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McCoon P, Wang Y, Lai Z, Zhang Q, Li W, Wildsmith S, Morsli N, Raja R, Holoweckyj N, Walker J, de los Reyes M, Mesía R, Licitra L, Ferris RL, Fayette J, Zandberg DP, Siu LL, Haddad R. Mutational Landscape of Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma and Association with Immune Checkpoint Inhibitor Outcomes. Clin Cancer Res 2025; 31:1931-1942. [PMID: 40080442 PMCID: PMC12079100 DOI: 10.1158/1078-0432.ccr-24-2198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 12/10/2024] [Accepted: 03/11/2025] [Indexed: 03/15/2025]
Abstract
PURPOSE Understanding the mutational landscape of recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is important in identifying biomarkers to determine which patients may benefit from immune checkpoint inhibitors (ICI). EXPERIMENTAL DESIGN The HAWK (NCT02207530), CONDOR (NCT02319044), and EAGLE (NCT02369874) studies evaluated R/M HNSCC treatment with durvalumab or durvalumab-tremelimumab. Tumor tissue samples pooled from HAWK/CONDOR (n = 153) and plasma cell-free DNA samples from EAGLE (n = 285) were analyzed to identify somatic alterations and association with survival. RESULTS The mutational landscape was similar in tissue and plasma. Compared with the wild type, TP53 mutations were associated with significantly shorter overall survival (OS; HR; 95% confidence interval) with standard of care (SoC; EAGLE: 2.12; 1.20-3.78) and ICIs (HAWK/CONDOR: 1.49; 1.05-2.12 and EAGLE: 1.44; 0.99-2.10). In EAGLE, patients with TP53 mutations had significantly longer OS with durvalumab-tremelimumab versus SoC (P = 0.045). KMT2D mutations were associated with a trend toward longer OS (HR; 95% confidence interval) versus the wild type in HAWK/CONDOR (0.81; 0.56-1.19) and a trend toward longer OS with ICIs versus SoC in EAGLE. For both mutations, a European Cooperative Oncology Group performance status of 1 was associated with worsened OS, and PD-L1 positivity was associated with improved OS. CONCLUSIONS This is the first large-scale study to show the mutational landscape of R/M HNSCC and its association with clinical outcomes in patients treated with ICIs or SoC. The TP53 mutation was a negative prognostic marker; however, treatment with durvalumab-tremelimumab significantly improved survival over SoC. Further investigation of KMT2D as a predictive biomarker for immunotherapy in R/M HNSCC is warranted.
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Affiliation(s)
| | | | | | - Qu Zhang
- AstraZeneca, Gaithersburg, Maryland
| | | | | | | | | | | | | | | | - Ricard Mesía
- Catalan Institute of Oncology, B-ARGO Group, IGTP, Badalona, Spain
| | - Lisa Licitra
- Head and Neck Medical Oncology, IRCCS Istituto Nazionale Tumori Milan and University of Milan, Milan, Italy
| | - Robert L. Ferris
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Dan P. Zandberg
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania
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2
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Batsaki P, Fortis SP, Gritzapis AD, Razou A, Sakellaridis AC, Grouzi E, Moschandreou D, Koukourakis MI, Zoumpourlis V, Baxevanis CN, Goulielmaki M. Identification of a Novel Immune-Gene Signature with Prognostic Value in Patients with Head and Neck Cancer: A Pilot Study. Biochem Genet 2025:10.1007/s10528-024-11017-8. [PMID: 39779579 DOI: 10.1007/s10528-024-11017-8] [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: 04/25/2024] [Accepted: 12/28/2024] [Indexed: 01/11/2025]
Abstract
The tumor microenvironment has a significant input on prognosis and also for predicting clinical outcomes in various types of cancers. However, tumor tissue is not always available, thus, rendering peripheral blood a preferable alternative in the search for prognostic and predictive gene signatures. Head and neck squamous cell carcinoma (HNSCC) constitutes a quite heterogeneous disease characterized by poor prognosis. Therefore, the discovery of novel therapeutics based on prognostic gene signatures for effective disease governance is of paramount importance. In this study, we report for the first time an immune-gene signature identified in the peripheral blood of HNSCC patients comprising five genes (CLEC4C, IL23A, LCK, LY9, and CD19) which were more than threefold downregulated as compared to healthy individuals and were associated with poor prognosis. By performing analyses of HNSCC tumor samples from The Cancer Genome Atlas (TCGA) database, we discovered that decreased expression of these genes, both as single genes and as a 5-gene signature (5-GS), was significantly correlated with worse overall survival (OS). Our data show that the levels of expression of the 5-GS represent an immune profile predicting OS in patients with HNSCC.
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Grants
- Τ2EDK-03266 European Regional Development Fund and Greek funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call Research-Create-Innovate
- Τ2EDK-03266 European Regional Development Fund and Greek funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call Research-Create-Innovate
- Τ2EDK-03266 European Regional Development Fund and Greek funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call Research-Create-Innovate
- Τ2EDK-03266 European Regional Development Fund and Greek funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call Research-Create-Innovate
- Τ2EDK-03266 European Regional Development Fund and Greek funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call Research-Create-Innovate
- Τ2EDK-03266 European Regional Development Fund and Greek funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call Research-Create-Innovate
- Τ2EDK-03266 European Regional Development Fund and Greek funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call Research-Create-Innovate
- Τ2EDK-03266 European Regional Development Fund and Greek funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call Research-Create-Innovate
- Τ2EDK-03266 European Regional Development Fund and Greek funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call Research-Create-Innovate
- Τ2EDK-03266 European Regional Development Fund and Greek funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call Research-Create-Innovate
- Τ2EDK-03266 European Regional Development Fund and Greek funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call Research-Create-Innovate
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Affiliation(s)
- Panagiota Batsaki
- Cancer Immunology and Immunotherapy Center, Cancer Research Center, Saint Savas Cancer Hospital, 11522, Athens, Greece
| | - Sotirios P Fortis
- Cancer Immunology and Immunotherapy Center, Cancer Research Center, Saint Savas Cancer Hospital, 11522, Athens, Greece
| | - Angelos D Gritzapis
- Cancer Immunology and Immunotherapy Center, Cancer Research Center, Saint Savas Cancer Hospital, 11522, Athens, Greece
| | - Andriana Razou
- Department of Otorhinolaryngology/Head & Neck Surgery, Saint Savas Cancer Hospital, 11522, Athens, Greece
| | - Athanasios C Sakellaridis
- Department of Otorhinolaryngology/Head & Neck Surgery, Saint Savas Cancer Hospital, 11522, Athens, Greece
| | - Elisavet Grouzi
- Department of Transfusion Service and Clinical Hemostasis, Saint Savas Cancer Hospital, 11522, Athens, Greece
| | - Dimitra Moschandreou
- Department of Transfusion Service and Clinical Hemostasis, Saint Savas Cancer Hospital, 11522, Athens, Greece
| | - Michael I Koukourakis
- Department of Radiotherapy/Oncology, Democritus University of Thrace, 68100, Alexandroupolis, Greece
| | - Vassilios Zoumpourlis
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 11635, Athens, Greece
| | - Constantin N Baxevanis
- Cancer Immunology and Immunotherapy Center, Cancer Research Center, Saint Savas Cancer Hospital, 11522, Athens, Greece
| | - Maria Goulielmaki
- Cancer Immunology and Immunotherapy Center, Cancer Research Center, Saint Savas Cancer Hospital, 11522, Athens, Greece.
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3
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Pracha SH, Shrestha S, Ryan N, Upadhaya P, Lamenza FF, Jagadeesha S, Jordanides P, Roth P, Springer A, Oghumu S. Targeting macrophage migration inhibitory factor to inhibit T cell immunosuppression in the tumor microenvironment and improve cancer outcomes in head and neck squamous cell carcinoma. Oral Oncol 2025; 160:107126. [PMID: 39644862 PMCID: PMC11723708 DOI: 10.1016/j.oraloncology.2024.107126] [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: 08/01/2024] [Revised: 11/20/2024] [Accepted: 11/23/2024] [Indexed: 12/09/2024]
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the 7th most common cancer globally with a 40-50 % survival rate. Although macrophage migration inhibitory factor (MIF) is overexpressed in most solid tumors and promotes tumor growth and invasion, the therapeutic potential of MIF inhibition in HNSCC is yet to be explored. In this study, we investigated the efficacy of CPSI-1306, a small-molecule MIF inhibitor, on HNSCC cell growth and cancer associated signaling pathways in vitro, as well as its impact on T cells in the HNSCC tumor microenvironment in vivo. CPSI-1306 did not reduce HNSCC cell proliferation in vitro, and mildly decreased VEGF and EGFR expression. However, CPSI-1306 significantly reduced tumor development in two orthotopic mouse oral cancer (MOC-2 and MOC-1) HNSCC models. Interestingly, CPSI-1306 treatment increased T cell infiltration to the tumor microenvironment and completely abrogated immunosuppressive checkpoint markers TIGIT, TIM3, and CTLA-4, but not PD-1 on tumor infiltrating CD8+ T cells. This was accompanied by increased CD8+ T cell expression of antitumoral cytokines IFN-γ and TNF-α in the draining lymph nodes and Granzyme B in the tumor microenvironment of CPSI-1306 treated tumor bearing mice. Our studies demonstrate that the small molecule MIF inhibitor CPSI-1306 potently inhibits T cell immunosuppression in the tumor microenvironment and reduces tumor growth in HNSCC. These studies open a novel therapeutic option for modulating anti-tumoral T cell immunity to improve HNSCC outcomes by targeting MIF.
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Affiliation(s)
- S Hasan Pracha
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Suvekshya Shrestha
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA; Department of Microbiology, The Ohio State University, Columbus, OH, USA
| | - Nathan Ryan
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Puja Upadhaya
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Felipe F Lamenza
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA; Department of Microbiology, The Ohio State University, Columbus, OH, USA
| | - Sushmitha Jagadeesha
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Pete Jordanides
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Peyton Roth
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Anna Springer
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Steve Oghumu
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
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4
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Patel HV, Shah FD. Mapping the intricacies of GLI1 in hedgehog signaling: A combined bioinformatics and clinical analysis in Head & Neck cancer in Western India. Curr Probl Cancer 2024; 53:101146. [PMID: 39265246 DOI: 10.1016/j.currproblcancer.2024.101146] [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: 04/12/2024] [Revised: 08/09/2024] [Accepted: 09/05/2024] [Indexed: 09/14/2024]
Abstract
BACKGROUND Activation of various cancer stem cell pathways are thought to be responsible for treatment failure and loco-regional recurrence in Head and Neck cancer. Hedgehog signaling, a major cancer stem signaling pathway plays a major role in relapse of disease. GLI1, a transcription activator, plays an important role in canonical/non-canonical activation of Hedgehog signaling. METHODS Data for H&N cancer patients were collected from The Cancer Genome Atlas- H&N Cancer (TCGA-HNSC). GLI1 co-expressed genes in TCGA-HNSC were then identified using cBioPortal and subjected to KEGG pathway analysis by DAVID tool. Network Analyzer and GeneMania plugins from CytoScape were used to identify hub genes and predict a probable pathway from the identified hub genes respectively. To confirm the hypothesis, real-time gene expression was carried out in 75 patients of head and neck cancer. RESULTS Significantly higher GLI1 expression was observed in tumor tissues of H&N cancer and it also showed worst overall survival. Using cBioPortal tool, 2345 genes were identified that were significantly co-expressed with GLI1. From which, 15 hub genes were identified through the Network Analyzer plugin in CytoScape. A probable pathway prediction based on hub genes showed the interconnected molecular mechanism and its role in non-canonical activation of Hedgehog pathway by altering the GLI1 activity. The expressions of SHH, GLI1 and AKT1 were significant with each other and were found to be significantly associated with Age, Lymph-Node status and Keratin. CONCLUSION The study emphasizes the critical role of the Hh pathway's activation modes in H&N cancer, particularly highlighting the non-canonical activation through GLI1 and AKT1. The identification of SHH, GLI1 and AKT1 as potential diagnostic biomarkers and their association with clinic-pathological parameters underscores their relevance in prognostication and treatment planning. Hh pathway activation through GLI1 and its cross-talk with various pathways opens up the possibility of newer treatment strategies and developing a panel of therapeutic targets in H&N cancer patients.
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Affiliation(s)
- Hitarth V Patel
- Junior Research Fellow, Molecular Diagnostic and Research Lab-3, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India
| | - Franky D Shah
- Junior Research Fellow, Molecular Diagnostic and Research Lab-3, Department of Cancer Biology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India.
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5
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Spinato G, Schiavon V, Torvilli S, Carraro S, Amato F, Daloiso A, Di Fiore A, Favero V, Franz L, Marioni G, de Filippis C, Fabbris C, Emanuelli E, Nicolai P. Oral Care in Head and Neck Radiotherapy: Proposal for an Oral Hygiene Protocol. J Pers Med 2024; 14:1013. [PMID: 39338267 PMCID: PMC11433007 DOI: 10.3390/jpm14091013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Revised: 09/18/2024] [Accepted: 09/19/2024] [Indexed: 09/30/2024] Open
Abstract
This review aims to provide a comprehensive overview of the literature on the oral side effects caused by radiotherapy for head and neck cancers. Various treatments are examined to mitigate these sequelae, and a protocol is proposed for dentists and dental hygienists to manage oncological patients. A literature search was conducted to select relevant articles addressing the effects of radiotherapy treatments on the oral cavity, with a particular focus on the development of mucositis, candidiasis, changes in salivary pH, trismus, fibrosis, and alterations in the oral biofilm. PubMed and MedLine were used as search engines, with keyword combinations including: head and neck cancer, mucositis, candida, dental care, dental hygiene, epidemiology, oral microbiome, biofilm, trismus, fibrosis, and salivary pH. A total of 226 articles were identified, spanning the period from 1998 to 2023. Articles deemed inappropriate or in languages other than English or Italian were excluded. A management protocol for oncological patients was proposed, divided into two phases: home-based and professional. Despite the advancements in intensity-modulated radiation therapy, it is impossible to completely avoid damage to healthy tissues. Preventive education and counseling in the dental chair, ongoing motivation, and education about oral hygiene are crucial to combine a good therapeutic outcome with an improved quality of life for the patient.
