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Nakako Y, Hasegawa K, Fujii S, Kami Y, Sakamoto T, Sakamoto M, Moriyama M, Kurppa KJ, Heikinheimo K, Yoshiura K, Kawano S, Kiyoshima T. Wnt/β-catenin-YAP axis in the pathogenesis of primary intraosseous carcinoma NOS, deriving from odontogenic keratocyst. Pathol Res Pract 2024; 260:155420. [PMID: 38908335 DOI: 10.1016/j.prp.2024.155420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 06/14/2024] [Accepted: 06/19/2024] [Indexed: 06/24/2024]
Abstract
Odontogenic tumors (OGTs), which originate from cells of odontogenic apparatus and their remnants, are rare entities. Primary intraosseous carcinoma NOS (PIOC), is one of the OGTs, but it is even rarer and has a worse prognosis. The precise characteristics of PIOC, especially in immunohistochemical features and its pathogenesis, remain unclear. We characterized a case of PIOC arising from the left mandible, in which histopathological findings showed a transition from the odontogenic keratocyst to the carcinoma. Remarkably, the tumor lesion of this PIOC prominently exhibits malignant attributes, including invasive growth of carcinoma cell infiltration into the bone tissue, an elevated Ki-67 index, and lower signal for CK13 and higher signal for CK17 compared with the non-tumor region, histopathologically and immunohistopathologically. Further immunohistochemical analyses demonstrated increased expression of ADP-ribosylation factor (ARF)-like 4c (ARL4C) (accompanying expression of β-catenin in the nucleus) and yes-associated protein (YAP) in the tumor lesion. On the other hand, YAP was expressed and the expression of ARL4C was hardly detected in the non-tumor region. In addition, quantitative RT-PCR analysis using RNAs and dot blot analysis using genomic DNA showed the activation of Wnt/β-catenin signaling and epigenetic alterations, such as an increase of 5mC levels and a decrease of 5hmC levels, in the tumor lesion. A DNA microarray and a gene set enrichment analysis demonstrated that various types of intracellular signaling would be activated and several kinds of cellular functions would be altered in the pathogenesis of PIOC. Experiments with the GSK-3 inhibitor revealed that β-catenin pathway increased not only mRNA levels of ankyrin repeat domain1 (ANKRD1) but also protein levels of YAP and transcriptional co-activator with PDZ-binding motif (TAZ) in oral squamous cell carcinoma cell lines. These results suggested that further activation of YAP signaling by Wnt/β-catenin signaling may be associated with the pathogenesis of PIOC deriving from odontogenic keratocyst in which YAP signaling is activated.
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Affiliation(s)
- Yusuke Nakako
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Kana Hasegawa
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Shinsuke Fujii
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Dento-craniofacial Development and Regeneration Research Center, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Institute of Biomedicine and MediCity Research Laboratories, University of Turku, and Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku 20520, Finland.
| | - Yukiko Kami
- Department of Oral and Maxillofacial Radiology, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Taiki Sakamoto
- Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Mizuki Sakamoto
- Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Masafumi Moriyama
- Section of Oral and Maxillofacial Surgery, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Kari J Kurppa
- Institute of Biomedicine and MediCity Research Laboratories, University of Turku, and Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku 20520, Finland
| | - Kristiina Heikinheimo
- Department of Oral and Maxillofacial Surgery, Institute of Dentistry, University of Turku and Turku University Hospital, 20520, Finland
| | - Kazunori Yoshiura
- Department of Oral and Maxillofacial Radiology, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Shintaro Kawano
- Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Tamotsu Kiyoshima
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
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Lechner A, Kumbrink J, Walz C, Jung A, Baumeister P, Flach S. Molecular characterization of the evolution of premalignant lesions in the upper aerodigestive tract. Front Oncol 2024; 14:1364958. [PMID: 38706595 PMCID: PMC11067708 DOI: 10.3389/fonc.2024.1364958] [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: 01/03/2024] [Accepted: 04/03/2024] [Indexed: 05/07/2024] Open
Abstract
