade, Serbia
| | - Ilona Đorić
- Department for Endocrinology and Radioimmunology, Institute for the Application of Nuclear Energy (INEP), University of Belgrade, Banatska 31b, 11080, Belgrade, Serbia
| | - Jelena Janković Miljuš
- Department for Endocrinology and Radioimmunology, Institute for the Application of Nuclear Energy (INEP), University of Belgrade, Banatska 31b, 11080, Belgrade, Serbia
| | - Vladan Živaljević
- Clinic for Endocrine Surgery, Clinical Center of Serbia, Koste Todorovića 8, 11000, Belgrade, Serbia
| | - Tijana Išić Denčić
- Department for Endocrinology and Radioimmunology, Institute for the Application of Nuclear Energy (INEP), University of Belgrade, Banatska 31b, 11080, Belgrade, Serbia.
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VanderLaan PA, Roy-Chowdhuri S, Griffith CC, Weiss VL, Booth CN. Molecular testing of cytology specimens: overview of assay selection with focus on lung, salivary gland, and thyroid testing. J Am Soc Cytopathol 2022; 11:403-414. [PMID: 36184436 PMCID: PMC10225070 DOI: 10.1016/j.jasc.2022.08.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 08/12/2022] [Indexed: 11/22/2022]
Abstract
Ancillary and molecular testing of cytopathology specimens has emerged as a reliable and useful tool to provide diagnostic information and treatment-related biomarker status for the management of cancer patients. The cytology specimens obtained through minimally invasive means have proven suitable testing substrates for a variety of ancillary tests, including immunohistochemistry, fluorescence in situ hybridization, as well as polymerase chain reaction and next generation sequencing molecular techniques. By focusing specifically on the cytology specimen, this review provides an overview of basic testing considerations and assay selection in addition to updates on the ancillary testing of cytologic tumor specimens from the lung, salivary gland, and thyroid.
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Affiliation(s)
- Paul A VanderLaan
- Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
| | - Sinchita Roy-Chowdhuri
- Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
| | | | - Vivian L Weiss
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
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Ahmed R, Samanta S, Banerjee J, Kar SS, Dash SK. Modulatory role of miRNAs in thyroid and breast cancer progression and insights into their therapeutic manipulation. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2022; 3:100131. [PMID: 36568259 PMCID: PMC9780070 DOI: 10.1016/j.crphar.2022.100131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/22/2022] [Accepted: 09/25/2022] [Indexed: 11/07/2022] Open
Abstract
Over the past few decades, thyroid cancer has become one of the most common types of endocrine cancer, contributing to an increase in prevalence. In the year 2020, there were 586,202 newly diagnosed cases of thyroid cancer around the world. This constituted approximately 3.0% of all patients diagnosed with cancer. The World Health Organization reported that there will be 2.3 million women receiving treatment for breast cancer in 2020, with 685,000. Despite the fact that carcinoma is one of the world's leading causes of death, there is still a paucity of information about its biology. MicroRNAs (miRNAs; miRs) are non-coding RNAs that can reduce gene expression by cleaving the 3' untranslated regions of mRNA. These factors make them a potential protein translation inhibitor. Diverse biological mechanisms implicated in the genesis of cancer are modulated by miRNA. The investigation of global miRNA expression in cancer showed regulatory activity through up regulation and down-regulation in several cancers, including thyroid cancer and breast cancer. In thyroid cancer, miRNA influences several cancers related signaling pathways through modulating MAPK, PI3K, and the RAS pathway. In breast cancer, the regulatory activity of miRNA was played through the cyclin protein family, protein kinases and their inhibitors, and other growth promoters or suppressors, which modulated cell proliferation and cell cycle progression. This article's goal is to discuss key miRNA expressions that are involved in the development of thyroid and breast cancer as well as their therapeutic manipulation for these two specific cancer types.
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Affiliation(s)
- Rubai Ahmed
- Department of Physiology, University of Gour Banga, Malda, 732103, West Bengal, India
| | - Sovan Samanta
- Department of Physiology, University of Gour Banga, Malda, 732103, West Bengal, India
| | - Jhimli Banerjee
- Department of Physiology, University of Gour Banga, Malda, 732103, West Bengal, India
| | - Suvrendu Sankar Kar
- Department of Medicine, R.G.Kar Medical College and Hospital, Kolkata, 700004, West Bengal, India
| | - Sandeep Kumar Dash
- Department of Physiology, University of Gour Banga, Malda, 732103, West Bengal, India,Corresponding author.
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Matulić M, Gršković P, Petrović A, Begić V, Harabajsa S, Korać P. miRNA in Molecular Diagnostics. Bioengineering (Basel) 2022; 9:bioengineering9090459. [PMID: 36135005 PMCID: PMC9495386 DOI: 10.3390/bioengineering9090459] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 08/05/2022] [Accepted: 09/07/2022] [Indexed: 11/17/2022] Open
Abstract
MicroRNAs are a class of small non-coding RNA molecules that regulate gene expression on post-transcriptional level. Their biogenesis consists of a complex series of sequential processes, and they regulate expression of many genes involved in all cellular processes. Their function is essential for maintaining the homeostasis of a single cell; therefore, their aberrant expression contributes to development and progression of many diseases, especially malignant tumors and viral infections. Moreover, they can be associated with certain states of a specific disease, obtained in the least invasive manner for patients and analyzed with basic molecular methods used in clinical laboratories. Because of this, they have a promising potential to become very useful biomarkers and potential tools in personalized medicine approaches. In this review, miRNAs biogenesis, significance in cancer and infectious diseases, and current available test and methods for their detection are summarized.
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Affiliation(s)
- Maja Matulić
- Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
| | - Paula Gršković
- Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
| | - Andreja Petrović
- Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
- Institute of Clinical Pathology and Cytology, Merkur University Hospital, 10000 Zagreb, Croatia
| | - Valerija Begić
- Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
- Primary School “Sesvetski Kraljevec”, 10361 Sesvetski Kraljevec, Croatia
| | - Suzana Harabajsa
- Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
- Department of Pathology and Cytology, Division of Pulmonary Cytology Jordanovac, University Hospital Centre Zagreb, 10000 Zagreb, Croatia
| | - Petra Korać
- Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
- Correspondence: ; Tel.: +385-1-4606-278
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Uslu-Beşli L. Circulating Biomarkers in Thyroid Cancer. Biomark Med 2022. [DOI: 10.2174/9789815040463122010006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Thyroid cancer is the most important endocrine cancer with increasing
incidence. While thyroid cancers, especially papillary thyroid cancers, are known to
exhibit generally a favorable outcome with excellent survival rates, some thyroid
cancers are more aggressive with a poor prognosis. Several different biomarkers have
been introduced for the diagnosis of disease, identification of tumor load, assessment of
therapy response, and the detection of recurrence during follow-up of the thyroid
cancer patients. This chapter gives a brief overview of the circulating biomarkers used
in thyroid cancer patients.