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Affiliation(s)
- Giacomo Spinato
- Department of Neuroscience, Section of Otolaryngology, University of Padova, 35121 Padova, Italy
| | - Valentina Schiavon
- Department of Neuroscience, School of Dentistry, University of Padova, 35121 Padova, Italy
| | - Sara Torvilli
- Department of Neuroscience, School of Dentistry, University of Padova, 35121 Padova, Italy
| | - Stefano Carraro
- Department of Neuroscience, Section of Otolaryngology, University of Padova, 35121 Padova, Italy
| | - Federica Amato
- Department of Neuroscience, Section of Otolaryngology, University of Padova, 35121 Padova, Italy
| | - Antonio Daloiso
- Department of Neuroscience, Section of Otolaryngology, University of Padova, 35121 Padova, Italy
| | - Adolfo Di Fiore
- Department of Neuroscience, School of Dentistry, University of Padova, 35121 Padova, Italy
| | - Vittorio Favero
- Department of Neuroscience, Section of Maxillofacial Surgery, University of Padova, 35121 Padova, Italy
| | - Leonardo Franz
- Department of Neuroscience, Section of Audiology and Phoniatry, University of Padova, Treviso Hospital, 31100 Treviso, Italy
| | - Gino Marioni
- Department of Neuroscience, Section of Audiology and Phoniatry, University of Padova, Treviso Hospital, 31100 Treviso, Italy
| | - Cosimo de Filippis
- Department of Neuroscience, Section of Audiology and Phoniatry, University of Padova, Treviso Hospital, 31100 Treviso, Italy
| | - Cristoforo Fabbris
- Department of Medicine DIMED, University of Padova, 35122 Padova, Italy
- ENT Unit, Department of Surgery, South Padova United Hospitals, 35043 Padova, Italy
| | - Enzo Emanuelli
- AULSS 2 Marca Trevigiana, Section of Otolaryngology, Treviso Hospital, 31100 Treviso, Italy
| | - Piero Nicolai
- Department of Neuroscience, Section of Otolaryngology, University of Padova, 35121 Padova, Italy
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6
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Molon AC, Heguedusch D, Nunes FD, Cecatto RB, Dos Santos Franco AL, de Oliveira Rodini Pegoraro C, Rodrigues MFSD. A 5-ALA mediated photodynamic therapy increases natural killer cytotoxicity against oral squamous cell carcinoma cell lines. JOURNAL OF BIOPHOTONICS 2024:e202400176. [PMID: 39023037 DOI: 10.1002/jbio.202400176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 06/03/2024] [Accepted: 06/25/2024] [Indexed: 07/20/2024]
Abstract
Oral squamous cell carcinoma (OSCC) constitutes over 90% of oral cancers, known for its aggressiveness and poor prognosis. Photodynamic therapy (PDT) has emerged as a promising adjuvant therapy and is linked to immunogenic cell death, activating innate and adaptive anti-tumor responses. Natural Killer (NK) cells, key players in malignant cell elimination, have not been extensively studied in PDT. This study evaluates whether PDT increases OSCC cell lines' susceptibility to NK cell cytotoxicity. PDT, using 5-aminolevulinic acid (5-ALA) and LED irradiation, was applied to Ca1 and Luc4 cell lines. Results showed a dose-dependent viability decrease post-PDT. Gene expression analysis revealed upregulation of NK cell-activating ligands (ULBP1-4, MICA/B) and decreased MHC class I expression in Ca1, suggesting increased NK cell susceptibility. Enhanced NK cell cytotoxicity was confirmed in Ca1 but not in Luc4 cells. These findings indicate that PDT may enhance NK cell-mediated cytotoxicity in OSCC, offering potential for improved treatment strategies.
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Affiliation(s)
- Angela Cristina Molon
- Post Graduate Program in Biophotonics Applied to Health Sciences, Nove de Julho University, São Paulo, Brazil
| | - Daniele Heguedusch
- Department of Stomatology, Discipline of Oral and Maxillofacial Pathology, School of Dentistry, University of São Paulo, São Paulo, Brazil
| | - Fabio Daumas Nunes
- Department of Stomatology, Discipline of Oral and Maxillofacial Pathology, School of Dentistry, University of São Paulo, São Paulo, Brazil
| | - Rebeca Boltes Cecatto
- Post Graduate Program in Biophotonics Applied to Health Sciences, Nove de Julho University, São Paulo, Brazil
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7
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Ou D, Wu Y, Zhang J, Liu J, Liu Z, Shao M, Guo X, Cui S. MYEOV with High Frequencies of Mutations in Head and Neck Cancers Facilitates Cancer Cell Malignant Behaviors. Biochem Genet 2024; 62:1657-1674. [PMID: 37667096 DOI: 10.1007/s10528-023-10484-9] [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: 02/24/2023] [Accepted: 08/06/2023] [Indexed: 09/06/2023]
Abstract
Cancer driver genes (CDGs) and the driver mutations disrupt the homeostasis of numerous critical cell activities, thereby playing a critical role in tumor initiation and progression. In this study, integrative bioinformatics analyses were performed based on a series of online databases, aiming to identify driver genes with high frequencies of mutations in head and neck cancers. Higher myeloma overexpressed (MYEOV) genetic variation frequency and expression level were connected to a poorer prognosis in head and neck cancer patients. MYEOV was dramatically upregulated within head and neck tumor samples and cells. Consistently, MYEOV overexpression remarkably enhanced the aggressiveness of head and neck cancer cells by promoting colony formation, cell invasion, and cell migration. Conversely, MYEOV knockdown attenuated cancer cell aggressiveness and inhibited tumor growth and metastasis in the oral orthotopic tumor model. In conclusion, MYEOV is overexpressed in head and neck cancer, with greater mutation frequencies correlating to a poorer prognosis in head and neck cancer patients. MYEOV serves as an oncogene in head and neck cancer through the promotion of tumor cell colony formation, invasion, and migration, as well as promoting tumor growth and metastasis in the oral orthotopic tumor model.
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Affiliation(s)
- Deming Ou
- Department of Stomatology, Panyu Central Hospital, Guangzhou, 511400, China.
| | - Ying Wu
- Department of Stomatology, Foshan Hospital of Traditional Chinese Medicine, Foshan, 528000, China
| | - Jibin Zhang
- Department of Stomatology, Panyu Central Hospital, Guangzhou, 511400, China
| | - Jun Liu
- Department of Stomatology, Panyu Central Hospital, Guangzhou, 511400, China
| | - Zeyu Liu
- Department of Stomatology, Panyu Central Hospital, Guangzhou, 511400, China
| | - Minfeng Shao
- Department of Stomatology, Panyu Central Hospital, Guangzhou, 511400, China
| | - Xiaoying Guo
- Department of Stomatology, Panyu Central Hospital, Guangzhou, 511400, China
| | - Shiman Cui
- Department of Stomatology, Panyu Central Hospital, Guangzhou, 511400, China
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8
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Seiwert TY, Wildsmith S, Fayette J, Harrington K, Gillison M, Ahn MJ, Takahashi S, Weiss J, Machiels JP, Baxi S, Baker V, Evans B, Morsli N, Jill Walker, Real K, L'Hernault A, Psyrri A. Outcomes in biomarker-selected subgroups from the KESTREL study of durvalumab and tremelimumab in recurrent or metastatic head and neck squamous cell carcinoma. Cancer Immunol Immunother 2024; 73:70. [PMID: 38430375 PMCID: PMC10908636 DOI: 10.1007/s00262-024-03643-3] [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: 12/14/2023] [Accepted: 01/26/2024] [Indexed: 03/03/2024]
Abstract
BACKGROUND Selective biomarkers may improve outcomes in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) treated with immune checkpoint inhibitor therapy. We investigated three independent biomarkers for association with efficacy in the randomized, phase III KESTREL study (NCT02551159) of first-line durvalumab monotherapy or durvalumab plus tremelimumab versus the EXTREME regimen: programmed cell death ligand-1 (PD-L1) immunohistochemistry, blood tumor mutational burden (bTMB) via circulating tumor DNA, and neutrophil-to-lymphocyte ratio (NLR). METHODS Tumor or blood samples from patients enrolled in the KESTREL study were analyzed for PD-L1, bTMB, and NLR. Associations with overall survival (OS) or objective response rates (ORRs) were evaluated based on prespecified cut-offs for PD-L1 (tumor cell [TC] ≥ 50%/immune cell ≥ 25% or TC ≥ 25%), bTMB (≥ 16 mutations [mut] per megabase [Mb]), and NLR (≤ 7). Ad hoc analyses of exploratory cut-offs were performed. RESULTS Prespecified or exploratory cut-offs for PD-L1 did not enrich for ORR or OS for durvalumab monotherapy or durvalumab plus tremelimumab versus EXTREME. In the bTMB ≥ 16 mut/Mb subgroup, OS hazard ratios (95% confidence interval) for durvalumab monotherapy and durvalumab plus tremelimumab versus EXTREME were 0.90 (0.48-1.72) and 0.69 (0.39-1.25), respectively. Complete response rates were 8.6% with durvalumab plus tremelimumab and 4.3% with EXTREME (≥ 16 mut/Mb subgroup). No improvement in OS was observed for durvalumab monotherapy or durvalumab plus tremelimumab versus EXTREME at prespecified or exploratory NLR cut-offs. CONCLUSIONS bTMB demonstrated potential utility for selecting patients with R/M HNSCC who benefited from durvalumab with or without tremelimumab versus EXTREME. Trial registration ClinicalTrials.gov identifier NCT02551159.
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Affiliation(s)
- Tanguy Y Seiwert
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | | | - Jérôme Fayette
- Centre de Lutte Contre le Cancer Léon Bérard, Lyon-I University, Lyon, France
| | - Kevin Harrington
- Division of Radiotherapy and Imaging, The Royal Marsden/The Institute of Cancer Research NIHR Biomedical Research Centre, London, UK
| | - Maura Gillison
- Department of Thoracic Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Myung-Ju Ahn
- Division of Hematology-Oncology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, South Korea
| | - Shunji Takahashi
- Department of Medical Oncology, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Jared Weiss
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - Jean-Pascal Machiels
- Department of Medical Oncology, Institut Roi Albert II, Cliniques Universitaires Saint-Luc and Institute for Experimental and Clinical Research (IREC, pôle MIRO), Université Catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Shrujal Baxi
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Brent Evans
- Statistics, AstraZeneca, Gaithersburg, MD, USA
| | | | | | - Katia Real
- Oncology R&D, AstraZeneca, Cambridge, UK
| | | | - Amanda Psyrri
- Department of Internal Medicine, Section of Medical Oncology, Attikon University Hospital, National Kapodistrian University of Athens, Athens, Greece
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9
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Wu YC, Huang CS, Hsieh MS, Huang CM, Setiawan SA, Yeh CT, Kuo KT, Liu SC. Targeting of FSP1 regulates iron homeostasis in drug-tolerant persister head and neck cancer cells via lipid-metabolism-driven ferroptosis. Aging (Albany NY) 2024; 16:627-647. [PMID: 38206305 PMCID: PMC10817390 DOI: 10.18632/aging.205409] [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: 05/17/2023] [Accepted: 11/15/2023] [Indexed: 01/12/2024]
Abstract
BACKGROUND Research has demonstrated that some tumor cells can transform into drug-tolerant persisters (DTPs), which serve as a reservoir for the recurrence of the disease. The persister state in cancer cells arises due to temporary molecular reprogramming, and exploring the genetic composition and microenvironment during the development of head and neck squamous cell carcinoma (HNSCC) can enhance our comprehension of the types of cell death that HNSCC, thus identifying potential targets for innovative therapies. This project investigated lipid-metabolism-driven ferroptosis and its role in drug resistance and DTP generation in HNSCC. METHODS High levels of FSP1 were discovered in the tissues of patients who experienced relapse after cisplatin treatment. RNA sequencing indicated that a series of genes related to lipid metabolism were also highly expressed in tissues from these patients. Consistent results were obtained in primary DTP cells isolated from patients who experienced relapse. The Cancer Genome Atlas database confirmed this finding. This revealed that the activation of drug resistance in cancer cells is influenced by FSP1, intracellular iron homeostasis, and lipid metabolism. The regulatory roles of ferroptosis suppressor protein 1 (FSP1) in HNSCC metabolic regulation were investigated. RESULTS We generated human oral squamous cell carcinoma DTP cells (HNSCC cell line) to cisplatin and observed higher expression of FSP1 and lipid-metabolism-related targets in vitro. The shFSP1 blockade attenuated HNSCC-DTP cell stemness and downregulated tumor invasion and the metastatic rate. We found that cisplatin induced FSP1/ACSL4 axis expression in HNSC-DTPC cells. Finally, we evaluated the HNSCC CSC-inhibitory functions of iFSP1 (a metabolic drug and ferroptosis inducer) used for neo-adjuvant chemotherapy; this was achieved by inducing ferroptosis in a patient-derived xenograft mouse model. CONCLUSIONS The present findings elucidate the link between iron homeostasis, ferroptosis, and cancer metabolism in HNSCC-DTP generation and acquisition of chemoresistance. The findings may serve as a suitable model for cancer treatment testing and prediction of precision treatment outcomes. In conclusion, this study provides clinically oriented platforms for evaluating metabolism-modulating drugs (FSP1 inhibitors) and new drug candidates of drug resistance and ferroptotic biomarkers.
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Affiliation(s)
- Yang-Che Wu
- Department of Dentistry, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei City 11031, Taiwan
| | - Chin-Sheng Huang
- Department of Dentistry, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei City 11031, Taiwan
| | - Ming-Shou Hsieh
- Department of Dentistry, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei City 11031, Taiwan
| | - Chih-Ming Huang
- Department of Otolaryngology, Taitung Mackay Memorial Hospital, Taitung City 950408, Taiwan
- Department of Nursing, Tajen University, Yanpu 90741, Pingtung County, Taiwan
| | - Syahru Agung Setiawan
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei City 11031, Taiwan
- Department of Medical Research and Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan
| | - Chi-Tai Yeh
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei City 11031, Taiwan
- Department of Medical Research and Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan
- Continuing Education Program of Food Biotechnology Applications, College of Science and Engineering, National Taitung University, Taitung City 95092, Taiwan
| | - Kuang-Tai Kuo
- Division of Thoracic Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei City 11031, Taiwan
- Division of Thoracic Surgery, Department of Surgery, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan
| | - Shao-Cheng Liu
- Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei City 114, Taiwan
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10
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Wei D, Liu J, Ma J. The value of lymphocyte to monocyte ratio in the prognosis of head and neck squamous cell carcinoma: a meta-analysis. PeerJ 2023; 11:e16014. [PMID: 37719125 PMCID: PMC10501369 DOI: 10.7717/peerj.16014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Accepted: 08/10/2023] [Indexed: 09/19/2023] Open
Abstract
Objectives Although lymphocyte-monocyte ratio (LMR) is a potential prognostic biomarker in many tumor indications, a doubt occurs around its association with head and neck squamous cell carcinoma (HNSCC). We aimed to evaluate the predictive value of LMR in patients with HNSCC. Methods We searched PubMed, Web of Science, EMBASE, and the Cochrane database from inception to May 8, 2023 for systematic review and meta-analysis on LMR and outcomes related to HNSCC development. STATA software was used to estimate the correlation between LMR and prognosis. The risk ratio (hazard ratio, HR) and 95% confidence interval l (CI) for overall survival (OS), disease-free survival (DFS), cancer-specific survival (CSS), and progression-free survival (PFS) were calculated, and the association between LMR and OS was further validated by subgroup analysis. The source of heterogeneity with the results of subgroup analysis was analyzed by meta-regression analysis. This meta-analysis was registered at PROSPERO (CRD42023418766). Results After a comprehensive exploration, the results of 16 selected articles containing 5,234 subjects were evaluated. A raised LMR was connected to improved OS (HR = 1.36% CI [1.14-1.62] P = 0.018), DFS (HR = 0.942, 95% CI [0.631-1.382], P = 0.02), and PFS (HR = 0.932, 95% CI [0.527-1.589], P < 0.022). Subgroup analysis indicated that patients with a low LMR level had a poor prognosis with a critical value of ≥4. The LMR was found to be prognostic for cases with an LMR of <4. The meta-regression analysis showed that the cut-off values and treatment methods were the primary sources of high heterogeneity in patients with HNSCC. Conclusions Our study suggested that an elevated LMR is a potential prognostic biomarker in patients with HNSCC and could be used to predict patient outcomes.