Introduction Early relapse and development of metastatic disease are some of the primary reasons for the poor prognosis of patients with head and neck squamous cell carcinoma (HNSCC). HNSCC is a heterogeneous disease which may develop in large premalignant fields of genetically altered cells. Yet knowing which individuals will progress and develop clinically significant cancers during their lifetimes remains one of the most important challenges of reducing HNSCC morbidity and mortality. To further elucidate the molecular mechanisms, we performed a focused analysis of the genome and immune microenvironment from multiple, matched normal squamous tissue, premalignant lesions, as well as primary and recurrent tumors from seven patients with p16-negative HNSCC. Methods We performed targeted panel Next Generation Sequencing (161 genes) to analyze somatic variants from sequentially collected, matched formalin-fixed paraffin-embedded tissue (normal, premalignant, HNSCC) from two patients. These samples plus samples from five additional patients were analyzed with the Nanostring PanCancer Immune Panel. In addition, we performed shallow whole genome sequencing (0.5x coverage on average) on samples from three of these patients. Patients were, apart from one case, primarily treated with curative-intent surgery, and received subsequent adjuvant treatment, if indicated. Results The most frequently mutated genes were TP53 and NOTCH1. Other mutated genes included NOTCH3 and CDKN2A, among others. A significant number of mutations were private to dysplasia and invasive carcinoma, respectively, however, almost 20% were shared between them. Increasing genomic instability was observed when comparing histologically normal squamous mucosa with higher levels of dysplasia. High-grade dysplasia showed similarly rearranged genomes as invasive carcinoma. Pathways related to interferon alpha and gamma response were upregulated even in moderate dysplastic lesions with increasing expression in higher grades of dysplasia and carcinoma. SPINK5, a known tumor suppressor gene in HNSCC, was already downregulated in low-grade dysplastic lesions, indicating an early deactivation in the evolution of the disease. Conclusion Genomic alterations as well as aberrant immune gene expression can be observed early in the evolution of tumors of the upper aerodigestive tract, highlighting the potential for targeting early mechanisms of disease progression.
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Affiliation(s)
- Axel Lechner
- Department of Otorhinolaryngology, Head and Neck Surgery, Ludwig-Maximilians-Universität (LMU) Munich University Hospital, Munich, Germany
| | - Jörg Kumbrink
- Department of Pathology, LMU Munich University Hospital, Munich, Germany
| | - Christoph Walz
- Department of Pathology, LMU Munich University Hospital, Munich, Germany
| | - Andreas Jung
- Department of Pathology, LMU Munich University Hospital, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Philipp Baumeister
- Department of Otorhinolaryngology, Head and Neck Surgery, Ludwig-Maximilians-Universität (LMU) Munich University Hospital, Munich, Germany
| | - Susanne Flach
- Department of Otorhinolaryngology, Head and Neck Surgery, Ludwig-Maximilians-Universität (LMU) Munich University Hospital, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
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Vukovic Đerfi K, Vasiljevic T, Matijevic Glavan T. Recent Advances in the Targeting of Head and Neck Cancer Stem Cells. APPLIED SCIENCES 2023; 13:13293. [DOI: 10.3390/app132413293] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a very heterogeneous cancer with a poor overall response to therapy. One of the reasons for this therapy resistance could be cancer stem cells (CSCs), a small population of cancer cells with self-renewal and tumor-initiating abilities. Tumor cell heterogeneity represents hurdles for therapeutic elimination of CSCs. Different signaling pathway activations, such as Wnt, Notch, and Sonic-Hedgehog (SHh) pathways, lead to the expression of several cancer stem factors that enable the maintenance of CSC features. Identification and isolation of CSCs are based either on markers (CD133, CD44, and aldehyde dehydrogenase (ALDH)), side populations, or their sphere-forming ability. A key challenge in cancer therapy targeting CSCs is overcoming chemotherapy and radiotherapy resistance. However, in novel therapies, various approaches are being employed to address this hurdle such as targeting cell surface markers, other stem cell markers, and different signaling or metabolic pathways, but also, introducing checkpoint inhibitors and natural compounds into the therapy can be beneficial.