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Affiliation(s)
- Lebriz Uslu-Beşli
- Department of Nuclear Medicine, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa,
Istanbul, Turkey
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32
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Yigider AP, Yigit O. Biomarkers in Otorhinolaryngology. Biomark Med 2022. [DOI: 10.2174/9789815040463122010013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Biomarkers of otorhinolaryngologic diseases with higher insult over a
person’s him/herself and overall health services are summarized in brief. In order to
define, diagnose, treat and monitor any disease markers are needed.
Otorhinolaryngology (ORL) is interested in special disease entities of the region
besides otorhinolaryngologic involvements of the systemic diseases and unique forms
of pathologies such as cholesteatoma, Meniere’s disease and otosclerosis. Neoplasia is
another heading to deal with. In the following chapter, one will find an overview of
molecules that have been used as a biomarker as well as the end points of the present
research on the issue relevant with ORL. Day by day, new molecules are being named
however, the pathways of action are rather the same. Readers will find the headings
related to the most common diseases of the field, informing them about where to look
for defining new strategies of understanding of each disease.
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Affiliation(s)
- Ayse Pelin Yigider
- Istanbul Research and Training Hospital Otorhinolaryngology,Istanbul Research and Training Hospital Otorhinolaryngology, Istanbul,Turkey
| | - Ozgur Yigit
- Istanbul Research and Training Hospital Otorhinolaryngology, Istanbul, Turkey
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De Martino M, Esposito F, Capone M, Pallante P, Fusco A. Noncoding RNAs in Thyroid-Follicular-Cell-Derived Carcinomas. Cancers (Basel) 2022; 14:cancers14133079. [PMID: 35804851 PMCID: PMC9264824 DOI: 10.3390/cancers14133079] [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: 04/21/2022] [Revised: 06/13/2022] [Accepted: 06/21/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary Thyroid tumors represent the most common neoplastic pathology of the endocrine system. Mutations occurring in oncogenes and tumor suppressor genes are responsible for thyroid carcinogenesis; however, the complete mutational landscape characterizing these neoplasias has not been completely unveiled. It has been established that only the 2% of the human genome codes for proteins, suggesting that the vast majority of the genome has regulatory capabilities, which, if altered, could account for the onset of cancer. Hence, many scientific efforts are currently focused on the characterization of the heterogeneous class of noncoding RNAs, which represent an abundant part of the transcribed noncoding genome. In this review, we mainly focus on the involvement of microRNAs, long noncoding RNAs, and pseudogenes in thyroid cancer. The determination of the diagnosis, prognosis, and treatment of thyroid cancers based on the evaluation of the noncoding RNA network could allow the implementation of a more personalized approach to fighting these pathologies. Abstract Among the thyroid neoplasias originating from follicular cells, we can include well-differentiated carcinomas, papillary (PTC) and follicular (FTC) thyroid carcinomas, and the undifferentiated anaplastic (ATC) carcinomas. Several mutations in oncogenes and tumor suppressor genes have already been observed in these malignancies; however, we are still far from the comprehension of their full regulation-altered landscape. Even if only 2% of the human genome has the ability to code for proteins, most of the noncoding genome is transcribed, constituting the heterogeneous class of noncoding RNAs (ncRNAs), whose alterations are associated with the development of several human diseases, including cancer. Hence, many scientific efforts are currently focused on the elucidation of their biological role. In this review, we analyze the scientific literature regarding the involvement of microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and pseudogenes in FTC, PTC, and ATC. Recent findings emphasized the role of lncRNAs in all steps of cancer progression. In particular, lncRNAs may control progression steps by regulating the expression of genes and miRNAs involved in cell proliferation, apoptosis, epithelial–mesenchymal transition, and metastatization. In conclusion, the determination of the diagnosis, prognosis, and treatment of cancer based on the evaluation of the ncRNA network could allow the implementation of a more personalized approach to fighting thyroid tumors.
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Affiliation(s)
- Marco De Martino
- Istituto per l’Endocrinologia e l’Oncologia Sperimentale (IEOS) “G. Salvatore”, Consiglio Nazionale delle Ricerche (CNR), Via S. Pansini 5, 80131 Napoli, Italy; (M.D.M.); (F.E.); (M.C.)
| | - Francesco Esposito
- Istituto per l’Endocrinologia e l’Oncologia Sperimentale (IEOS) “G. Salvatore”, Consiglio Nazionale delle Ricerche (CNR), Via S. Pansini 5, 80131 Napoli, Italy; (M.D.M.); (F.E.); (M.C.)
| | - Maria Capone
- Istituto per l’Endocrinologia e l’Oncologia Sperimentale (IEOS) “G. Salvatore”, Consiglio Nazionale delle Ricerche (CNR), Via S. Pansini 5, 80131 Napoli, Italy; (M.D.M.); (F.E.); (M.C.)
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), Università degli Studi di Napoli “Federico II”, Via S. Pansini 5, 80131 Napoli, Italy
| | - Pierlorenzo Pallante
- Istituto per l’Endocrinologia e l’Oncologia Sperimentale (IEOS) “G. Salvatore”, Consiglio Nazionale delle Ricerche (CNR), Via S. Pansini 5, 80131 Napoli, Italy; (M.D.M.); (F.E.); (M.C.)
- Correspondence: (P.P.); (A.F.)
| | - Alfredo Fusco
- Istituto per l’Endocrinologia e l’Oncologia Sperimentale (IEOS) “G. Salvatore”, Consiglio Nazionale delle Ricerche (CNR), Via S. Pansini 5, 80131 Napoli, Italy; (M.D.M.); (F.E.); (M.C.)
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), Università degli Studi di Napoli “Federico II”, Via S. Pansini 5, 80131 Napoli, Italy
- Correspondence: (P.P.); (A.F.)
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Diagnostic Significance of FNAB miRNA Expression in Papillary Thyroid Carcinoma. Diagnostics (Basel) 2022; 12:diagnostics12061384. [PMID: 35741194 PMCID: PMC9221779 DOI: 10.3390/diagnostics12061384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 05/31/2022] [Accepted: 06/02/2022] [Indexed: 12/01/2022] Open
Abstract
The aim of the study was to evaluate the diagnostic utility of specific miRNAs in the preoperative assessment of thyroid nodules. One hundred and sixty thyroid fine needle aspiration biopsy (FNAB) samples with suspected thyroid carcinoma were collected. To detect the levels of miRNA expression in FNAB, next generation small RNA sequencing was performed in 60 samples. Based on the results obtained, three miRNAs (miR125A, miR200B, miR4324) were selected for further analysis. Based on the most frequently reported miRNAs in the literature associated with thyroid papillary carcinoma (PTC), two more miRNA (miR146B, miR221) were selected for further validation, using real-time reverse transcriptase polymerase chain reaction (RT-PCR) in 36 benign and 64 PTC samples. Expression of miR125A, miR146B, miR221, and miR4324 was significantly higher in patients with PTC compared with benign thyroid nodules (p ˂ 0.05). miR125A and miR4324 were also significantly more highly expressed in patients with extrathyroidal tumor extension compared to those without extrathyroidal PTC extension (p < 0.001). We also found a significantly higher expression of miR221 (p = 0.043) in patients with multifocal carcinomas compared to patients with single foci carcinomas. This prospective study showed that the expression analysis of four miRNAs (miR125A, miR146B, miR221, and miR4324) improve accuracy of FNAB, which could allow a better pre-operative diagnostic and prognostic assessment of thyroid malignancies.