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Affiliation(s)
- Deyou Wei
- Department of Otolaryngology, Yantai Hospital of Traditional Chinese Medicine, Yantai, China
| | - Jiajia Liu
- Department of Otolaryngology, Yantai Hospital of Traditional Chinese Medicine, Yantai, China
| | - Jipeng Ma
- Department of Oncology, Yantai Hospital of Traditional Chinese Medicine, Yantai, China
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11
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Jia W, Chen S, Wei R, Yang X, Zhang M, Qian Y, Liu H, Lei D. CYP4F12 is a potential biomarker and inhibits cell migration of head and neck squamous cell carcinoma via EMT pathway. Sci Rep 2023; 13:10956. [PMID: 37414830 PMCID: PMC10326030 DOI: 10.1038/s41598-023-37950-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 06/30/2023] [Indexed: 07/08/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSC) is the most common malignant tumor of head and neck. Due to the insidious nature of HNSC and the lack of effective early diagnostic indicators, the development of novel biomarkers to improve patient prognosis is particularly urgent. In this study, we explored and validated the correlation between cytochrome P450 family 4 subfamily F member 12 (CYP4F12) expression levels and HNSC progression using data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) datasets and collected patient samples. We analyzed the association of CYP4F12 expression with clinicopathological features, immune correlation and prognosis. Finally, we analyzed the correlation between CYP4F12 and pathways, and verified by experiments. The results showed that CYP4F12 was low expressed in tumor tissues, participated in a variety of phenotypic changes of HNSC and affected immune cell infiltration. Pathway analysis indicated that CYP4F12 may play a key role in tumor cell migration and apoptosis. Experimental results showed that over-expression of CYP4F12 inhibited cell migration and enhanced the adhesion between cells and matrix by inhibiting epithelial-mesenchymal transition (EMT) pathway in HNSC cells. In conclusion, our study provided insights into the role of CYP4F12 in HNSC and revealed that CYP4F12 may be a potential therapeutic target for HNSC.
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Affiliation(s)
- Wenming Jia
- Department of Otorhinolaryngology, Qilu Hospital of Shandong University, National Health Commission (NHC) Key Laboratory of Otorhinolaryngology (Shandong University), Jinan, China
| | - Shuai Chen
- Department of Otorhinolaryngology, Qilu Hospital of Shandong University, National Health Commission (NHC) Key Laboratory of Otorhinolaryngology (Shandong University), Jinan, China
| | - Ran Wei
- Department of Otorhinolaryngology, Qilu Hospital of Shandong University, National Health Commission (NHC) Key Laboratory of Otorhinolaryngology (Shandong University), Jinan, China
| | - Xiaoqi Yang
- Department of Otorhinolaryngology, Qilu Hospital of Shandong University, National Health Commission (NHC) Key Laboratory of Otorhinolaryngology (Shandong University), Jinan, China
| | - Minfa Zhang
- Department of Otolaryngology/Head and Neck Surgery, Institute of Otolaryngology, Affiliated Hospital of Binzhou Medical University, Binzhou, China
| | - Ye Qian
- Department of Otorhinolaryngology, Qilu Hospital of Shandong University, National Health Commission (NHC) Key Laboratory of Otorhinolaryngology (Shandong University), Jinan, China
| | - Heng Liu
- Department of Otorhinolaryngology, Qilu Hospital of Shandong University, National Health Commission (NHC) Key Laboratory of Otorhinolaryngology (Shandong University), Jinan, China.
| | - Dapeng Lei
- Department of Otorhinolaryngology, Qilu Hospital of Shandong University, National Health Commission (NHC) Key Laboratory of Otorhinolaryngology (Shandong University), Jinan, China.
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12
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Świętek A, Gołąbek K, Hudy D, Gaździcka J, Biernacki K, Miśkiewicz-Orczyk K, Zięba N, Misiołek M, Strzelczyk JK. The Potential Association between E2F2, MDM2 and p16 Protein Concentration and Selected Sociodemographic and Clinicopathological Characteristics of Patients with Oral Squamous Cell Carcinoma. Curr Issues Mol Biol 2023; 45:3268-3278. [PMID: 37185737 PMCID: PMC10137059 DOI: 10.3390/cimb45040213] [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: 03/06/2023] [Revised: 04/05/2023] [Accepted: 04/06/2023] [Indexed: 05/17/2023] Open
Abstract
BACKGROUND E2F transcription factor 2 (E2F2), murine double minute 2 (MDM2) and p16 are some of the key proteins associated with the control of the cell cycle. The aim of this study was to evaluate E2F2, MDM2 and p16 concentrations in the tumour and margin samples of oral squamous cell carcinoma and to assess their association with some selected sociodemographic and clinicopathological characteristics of the patients. METHODS The study group consisted of 73 patients. Protein concentrations were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS There were no statistically significant differences in the levels of E2F2, MDM2 or p16 in the tumour samples as compared to the margin specimens. We found that patients with N0 showed significantly lower E2F2 concentrations than patients with N1 in the tumour samples and the median protein concentration of E2F2 was higher in HPV-negative patients in the tumour samples. Moreover, the level of p16 in the margin samples was lower in alcohol drinkers as compared to non-drinkers. Similar observations were found in concurrent drinkers and smokers compared to non-drinkers and non-smokers. CONCLUSIONS E2F2 could potentially promote tumour progression and metastasis. Moreover, our results showed a differential level of the analysed proteins in response to alcohol consumption and the HPV status.
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Affiliation(s)
- Agata Świętek
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 19 Jordana St., 41-808 Zabrze, Poland
- Silesia LabMed Research and Implementation Centre, Medical University of Silesia in Katowice, 19 Jordana St., 41-808 Zabrze, Poland
| | - Karolina Gołąbek
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 19 Jordana St., 41-808 Zabrze, Poland
| | - Dorota Hudy
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 19 Jordana St., 41-808 Zabrze, Poland
| | - Jadwiga Gaździcka
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 19 Jordana St., 41-808 Zabrze, Poland
| | - Krzysztof Biernacki
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 19 Jordana St., 41-808 Zabrze, Poland
| | - Katarzyna Miśkiewicz-Orczyk
- Department of Otorhinolaryngology and Oncological Laryngology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 10 C Skłodowskiej St., 41-800 Zabrze, Poland
| | - Natalia Zięba
- Department of Otorhinolaryngology and Oncological Laryngology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 10 C Skłodowskiej St., 41-800 Zabrze, Poland
| | - Maciej Misiołek
- Department of Otorhinolaryngology and Oncological Laryngology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 10 C Skłodowskiej St., 41-800 Zabrze, Poland
| | - Joanna Katarzyna Strzelczyk
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 19 Jordana St., 41-808 Zabrze, Poland
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13
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Yeh TJ, Luo CW, Du JS, Huang CT, Wang MH, Chuang TM, Gau YC, Cho SF, Liu YC, Hsiao HH, Chen LT, Pan MR, Wang HC, Moi SH. Deciphering the Functions of Telomerase Reverse Transcriptase in Head and Neck Cancer. Biomedicines 2023; 11:691. [PMID: 36979671 PMCID: PMC10044978 DOI: 10.3390/biomedicines11030691] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 02/19/2023] [Accepted: 02/22/2023] [Indexed: 03/30/2023] Open
Abstract
Head and neck cancers (HNCs) are among the ten leading malignancies worldwide. Despite significant progress in all therapeutic modalities, predictive biomarkers, and targeted therapies for HNCs are limited and the survival rate is unsatisfactory. The importance of telomere maintenance via telomerase reactivation in carcinogenesis has been demonstrated in recent decades. Several mechanisms could activate telomerase reverse transcriptase (TERT), the most common of which is promoter alternation. Two major hotspot TERT promoter mutations (C228T and C250T) have been reported in different malignancies such as melanoma, genitourinary cancers, CNS tumors, hepatocellular carcinoma, thyroid cancers, sarcomas, and HNCs. The frequencies of TERT promoter mutations vary widely across tumors and is quite high in HNCs (11.9-64.7%). These mutations have been reported to be more enriched in oral cavity SCCs and HPV-negative tumors. The association between TERT promoter mutations and poor survival has also been demonstrated. Till now, several therapeutic strategies targeting telomerase have been developed although only a few drugs have been used in clinical trials. Here, we briefly review and summarize our current understanding and evidence of TERT promoter mutations in HNC patients.
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Affiliation(s)
- Tsung-Jang Yeh
- Division of Hematology & Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Chi-Wen Luo
- Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Department of Cosmetic Science and Institute of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan
| | - Jeng-Shiun Du
- Division of Hematology & Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Chien-Tzu Huang
- Division of Hematology & Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Min-Hung Wang
- Division of Hematology & Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Tzer-Ming Chuang
- Division of Hematology & Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Yuh-Ching Gau
- Division of Hematology & Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Shih-Feng Cho
- Division of Hematology & Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Yi-Chang Liu
- Division of Hematology & Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Hui-Hua Hsiao
- Division of Hematology & Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Li-Tzong Chen
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan
| | - Mei-Ren Pan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
| | - Hui-Ching Wang
- Division of Hematology & Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Sin-Hua Moi
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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14
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Blocker SJ, Morrison S, Everitt JI, Cook J, Luo S, Watts TL, Mowery YM. Whole-Slide Cytometric Feature Mapping for Distinguishing Tumor Genomic Subtypes in Head and Neck Squamous Cell Carcinoma Whole-Slide Images. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:182-190. [PMID: 36414086 PMCID: PMC9885294 DOI: 10.1016/j.ajpath.2022.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 10/24/2022] [Accepted: 11/03/2022] [Indexed: 11/21/2022]
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease where, in advanced stages, clinical and pathologic stages do not correlate with outcome. Molecular and genomic biomarkers for HNSCC classification have shown promise for prognostic and therapeutic applications. This study utilized automated image analysis techniques in whole-slide images of HNSCC tumors to identify relationships between cytometric features and genomic phenotypes. Hematoxylin and eosin-stained slides of HNSCC tumors (N = 49) were obtained from The Cancer Imaging Archive, along with accompanying clinical, pathologic, genomic, and proteomic reports. Automated nuclear detection was performed across the entirety of slides, and cytometric feature maps were generated. Forty-one cytometric features were evaluated for associations with tumor grade, tumor stage, tumor subsite, and integrated genomic subtype. Thirty-two features demonstrated significant association with integrated genomic subtype when corrected for multiple comparisons. In particular, the basal subtype was visually distinguishable from the chromosomal instability and immune subtypes based on cytometric feature measurements. No features were significantly associated with tumor grade, stage, or subsite. This study provides preliminary evidence that features derived from tissue pathology slides could provide insights into genomic phenotypes of HNSCC.
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Affiliation(s)
- Stephanie J Blocker
- Center for In Vivo Microscopy, Department of Radiology, Duke University School of Medicine, Durham, North Carolina.
| | - Samantha Morrison
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North Carolina
| | - Jeffrey I Everitt
- Department of Pathology, Duke University School of Medicine, Durham, North Carolina
| | - James Cook
- Center for In Vivo Microscopy, Department of Radiology, Duke University School of Medicine, Durham, North Carolina
| | - Sheng Luo
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North Carolina
| | - Tammara L Watts
- Department of Head and Neck Surgery and Communication Sciences, Duke University School of Medicine, Durham, North Carolina
| | - Yvonne M Mowery
- Department of Head and Neck Surgery and Communication Sciences, Duke University School of Medicine, Durham, North Carolina; Department of Radiation Oncology, Duke University School of Medicine, Durham, North Carolina
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15
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Wang Q, Liao C, Tan Z, Li X, Guan X, Li H, Tian Z, Liu J, An J. FUT6 inhibits the proliferation, migration, invasion, and EGF-induced EMT of head and neck squamous cell carcinoma (HNSCC) by regulating EGFR/ERK/STAT signaling pathway. Cancer Gene Ther 2023; 30:182-191. [PMID: 36151332 DOI: 10.1038/s41417-022-00530-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 08/10/2022] [Accepted: 08/26/2022] [Indexed: 02/07/2023]
Abstract
Glycosylation change is one of the landmark events of tumor occurrence and development, and tumor cells may be inhibited by regulating the aberrant expression of glycosyltransferases. Currently, fucosyltransferase VI (FUT6), which is involved in the synthesis of α-1, 3 fucosyl bond, has been detected to be closely associated with multiple tumors, but its function and mechanism in head and neck squamous cell carcinoma (HNSCC) still need further research. In this study, FUT6 knockdown and overexpression strategies were used to investigate the effects of FUT6 on cell proliferation, migration, and invasion, as well as the growth and metastasis of HNSCC in a xenografts mouse model. The protein expression levels of epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK), Signal Transducer and Activator of Transcription (STAT), protein kinase B (AKT), c-Myc, and epithelial-mesenchymal transition (EMT) markers were determined by western blot analysis. Our research found that the mRNA expression of FUT6 was lower in HNSCC tissues than in normal mucosal epithelial tissues. In Cal-27 and FaDu cells, FUT6 overexpression inhibited cell proliferation, migration and invasion, causing upregulation of ZO-1 and E-cadherin, downregulation of N-cadherin and Vimentin, and finally decreased the phosphorylation levels of EGFR, ERK, STAT, and c-Myc. In HSC-3 cells, knockdown of FUT6 promoted cell proliferation, migration and invasion, downregulating ZO-1 and E-cadherin, upregulating N-cadherin and Vimentin, and increased the phosphorylation levels of EGFR, ERK, STAT, and c-Myc. In the HNSCC xenografts mouse, FUT6 overexpression inhibited tumor growth and metastasis. In summary, FUT6 controls the proliferation, migration, invasion, and EGF-induced EMT of HNSCC by regulating EGFR/ERK/STAT signaling pathway, indicating its potential future therapeutic application for HNSCC.
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Affiliation(s)
- Qian Wang
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, 563000, Zunyi, Guizhou Province, China
| | - Chengcheng Liao
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, 563000, Zunyi, Guizhou Province, China.,Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, 563000, Zunyi, Guizhou Province, China
| | - Zhangxue Tan
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, 563000, Zunyi, Guizhou Province, China
| | - Xiaolan Li
- Microbial Resources and Drug Development Key Laboratory of Guizhou Tertiary Institution, Life Sciences Institute, Zunyi Medical University, 563000, Zunyi, China
| | - Xiaoyan Guan
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, 563000, Zunyi, Guizhou Province, China
| | - Hao Li
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, 563000, Zunyi, Guizhou Province, China
| | - Zhongjia Tian
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, 563000, Zunyi, Guizhou Province, China
| | - Jianguo Liu
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, 563000, Zunyi, Guizhou Province, China.
| | - Jiaxing An
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, 563000, Zunyi, Guizhou Province, China.
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16
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Han YK, Park HY, Park SG, Hwang JJ, Park HR, Yi JM. Promoter Methylation of Cancer Stem Cell Surface Markers as an Epigenetic Biomarker for Prognosis of Oral Squamous Cell Carcinoma. Int J Mol Sci 2022; 23:ijms232314624. [PMID: 36498950 PMCID: PMC9737199 DOI: 10.3390/ijms232314624] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/20/2022] [Accepted: 11/21/2022] [Indexed: 11/24/2022] Open
Abstract
Growing evidence suggests that genetic and epigenetic factors, including environmental factors, contribute to the development of oral squamous cell carcinoma (OSCC). Here, we investigated the transcriptional silencing of the CD24, CD44, CD133, and CD147 genes, which are well-known cancer stem cell surface markers in various cancer types, including OSCC. We first examined the correlation between the transcriptional expression level and reactivation by 5-aza-2′-deoxycytidine (5-aza-dC) and the promoter methylation levels of the four genes in several OSCC cell lines. We observed promoter hypermethylation for the CD24, CD133, and CD147 genes at 70%, 75%, and 70%, respectively, in OSCC cell lines compared to normal oral mucosa tissues (<53%), indicating that this methylation pattern is cancer-specific, which was confirmed by bisulfite sequencing analysis. More specifically, the expression and methylation profiles of CD133 and CD147 extracted from The Cancer Genome Atlas (TCGA) database were negatively correlated, supporting their epigenetic regulation in primary OSCC tumors. The methylation status of CD133 and CD147 was associated with poor survival in patients with OSCC using the TCGA database. Our findings provide additional insight into the abnormal DNA methylation of CD133 and that CD147 could be used for the diagnosis and therapeutic treatment of patients with OSCC.