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Affiliation(s)
- Kristina Vukovic Đerfi
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Ruđer Boskovic Institute, Bijenicka 54, 10000 Zagreb, Croatia
| | - Tea Vasiljevic
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Ruđer Boskovic Institute, Bijenicka 54, 10000 Zagreb, Croatia
| | - Tanja Matijevic Glavan
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Ruđer Boskovic Institute, Bijenicka 54, 10000 Zagreb, Croatia
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Alkhatib DZR, Thi Kim Truong T, Fujii S, Hasegawa K, Nagano R, Tajiri Y, Kiyoshima T. Stepwise activation of p63 and the MEK/ERK pathway induces the expression of ARL4C to promote oral squamous cell carcinoma cell proliferation. Pathol Res Pract 2023; 246:154493. [PMID: 37141698 DOI: 10.1016/j.prp.2023.154493] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/25/2023] [Accepted: 04/25/2023] [Indexed: 05/06/2023]
Abstract
Carcinogenesis is a multistep process wherein cells accumulate multiple genetic alterations and progress to a more malignant phenotype. It has been proposed that sequential accumulation of gene abnormalities in specific genes drives the transition from non-tumorous epithelia through a preneoplastic lesion/benign tumor to cancer. Histologically, oral squamous cell carcinoma (OSCC) progresses in multiple ordered steps that begin with mucosal epithelial cell hyperplasia, which is followed by dysplasia, carcinoma in situ and invasive carcinoma. It is therefore hypothesized that genetic alteration-mediated multistep carcinogenesis would be involved in the development of OSCC; however, the detailed molecular mechanisms are unknown. We clarified the comprehensive gene expression patterns and carried out an enrichment analysis using DNA microarray data from a pathological specimen of OSCC (including a non-tumor region, carcinoma in situ lesion and invasive carcinoma lesion). The expression of numerous genes and signal activation were altered in the development of OSCC. Among these, the p63 expression was increased and the MEK/ERK-MAPK pathway was activated in carcinoma in situ lesion and in invasive carcinoma lesion. Immunohistochemical analyses revealed that p63 was initially upregulated in carcinoma in situ and ERK was sequentially activated in invasive carcinoma lesions in OSCC specimens. ADP-ribosylation factor (ARF)-like 4c (ARL4C), the expression of which is reportedly induced by p63 and/or the MEK/ERK-MAPK pathway in OSCC cells, has been shown to promote tumorigenesis. Immunohistochemically, in OSCC specimens, ARL4C was more frequently detected in tumor lesions, especially in invasive carcinoma lesions, than in carcinoma in situ lesions. Additionally, ARL4C and phosphorylated ERK were frequently merged in invasive carcinoma lesions. Loss-of-function experiments using inhibitors and siRNAs revealed that p63 and MEK/ERK-MAPK cooperatively induce the expression of ARL4C and cell growth in OSCC cells. These results suggest that the stepwise activation of p63 and MEK/ERK-MAPK contributes to OSCC tumor cell growth through regulation of ARL4C expression.
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Affiliation(s)
- Dania Zuhier Ragheb Alkhatib
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Thinh Thi Kim Truong
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Shinsuke Fujii
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Dento-craniofacial Development and Regeneration Research Center, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
| | - Kana Hasegawa
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Ryoko Nagano
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Department of Endodontology and Operative Dentistry, Division of Oral Rehabilitation, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Yudai Tajiri
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Department of Dentistry and Oral Surgery, National Hospital Organization, Fukuokahigashi Medical Center, 1-1-1 Chidori, Koga, Fukuoka 811-3195, Japan
| | - Tamotsu Kiyoshima
- Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
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Afshari K, Sohal KS. Potential Alternative Therapeutic Modalities for Management Head and Neck Squamous Cell Carcinoma: A Review. Cancer Control 2023; 30:10732748231185003. [PMID: 37328298 DOI: 10.1177/10732748231185003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/18/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) includes malignancies of the lip and oral cavity, oropharynx, nasopharynx, larynx, and hypopharynx. It is among the most common malignancy worldwide, affecting nearly 1 million people annually. The traditional treatment options for HNSCC include surgery, radiotherapy, and conventional chemotherapy. However, these treatment options have their specific sequelae, which produce high rates of recurrence and severe treatment-related disabilities. Recent technological advancements have led to tremendous progress in understanding tumor biology, and hence the emergence of several alternative therapeutic modalities for managing cancers (including HNSCC). These treatment options are stem cell targeted therapy, gene therapy, and immunotherapy. Therefore, this review article aims to provide an overview of these alternative treatments of HNSCC.