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CircSND1/miR-182-5p Axis Promotes Proliferative and Invasive Abilities of Thyroid Cancer via Binding Targeting MET. JOURNAL OF ONCOLOGY 2022; 2022:9175084. [PMID: 35677888 PMCID: PMC9170435 DOI: 10.1155/2022/9175084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/11/2022] [Accepted: 03/18/2022] [Indexed: 12/24/2022]
Abstract
Objective. To monitor the impacts of circSND1 upon thyroid cancer (TC) tissues and cells and its mechanisms. Methods. Thiazole blue (MTT) was adopted to monitor the impacts of circSND1 upon the proliferative abilities of TPC-1 and SW1736 cells. 5-Bromodeoxyuridine (BrdU) combined with flow cytometry was adopted to monitor the impacts of circSND1 upon the DNA synthesis of TPC-1 and SW1736 cells. We adopted transwell experiment to examine the impacts of circSND1 on cell invasive abilities of TPC-1 and SW1736 cells. The mRNA quantitative levels of circSND1, miR-182-5p, and mesenchymal epidermal transformation factor (MET) in TC tissues were detected by qRT-PCR experiment. We also adopted luciferase assay to verify the targeting interaction between miR-182-5p and MET or miR-182-5p and circSND1. Results. CircSND1 mRNA and MET mRNA were upregulated in thyroid cancer tissues. MiR-182-5p quantification was attenuated in thyroid cancer tissues. Downregulation of circSND1 suppressed TC progression in vivo and in vitro. Furthermore, luciferase report assay uncovered that miR-182-5p was a direct binding target of circSND1 and MET was a direct binding target of miR-182-5p. Besides, circSND1 regulated MET expression and thyroid cancer cell function via binding miR-182-5p. Conclusion. Overexpression of circSND1 in TC tissues and cells facilitates TC tumorigenesis and metastasis via suppressing the quantitative level of miR-182-5p and inducing the upregulation of MET mRNA and protein expression, which expected to offer fresh clues for the administration of TC.
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Galuppini F, Censi S, Merante Boschin I, Fassan M, Sbaraglia M, Valeri N, Hahne JC, Bertazza L, Munari G, Galasso M, Cascione L, Barollo S, Rugge M, Vianello F, Dei Tos AP, Mian C, Pennelli G. Papillary Thyroid Carcinoma: Molecular Distinction by MicroRNA Profiling. Front Endocrinol (Lausanne) 2022; 13:834075. [PMID: 35282462 PMCID: PMC8904882 DOI: 10.3389/fendo.2022.834075] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 01/26/2022] [Indexed: 12/15/2022] Open
Abstract
Papillary thyroid carcinoma (PTC) is a miscellaneous disease with a variety of histological variants, each with its own mutational profile, and clinical and prognostic characteristics. Identification of microRNA (miRNA) expression profiles represents an important benchmark for understanding the molecular mechanisms underlying the biological behavior of these unique PTC subtypes in order that they be better characterized. We considered a series of 35 PTC samples with a histological diagnosis of either hobnail (17 cases) or classical variant (nine cases) and with a specific BRAF p.K601E mutation (nine cases). We determined the overall miRNA expression profile with NanoString technology, and both quantitative reverse transcription-PCR and in situ hybridization were used to confirm selected miRNAs. The miRNA signature was found to consistently differentiate specific histotypes and mutational profiles. In contrast to the BRAF p.K601E mutation and classic PTCs, three miRNAs (miR-21-5p, miR-146b-5p, and miR-205-5p) were substantially overexpressed in the hobnail variant. The current study found that different miRNA signature profiles were linked to unique histological variants and BRAF mutations in PTC. Further studies focusing on the downstream pathogenetic functions of mRNAs in thyroid neoplasms are warranted.
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Affiliation(s)
- Francesca Galuppini
- Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Simona Censi
- Endocrinology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | | | - Matteo Fassan
- Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
- Veneto Institute of Oncology, Istituto Di Ricovero E Cura a Carattere Scientifico (IRCCS), Padua, Italy
| | - Marta Sbaraglia
- Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Nicola Valeri
- Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom
| | - Jens Claus Hahne
- Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom
| | - Loris Bertazza
- Endocrinology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Giada Munari
- Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Marco Galasso
- Laboratorio per le Tecnologie delle Terapie Avanzate (LTTA), Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Luciano Cascione
- Bioinformatics Core Unit, Institute of Oncology Research, Bellinzona, Switzerland
| | - Susi Barollo
- Endocrinology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Massimo Rugge
- Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Federica Vianello
- Department of Radiotherapy, Veneto Institute of Oncology, Istituto Di Ricovero E Cura a Carattere Scientifico (IRCCS), Padua, Italy
| | - Angelo Paolo Dei Tos
- Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Caterina Mian
- Endocrinology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Gianmaria Pennelli
- Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
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Stawski R, Nowak D, Perdas E. Cell-Free DNA: Potential Application in COVID-19 Diagnostics and Management. Viruses 2022; 14:321. [PMID: 35215914 PMCID: PMC8880801 DOI: 10.3390/v14020321] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/28/2022] [Accepted: 02/01/2022] [Indexed: 12/04/2022] Open
Abstract
WHO has declared COVID-19 as a worldwide, public health emergency. The elderly, pregnant women, and people with associated co-morbidities, including pulmonary disease, heart failure, diabetes, and cancer are the most predisposed population groups to infection. Cell-free DNA is a very commonly applied marker, which is elevated in various pathological conditions. However, it has a much higher sensitivity than standard biochemical markers. cfDNA appears to be an effective marker of COVID-19 complications, and also serves as a marker of certain underlying health conditions and risk factors of severe illness during COVID-19 infection. We aimed to present the possible mechanisms and sources of cfDNA released during moderate and severe infections. Moreover, we attempt to verify how efficiently cfDNA increase could be applied in COVID-19 risk assessment and how it corresponds with epidemiological data.