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Affiliation(s)
- Yu Kyeong Han
- Department of Microbiology and Immunology, College of Medicine, Inje University, Busan 47392, Republic of Korea
| | - Ha Young Park
- Department of Pathology, College of Medicine, Inje University, Busan 47392, Republic of Korea
| | - Sae-Gwang Park
- Department of Microbiology and Immunology, College of Medicine, Inje University, Busan 47392, Republic of Korea
| | - Jae Joon Hwang
- Department of Oral and Maxillofacial Radiology, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
- Dental and Life Science Institute & Dental Research Institute, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Hae Ryoun Park
- Department of Oral Pathology, School of Dentistry, Pusan National University, Yangsan 50612, Republic of Korea
| | - Joo Mi Yi
- Department of Microbiology and Immunology, College of Medicine, Inje University, Busan 47392, Republic of Korea
- Correspondence: ; Tel.: +82-51-890-6734
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Gołąbek K, Rączka G, Gaździcka J, Miśkiewicz-Orczyk K, Zięba N, Krakowczyk Ł, Misiołek M, Strzelczyk JK. Expression Profiles of CDKN2A, MDM2, E2F2 and LTF Genes in Oral Squamous Cell Carcinoma. Biomedicines 2022; 10:biomedicines10123011. [PMID: 36551770 PMCID: PMC9775533 DOI: 10.3390/biomedicines10123011] [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: 11/01/2022] [Revised: 11/17/2022] [Accepted: 11/20/2022] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Oral squamous cell carcinoma (OSCC) is one of the most commonly detected neoplasms worldwide. Not all mechanisms associated with cell cycle disturbances are known in OSCC. Examples of genes involved in the control of the cell cycle are CDKN2A, MDM2, E2F2 and LTF. The aim of this study was to examine the possible association between CDKN2A, MDM2, E2F2 and LTF mRNA expression and influence on clinical variables. METHODS The study group consisted of 88 Polish patients. The gene expression levels were assessed by quantitative reverse transcription PCR. RESULTS We found no statistically significant differences in the expression level of CDKN2A, MDM2, E2F2 and LTF genes in tumour samples compared to margin samples. No association was found between the gene expression levels and clinical parameters, except E2F2. The patients with G2 tumours had a significantly higher gene expression level of E2F2 than patients with low-grade G1 tumours. CONCLUSIONS We have not demonstrated that a change in expression profiles of genes has a significant impact on the pathogenesis of OSCC. It may also be useful to conduct further studies on the use of E2F2 expression profile changes as a factor to describe the invasiveness and dynamics of OSCC development.
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Affiliation(s)
- Karolina Gołąbek
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 19 Jordana Str., 41-808 Zabrze, Poland
- Correspondence:
| | - Grzegorz Rączka
- Department of Forest Management Planning, Poznań University of Life Sciences, 71 C Wojska Polskiego Str., 60-625 Poznan, Poland
| | - Jadwiga Gaździcka
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 19 Jordana Str., 41-808 Zabrze, Poland
| | - Katarzyna Miśkiewicz-Orczyk
- Department of Otorhinolaryngology and Oncological Laryngology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 10 C Skłodowskiej Str., 41-800 Zabrze, Poland
| | - Natalia Zięba
- Department of Otorhinolaryngology and Oncological Laryngology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 10 C Skłodowskiej Str., 41-800 Zabrze, Poland
| | - Łukasz Krakowczyk
- Clinic of Oncological and Reconstructive Surgery, Maria Sklodowska-Curie National Research Institute of Oncology, 15 Wybrzeże Armii Krajowej Str., 44-102 Gliwice, Poland
| | - Maciej Misiołek
- Department of Otorhinolaryngology and Oncological Laryngology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 10 C Skłodowskiej Str., 41-800 Zabrze, Poland
| | - Joanna Katarzyna Strzelczyk
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 19 Jordana Str., 41-808 Zabrze, Poland
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18
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Darragh LB, Knitz MM, Hu J, Clambey ET, Backus J, Dumit A, Samedi V, Bubak A, Greene C, Waxweiler T, Mehrotra S, Bhatia S, Gadwa J, Bickett T, Piper M, Fakhoury K, Liu A, Petit J, Bowles D, Thaker A, Atiyeh K, Goddard J, Hoyer R, Van Bokhoven A, Jordan K, Jimeno A, D'Alessandro A, Raben D, McDermott JD, Karam SD. A phase I/Ib trial and biological correlate analysis of neoadjuvant SBRT with single-dose durvalumab in HPV-unrelated locally advanced HNSCC. NATURE CANCER 2022; 3:1300-1317. [PMID: 36434392 PMCID: PMC9701140 DOI: 10.1038/s43018-022-00450-6] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 09/21/2022] [Indexed: 11/27/2022]
Abstract
Five-year survival for human papilloma virus-unrelated head and neck squamous cell carcinomas remain below 50%. We assessed the safety of administering combination hypofractionated stereotactic body radiation therapy with single-dose durvalumab (anti-PD-L1) neoadjuvantly (n = 21) ( NCT03635164 ). The primary endpoint of the study was safety, which was met. Secondary endpoints included radiographic, pathologic and objective response; locoregional control; progression-free survival; and overall survival. Among evaluable patients at an early median follow-up of 16 months (448 d or 64 weeks), overall survival was 80.1% with 95% confidence interval (95% CI) (62.0%, 100.0%), locoregional control and progression-free survival were 75.8% with 95% CI (57.5%, 99.8%), and major pathological response or complete response was 75% with 95% exact CI (51.6%, 100.0%). For patients treated with 24 Gy, 89% with 95% CI (57.1%, 100.0%) had MPR or CR. Using high-dimensional multi-omics and spatial data as well as biological correlatives, we show that responders had: (1) an increase in effector T cells; (2) a decrease in immunosuppressive cells; and (3) an increase in antigen presentation post-treatment.
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Affiliation(s)
- Laurel B Darragh
- Radiation Oncology, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USA
- Department of Immunology, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USA
| | - Michael M Knitz
- Radiation Oncology, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USA
| | - Junxiao Hu
- Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Denver, Aurora, CO, USA
| | - Eric T Clambey
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Jennifer Backus
- Radiation Oncology, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USA
| | - Andrew Dumit
- Radiation Oncology, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USA
| | - Von Samedi
- Department of Pathology, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USA
| | - Andrew Bubak
- Department of Neurology, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USA
| | - Casey Greene
- Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Denver, Aurora, CO, USA
- Department of Biochemistry and Molecular Genetics, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USA
| | - Timothy Waxweiler
- Radiation Oncology, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USA
| | - Sanjana Mehrotra
- Department of Pathology, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USA
| | - Shilpa Bhatia
- Radiation Oncology, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USA
| | - Jacob Gadwa
- Radiation Oncology, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USA
| | - Thomas Bickett
- Radiation Oncology, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USA
| | - Miles Piper
- Radiation Oncology, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USA
| | - Kareem Fakhoury
- Radiation Oncology, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USA
| | - Arthur Liu
- Department of Radiation Oncology, University of Colorado, Poudre Valley Hospital, Fort Collins, CO, USA
| | - Joshua Petit
- Department of Radiation Oncology, University of Colorado, Poudre Valley Hospital, Fort Collins, CO, USA
| | - Daniel Bowles
- Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Ashesh Thaker
- Department of Radiology, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USA
| | - Kimberly Atiyeh
- Department of Otolaryngology Head and Neck Surgery, University of Colorado, Memorial South Hospital, Colorado Springs, CO, USA
| | - Julie Goddard
- Department of Otolaryngology Head and Neck Surgery, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USA
| | - Robert Hoyer
- Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Adrie Van Bokhoven
- Department of Pathology, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USA
| | - Kimberly Jordan
- Department of Immunology, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USA
| | - Antonio Jimeno
- Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Angelo D'Alessandro
- Department of Biochemistry and Molecular Genetics, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USA
| | - David Raben
- Radiation Oncology, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USA
| | - Jessica D McDermott
- Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Sana D Karam
- Radiation Oncology, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USA.
- Department of Immunology, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USA.
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Akafzadeh N, Baghaei F, Derakhshan S, Moradzadeh Khiavi M, Kharazifard M, Aminishakib P. Combination of Binary System with Ki67 Immunohistochemical Staining: a Reliable Grading Method for Oral Epithelial Dysplasia. JOURNAL OF DENTISTRY (SHIRAZ, IRAN) 2022; 23:377-382. [PMID: 36588968 PMCID: PMC9789337 DOI: 10.30476/dentjods.2021.91032.1546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 07/12/2021] [Accepted: 08/29/2021] [Indexed: 01/03/2023]
Abstract
Statement of the Problem Oral epithelial dysplasia (OED) is a common potentially malignant lesion of oral cavity that should be managed to prevent likely malignant transformation. Purpose Here, we present a combination of binary grading system with complementary immunohistochemical (IHC) staining for Ki67 biomarker to provide a reproducible OED grading system. Materials and Method In this cross-sectional study, seventy out of one hundred OED specimens, which were accompanied by IHC stained microscopic slides for Ki67 antigen were evaluated by four independent oral pathologists. Both three-tier and binary grading systems based on WHO microscopic criteria were employed , blindly in a four-step method with at least two-week interval between each observation. Intra- and inter-observational reliability was assessed using Kappa statistical analysis. Results OED diagnosis based on binary system showed significant intra-observer reliability comparing to three-tier system without biomarker. Moreover, OED diagnosis based on binary system using Ki67 biomarker showed significant inter-observer reliability comparing to diagnosis in three tier system and based on binary system without Ki67 biomarker showed significant inter-observer reliability comparing to diagnosis based on three-tier system without Ki67. Conclusion Here, we found that application of IHC staining for Ki67 biomarker in binary system might provide a more reliable grading method for oral pathologist form different educational background.
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Affiliation(s)
- Negar Akafzadeh
- Postgraduate Student of Pediatric Dentistry, Dept. of Pediatric Dentistry, School of Dentistry, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Fereshteh Baghaei
- Retired Professor, Dept. of Oral and Maxillofacial Pathology, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
| | - Samira Derakhshan
- Dept. of Oral and Maxillofacial Pathology, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
| | - Monir Moradzadeh Khiavi
- Dept. of Oral and Maxillofacial Pathology, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohamadjavad Kharazifard
- Researcher, Dental Research Center, Dentistry Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Pouyan Aminishakib
- Dept. of Oral and Maxillofacial Pathology, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
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The effect of aflibercept and arsenic trioxide on the proliferation, migration and apoptosis of oral squamous cell carcinoma in vitro. Mol Biol Rep 2021; 48:3223-3235. [PMID: 33929648 DOI: 10.1007/s11033-021-06341-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 04/07/2021] [Indexed: 10/21/2022]
Abstract
Aflibercept and arsenic trioxide drugs apply a cytotoxic effect on some human cancer cell lines. However, no more study has followed the effects of both drugs, especially arsenic trioxide, on oral squamous cell carcinoma (OCC). We used three OCC lines as a model to show the effect of these drugs on the genetically complex disease and investigate its targeted therapy. In this study, three human OCC cell lines were used from different patients. We treated cell lines with both medications to detect the effect and relevant molecular basis. First, methyl thiazolyl tetrazolium (MTT) assay was performed to detect the cytotoxicity effect and cell growth. Second, flow cytometry, gene and protein expression were performed to evaluate the anti-angiogenic effect on OCC lines. Next apoptosis was analyzed by flow cytometry. Finally, clonogenesis capacity and cell migration were assessed by colony formation assay and wound healing, respectively. Aflibercept had no cytotoxic effect on the three OCC cell lines but decreased cell growth rate. Arsenic trioxide had a significant cytotoxic effect on three cell lines. Our results demonstrated that both drugs significantly decreased endoglin, VEGFA, and VEGFB expression. In addition, Migration and colony formation assays confirmed that these drugs have significant anti-proliferative and anti-migration effect on oral carcinoma cells. These results revealed that both medications might be a potential drug for the management of oral cancer patients.
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21
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Zhou Z, Wu W, Li J, Liu C, Xiao Z, Lai Q, Qin R, Shen M, Shi S, Kang M. Bioinformatics analysis of the expression and role of microRNA-221-3p in head and neck squamous cell carcinoma. BMC Cancer 2021; 21:395. [PMID: 33845800 PMCID: PMC8042693 DOI: 10.1186/s12885-021-08039-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 03/15/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, associated with a high rate of morbidity and mortality. However, the target genes of miR-221-3p and the underlying mechanism involved in HNSCC are still not clear. Therefore, in the current study, we studied the role of miR-221-3p in the HNSCC. METHODS Tissues collected from 48 control and 21 HNSCC patients were processed to check the differential expression of miR-221-3p by RT-qPCR. Overexpression of microRNA-221-3p (miR-221-3p) is significantly correlated to the onset and progression of HNSCC. We also conducted the meta-analysis of the cancer literature from the cancer genome atlas (TCGA) and the Gene Expression Omnibus (GEO) database to estimate the expression of miR-221-3p in HNSCC. The miR-221-3p target genes in the HNSCC were predicted with the miRWalk and TCGA databases, and functionally annotated via the Gene Ontology. Finally, Spearman's analysis was used to determine the role of the related target genes in important pathways involved in the development of HNSCC. RESULTS We observed a significantly higher expression of miR-221-3p in HNSCC compared to the normal with a summary receiver operating characteristic (sROC) of 0.86(95% Cl: 0.83,0.89). The KEGG and GO comprehensive analysis predicted that miR-221-3p might be involved in the development of HNSCC through the following metabolic pathways, viz. Drug metabolism - cytochrome P450 UGT1A7 and MAOB may be important genes for the role of miR-221-3p. CONCLUSION Based on bioinformatics analysis, our results indicate that miR-221-3p may be used as a non-invasive and hypersensitive biomarker in the diagnosis. Thus, it can be concluded that miR-221-3p may be an extremely important gene locus involved in the process of the deterioration and eventual tumorigenesis of HNSCC. Hopefully, additional work will validate its usefulness as a target for future clinical research.
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Affiliation(s)
- Ziyan Zhou
- Department of Radiation Oncology, Guangxi Medical University First Affiliated Hospital, Nanning, 530021, Guangxi, People's Republic of China.,Guangxi Tumor Radiation Therapy Clinical Medical Research Center, Nanning, 530021, Guangxi, People's Republic of China
| | - Wenling Wu
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, People's Republic of China
| | - Jixi Li
- Department of Radiation Oncology, Guangxi Medical University First Affiliated Hospital, Nanning, 530021, Guangxi, People's Republic of China.,Guangxi Tumor Radiation Therapy Clinical Medical Research Center, Nanning, 530021, Guangxi, People's Republic of China
| | - Chang Liu
- Guangxi Medical University, Nanning, 530021, Guangxi, People's Republic of China
| | - Zixi Xiao
- Guangxi Medical University, Nanning, 530021, Guangxi, People's Republic of China
| | - Qinqiao Lai
- Guangxi Medical University, Nanning, 530021, Guangxi, People's Republic of China
| | - Rongxing Qin
- Guangxi Medical University, Nanning, 530021, Guangxi, People's Republic of China
| | - Mingjun Shen
- Department of Radiation Oncology, Guangxi Medical University First Affiliated Hospital, Nanning, 530021, Guangxi, People's Republic of China.,Guangxi Tumor Radiation Therapy Clinical Medical Research Center, Nanning, 530021, Guangxi, People's Republic of China
| | - Shuo Shi
- Department of Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Min Kang
- Department of Radiation Oncology, Guangxi Medical University First Affiliated Hospital, Nanning, 530021, Guangxi, People's Republic of China. .,Guangxi Tumor Radiation Therapy Clinical Medical Research Center, Nanning, 530021, Guangxi, People's Republic of China.