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Affiliation(s)
- Robert Stawski
- Department of Clinical Physiology, Medical University of Lodz, 92-215 Lodz, Poland;
| | - Dariusz Nowak
- Department of Clinical Physiology, Medical University of Lodz, 92-215 Lodz, Poland;
| | - Ewelina Perdas
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland
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Mortoglou M, Buha Djordjevic A, Djordjevic V, Collins H, York L, Mani K, Valle E, Wallace D, Uysal-Onganer P. Role of microRNAs in response to cadmium chloride in pancreatic ductal adenocarcinoma. Arch Toxicol 2022; 96:467-485. [PMID: 34905088 PMCID: PMC8837568 DOI: 10.1007/s00204-021-03196-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 11/10/2021] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal and aggressive malignancies with a 5-year survival rate less than 9%. Early detection is particularly difficult due to the lack of symptoms even in advanced stages. microRNAs (miRs/miRNAs) are small (~ 18-24 nucleotides), endogenous, non-coding RNAs, which are involved in the pathogenesis of several malignancies including PDAC. Alterations of miR expressions can lead to apoptosis, angiogenesis, and metastasis. The role of environmental pollutants such as cadmium (Cd) in PDAC has been suggested but not fully understood. This study underlines the role of miRs (miR-221, miR-155, miR-126) in response to cadmium chloride (CdCl2) in vitro. Lethal concentration (LC50) values for CdCl2 resulted in a toxicity series of AsPC-1 > HPNE > BxPC-3 > Panc-1 = Panc-10.5. Following the treatment with CdCl2, miR-221 and miR-155 were significantly overexpressed, whereas miR-126 was downregulated. An increase in epithelial-mesenchymal transition (EMT) via the dysregulation of mesenchymal markers such as Wnt-11, E-cadherin, Snail, and Zeb1 was also observed. Hence, this study has provided evidence to suggest that the environmental pollutant Cd can have a significant role in the development of PDAC, suggesting a significant correlation between miRs and Cd exposure during PDAC progression. Further studies are needed to investigate the precise role of miRs in PDAC progression as well as the role of Cd and other environmental pollutants.
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Affiliation(s)
- Maria Mortoglou
- Cancer Research Group, School of Life Sciences, University of Westminster, London, W1W 6UW UK
| | | | | | - Hunter Collins
- College of Medicine and the Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, 1111 West 17th Street, Tulsa, OK 74107-1898 USA
| | - Lauren York
- College of Medicine and the Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, 1111 West 17th Street, Tulsa, OK 74107-1898 USA
| | - Katherine Mani
- College of Medicine and the Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, 1111 West 17th Street, Tulsa, OK 74107-1898 USA
| | - Elizabeth Valle
- College of Medicine and the Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, 1111 West 17th Street, Tulsa, OK 74107-1898 USA
| | - David Wallace
- College of Medicine and the Department of Pharmacology and Physiology, Oklahoma State University Center for Health Sciences, 1111 West 17th Street, Tulsa, OK 74107-1898 USA
| | - Pinar Uysal-Onganer
- Cancer Research Group, School of Life Sciences, University of Westminster, London, W1W 6UW UK
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Zhang X, Ze Y, Sang J, Shi X, Bi Y, Shen S, Zhang X, Zhu D. Risk factors and diagnostic prediction models for papillary thyroid carcinoma. Front Endocrinol (Lausanne) 2022; 13:938008. [PMID: 36133306 PMCID: PMC9483149 DOI: 10.3389/fendo.2022.938008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 08/15/2022] [Indexed: 12/07/2022] Open
Abstract
Thyroid nodules (TNs) represent a common scenario. More accurate pre-operative diagnosis of malignancy has become an overriding concern. This study incorporated demographic, serological, ultrasound, and biopsy data and aimed to compare a new diagnostic prediction model based on Back Propagation Neural Network (BPNN) with multivariate logistic regression model, to guide the decision of surgery. Records of 2,090 patients with TNs who underwent thyroid surgery were retrospectively reviewed. Multivariate logistic regression analysis indicated that Bethesda category (OR=1.90, P<0.001), TIRADS (OR=2.55, P<0.001), age (OR=0.97, P=0.002), nodule size (OR=0.53, P<0.001), and serum levels of Tg (OR=0.994, P=0.004) and HDL-C (OR=0.23, P=0.001) were statistically significant independent differentiators for patients with PTC and benign nodules. Both BPNN and regression models showed good accuracy in differentiating PTC from benign nodules (area under the curve [AUC], 0.948 and 0.924, respectively). Notably, the BPNN model showed a higher specificity (88.3% vs. 73.9%) and negative predictive value (83.7% vs. 45.8%) than the regression model, while the sensitivity (93.1% vs. 93.9%) was similar between two models. Stratified analysis based on Bethesda indeterminate cytology categories showed similar findings. Therefore, BPNN and regression models based on a combination of demographic, serological, ultrasound, and biopsy data, all of which were readily available in routine clinical practice, might help guide the decision of surgery for TNs.
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Affiliation(s)
- Xiaowen Zhang
- Department of Endocrinology and Metabolism, Endocrine and Metabolic Disease Medical Center, Nanjing University Medical School Affiliated Drum Tower Hospital, Nanjing, China
| | - Yuyang Ze
- Department of Endocrinology and Metabolism, The Fifth People’s Hospital of Suzhou Wujiang, Suzhou, China
| | - Jianfeng Sang
- Department of Thyroid Surgery, Nanjing University Medical School Affiliated Drum Tower Hospital, Nanjing, China
| | - Xianbiao Shi
- Department of Thyroid Surgery, Nanjing University Medical School Affiliated Drum Tower Hospital, Nanjing, China
| | - Yan Bi
- Department of Endocrinology and Metabolism, Endocrine and Metabolic Disease Medical Center, Nanjing University Medical School Affiliated Drum Tower Hospital, Nanjing, China
| | - Shanmei Shen
- Department of Endocrinology and Metabolism, Endocrine and Metabolic Disease Medical Center, Nanjing University Medical School Affiliated Drum Tower Hospital, Nanjing, China
| | - Xinlin Zhang
- Department of Cardiology, Nanjing University Medical School Affiliated Drum Tower Hospital, Nanjing, China
- *Correspondence: Xinlin Zhang, ; Dalong Zhu,
| | - Dalong Zhu
- Department of Endocrinology and Metabolism, Endocrine and Metabolic Disease Medical Center, Nanjing University Medical School Affiliated Drum Tower Hospital, Nanjing, China
- *Correspondence: Xinlin Zhang, ; Dalong Zhu,
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40
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Maleki M, Karajibani M, Sarvani M, Montazerifar F, Salimi S, Heidari6 Z. Correlation between adiponectin rs2241766 and rs266729 polymorphisms and risk of papillary thyroid cancer. MOLECULAR BIOLOGY RESEARCH COMMUNICATIONS 2022; 11:113-118. [PMID: 36718238 PMCID: PMC9661673 DOI: 10.22099/mbrc.2022.43012.1714] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
About 60-80% of thyroid cancer (TC) cases are papillary thyroid cancer (PTC). Studies have shown that serum adiponectin levels are inversely related to the risk of TC and PTC. Aim of the present study was to evaluate the association between adiponectin rs2241766 and rs266729 polymorphisms and risk of PTC. 122 PTC patients and 128 healthy subjects were enrolled in the study. PCR-RFLP and ARMS-PCR methods were used for genotype analysis. The rs266729 polymorphism did not correlate with risk of PTC. As regard rs2241766 polymorphism, the frequency of the GG genotype did not have a significant difference between the two groups, although, PTC cases showed higher frequency of GT genotype compared to controls (OR=2.87, 95% CI=1.56-5.28, P=0.001). We observed a significant association between adiponectin rs2241766 polymorphism and PTC, however, our result showed no significant relationship between adiponectin rs266729 polymorphism and risk of PTC.
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Affiliation(s)
- Mohsen Maleki
- Department of Nutrition, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Mansour Karajibani
- Health Promotion Research Center, Department of Nutrition, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran,Mansour Karajibani and Mohsen Sarvani contributed equally to the project.,Corresponding Author: Health Promotion Research Center, Department of Nutrition, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran. Tel: +98 54 33295717-20; Fax: +98 54 32295728; E. mail: and
| | - Mohsen Sarvani
- Cellular and Molecular Research Center, Research Institue of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran,Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran,Mansour Karajibani and Mohsen Sarvani contributed equally to the project
| | - Farzaneh Montazerifar
- Pregnancy Health Research Center, Department of Nutrition, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Saeedeh Salimi
- Cellular and Molecular Research Center, Research Institue of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran,Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Zahra Heidari6
- Department of Endocrinology and Metabolism, Zahedan University of Medical Sciences, Zahedan, Iran
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Rossi ED, Locantore P, Bruno C, Dell’Aquila M, Tralongo P, Curatolo M, Revelli L, Raffaelli M, Larocca LM, Pantanowitz L, Pontecorvi A. Molecular Characterization of Thyroid Follicular Lesions in the Era of "Next-Generation" Techniques. Front Endocrinol (Lausanne) 2022; 13:834456. [PMID: 35634500 PMCID: PMC9134849 DOI: 10.3389/fendo.2022.834456] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 03/29/2022] [Indexed: 12/26/2022] Open
Abstract
It is unequivocally recognized that thyroid nodules are frequently detected in the adult population and mostly characterized by benign lesions (up to 70% of them), with only 5%-15% malignant lesions. The evaluation of thyroid lesions with fine-needle aspiration cytology (FNAC) represents one of the first and most useful diagnostic tools in the definition of their nature. Despite the fact that the majority of thyroid lesions are correctly diagnosed as either benign (70%-75%) or malignant (5%-10%) entities, the remaining nodules (20%-25%) represent the "gray zone" of follicular lesions, which belong to indeterminate categories, according to the different classification systems. This indeterminate group of lesions includes both benign and malignant entities, which cannot be easily discriminate with morphology alone. In these last decades, the increasing role of molecular testings, feasibly performed on cytological material combined with the discoveries of specific genetic alterations in the field of thyroid pathology, has opened the pace to their more accurate and specific contribution on cytology. In fact, in 2015, in the revised management guidelines for patients with thyroid nodules and well-differentiated thyroid cancers (WDTCs), the American Thyroid Association (ATA) confirmed the performance of molecular testing in thyroid indeterminate cytology, and the same performance was addressed in recent update of the management of thyroid nodules in the second edition of the Bethesda system for reporting thyroid cytopathology (TBSRTC). In the current review, we discuss the role of molecular tests for the different thyroid diagnostic categories of the Bethesda system for reporting thyroid cytopathology, mostly focusing our attention on the follicular and indeterminate lesions.
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Affiliation(s)
- Esther Diana Rossi
- Division of Anatomic Pathology and Histology, Fondazione Policlinico Universitario “Agostino Gemelli” - IRCCS, Rome, Italy
- *Correspondence: Esther Diana Rossi,
| | - Pietro Locantore
- Division of Endocrinology, Fondazione Policlinico Universitario “Agostino Gemelli” - IRCCS, Rome, Italy
| | - Carmine Bruno
- Division of Endocrinology, Fondazione Policlinico Universitario “Agostino Gemelli” - IRCCS, Rome, Italy
| | - Marco Dell’Aquila
- Division of Anatomic Pathology and Histology, Fondazione Policlinico Universitario “Agostino Gemelli” - IRCCS, Rome, Italy
| | - Pietro Tralongo
- Division of Anatomic Pathology and Histology, Fondazione Policlinico Universitario “Agostino Gemelli” - IRCCS, Rome, Italy
| | - Mariangela Curatolo
- Division of Anatomic Pathology and Histology, Fondazione Policlinico Universitario “Agostino Gemelli” - IRCCS, Rome, Italy
| | - Luca Revelli
- Division of Endocrine Surgery, Fondazione Policlinico Universitario “Agostino Gemelli”- IRCCS, Rome, Italy
| | - Marco Raffaelli
- Division of Endocrine Surgery, Fondazione Policlinico Universitario “Agostino Gemelli”- IRCCS, Rome, Italy
| | - Luigi Maria Larocca
- Division of Anatomic Pathology and Histology, Fondazione Policlinico Universitario “Agostino Gemelli” - IRCCS, Rome, Italy
| | - Liron Pantanowitz
- Department of Pathology, University of Michigan, Ann Arbor, MI, United States
| | - Alfredo Pontecorvi
- Division of Endocrinology, Fondazione Policlinico Universitario “Agostino Gemelli” - IRCCS, Rome, Italy
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Wu J, Sun Y, Li J, Ai M, You L, Shi J, Yu F. Analysis of Prognostic Alternative Splicing Reveals the Landscape of Immune Microenvironment in Thyroid Cancer. Front Oncol 2021; 11:763886. [PMID: 34733794 PMCID: PMC8558422 DOI: 10.3389/fonc.2021.763886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 09/28/2021] [Indexed: 11/28/2022] Open
Abstract
Background The incidence of thyroid cancer (THCA) continues to increase in recent decades. Accumulating evidence showed that the unbalanced alternative splicing (AS) promotes the occurrence of cancers and leads to poor prognosis of patients. However, the research on alternative splicing events in THCA is lacking, and its underlying mechanism is not fully understood. This study identifies a novel prognostic signature based on AS events to reveal the relationship of AS with tumor immune microenvironment. Methods Based on the AS data, transcriptional data, and clinical information, the differentially expressed alternative splicings (DEASs) were screened out. Least absolute shrinkage and selection operator (LASSO) regression and multi-Cox regression analyses were employed to identify prognostic results related to AS events and establish a prognostic signature. The predictive ability of the signature was assessed by Kaplan-Meier (K-M) survival curve, risk plots, and receiver operating characteristic (ROC) curves. Furthermore, correlations between tumor-infiltrating immune cells, immune checkpoints, immune score and prognostic signature were analyzed. Results According to the LASSO regression analysis, a total of five AS events were selected to construct the signature. K-M survival curve showed that the higher the risk score, the worse the OS of the patients. Risk plots further confirmed this result. ROC curves indicated the high predictive efficiency of the prognostic signature. As for tumor immune microenvironment, patients in the high-risk group had a higher proportion of immune cells, including plasma cell, CD8+ T cell, macrophages (M0 and M2), and activated dendritic cell. Immune checkpoint proteins, such as PDCD1LG2, HAVCR2, CD274, etc., were significantly higher in the high-risk group. We also found that the ESTIMATE score, stromal score, and immune score were lower in the high-risk group, while the result of tumor purity was the opposite. Conclusions Collectively, a prognostic signature consisting of five AS events in THCA was established. Furthermore, there was an inextricable correlation between immune cell infiltration, immune checkpoint proteins, and AS events. This study will provide a basis for THCA immunotherapy in the future.