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22
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Rasmussen JH, Olin AB, Lelkaitis G, Hansen AE, Andersen FL, Johannesen HH, Kjaer A, Fischer BM, Specht L, Bentzen SM, von Buchwald C, Wessel I, Vogelius IR. Intratumor heterogeneity is biomarker specific and challenges the association with heterogeneity in multimodal functional imaging in head and neck squamous cell carcinoma. Eur J Radiol 2021; 139:109668. [PMID: 33848777 DOI: 10.1016/j.ejrad.2021.109668] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 02/27/2021] [Accepted: 03/11/2021] [Indexed: 12/24/2022]
Abstract
RATIONALE Tumor biopsy cannot detect heterogeneity and an association between heterogeneity in functional imaging and molecular biology will have an impact on both diagnostics and treatment possibilities. PURPOSE Multiparametric imaging can provide 3D information on functional aspects of a tumor and may be suitable for predicting intratumor heterogeneity. Here, we investigate the correlation between intratumor heterogeneity assessed with multiparametric imaging and multiple-biopsy immunohistochemistry. METHODS In this prospective study, patients with primary or recurrent head and neck squamous cell carcinoma (HNSCC) underwent PET/MRI scanning prior to surgery. Tumors were removed en bloc and six core biopsies were used for immunohistochemical (IHC) staining with a predefined list of biomarkers: p40, p53, EGFR, Ki-67, GLUT1, VEGF, Bcl-2, CAIX, PD-L1. Intratumor heterogeneity of each IHC biomarker was quantified by calculating the coefficient of variation (CV) in tumor proportion score among the six core biopsies within each tumor lesion. The heterogeneity in the imaging biomarkers was assessed by calculating CV in 18F-fluorodeoxyglucose (FDG)-uptake, diffusion and perfusion. Concordance of the two variance measures was quantified using Spearman's rank correlation RESULTS: Twenty-eight patients with a total of 33 lesions were included. There was considerable heterogeneity in most of the IHC biomarkers especially in GLUT1, PD-L1, Ki-67, CAIX and p53, however we only observed a correlation between the heterogeneity in GLUT1 and p53 and between Ki-67 and EGFR. Heterogeneity in FDG uptake and diffusion correlated with heterogeneity in cell density. CONCLUSION Considerable heterogeneity of IHC biomarkers was found, however, only few and weak correlations between the studied IHC markers were observed. The studied functional imaging biomarkers showed weak associations with heterogeneity in some of the IHC biomarkers. Thus, biological heterogeneity is not a general tumor characteristic but depends on the specific biomarker or imaging modality.
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Affiliation(s)
- Jacob H Rasmussen
- Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Department of Otorhinolaryngology and Maxillofacial Surgery, Zealand University Hospital, Køge, Denmark.
| | - Anders B Olin
- Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Giedrius Lelkaitis
- Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Adam E Hansen
- Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Department of Diagnostic Radiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Flemming L Andersen
- Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Helle H Johannesen
- Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Andreas Kjaer
- Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Barbara M Fischer
- Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; PET Centre, School of Biomedical Engineering and Imaging Sciences KCL, St Thomas' Hospital, Westminster Bridge Road, London, SE1 7EH, UK
| | - Lena Specht
- Department of Oncology, Section of Radiotherapy, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Søren M Bentzen
- Division of Biostatistics and Bioinformatics, University of Maryland Greenebaum Cancer Center, and Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, USA
| | - Christian von Buchwald
- Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Irene Wessel
- Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Ivan R Vogelius
- Department of Oncology, Section of Radiotherapy, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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Diagnostic efficacy of PET-CT, CT, and MRI in preoperative assessment of mandibular invasion caused by head and neck cancer: A systematic review and meta-analysis. Oral Oncol 2021; 116:105264. [PMID: 33756286 DOI: 10.1016/j.oraloncology.2021.105264] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/24/2021] [Accepted: 03/11/2021] [Indexed: 02/05/2023]
Abstract
OBJECTIVE This study aims to conduct a systematic review and meta-analysis of the performance of PET-CT, CT, and MRI in diagnosing mandible invasion induced by head and neck cancer (HNC). MATERIALS AND METHODS The MEDLINE, Embase, Science Direct, CNKI and CQVIP databases were searched from inception until August 1, 2020. Then, a meta-analysis was conducted to calculate the combined diagnostic values with the corresponding 95% CIs. Two independent researchers completed the full text screening, data abstraction, and risk assessment. RESULTS This meta-analysis included 53 studies (N = 2 946 participants). For the pooled sensitivity (SEN), MRI (SEN: 0.88, 95% CI: 0.81-0.93) was found to have a significantly higher SEN (P = 0.0045), when compared to CT (SEN: 0.77, 95% CI: 0.71-0.82), while compared with PET-CT (SEN: 0.88, 95% CI: 0.64-0.97), the SEN was approximately equal (P > 0.05). The analysis revealed that the combined specificity (SPE) of MRI (SPE: 0.83, 95% CI: 0.74-0.89) and PET-CT (SPE: 0.81, 95% CI: 0.57-0.93) was lower than that of CT (SPE: 0.87, 95% CI: 0.83-0.90), but there was no statistical significance among these (P > 0.05). The comparison of the area under curve (AUC) reflected that PET-CT, CT and MRI have approximately equal summary diagnostic power in detecting mandibular invasion (P > 0.05). CONCLUSION The findings suggest that compared with CT, MRI is significantly superior for higher SEN in diagnosing mandibular invasion. The SEN of MRI and PET-CT were approximately equal. For the summary of diagnostic power, more prospective clinical trials that directly compare these three methods are needed in the future.
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24
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Jiang P, Li Y, Xu Z, He S. A signature of 17 immune-related gene pairs predicts prognosis and immune status in HNSCC patients. Transl Oncol 2021; 14:100924. [PMID: 33221687 PMCID: PMC7689340 DOI: 10.1016/j.tranon.2020.100924] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 10/04/2020] [Accepted: 10/16/2020] [Indexed: 02/08/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is an invasive malignancy with high worldwide mortality. Growing evidence has indicated a pivotal correlation between HNSCC prognosis and immune signature. This study investigated an immune-related gene pairs (IRGPs) signature to predict the prognostic value of HNSCC patients. We constructed IRGPs via integrating multiple IRG expression data sets. Moreover, we established the predictive model base on the IRGPs for HNSCC, and utilized multidimensional bioinformatics methods to validate the robustness of prognostic value of the IRGPs signature. In addition, we explored the relationship between the IRGPs model and immune status. Seventeen IRGPs signature was built as the predictive model which predicted prognosis independently and reliably for HNSCC. Compared to the high-risk group, the low-risk group demonstrated a distinctly favorable prognosis including overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS). The low-risk group showed higher-immune score and lower-tumor purity than the high-risk group. In addition, the low-risk group exhibited higher expression of Programmed cell death 1 ligand 1 (PD-L1) and Microsatellite instability (MSI) score, and lower expression of Tumor Immune Dysfunction and Exclusion (TIDE), which indicated the low-risk group was much more sensitive to immunotherapy. Lastly, the IRGs signature has achieved a higher accuracy than clinical properties for estimation of survival. The IRGPs model is an independent biomarker for estimating the prognosis, and could be also used to predict immunotherapeutic response in HNSCC patients. These findings may provide new ideas for novel biomarkers and may be helpful to formulate personalized immunotherapy strategy.
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Affiliation(s)
- Pan Jiang
- Department of stomatology, Sanya Central Hospital, 146 the Fourth of Jiefang Road, 572000, Sanya, Hainan Province, China.
| | - Yanli Li
- Department of stomatology, Sanya Central Hospital, 146 the Fourth of Jiefang Road, 572000, Sanya, Hainan Province, China
| | - Zheng Xu
- Department of stomatology, Sanya Central Hospital, 146 the Fourth of Jiefang Road, 572000, Sanya, Hainan Province, China
| | - Shengteng He
- Department of stomatology, Sanya Central Hospital, 146 the Fourth of Jiefang Road, 572000, Sanya, Hainan Province, China.
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Madhukar G, Subbarao N. Current and Future Therapeutic Targets: A Review on Treating Head and Neck Squamous Cell Carcinoma. Curr Cancer Drug Targets 2020; 21:386-400. [PMID: 33372876 DOI: 10.2174/1568009620666201229120332] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 11/03/2020] [Accepted: 11/04/2020] [Indexed: 12/24/2022]
Abstract
Head and neck squamous cell carcinoma (HNSCC) continues to be a global public health burden even after a tremendous development in its treatment. It is a heterogeneous cancer of upper aero-digestive tract. The contemporary strategy to treat cancer is the use of anticancer drugs against proteins possessing abnormal expression. Targeted chemotherapy was found successful in HNSCC, but, there is still a stagnant improvement in the survival rates and high recurrence rates due to undesirable chemotherapy reactions, non-specificity of drugs, resistance against drugs and drug toxicity on non-cancerous tissues and cells. Various extensive studies lead to the identification of drug targets capable to treat HNSCC effectively. The current review article gives an insight into these promising anticancer targets along with knowledge of drugs under various phases of development. In addition, new potential targets that are not yet explored against HNSCC are also described. We believe that exploring and developing drugs against these targets might prove beneficial in treating HNSCC.
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Affiliation(s)
- Geet Madhukar
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Naidu Subbarao
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India
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Madhukar G, Subbarao N. In-silico prediction of potential inhibitors against phosphatidylinositol 3-kinase catalytic subunit alpha involved in head and neck squamous cell carcinomas. J Biomol Struct Dyn 2020; 40:4697-4712. [PMID: 33356909 DOI: 10.1080/07391102.2020.1861980] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers, globally. Its high mortality rates remained unaltered in the last three decades, therefore, there is an enormous need for novel therapeutics. The most frequent somatically mutated oncogenic pathway in HNSCC tumors is the Phosphatidylinositol-3-kinases (PI3K) pathway. PI3Ks are lipid kinases involved in the regulation of cell survival, growth and metabolism. PI3Ks phosphorylates PI (4,5) P2 (PIP2) converting it to PI (3, 4, 5) P3 (PIP3). Alterations such as mutation, gene amplification and overexpression in PIK3CA, encoding the catalytic subunit p110α of PI3K pathway were found to be prevalent. The aberrant activation leads to irregulated cell growth due to improper p110α enzymatic activity. p110α is therefore, considered a potential oncogenic target for cancer therapy. The only FDA approved specific inhibitor of p110α is Alpelisib (BYL719). Therefore, designing more effective and specific p110α inhibitors could be a promising strategy in the treatment of HNSCC. The present study aims to find out the potent and novel inhibitors of p110α using High Throughput Screening (HTS) of huge databases (National Cancer Institute (NCI), Life Chemicals, ChemDiv and ChEMBL) and Molecular Dynamic Simulations. As a result, from more than 400,000 compounds, a total of 3 best candidate compounds (Echinacoside, Isoacteoside, K284-4402) were selected and validated for their binding to catalytic site of p110α and stability during Molecular Dynamics (MD) simulations. The binding free energy (calculated from MM-PBSA) of the selected compounds, Echinacoside, Isoacteoside, K284-4402 were -23.43 kcal/mol, -33.02 kcal/mol and -30.57 kcal/mol, respectively, which suggested these compounds bind to p110α with higher affinity than Alpelisib which has binding free energy -20.9 kcal/mol. This study provides a significant in-depth understanding of p110α inhibitors that can be used in the development of potential therapeutics against HNSCC.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Geet Madhukar
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Naidu Subbarao
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India
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Jiang P, He S, Li Y, Xu Z. Identification of Therapeutic and Prognostic Biomarkers of Lamin C (LAMC) Family Members in Head and Neck Squamous Cell Carcinoma. Med Sci Monit 2020; 26:e925735. [PMID: 32860673 PMCID: PMC7477928 DOI: 10.12659/msm.925735] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Background Head and neck squamous cell carcinoma (HNSC) is an invasive malignancy with a high worldwide mortality, despite considerable recent advancements in diagnosis and treatment. Increasing evidence indicates that the Lamin C (LAMC) gene family is associated with the progression of diverse cancers, nevertheless, this association is not well understood. Material/Methods A systematic study addressing the expression and prognostic value of LAMC, and the relationship between LAMC and tumor immune response in HNSC was done. Finally, we performed drug screening to identify specific drugs. Results Compared to normal samples, expressions of LAMC1 and LAMC2 were significantly increased in HNSC, and LAMC2 was obviously correlated with an adverse prognosis for patients. LAMC2 expression level was significantly correlated with the infiltrating levels of B cells, CD8+ T cells, CD4+ T cells, and macrophages. Moreover, LAMC2 exhibited strong correlations with diverse immune markers, immune microenvironment, and immune checkpoint molecules. Finally, candidate drugs that targeted LAMC2 were identified. Conclusions This study suggests that LAMC2 could serve as a new prognostic biomarker, and it could be used for efficacy of target for immune response and for drug sensitivity prediction in HNSC.
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Affiliation(s)
- Pan Jiang
- Department of Stomatology, The Third People Hospital of Hainan Province, Sanya, Hainan, China (mainland)
| | - Shengteng He
- Department of Stomatology, The Third People Hospital of Hainan Province, Sanya, Hainan, China (mainland)
| | - Yanli Li
- Department of Stomatology, The Third People Hospital of Hainan Province, Sanya, Hainan, China (mainland)
| | - Zheng Xu
- Department of Stomatology, The Third People Hospital of Hainan Province, Sanya, Hainan, China (mainland)
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Pyle MP, Hoa M. Applications of single-cell sequencing for the field of otolaryngology: A contemporary review. Laryngoscope Investig Otolaryngol 2020; 5:404-431. [PMID: 32596483 PMCID: PMC7314468 DOI: 10.1002/lio2.388] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 04/02/2020] [Accepted: 04/03/2020] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVES Single-cell RNA sequencing (scRNA-Seq) is a new technique used to interrogate the transcriptome of individual cells within native tissues that have already resulted in key discoveries in auditory basic science research. Rapid advances in scRNA-Seq make it likely that it will soon be translated into clinical medicine. The goal of this review is to inspire the use of scRNA-Seq in otolaryngology by giving examples of how it can be applied to patient samples and how this information can be used clinically. METHODS Studies were selected based on the scientific quality and relevance to scRNA-Seq. In addition to mouse auditory system (inner ear including hair cells and supporting cells, spiral ganglion neurons, and inner ear organoids), recent studies using human primary cell samples are discussed. We also perform our own analysis on publicly available, published scRNA-Seq data from oral head and neck squamous cell carcinoma (HNSCC) samples to serve as an example of a clinically relevant application of scRNA-Seq. RESULTS Studies focusing on patient tissues show that scRNA-Seq reveals tissue heterogeneity and rare-cell types responsible for disease pathogenesis. The heterogeneity detected by scRNA-Seq can result in both the identification of known or novel disease biomarkers and drug targets. Our analysis of HNSCC data gives an example for how otolaryngologists can use scRNA-Seq for clinical use. CONCLUSIONS Although there are limitations to the translation of scRNA-Seq to the clinic, we show that its use in otolaryngology can give physicians insight into the tissue heterogeneity within their patient's diseased tissue giving them information on disease pathogenesis, novel disease biomarkers or druggable targets, and aid in selecting patient-specific drug cocktails.