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Affiliation(s)
- Jian Wu
- Department of Otorhinolaryngology-Head and Neck Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, China
| | - Yifang Sun
- Department of Ophthalmology, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, China
| | - Junzheng Li
- Department of Otorhinolaryngology-Head and Neck Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, China
| | - Maomao Ai
- Department of Otorhinolaryngology-Head and Neck Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, China
| | - Lihua You
- Department of Otorhinolaryngology-Head and Neck Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, China
| | - Jianbo Shi
- Department of Otorhinolaryngology-Head and Neck Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, China.,Department of Otorhinolaryngology, The First Affiliated Hospital of Sun Yat-Sen University, Sun Yat-Sen University, Guangzhou, China
| | - Feng Yu
- Department of Otorhinolaryngology-Head and Neck Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, China
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43
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Rogucki M, Buczyńska A, Krętowski AJ, Popławska-Kita A. The Importance of miRNA in the Diagnosis and Prognosis of Papillary Thyroid Cancer. J Clin Med 2021; 10:4738. [PMID: 34682861 PMCID: PMC8537372 DOI: 10.3390/jcm10204738] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/06/2021] [Accepted: 10/12/2021] [Indexed: 12/14/2022] Open
Abstract
In recent years, the global incidence of thyroid cancer has been increasing. Despite the significant progress in the diagnostic tools applied for papillary thyroid cancer (PTC) diagnosis, commonly used methods require undergoing invasive diagnostic procedures, such as liquid biopsy, which still, in some cases, remains imprecise. In this case, novel screening and diagnostic biomarkers are still being evaluated using highly specialized techniques, which could increase PTC detection. Currently, a number of genes and proteins associated with PTC development are currently under investigation to assess their clinical utility. Accordingly, a literature search was undertaken to collect novel information about the diagnosis of and prognosis for PTC with a particular emphasis on the role of microRNA (miRNA) evaluation. The early identification of novel biomarkers is essential for facilitating appropriate therapeutic decisions. Moreover, the evaluation of plasma- and serum-derived miRNA measurements could be considered as equivalent thyroid cancer screening tools in the future. On the other hand, the PTC pathogenesis could be evaluated further with the use of miRNA evaluation, which may bring novel insights for potential medical target determination.
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Affiliation(s)
- Mariusz Rogucki
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, 15-276 Bialystok, Poland; (A.J.K.); (A.P.-K.)
| | - Angelika Buczyńska
- Clinical Research Centre, Medical University of Bialystok, 15-276 Bialystok, Poland;
| | - Adam Jacek Krętowski
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, 15-276 Bialystok, Poland; (A.J.K.); (A.P.-K.)
- Clinical Research Centre, Medical University of Bialystok, 15-276 Bialystok, Poland;
| | - Anna Popławska-Kita
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, 15-276 Bialystok, Poland; (A.J.K.); (A.P.-K.)
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MicroRNA-Based Risk Score for Predicting Tumor Progression Following Radioactive Iodine Ablation in Well-Differentiated Thyroid Cancer Patients: A Propensity-Score Matched Analysis. Cancers (Basel) 2021; 13:cancers13184649. [PMID: 34572876 PMCID: PMC8468667 DOI: 10.3390/cancers13184649] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 08/07/2021] [Accepted: 08/27/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The three-tiered American Thyroid Association (ATA) risk stratification helps clinicians tailor decisions regarding follow-up modalities and the need for postoperative radioactive iodine (RAI) ablation and radiotherapy. However, a significant number of well-differentiated thyroid cancers (DTC) progress after treatment. Current follow-up modalities have also been proposed to detect disease relapse and recurrence but have failed to be sufficiently sensitive or specific to detect, monitor, or determine progression. Therefore, we assessed the predictive accuracy of the microRNA-based risk score in DTC with and without postoperative RAI. We confirm the prognostic role of triad biomarkers (miR-2f04, miR-221, and miR-222) with higher sensitivity and specificity for predicting disease progression than the ATA risk score. Compared to indolent tumors, a higher risk score was found in progressive samples and was associated with shorter survival. Consequently, our prognostic microRNA signature and nomogram provide a clinically practical and reliable ancillary measure to determine the prognosis of DTC patients. Abstract To identify molecular markers that can accurately predict aggressive tumor behavior at the time of surgery, a propensity-matching score analysis of archived specimens yielded two similar datasets of DTC patients (with and without RAI). Bioinformatically selected microRNAs were quantified by qRT-PCR. The risk score was generated using Cox regression and assessed using ROC, C-statistic, and Brier-score. A predictive Bayesian nomogram was established. External validation was performed, and causal network analysis was generated. Within the eight-year follow-up period, progression was reported in 51.5% of cases; of these, 48.6% had the T1a/b stage. Analysis showed upregulation of miR-221-3p and miR-222-3p and downregulation of miR-204-5p in 68 paired cancer tissues (p < 0.001). These three miRNAs were not differentially expressed in RAI and non-RAI groups. The ATA risk score showed poor discriminative ability (AUC = 0.518, p = 0.80). In contrast, the microRNA-based risk score showed high accuracy in predicting tumor progression in the whole cohorts (median = 1.87 vs. 0.39, AUC = 0.944) and RAI group (2.23 vs. 0.37, AUC = 0.979) at the cutoff >0.86 (92.6% accuracy, 88.6% sensitivity, 97% specificity) in the whole cohorts (C-statistics = 0.943/Brier = 0.083) and RAI subgroup (C-statistic = 0.978/Brier = 0.049). The high-score group had a three-fold increased progression risk (hazard ratio = 2.71, 95%CI = 1.86–3.96, p < 0.001) and shorter survival times (17.3 vs. 70.79 months, p < 0.001). Our prognostic microRNA signature and nomogram showed excellent predictive accuracy for progression-free survival in DTC.
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Augenlicht A, Saiselet M, Decaussin-Petrucci M, Andry G, Dumont JE, Maenhaut C. MiR-7-5p inhibits thyroid cell proliferation by targeting the EGFR/MAPK and IRS2/PI3K signaling pathways. Oncotarget 2021; 12:1587-1599. [PMID: 34381564 PMCID: PMC8351599 DOI: 10.18632/oncotarget.28030] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 07/13/2021] [Indexed: 12/14/2022] Open
Abstract
The aberrant expression of miRNAs is often correlated to tumor development. MiR-7-5p is a recently discovered downregulated miRNA in thyroid papillary carcinoma (PTC). The goal of this project was to characterize its functional role in thyroid tumorigenesis and to identify the targeted modulated pathways. MiR-7-5p overexpression following transfection in TPC1 and HT-ori3 cells decreased proliferation of the two thyroid cell lines. Analysis of global transcriptome modifications showed that miR-7-5p inhibits thyroid cell proliferation by modulating the MAPK and PI3K signaling pathways which are both necessary for normal thyroid proliferation and play central roles in PTC tumorigenesis. Several effectors of these pathways are indeed targets of miR-7-5p, among which EGFR and IRS2, two upstream activators. We confirmed the upregulation of IRS2 and EGFR in human PTC and showed the existence of a negative correlation between the decreased expression of miR-7-5p and the increased expression of IRS2 or EGFR. Our results thus support a tumor-suppressor activity of miR-7-5p. The decreased expression of miR-7-5p during PTC tumorigenesis might give the cells a proliferative advantage and delivery of miR-7-5p may represent an innovative approach for therapy.
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Affiliation(s)
- Alice Augenlicht
- Institute of Interdisciplinary Research, Université libre de Bruxelles, Brussels, Belgium
| | - Manuel Saiselet
- Institute of Interdisciplinary Research, Université libre de Bruxelles, Brussels, Belgium
| | - Myriam Decaussin-Petrucci
- Service d'Anatomie et Cytologie Pathologiques, Centre Hospitalier Lyon Sud, Université Lyon 1, Pierre Benite Cedex 69495, France
| | - Guy Andry
- Surgery Department, J. Bordet Institute, Brussels 1000, Belgium
| | - Jacques E Dumont
- Institute of Interdisciplinary Research, Université libre de Bruxelles, Brussels, Belgium
| | - Carine Maenhaut
- Institute of Interdisciplinary Research, Université libre de Bruxelles, Brussels, Belgium
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de Santa-Inez DC, Fuziwara CS, Saito KC, Kimura ET. Targeting the Highly Expressed microRNA miR-146b with CRISPR/Cas9n Gene Editing System in Thyroid Cancer. Int J Mol Sci 2021; 22:ijms22157992. [PMID: 34360757 PMCID: PMC8348963 DOI: 10.3390/ijms22157992] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 06/23/2021] [Accepted: 06/25/2021] [Indexed: 12/18/2022] Open
Abstract
Thyroid cancer is the most common endocrine malignancy, and the characterization of the genetic alterations in coding-genes that drive thyroid cancer are well consolidated in MAPK signaling. In the context of non-coding RNAs, microRNAs (miRNAs) are small non-coding RNAs that, when deregulated, cooperate to promote tumorigenesis by targeting mRNAs, many of which are proto-oncogenes and tumor suppressors. In thyroid cancer, miR-146b-5p is the most overexpressed miRNA associated with tumor aggressiveness and progression, while the antisense blocking of miR-146b-5p results in anti-tumoral effect. Therefore, inactivating miR-146b has been considered as a promising strategy in thyroid cancer therapy. Here, we applied the CRISPR/Cas9n editing system to target the MIR146B gene in an aggressive anaplastic thyroid cancer (ATC) cell line. For that, we designed two single-guide RNAs cloned into plasmids to direct Cas9 nickase (Cas9n) to the genomic region of the pre-mir-146b structure to target miR-146b-5p and miR-146b-3p sequences. In this plasmidial strategy, we cotransfected pSp-Cas9n-miR-146b-GuideA-puromycin and pSp-Cas9n-miR-146b-GuideB-GFP plasmids in KTC2 cells and selected the puromycin resistant + GFP positive clones (KTC2-Cl). As a result, we observed that the ATC cell line KTC2-Cl1 showed a 60% decrease in the expression of miR-146b-5p compared to the control, also showing reduced cell viability, migration, colony formation, and blockage of tumor development in immunocompromised mice. The analysis of the MIR146B edited sequence shows a 5 nt deletion in the miR-146b-5p region and a 1 nt deletion in the miR-146b-3p region in KTC2-Cl1. Thus, we developed an effective CRISPR/Cas9n system to edit the MIR146B miRNA gene and reduce miR-146b-5p expression which constitutes a potential molecular tool for the investigation of miRNAs function in thyroid cancer.
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Qiao DH, He XM, Deng X, Ji YC, Yang H, Cheng L, Zhou XY. Aberrant expression of five miRNAs in papillary thyroid carcinomas. J Clin Lab Anal 2021; 35:e23907. [PMID: 34268792 PMCID: PMC8418488 DOI: 10.1002/jcla.23907] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 06/29/2021] [Accepted: 06/30/2021] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND The miRNAs play critical roles in the progression of various tumors. Our study aimed to screen and identify miRNAs to investigate their diagnostic and prognostic value for papillary thyroid carcinoma (PTC). METHODS miRNAs were evaluated in PTC (n = 30) tissues, A-PTC (n = 30), benign nodules (n = 35) and A-benign nodules (n = 35). The expression levels of five miRNAs were quantified using real-time, quantitative PCR. ROC analysis was used to evaluate the miRNA diagnostic value. RESULTS The expression of miR-1296-5p, miR-1301-3p, and miR-532-5p was significantly downregulated (p = 0.0001, p = 0.0006, p = 0.0024, respectively), while miR-551b-3p and miR-455-3p were significantly upregulated in PTC tissues compared to A-PTC tissues (p = 0.0005, p = 0.0046, respectively). Interestingly, the expression of miR-1296-5p was downregulated, while miR-551b-3p and miR-455-3p were upregulated in the A-PTC group compared to the A-benign group. Moreover, the miR-1296-5p expression level was associated with tumor size, the number of foci and the TNM stage; the miR-455-3p expression level was correlated with patient age, tumor size, and TNM stage; and the miR-532-5p expression level was correlated with patient age, lymph node metastasis and TNM stage correspondingly. ROC analysis revealed that the AUCs for miR-1301-3p, miR-1296-5p, miR-455-3p, miR-532-5p, and miR-551b-3p were 0.773, 0.790, 0.783, 0.744, and 0.650, respectively. CONCLUSIONS Our results indicated that miR-1296-5p, miR-1301-3p, miR-532-5p, miR-551b-3p, and miR-455-3p are aberrantly expressed in papillary thyroid carcinomas and correlated with clinicopathological features. ROC curve analysis indicated that these five miRNAs have a potential diagnostic value. Consequently, we speculate that the five altered miRNAs may serve as potential diagnostic and prognostic biomarkers for PTC.