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Affiliation(s)
- Madeline P. Pyle
- Division of Intramural Research, Section on Auditory Development and Restoration, National Institute on Deafness and Other Communication Disorders (NIDCD) Otolaryngology Surgeon‐Scientist ProgramNational Institutes of HealthBethesdaMarylandUSA
| | - Michael Hoa
- Division of Intramural Research, Section on Auditory Development and Restoration, National Institute on Deafness and Other Communication Disorders (NIDCD) Otolaryngology Surgeon‐Scientist ProgramNational Institutes of HealthBethesdaMarylandUSA
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Mukherjee P, Cintra M, Huang C, Zhou M, Zhu S, Colevas AD, Fischbein N, Gevaert O. CT-based Radiomic Signatures for Predicting Histopathologic Features in Head and Neck Squamous Cell Carcinoma. Radiol Imaging Cancer 2020; 2:e190039. [PMID: 32550599 DOI: 10.1148/rycan.2020190039] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 01/08/2020] [Accepted: 01/22/2020] [Indexed: 12/15/2022]
Abstract
Purpose To determine the performance of CT-based radiomic features for noninvasive prediction of histopathologic features of tumor grade, extracapsular spread, perineural invasion, lymphovascular invasion, and human papillomavirus status in head and neck squamous cell carcinoma (HNSCC). Materials and Methods In this retrospective study, which was approved by the local institutional ethics committee, CT images and clinical data from patients with pathologically proven HNSCC from The Cancer Genome Atlas (n = 113) and an institutional test cohort (n = 71) were analyzed. A machine learning model was trained with 2131 extracted radiomic features to predict tumor histopathologic characteristics. In the model, principal component analysis was used for dimensionality reduction, and regularized regression was used for classification. Results The trained radiomic model demonstrated moderate capability of predicting HNSCC features. In the training cohort and the test cohort, the model achieved a mean area under the receiver operating characteristic curve (AUC) of 0.75 (95% confidence interval [CI]: 0.68, 0.81) and 0.66 (95% CI: 0.45, 0.84), respectively, for tumor grade; a mean AUC of 0.64 (95% CI: 0.55, 0.62) and 0.70 (95% CI: 0.47, 0.89), respectively, for perineural invasion; a mean AUC of 0.69 (95% CI: 0.56, 0.81) and 0.65 (95% CI: 0.38, 0.87), respectively, for lymphovascular invasion; a mean AUC of 0.77 (95% CI: 0.65, 0.88) and 0.67 (95% CI: 0.15, 0.80), respectively, for extracapsular spread; and a mean AUC of 0.71 (95% CI: 0.29, 1.0) and 0.80 (95% CI: 0.65, 0.92), respectively, for human papillomavirus status. Conclusion Radiomic CT models have the potential to predict characteristics typically identified on pathologic assessment of HNSCC.Supplemental material is available for this article.© RSNA, 2020.
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Affiliation(s)
- Pritam Mukherjee
- Department of Medicine, Stanford Center for Biomedical Informatics Research (BMIR), Stanford, Calif (P.M., M.C., C.H., M.Z., O.G.); Department of Radiology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil (M.C.); Department of Nutrition and Food Hygiene, Chronic Disease Research Institute, School of Public Health, School of Medicine, Zhejiang University, Zhejiang, China (C.H., S.Z.); Division of Oncology, Department of Medicine (A.D.C.), Department of Radiology (N.F.), and Department of Biomedical Data Science (O.G.), Stanford University, 1265 Welch Rd, Stanford, CA 94305-5479
| | - Murilo Cintra
- Department of Medicine, Stanford Center for Biomedical Informatics Research (BMIR), Stanford, Calif (P.M., M.C., C.H., M.Z., O.G.); Department of Radiology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil (M.C.); Department of Nutrition and Food Hygiene, Chronic Disease Research Institute, School of Public Health, School of Medicine, Zhejiang University, Zhejiang, China (C.H., S.Z.); Division of Oncology, Department of Medicine (A.D.C.), Department of Radiology (N.F.), and Department of Biomedical Data Science (O.G.), Stanford University, 1265 Welch Rd, Stanford, CA 94305-5479
| | - Chao Huang
- Department of Medicine, Stanford Center for Biomedical Informatics Research (BMIR), Stanford, Calif (P.M., M.C., C.H., M.Z., O.G.); Department of Radiology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil (M.C.); Department of Nutrition and Food Hygiene, Chronic Disease Research Institute, School of Public Health, School of Medicine, Zhejiang University, Zhejiang, China (C.H., S.Z.); Division of Oncology, Department of Medicine (A.D.C.), Department of Radiology (N.F.), and Department of Biomedical Data Science (O.G.), Stanford University, 1265 Welch Rd, Stanford, CA 94305-5479
| | - Mu Zhou
- Department of Medicine, Stanford Center for Biomedical Informatics Research (BMIR), Stanford, Calif (P.M., M.C., C.H., M.Z., O.G.); Department of Radiology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil (M.C.); Department of Nutrition and Food Hygiene, Chronic Disease Research Institute, School of Public Health, School of Medicine, Zhejiang University, Zhejiang, China (C.H., S.Z.); Division of Oncology, Department of Medicine (A.D.C.), Department of Radiology (N.F.), and Department of Biomedical Data Science (O.G.), Stanford University, 1265 Welch Rd, Stanford, CA 94305-5479
| | - Shankuan Zhu
- Department of Medicine, Stanford Center for Biomedical Informatics Research (BMIR), Stanford, Calif (P.M., M.C., C.H., M.Z., O.G.); Department of Radiology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil (M.C.); Department of Nutrition and Food Hygiene, Chronic Disease Research Institute, School of Public Health, School of Medicine, Zhejiang University, Zhejiang, China (C.H., S.Z.); Division of Oncology, Department of Medicine (A.D.C.), Department of Radiology (N.F.), and Department of Biomedical Data Science (O.G.), Stanford University, 1265 Welch Rd, Stanford, CA 94305-5479
| | - A Dimitrios Colevas
- Department of Medicine, Stanford Center for Biomedical Informatics Research (BMIR), Stanford, Calif (P.M., M.C., C.H., M.Z., O.G.); Department of Radiology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil (M.C.); Department of Nutrition and Food Hygiene, Chronic Disease Research Institute, School of Public Health, School of Medicine, Zhejiang University, Zhejiang, China (C.H., S.Z.); Division of Oncology, Department of Medicine (A.D.C.), Department of Radiology (N.F.), and Department of Biomedical Data Science (O.G.), Stanford University, 1265 Welch Rd, Stanford, CA 94305-5479
| | - Nancy Fischbein
- Department of Medicine, Stanford Center for Biomedical Informatics Research (BMIR), Stanford, Calif (P.M., M.C., C.H., M.Z., O.G.); Department of Radiology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil (M.C.); Department of Nutrition and Food Hygiene, Chronic Disease Research Institute, School of Public Health, School of Medicine, Zhejiang University, Zhejiang, China (C.H., S.Z.); Division of Oncology, Department of Medicine (A.D.C.), Department of Radiology (N.F.), and Department of Biomedical Data Science (O.G.), Stanford University, 1265 Welch Rd, Stanford, CA 94305-5479
| | - Olivier Gevaert
- Department of Medicine, Stanford Center for Biomedical Informatics Research (BMIR), Stanford, Calif (P.M., M.C., C.H., M.Z., O.G.); Department of Radiology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil (M.C.); Department of Nutrition and Food Hygiene, Chronic Disease Research Institute, School of Public Health, School of Medicine, Zhejiang University, Zhejiang, China (C.H., S.Z.); Division of Oncology, Department of Medicine (A.D.C.), Department of Radiology (N.F.), and Department of Biomedical Data Science (O.G.), Stanford University, 1265 Welch Rd, Stanford, CA 94305-5479
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Dong W, Chen Y, Qian N, Sima G, Zhang J, Guo Z, Wang C. SATB2 knockdown decreases hypoxia-induced autophagy and stemness in oral squamous cell carcinoma. Oncol Lett 2020; 20:794-802. [PMID: 32566006 PMCID: PMC7285822 DOI: 10.3892/ol.2020.11589] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Accepted: 03/13/2020] [Indexed: 12/30/2022] Open
Abstract
Increasing evidence has suggested that special AT-rich sequence-binding protein 2 (SATB2) may be involved in the progression of numerous types of human cancer; however, the biological function of SATB2 in oral squamous cell carcinoma (OSCC) occurrence and progression remains relatively unknown. The present study aimed to investigate the potential role of SATB2 in the regulation of biological characteristics of OSSC during hypoxia. The expression of SATB2 in SCC9 cells was knocked down using small interfering RNA. Western blotting was used to determine the protein expression levels of SATB2, autophagy-related proteins microtubule-associated protein light chain (LC)3-I/II and Beclin-1, and stemness markers such as Oct-4 (POU class 5 homeobox 1), Sox-2 (SRY-box 2) and Nanog (nanog homeobox). Transmission electron microscopy and monodansylcadaverine staining were used to detect the presence of autophagosomes. Furthermore, the self-renewal capacity of cells was analyzed using colony forming assays; the cell proliferative, migratory and invasive ability were evaluated using CCK-8, wound healing and Transwell assays, respectively; and the cell cycle distribution and rate of apoptosis were detected using flow cytometry. The expression levels of SATB2, autophagy-related proteins and stemness markers were significantly increased in SCC9 cells following hypoxic treatment. Meanwhile, the genetic knockdown of SATB2 inhibited hypoxia-mediated autophagy by decreasing the expression levels of Beclin-1, and preventing the conversion of LC3-I to LC3-II and the accumulation of autophagosomes. The knockdown of SATB2 also inhibited the hypoxia-induced colony-forming ability and the expression of stemness markers. Functionally, it also inhibited the proliferative, migratory and invasive abilities of SCC9 cells, while inducing apoptosis and cell cycle arrest under hypoxia. In conclusion, the present study suggested that SATB2 may function as an oncogene in OSCC cells, and targeting SATB2 may be a potential therapeutic strategy for the treatment of OSCC.
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Affiliation(s)
- Weijie Dong
- Department of Stomatology, The First Hospital of Jiaxing, Jiaxing, Zhejiang 314000, P.R. China.,Department of Stomatology, First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Yawen Chen
- Department of Stomatology, The First Hospital of Jiaxing, Jiaxing, Zhejiang 314000, P.R. China.,Department of Stomatology, First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Naiying Qian
- Department of Stomatology, The First Hospital of Jiaxing, Jiaxing, Zhejiang 314000, P.R. China.,Department of Stomatology, First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Guoqi Sima
- Department of Stomatology, The First Hospital of Jiaxing, Jiaxing, Zhejiang 314000, P.R. China.,Department of Stomatology, First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Jianming Zhang
- Department of Stomatology, The First Hospital of Jiaxing, Jiaxing, Zhejiang 314000, P.R. China.,Department of Stomatology, First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Zhiqin Guo
- Department of Stomatology, The First Hospital of Jiaxing, Jiaxing, Zhejiang 314000, P.R. China.,Department of Stomatology, First Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Changlin Wang
- Department of Stomatology, Yancheng Hospital Affiliated to Medical School of Southeast University, Yancheng, Jiangsu 224001, P.R. China
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Xu J, Gross N, Zang Y, Cao S, Yang F, Yang Z, Yu W, Lei D, Pan X. Overexpression of S100A4 Predicts Migration, Invasion, and Poor Prognosis of Hypopharyngeal Squamous Cell Carcinoma. Mol Diagn Ther 2020; 23:407-417. [PMID: 30868407 DOI: 10.1007/s40291-019-00393-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Hypopharyngeal squamous cell carcinoma (HSCC) is among the most lethal tumors encountered in the head and neck and frequently involves regional metastasis. However, the mechanism underlying the aggressiveness of HSCC remains elusive. S100A4 is a well-established metastasis-promoting regulator in a variety of malignancies, but its role in HSCC has not yet been identified. OBJECTIVES Our objectives were to explore the expression levels of S100A4 in HSCC tumors and its association with clinicopathological parameters and the clinical prognosis of HSCC and to confirm its role in the metastatic process of the HSCC FaDu cell line in vitro. METHODS We assessed the expression levels of S100A4 with immunohistochemistry (IHC) in HSCC tumors (n = 71) and adjacent normal tissues (n = 44). In vitro experiments were performed to explore the impact of S100A4 knockdown on biological phenotypes of human HSCC FaDu cell line, including migration, invasion, proliferation, apoptosis, and cell cycle. RESULTS The expression of S100A4 was elevated in HSCC tumors compared with adjacent normal tissues and positively correlated with cervical lymph node metastasis in this HSCC patient cohort. In vitro experiments showed that S100A4 knockdown significantly impaired migration and invasion and increased the proportion of cells in G0/G1 phase with no change in proliferation or apoptosis in FaDu cells. Additionally, nuclear S100A4 expression proved to be an independent prognostic indicator in patients with HSCC. CONCLUSION This study demonstrated for the first time that S100A4 expression is upregulated in HSCC tumors and that this upregulation is positively correlated with cervical lymph node metastasis of this malignancy. The metastasis-promoting role of S100A4 was further validated in the HSCC FaDu cell line, indicating that S100A4 is a potential therapeutic target for HSCC. Furthermore, this study suggests that nuclear S100A4 expression could be considered a prognostic biomarker for HSCC.
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Affiliation(s)
- Jianing Xu
- NHC Key Laboratory of Otorhinolaryngology, Department of Otorhinolaryngology, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China
| | - Neil Gross
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Yuanwei Zang
- Department of Urology,Qilu Hospital, Shandong University, Jinan, Shandong, 250012, China
| | - Shengda Cao
- NHC Key Laboratory of Otorhinolaryngology, Department of Otorhinolaryngology, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China
| | - Feilong Yang
- Department of Urology,Qilu Hospital, Shandong University, Jinan, Shandong, 250012, China
| | - Zheng Yang
- Key Laboratory of Otolaryngology Head and Neck Surgery, Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Beijing Institute of Otolaryngology, Ministry of Education, Capital Medical University, Beijing, 100730, China
| | - Wenbin Yu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Head and Neck Surgery, Peking University Cancer Hospital and Institute, Beijing, China.
| | - Dapeng Lei
- NHC Key Laboratory of Otorhinolaryngology, Department of Otorhinolaryngology, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China
| | - Xinliang Pan
- NHC Key Laboratory of Otorhinolaryngology, Department of Otorhinolaryngology, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China.
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Wang L, Yang L, Han S, Zhu J, Li Y, Wang Z, Fan YH, Lin E, Zhang R, Sahoo N, Li Y, Zhang X, Wang X, Li T, Zhu XR, Zhu H, Heymach JV, Myers JN, Frank SJ. Patterns of protein expression in human head and neck cancer cell lines differ after proton vs photon radiotherapy. Head Neck 2020; 42:289-301. [PMID: 31710172 DOI: 10.1002/hed.26005] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 09/26/2019] [Accepted: 10/18/2019] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Proton radiotherapy (PRT) may be a less toxic alternative to photon radiotherapy (XRT) for patients with head and neck squamous cell carcinoma (HNSCC). However, the molecular responses of HNSCC cells to PRT vs XRT are unclear. METHODS Proteomics analyses of protein expression profiles by reverse-phase protein arrays were done for two human papillomavirus [HPV]-negative and two HPV+ cell lines. Expression patterns of 175 proteins involved in several signaling pathways were tested. RESULTS Compared with PRT, XRT tended to induce lower expression of DNA damage repair-and cell cycle arrest-related proteins and higher expression of cell survival- and proliferation-related proteins. CONCLUSIONS Under these experimental conditions, PRT and XRT induced different protein expression and activation profiles. Further preclinical verification is needed, as are studies of tumor pathway mutations as biomarkers for choice of treatment or as radiosensitization targets to improve the response of HNSCC to PRT or XRT.
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Affiliation(s)
- Li Wang
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Liuqing Yang
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Shichao Han
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jinming Zhu
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yuting Li
- Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Zeming Wang
- Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - You-Hong Fan
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Eric Lin
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ruiping Zhang
- Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Narayan Sahoo
- Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yupeng Li
- Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xiaodong Zhang
- Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xiaochun Wang
- Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Tengfei Li
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xiaorong R Zhu
- Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Hongtu Zhu
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - John V Heymach
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jeffrey N Myers
- Department of Head & Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Steven J Frank
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Misawa K, Mima M, Satoshi Y, Imai A, Mochizuki D, Ishikawa R, Kita J, Yamaguchi Y, Endo S, Misawa Y, Mineta H. Prostanoid receptor genes confer poor prognosis in head and neck squamous cell carcinoma via epigenetic inactivation. J Transl Med 2020; 18:31. [PMID: 31969157 PMCID: PMC6977280 DOI: 10.1186/s12967-020-02214-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 01/04/2020] [Indexed: 02/07/2023] Open
Abstract
Background Chronic inflammation is a risk factor for head and neck squamous cell carcinoma (HNSCC) and other diseases. Prostanoid receptors are clearly involved in the development of many types of cancer. However, their role is not simple and is poorly understood in HNSCC. Methods Methylation profiles of prostanoid receptor family genes were generated for tumour samples obtained from 274 patients with HNSCC, including 69 hypopharynx, 51 larynx, 79 oral cavity, and 75 oropharynx tumour samples, by quantitative methylation-specific PCR. Promoter methylation was then evaluated with respect to various clinical characteristics and patient survival. Results The mean number of methylated genes per sample was 2.05 ± 2.59 (range 0 to 9). Promoters of PTGDR1, PTGDR2, PTGER1, PTGER2, PTGER3, PTGER4, PTGFR, PTGIR, and TBXA2R were methylated in 43.8%, 18.2%, 25.5%, 17.5%, 41.2%, 8.0%, 19.3%, 20.4%, and 11.3% of the samples, respectively. Methylation indices for prostanoid receptor family genes tended to be higher as the number of TET methylation events increased. Patients with 5–9 methylated genes had a significantly lower survival rate than that of patients with 0–4 methylated genes (log-rank test, P= 0.007). In multivariate analyses, PTGDR1 methylation was most highly correlated with recurrence in patients with hypopharyngeal cancer (P = 0.014). A similar correlation was observed for PTGER4 in patients with laryngeal cancer (P = 0.046). Methylation of the PTGIR and TBXA2R promoters was positively correlated with recurrence in oropharyngeal cancer (P = 0.028 and P = 0.006, respectively). Moreover, Patients with 5–9 methylated genes were extremely lower of 5hmC levels (P = 0.035) and was correlated with increasing expression of DNMT3A and DNMT3B (P < 0.05 and P < 0.05, respectively). Conclusion We characterised the relationship between the methylation status of prostanoid receptor genes and recurrence in HNSCC. These results provide new perspectives for the development of molecular targeted treatment approaches.
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Affiliation(s)
- Kiyoshi Misawa
- Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Shizuoka, 431-3192, Japan.
| | - Masato Mima
- Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Shizuoka, 431-3192, Japan
| | - Yamada Satoshi
- Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Shizuoka, 431-3192, Japan
| | - Atsushi Imai
- Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Shizuoka, 431-3192, Japan
| | - Daiki Mochizuki
- Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Shizuoka, 431-3192, Japan
| | - Ryuji Ishikawa
- Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Shizuoka, 431-3192, Japan
| | - Junya Kita
- Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Shizuoka, 431-3192, Japan
| | - Yuki Yamaguchi
- Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Shizuoka, 431-3192, Japan
| | - Shiori Endo
- Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Shizuoka, 431-3192, Japan
| | - Yuki Misawa
- Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Shizuoka, 431-3192, Japan
| | - Hiroyuki Mineta
- Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Shizuoka, 431-3192, Japan
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HOXB5 acts as an oncogenic driver in head and neck squamous cell carcinoma via EGFR/Akt/Wnt/β-catenin signaling axis. Eur J Surg Oncol 2019; 46:1066-1073. [PMID: 31864826 DOI: 10.1016/j.ejso.2019.12.009] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 10/26/2019] [Accepted: 12/11/2019] [Indexed: 12/19/2022] Open
Abstract
INTRODUCTION Identification of therapeutic targets in head and neck squamous cell carcinoma (HNSCC) is essential because most of the patients with advanced HNSCC have a poor prognosis. Homeobox genes constitute a large cluster of transcription factors with important regulatory roles in mammalian embryonic development and cell differentiation. The oncogenic role of homeobox B5 (HOXB5) in HNSCC has not been investigated. MATERIALS AND METHODS We used The Cancer Genome Atlas (TCGA) data to evaluate the correlations between HOXB5 expression and various HNSCC clinicopathological factors. We knocked down HOXB5 expression in HNSCC cell lines and explored the in vitro and in vivo effects on cell proliferation and motility, and HOXB5 signaling. RESULTS The Cancer Genome Atlas (TCGA) data shows that HOXB5 is overexpressed in HNSCC compared to normal tissues and significantly associates with tumor stage (P = 0.003), lymph node metastasis (P = 0.031), disease stage (P = 0.002), and angiolymphatic invasion (P = 0.004). Our results also show that HOXB5 expression is up-regulated in HNSCC cell lines, and HOXB5 knockdown significantly reduced cell proliferation and tumor growth in vitro and in vivo. Inhibition of HOXB5 decreases cell migration and invasion via suppression of epithelial-to-mesenchymal transition (EMT)-associated proteins expression. Moreover, HOXB5 directly binds to the promoter region of EGFR and consequently regulates the activity of the Akt/Wnt/β-catenin signaling axis. CONCLUSION HOXB5 may be a novel therapeutic target as an oncogenic driver by regulating EGFR transcription in HNSCC.
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Zhang B, Wang H, Guo Z, Zhang X. Prediction of head and neck squamous cell carcinoma survival based on the expression of 15 lncRNAs. J Cell Physiol 2019; 234:18781-18791. [PMID: 30927266 DOI: 10.1002/jcp.28517] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Revised: 02/21/2019] [Accepted: 03/06/2019] [Indexed: 12/19/2022]
Abstract
Recent evidence suggests that long noncoding RNAs (lncRNAs) are essential regulators of many cancer-related processes, including cancer cell proliferation, invasion, and migration. There is thus a reason to believe that the detection of lncRNAs may be useful as a diagnostic and prognostic strategy for cancer detection, however, at present no effective genome-wide tests are available for clinical use, constraining the use of such a strategy. In this study, we performed a comprehensive assessment of lncRNAs expressed in samples in the head and neck squamous cell carcinoma (HNSCC) cohort available in The Cancer Genome Atlas database. A risk score (RS) model was constructed based on the expression data of these 15 lncRNAs in the validation data set of HNSCC patients and was subsequently validated in validation data set and the entire data set. We were able to stratify patients into high- and low-risk categories, using our lncRNA expression panel to determine an RS, with significant differences in overall survival (OS) between these two groups in our test set (median survival, 1.863 vs. 5.484 years; log-rank test, p < 0.001). We were able to confirm the predictive value of our 15-lncRNA signature using both a validation data set and a full data set, finding our signature to be reproducible and effective as a means of predicting HNSCC patient OS. Through the multivariate Cox regression and stratified analyses, we were further able to confirm that the predictive value of this RS was independent of other predictive factors such as clinicopathological parameters. The Gene set enrichment analysis revealed potential functional roles for these 15 lncRNAs in tumor progression. Our findings indicate that an RS established based on a panel of lncRNA expression signatures can effectively predict OS and facilitate patient stratification in HNSCC.
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Affiliation(s)
- Boxin Zhang
- Oral Research Center of CPLA, Affiliated First Hospital of Naval Military Medical University, Shanghai, People's Republic of China
| | - Haihui Wang
- Oral Research Center of CPLA, Affiliated First Hospital of Naval Military Medical University, Shanghai, People's Republic of China
| | - Ziyan Guo
- Oral Research Center of CPLA, Affiliated First Hospital of Naval Military Medical University, Shanghai, People's Republic of China
| | - Xinhai Zhang
- Oral Research Center of CPLA, Affiliated First Hospital of Naval Military Medical University, Shanghai, People's Republic of China
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36
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Wang L, Han S, Zhu J, Wang X, Li Y, Wang Z, Lin E, Wang X, Molkentine DP, Blanchard P, Yang Y, Zhang R, Sahoo N, Gillin M, Zhu XR, Zhang X, Myers JN, Frank SJ. Proton versus photon radiation-induced cell death in head and neck cancer cells. Head Neck 2018; 41:46-55. [PMID: 30561022 DOI: 10.1002/hed.25357] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 04/04/2018] [Accepted: 05/16/2018] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Photon (X-ray) radiotherapy (XRT) kills cells via DNA damage, however, how proton radiotherapy (PRT) causes cell death in head and neck squamous cell carcinoma (HNSCC) is unclear. We investigated mechanisms of HNSCC cell death after XRT versus PRT. METHODS We assessed type of death in 2 human papillomavirus (HPV)-positive and two HPV-negative cell lines: necrosis and apoptosis (Annexin-V fluorescein isothiocyanate [FITC]); senescence (β-galactosidase); and mitotic catastrophe (γ-tubulin and diamidino-phenylindole [DAPI]). RESULTS The XRT-induced or PRT-induced cellular senescence and mitotic catastrophe in all cell lines studied suggested that PRT caused cell death to a greater extent than XRT. After PRT, mitotic catastrophe peaked in HPV-negative and HPV-positive cells at 48 and 72 hours, respectively. No obvious differences were noted in the extent of cell necrosis or apoptosis after XRT versus PRT. CONCLUSION Under the conditions and in the cell lines reported here, mitotic catastrophe and senescence were the major types of cell death induced by XRT and PRT, and PRT may be more effective.
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Affiliation(s)
- Li Wang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Shichao Han
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Gynecology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Jinming Zhu
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Radiation Oncology, The Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
| | - Xiaochun Wang
- Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yuting Li
- Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Zeming Wang
- Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Eric Lin
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xiaofang Wang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - David P Molkentine
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Pierre Blanchard
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Radiation Oncology, Institut Gustave Roussy, Villejuif, France
| | - Yining Yang
- Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ruiping Zhang
- Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Narayan Sahoo
- Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Michael Gillin
- Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xiaorong Ronald Zhu
- Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xiaodong Zhang
- Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jeffrey N Myers
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Steven J Frank
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Rodrigues MFSD, Miguita L, De Andrade NP, Heguedusch D, Rodini CO, Moyses RA, Toporcov TN, Gama RR, Tajara EE, Nunes FD. GLI3 knockdown decreases stemness, cell proliferation and invasion in oral squamous cell carcinoma. Int J Oncol 2018; 53:2458-2472. [PMID: 30272273 PMCID: PMC6203148 DOI: 10.3892/ijo.2018.4572] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 06/29/2018] [Indexed: 12/24/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) is an extremely aggressive disease associated with a poor prognosis. Previous studies have established that cancer stem cells (CSCs) actively participate in OSCC development, progression and resistance to conventional treatments. Furthermore, CSCs frequently exhibit a deregulated expression of normal stem cell signalling pathways, thereby acquiring their distinctive abilities, of which self-renewal is an example. In this study, we examined the effects of GLI3 knockdown in OSCC, as well as the differentially expressed genes in CSC-like cells (CSCLCs) expressing high (CD44high) or low (CD44low) levels of CD44. The prognostic value of GLI3 in OSCC was also evaluated. The OSCC cell lines were sorted based on CD44 expression; gene expression was evaluated using a PCR array. Following this, we examined the effects of GLI3 knockdown on CD44 and ESA expression, colony and sphere formation capability, stem-related gene expression, proliferation and invasion. The overexpression of genes related to the Notch, transforming growth factor (TGF)β, FGF, Hedgehog, Wnt and pluripotency maintenance pathways was observed in the CD44high cells. GLI3 knockdown was associated with a significant decrease in different CSCLC fractions, spheres and colonies in addition to the downregulation of the CD44, Octamer-binding transcription factor 4 (OCT4; also known as POU5F1) and BMI1 genes. This downregulation was accompanied by an increase in the expression of the Involucrin (IVL) and S100A9 genes. Cellular proliferation and invasion were inhibited following GLI3 knockdown. In OSCC samples, a high GLI3 expression was associated with tumour size but not with prognosis. On the whole, the findings of this study demonstrate for the first time, at least to the best of our knowledge, that GLI3 contributes to OSCC stemness and malignant behaviour. These findings suggest the potential for the development of novel therapies, either in isolation or in combination with other drugs, based on CSCs in OSCC.
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Affiliation(s)
| | - Lucyene Miguita
- Department of Oral Pathology, School of Dentistry, University of São Paulo, São Paulo 05508000, Brazil
| | - Nathália Paiva De Andrade
- Department of Oral Pathology, School of Dentistry, University of São Paulo, São Paulo 05508000, Brazil
| | - Daniele Heguedusch
- Department of Oral Pathology, School of Dentistry, University of São Paulo, São Paulo 05508000, Brazil
| | | | - Raquel Ajub Moyses
- Department of Head and Neck Surgery, School of Medicine, University of São Paulo, São Paulo 03178200, Brazil
| | | | - Ricardo Ribeiro Gama
- Department of Head and Neck Surgery, Barretos Cancer Hospital, Barretos 014784400, Brazil
| | - Eloiza Elena Tajara
- Department of Molecular Biology, School of Medicine of São José do Rio Preto, São José do Rio Preto 15090000, Brazil
| | - Fabio Daumas Nunes
- Department of Oral Pathology, School of Dentistry, University of São Paulo, São Paulo 05508000, Brazil
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Qiao X, Liu W, Cao Y, Miao C, Yang W, Su N, Ye L, Li L, Li C. Performance of different imaging techniques in the diagnosis of head and neck cancer mandibular invasion: A systematic review and meta-analysis. Oral Oncol 2018; 86:150-164. [PMID: 30409295 DOI: 10.1016/j.oraloncology.2018.09.024] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 09/06/2018] [Accepted: 09/16/2018] [Indexed: 02/05/2023]
Abstract
BACKGROUND To assess diagnostic efficacy of imaging techniques for mandibular invasion by head and neck cancer. METHODS Thirteen databases were searched. Study inclusion, data-extraction and quality assessment were performed independently. STATA 14.0 were mainly used for meta-analysis. RESULTS Forty-nine studies were included. For mandibular invasion (cortex and marrow), CBCT, SPECT, CT, MRI, orthopantomography, PET-CT and bone-scintigraphy showed pooled sensitivities of 90%, 97%, 73%, 88%, 75%, 90%, 92%, specificities of 85%, 69% 91%, 90%, 83%, 89%, 79%, AUC of 0.9461, 0.9434, 0.8995, 0.9296, 0.8761, 0.9290, 0.9207, respectively. The combined SROC curves indicated CBCT and SPECT were superior to other techniques. For mandibular medullary invasion (marrow), CT and MRI showed pooled sensitivities of 85% and 93%, specificities of 86% and 84%. CONCLUSIONS CBCT was top-priority choice for bone invasion diagnosis. SPECT was recommended for exclusion, CT and MRI were suitable for conformation. Further investigations are needed for mandibular medullary involvement.
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Affiliation(s)
- Xianghe Qiao
- Department of Head and Neck Oncology, West China Hospital of Stomatology, State Key Laboratory of Oral Diseases, Sichuan University, Chengdu, China
| | - Wei Liu
- Department of Head and Neck Oncology, West China Hospital of Stomatology, State Key Laboratory of Oral Diseases, Sichuan University, Chengdu, China
| | - Yubin Cao
- Department of Head and Neck Oncology, West China Hospital of Stomatology, State Key Laboratory of Oral Diseases, Sichuan University, Chengdu, China
| | - Cheng Miao
- Department of Head and Neck Oncology, West China Hospital of Stomatology, State Key Laboratory of Oral Diseases, Sichuan University, Chengdu, China
| | - Wenbin Yang
- Department of Head and Neck Oncology, West China Hospital of Stomatology, State Key Laboratory of Oral Diseases, Sichuan University, Chengdu, China
| | - Naichuan Su
- Department of Prosthodontics, West China Hospital of Stomatology, State Key Laboratory of Oral Diseases, Sichuan University, Chengdu, China
| | - Li Ye
- Department of Head and Neck Oncology, West China Hospital of Stomatology, State Key Laboratory of Oral Diseases, Sichuan University, Chengdu, China
| | - Longjiang Li
- Department of Head and Neck Oncology, West China Hospital of Stomatology, State Key Laboratory of Oral Diseases, Sichuan University, Chengdu, China.
| | - Chunjie Li
- Department of Head and Neck Oncology, Department of Evidence-based Dentistry, West China Hospital of Stomatology, State Key Laboratory of Oral Diseases, Sichuan University, Chengdu, China.