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Affiliation(s)
- De-Hui Qiao
- Department of Thyroid Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xue-Mei He
- Department of Central Laboratory, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xian Deng
- Department of Thyroid Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yi-Chi Ji
- Department of Thyroid Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Hui Yang
- Department of Thyroid Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Lian Cheng
- Department of Thyroid Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xiang-Yu Zhou
- Department of Thyroid Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, China
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Celakovsky P, Kovarikova H, Chrobok V, Mejzlik J, Laco J, Vosmikova H, Chmelarova M, Ryska A. MicroRNA Deregulation in Papillary Thyroid Cancer and its Relationship With BRAF V600E Mutation. In Vivo 2021; 35:319-323. [PMID: 33402480 DOI: 10.21873/invivo.12262] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 11/26/2020] [Accepted: 11/30/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND MicroRNAs (miRNAs) are non-coding regulatory molecules 18-25 nucleotides in length that act as post-transcriptional regulators of gene expression. MiRNAs affect various biological processes including carcinogenesis. Deregulation of miRNAa expression has been described in a variety of tumors including papillary thyroid carcinoma (PTC). The aim of the present study was to investigate the role of selected miRNAs in PTC and find associations between miRNA expression and the BRAF (V600E) mutation. MATERIALS AND METHODS The study group comprised a total of 62 patients with surgically treated PTC. The control group consisted of 30 patients with nodular goitre that were surgically treated in the same time period. The expression status of miR-146b, miR-181a, miR-187, miR-221 and miR-222 was determined using quantitative real-time PCR. BRAF mutation analysis was performed by PCR with reverse hybridization. RESULTS MiR-146b, miR-181a, miR-187, miR-221 and miR-222 were up-regulated in PTC compared to normal thyroid gland tissue of the same patient. MiR-146b, miR-187, miR-221 and miR-222 were also up-regulated in PTC compared to nodular goitre. The recurrent tumors were statistically significantly associated with up-regulation of miR-221. The mutation V600E of BRAF gene was significantly associated with up-regulation of miR-146b and with down-regulation of miR-187. CONCLUSION Over-expression of selected miRNAs in PTC compared to normal thyroid gland tissue and nodular goitre was found. Moreover, miR-221 may serve as a prognostic marker as its over-expression was significantly associated with recurrent tumors.
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Affiliation(s)
- Petr Celakovsky
- Department of Otorhinolaryngology and Head and Neck Surgery, University Hospital Hradec Králové, Králové, Czech Republic;
| | - Helena Kovarikova
- Institute of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Králové, Czech Republic
| | - Viktor Chrobok
- Department of Otorhinolaryngology and Head and Neck Surgery, University Hospital Hradec Králové, Králové, Czech Republic
| | - Jan Mejzlik
- Department of Otorhinolaryngology and Head and Neck Surgery, University Hospital Hradec Králové, Králové, Czech Republic
| | - Jan Laco
- Fingerland Department of Pathology, University Hospital Hradec Králové, Králové, Czech Republic
| | - Hana Vosmikova
- Fingerland Department of Pathology, University Hospital Hradec Králové, Králové, Czech Republic
| | - Marcela Chmelarova
- Institute of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Králové, Czech Republic
| | - Ales Ryska
- Fingerland Department of Pathology, University Hospital Hradec Králové, Králové, Czech Republic
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49
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Liu Y, Li YF, Liu J, Deng ZG, Zeng L, Zhou WB. Long Noncoding RNA GAS5 Targeting miR-221-3p/Cyclin-Dependent Kinase Inhibitor 2B Axis Regulates Follicular Thyroid Carcinoma Cell Cycle and Proliferation. Pathobiology 2021; 88:289-300. [PMID: 34130294 DOI: 10.1159/000513338] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 11/22/2020] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Follicular thyroid carcinoma (FTC) is more aggressive than the most common papillary thyroid carcinoma (PTC). However, the current research on FTC is less than PTC. Here, we investigated the effects of long noncoding RNA (lncRNA) GAS5 and miR-221-3p in FTC. METHODS Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to detect GAS5 and miR-221-3p expression in the FTC tissues and cells. Cell proliferation was assessed by CCK8 and EdU assays. Flow cytometry was performed to determine the cell cycle. The dual-luciferase reporter assay was employed to validate the binding relationship of GAS5/miR-221-3p and miR-221-3p/cyclin-dependent kinase inhibitor 2B (CDKN2B). Western blot was conducted to measure the protein level of CDKN2B. RESULTS Our results displayed that GAS5 was downregulated, while miR-221-3p was upregulated in FTC tissues and cells. What's more, overexpression of GAS5 or miR-221-3p inhibition induced G0/G1 phase arrest and inhibited cell proliferation of FTC cells. GAS5 acted as a sponge of miR-221-3p, and CDKN2B was a target gene of miR-221-3p. Additionally, GAS5 inhibited cell cycle and proliferation of FTC cells via reducing miR-221-3p expression to enhance CDKN2B expression. CONCLUSION GAS5 induced G0/G1 phase arrest and inhibited cell proliferation via targeting miR-221-3p/CDKN2B axis in FTC. Thus, GAS5 may be a potential therapeutic target for the treatment of FTC.
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Affiliation(s)
- Yuan Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.,Department of Nuclear Medicine, The First People's Hospital of Chenzhou, Chenzhou, China
| | - Yi-Fang Li
- Center for Biomedical Engineering, Human Phenome Institute, Fudan University, Shanghai, China
| | - Jia Liu
- Department of Geriatrics, The First People's Hospital of Chenzhou, Chenzhou, China
| | - Zhi-Gang Deng
- Department of Nuclear Medicine, The First People's Hospital of Chenzhou, Chenzhou, China
| | - Li Zeng
- Department of Nuclear Medicine, Cancer Hospital of Hunan Provincial, Changsha, China
| | - Wei-Bing Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
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50
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Zheng YJ, Liang TS, Wang J, Zhao JY, Zhai SN, Yang DK, Wang LD. MicroRNA-155 acts as a diagnostic and prognostic biomarker for oesophageal squamous cell carcinoma. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2021; 48:977-982. [PMID: 32573268 DOI: 10.1080/21691401.2020.1773479] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
MicroRNA-155 is over-expressed in many human cancers, but researches on its association with malignant oesophageal squamous cell carcinoma (ESCC) are limited. The aim of the present study was to evaluate the potential value of miR-155 as a biomarker for ESCC diagnosis and prognosis. In this study, we found that miR-155 was significantly increased in ESCC tissues compared with the paired adjacent tissues and healthy normal controls (p < .001), according to qRT-PCR, which suggested that miR-155 might act as an oncogene in ESCC. In addition, clinical features such as the depth of tumour invasion, tumour size, and TNM stage were all proved to impact the expression of miR-155 (p < .01). Then, ROC curve analysis, reaching an AUC of 0.870, and a sensitivity and specificity of 83.5% and 77.5%, respectively, revealed that miR-155 was a predictive factor for ESCC. As well, high expression of miR-155 was associated with poor overall survival of the patients (log-rank test, p = .004), according to Kaplan-Meier analysis. MiR-155 might be an independent predictor for overall survival in ESCC patients, manifested by Cox regression analysis (HR = 16.94, 95%CI = 3.33-86.12, p = .001). Taken together, miR-155 could be an independent diagnostic and prognostic biomarker for ESCC.
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Affiliation(s)
- Ying-Juan Zheng
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Tian-Song Liang
- Department of Radiotherapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Juan Wang
- Department of Radiotherapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jing-Yi Zhao
- Department of Radiotherapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Su-Nan Zhai
- Department of Radiotherapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Dao-Ke Yang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Department of Radiotherapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Li-Dong Wang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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