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Ganjibakhsh M, Monshizadeh R, Nasimian A, Aminishakib P, Farzaneh P, Tavakoli Shiraji S, Gharajei A, Rahrotaban S, Baghaei F, Gohari NS. Anti-angiogenic efficacy of aflibercept and bevacizumab in primary oral squamous cell carcinoma cells. J Oral Pathol Med 2018; 47:575-582. [PMID: 29672933 DOI: 10.1111/jop.12717] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/12/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND In recent decades, anti-angiogenic treatment strategy has been well described in cancer treatment. The anti-angiogenic activity of both bevacizumab and aflibercept has been researched on 10 previously established primary oral squamous cell carcinoma (OSCC) cells of an Iranian population with different levels of purity, in an attempt to find the most effective anti-angiogenic-targeted drug. METHODS To investigate and compare the effect of bevacizumab and aflibercept on vascular endothelial growth factor (VEGF) secretion of 10 primary OSCC cells, cell proliferation and viability were assessed by ELISA and MTT assays. In addition, cell migration was studied using scratch assay. RESULTS The results showed that VEGF impressively expressed in all primary cancer cells. Although both drugs significantly reduced the secretion of VEGF, the effect of aflibercept was more prominent. Also, bevacizumab-treated cells migration was lower than the control group and the cells treated with aflibercept showed the lowest migration rate compared to bevacizumab and control groups. CONCLUSION The anti-angiogenic-targeted drugs, especially Af, might be effective in treatment of patients with OSCC in combination with conventional surgical treatments.
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Affiliation(s)
- Meysam Ganjibakhsh
- Human and Animal Cell Bank, Iranian Biological Resource Center (IBRC), ACECR, Tehran, Iran
| | - Roshanak Monshizadeh
- Department of Oral and Maxillofacial Pathology, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Nasimian
- Department of Clinical Biochemistry, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Pouyan Aminishakib
- Department of Oral and Maxillofacial Pathology, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran.,Dental Research Center, Dentistry Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Parvaneh Farzaneh
- Human and Animal Cell Bank, Iranian Biological Resource Center (IBRC), ACECR, Tehran, Iran
| | - Sahar Tavakoli Shiraji
- Hematology, Oncology and SCT Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ata Gharajei
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran.,Department of Head and Neck Surgical Oncology and Reconstructive Surgery, The Cancer Institute, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Sedigheh Rahrotaban
- Department of Oral and Maxillofacial Pathology, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
| | - Fereshteh Baghaei
- Dental Research Center, Dentistry Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Neda Sadat Gohari
- Human and Animal Cell Bank, Iranian Biological Resource Center (IBRC), ACECR, Tehran, Iran
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40
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Setúbal Destro Rodrigues MF, Gammon L, Rahman MM, Biddle A, Nunes FD, Mackenzie IC. Effects of Cetuximab and Erlotinib on the behaviour of cancer stem cells in head and neck squamous cell carcinoma. Oncotarget 2018; 9:13488-13500. [PMID: 29568372 PMCID: PMC5862593 DOI: 10.18632/oncotarget.24416] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Accepted: 01/20/2018] [Indexed: 01/06/2023] Open
Abstract
The therapeutic responses of many solid tumours to chemo- and radio-therapies are far from fully effective but therapies targeting malignancy-related cellular changes show promise for further control. In head and neck squamous cell carcinoma, the epidermal growth factor receptor (EGFR) is commonly overexpressed and investigation of agents that block this receptor indicate a limited response when used alone but an ability to enhance the actions of other drugs. The hierarchical stem cell patterns present in tumours generate cellular heterogeneity and this is further complicated by cancer stem cells (CSC) shifting between epithelial (Epi-CSC) and mesenchymal (EMT-CSC) states. To clarify how such heterogeneity influences responses to EGFR blocking, we examined the effects of Cetuximab and Erlotinib on the cell sub-populations in HNSCC cell lines. These agents reduced cell proliferation for all subpopulations but induced little cell death. They did however induce large shifts of cells between the EMT-CSC, Epi-CSC and differentiating cell compartments. Loss of EMT-CSCs reduced cell motility and is expected to reduce invasion and metastasis. EGFR blocking also induced shifts of Epi-CSCs into the differentiating cell compartment which typically has greater sensitivity to chemo/radiation, an effect expected to enhance the overall response of tumour cell populations to adjunctive therapies.
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Affiliation(s)
| | - Luke Gammon
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Muhammad M Rahman
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Adrian Biddle
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Fabio Daumas Nunes
- Oral Pathology Department, School of Dentistry, University of São Paulo, São Paulo, Brazil
| | - Ian C Mackenzie
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Spinato G, Stellin M, Azzarello G, Bonazza D, Zanconati F, Politi D, Cocuzza S, Di Mauro P, Ausoni S, Tonoli G, Costantini G, Maiolino L, Spinato R, Da Mosto MC, Baboci L, Del Mistro A, Serra A, Tirelli G. Multicenter research into the quality of life of patients with advanced oropharyngeal carcinoma with long-term survival associated with human papilloma virus. Oncol Lett 2017; 14:185-193. [PMID: 28693152 PMCID: PMC5494809 DOI: 10.3892/ol.2017.6152] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 11/28/2016] [Indexed: 01/22/2023] Open
Abstract
The treatment of advanced-stage oropharyngeal squamous cell carcinoma may utilize various modes, including combining surgery with chemoradiotherapy (CTRT), or primary CTRT followed by rescue surgery. In previous literature it has been revealed how patients treated with combined modes report a low quality of life (QoL) and severe consequences following surgery, radiotherapy and chemotherapy, in the short and in the long-term. The decrease in the QoL of patients treated with high-intensity multi-modal strategies highlights the necessity of modifying treatments, particularly for young HPV-positive patients, where an increased survival rate has already been reported. The modified treatment for HPV-positive tumors in the tonsils and at the base of the tongue is based on the deintensification of therapies aiming to reduce toxicity and thereby improve QoL in the long term, whilst still maintaining therapeutic effectiveness. The aim of the present study was to evaluate the QoL in patients with a long-term survival, who were treated with combined therapy for squamous cell tumors in the tonsils and at the base of the tongue, and to compare the results observed in HPV-positive and HPV-negative patients. According to statistical analysis, differences in the general QoL and in the single scales of the European Organization for the Research and Treatment of Cancer questionnaires were not correlated with the type of therapy selected for the particular patient. QoL considered the presence of HPV, the type of treatment, the subregion of the tonsils vs. the base of the tongue and the disease stage at the time of diagnosis, and was determined to be non-influential with regard to these specific variables.
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Affiliation(s)
- Giacomo Spinato
- Ear, Nose and Throat Department, Rovigo Provincial Hospital, I-45100 Rovigo, Italy
| | - Marco Stellin
- Department of Neurosciences, Ear, Nose and Throat Clinic and Regional Center for Head and Neck Cancer, University of Padua, Treviso Provincial Hospital, I-35122 Padua, Italy
| | | | - Deborah Bonazza
- Pathology Department, Cattinara Hospital, University of Trieste, I-34149 Trieste, Italy
| | - Fabrizio Zanconati
- Pathology Department, Cattinara Hospital, University of Trieste, I-34149 Trieste, Italy
| | - Doriano Politi
- Provincial Ear, Nose and Throat Department of Venice, Mestre Hospital, I-30174 Venice, Italy
| | - Salvatore Cocuzza
- Ear, Nose and Throat Department, University of Catania, I-95125 Catania, Italy
| | - Paola Di Mauro
- Ear, Nose and Throat Department, University of Catania, I-95125 Catania, Italy
| | - Simonetta Ausoni
- Department of Biomedical Sciences, University of Padua, I-35122 Padua, Italy
| | - Giovanni Tonoli
- Ear, Nose and Throat Department, Rovigo Provincial Hospital, I-45100 Rovigo, Italy
| | - Giulio Costantini
- Psychology Department, University of Milano-Bicocca, I-20126 Milan, Italy
| | - Luigi Maiolino
- Ear, Nose and Throat Department, University of Catania, I-95125 Catania, Italy
| | - Roberto Spinato
- Provincial Ear, Nose and Throat Department of Venice, Mestre Hospital, I-30174 Venice, Italy
| | - Maria Cristina Da Mosto
- Department of Neurosciences, Ear, Nose and Throat Clinic and Regional Center for Head and Neck Cancer, University of Padua, Treviso Provincial Hospital, I-35122 Padua, Italy
| | - Lorena Baboci
- Veneto Institute of Oncology IOV-IRCCS, Immunology and Molecular Oncology Unit, Padua, I-35128 Padova, Italy
| | - Annarosa Del Mistro
- Veneto Institute of Oncology IOV-IRCCS, Immunology and Molecular Oncology Unit, Padua, I-35128 Padova, Italy
| | - Agostino Serra
- Ear, Nose and Throat Department, University of Catania, I-95125 Catania, Italy
| | - Giancarlo Tirelli
- Ear, Nose and Throat Department, Cattinara Hospital, University of Trieste, I-34149 Trieste, Italy
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Seven LncRNA-mRNA based risk score predicts the survival of head and neck squamous cell carcinoma. Sci Rep 2017; 7:309. [PMID: 28331188 PMCID: PMC5428014 DOI: 10.1038/s41598-017-00252-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Accepted: 02/15/2017] [Indexed: 02/06/2023] Open
Abstract
Dysregulation of mRNAs and long non-coding RNAs (lncRNAs) is one of the most important features of carcinogenesis and cancer development. However, studies integrating the expression of mRNAs and lncRNAs to predict the survival of head and neck squamous cell carcinoma (HNSC) are still limited, hitherto. In current work, we identified survival related mRNAs and lncRNAs in three datasets (TCGA dataset, E-TABM-302, GSE41613). By random forest, seven gene signatures (six mRNAs and lncRNA) were further selected to develop the risk score model. The risk score was significantly associated with survival in both training and testing datasets (E-TABM-302, GSE41613, and E-MTAB-1324). Furthermore, correlation analyses showed that the risk score is independent from clinicopathological features. According to Cox multivariable hazard model and nomogram, the risk score contributes the most to survival than the other clinical information, including gender, age, histologic grade, and alcohol taking. The Gene Set Enrichment Analysis (GSEA) indicates that the risk score is associated with cancer related pathways. In summary, the lncRNA-mRNA based risk score model we developed successfully predicts the survival of 755 HNSC samples in five datasets and two platforms. It is independent from clinical information and performs better than clinical information for prognosis.
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Boscolo-Rizzo P, Da Mosto MC, Rampazzo E, Giunco S, Del Mistro A, Menegaldo A, Baboci L, Mantovani M, Tirelli G, De Rossi A. Telomeres and telomerase in head and neck squamous cell carcinoma: from pathogenesis to clinical implications. Cancer Metastasis Rev 2017; 35:457-74. [PMID: 27501725 PMCID: PMC5035656 DOI: 10.1007/s10555-016-9633-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Strongly associated with tobacco use, heavy alcohol consumption, and with high-risk human papillomavirus (HPV) infection, head and neck squamous cell carcinoma (HNSCC) is a frequently lethal, heterogeneous disease whose pathogenesis is a multistep and multifactorial process involving genetic and epigenetic events. The majority of HNSCC patients present with locoregional advanced stage disease and are treated with combined modality strategies that can markedly impair quality of life and elicit unpredictable results. A large fraction of those who undergo locoregional treatment and achieve a complete response later develop locoregional recurrences or second field tumors. Biomarkers that are thus able to stratify risk and enable clinicians to tailor treatment plans and to personalize post-therapeutic surveillance strategies are highly desirable. To date, only HPV status is considered a reliable independent predictor of treatment response and survival in patients with HNSCC arising from the oropharyngeal site. Recent studies suggest that telomere attrition, which may be an early event in human carcinogenesis, and telomerase activation, which is detected in up to 90 % of malignancies, could be potential markers of cancer risk and disease outcome. This review examines the current state of knowledge on and discusses the implications linked to telomere dysfunction and telomerase activation in the development and clinical outcome of HNSCC.
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MESH Headings
- Animals
- Biomarkers, Tumor
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/metabolism
- Carcinoma, Squamous Cell/mortality
- Carcinoma, Squamous Cell/pathology
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Gene Expression Regulation, Neoplastic
- Genetic Predisposition to Disease
- Genetic Variation
- Genomic Instability
- Head and Neck Neoplasms/genetics
- Head and Neck Neoplasms/metabolism
- Head and Neck Neoplasms/mortality
- Head and Neck Neoplasms/pathology
- Humans
- Leukocytes, Mononuclear/metabolism
- Leukocytes, Mononuclear/pathology
- Mice
- Prognosis
- Squamous Cell Carcinoma of Head and Neck
- Telomerase/metabolism
- Telomere/genetics
- Telomere Homeostasis
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Affiliation(s)
- Paolo Boscolo-Rizzo
- Section of Otolaryngology and Regional Centre for Head and Neck Cancer, Department of Neurosciences, University of Padova, Treviso, Italy
| | - Maria Cristina Da Mosto
- Section of Otolaryngology and Regional Centre for Head and Neck Cancer, Department of Neurosciences, University of Padova, Treviso, Italy
| | - Enrica Rampazzo
- Section of Oncology and Immunology, Department of Surgical Sciences, Oncology and Gastroenterology, University of Padova, via Gattamelata 64, 35128, Padova, Italy
| | - Silvia Giunco
- Section of Oncology and Immunology, Department of Surgical Sciences, Oncology and Gastroenterology, University of Padova, via Gattamelata 64, 35128, Padova, Italy
| | - Annarosa Del Mistro
- Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto-IRCCS, Padova, Italy
| | - Anna Menegaldo
- Section of Otolaryngology and Regional Centre for Head and Neck Cancer, Department of Neurosciences, University of Padova, Treviso, Italy
| | - Lorena Baboci
- Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto-IRCCS, Padova, Italy
| | - Monica Mantovani
- Section of Otolaryngology and Regional Centre for Head and Neck Cancer, Department of Neurosciences, University of Padova, Treviso, Italy
| | - Giancarlo Tirelli
- Department of Otorhinolaryngology and Head and Neck Surgery, University of Trieste, Trieste, Italy
| | - Anita De Rossi
- Section of Oncology and Immunology, Department of Surgical Sciences, Oncology and Gastroenterology, University of Padova, via Gattamelata 64, 35128, Padova, Italy.
- Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto-IRCCS, Padova, Italy.
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44
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Mallen-St Clair J, Alani M, Wang MB, Srivatsan ES. Human papillomavirus in oropharyngeal cancer: The changing face of a disease. Biochim Biophys Acta Rev Cancer 2016; 1866:141-150. [PMID: 27487173 DOI: 10.1016/j.bbcan.2016.07.005] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 07/14/2016] [Accepted: 07/29/2016] [Indexed: 12/18/2022]
Abstract
The last decade has brought about an unexpected rise in oropharyngeal squamous cell carcinoma (OPSCC) primarily in white males from the ages of 40-55years, with limited exposure to alcohol and tobacco. This subset of squamous cell carcinoma (SCC) has been found to be associated with human papillomavirus infection (HPV). Other Head and Neck Squamous Cell carcinoma (HNSCC) subtypes include oral cavity, hypopharyngeal, nasopharyngeal, and laryngeal SCC which tend to be HPV negative. HPV associated oropharyngeal cancer has proven to differ from alcohol and tobacco associated oropharyngeal carcinoma in regards to the molecular pathophysiology, presentation, epidemiology, prognosis, and improved response to chemoradiation therapy. Given the improved survival of patients with HPV associated SCC, efforts to de-intensify treatment to decrease treatment related morbidity are at the forefront of clinical research. This review will focus on the important differences between HPV and tobacco related oropharyngeal cancer. We will review the molecular pathogenesis of HPV related oropharyngeal cancer with an emphasis on new paradigms for screening and treating this disease.
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Affiliation(s)
- Jon Mallen-St Clair
- Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Mustafa Alani
- UCLA School of Dentistry, Los Angeles, CA, United States
| | - Marilene B Wang
- Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System/David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; Member of Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, United States
| | - Eri S Srivatsan
- Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System/David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; Member of Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, United States.
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