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Affiliation(s)
- Keihan Afshari
- Department of Oral and Maxillofacial Surgery, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania
| | - Karpal Singh Sohal
- Department of Oral and Maxillofacial Surgery, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania
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Renu K, Vinayagam S, Veeraraghavan VP, Mukherjee AG, Wanjari UR, Prabakaran DS, Ganesan R, Dey A, Vellingiri B, Kandasamy S, Ramanathan G, Doss C GP, George A, Gopalakrishnan AV. Molecular Crosstalk between the Immunological Mechanism of the Tumor Microenvironment and Epithelial–Mesenchymal Transition in Oral Cancer. Vaccines (Basel) 2022; 10:vaccines10091490. [PMID: 36146567 PMCID: PMC9504083 DOI: 10.3390/vaccines10091490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/02/2022] [Accepted: 09/05/2022] [Indexed: 11/30/2022] Open
Abstract
Oral cancer is a significant non-communicable disease affecting both emergent nations and developed countries. Squamous cell carcinoma of the head and neck represent the eight major familiar cancer types worldwide, accounting for more than 350,000 established cases every year. Oral cancer is one of the most exigent tumors to control and treat. The survival rate of oral cancer is poor due to local invasion along with recurrent lymph node metastasis. The tumor microenvironment contains a different population of cells, such as fibroblasts associated with cancer, immune-infiltrating cells, and other extracellular matrix non-components. Metastasis in a primary site is mainly due to multifaceted progression known as epithelial-to-mesenchymal transition (EMT). For the period of EMT, epithelial cells acquire mesenchymal cell functional and structural characteristics, which lead to cell migration enhancement and promotion of the dissemination of tumor cells. The present review links the tumor microenvironment and the role of EMT in inflammation, transcriptional factors, receptor involvement, microRNA, and other signaling events. It would, in turn, help to better understand the mechanism behind the tumor microenvironment and EMT during oral cancer.
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Affiliation(s)
- Kaviyarasi Renu
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600077, Tamil Nadu, India
- Correspondence: (K.R.); (A.V.G.)
| | - Sathishkumar Vinayagam
- Department of Biotechnology, Centre for Postgraduate and Research Studies, Periyar University, Dharmapuri 635205, Tamil Nadu, India
| | - Vishnu Priya Veeraraghavan
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600077, Tamil Nadu, India
| | - Anirban Goutam Mukherjee
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
| | - Uddesh Ramesh Wanjari
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
| | - D. S. Prabakaran
- Department of Radiation Oncology, College of Medicine, Chungbuk National University, Chungdae-ro 1, Seowon-gu, Cheongju 28644, Korea
- Department of Biotechnology, Ayya Nadar Janaki Ammal College (Autonomous), Srivilliputhur Main Road, Sivakasi 626124, Tamil Nadu, India
| | - Raja Ganesan
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Korea
| | - Abhijit Dey
- Department of Life Sciences, Presidency University, Kolkata 700073, West Bengal, India
| | - Balachandar Vellingiri
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641046, Tamil Nadu, India
| | - Sabariswaran Kandasamy
- Institute of Energy Research, Jiangsu University, No 301, Xuefu Road, Zhenjiang 212013, China
| | - Gnanasambandan Ramanathan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
| | - George Priya Doss C
- Department of Integrative Biology, School of BioSciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
| | - Alex George
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur 680005, Kerala, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
- Correspondence: (K.R.); (A.V.G.)
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Prime SS, Cirillo N, Cheong SC, Prime MS, Parkinson EK. Targeting the genetic landscape of oral potentially malignant disorders has the potential as a preventative strategy in oral cancer. Cancer Lett 2021; 518:102-114. [PMID: 34139286 DOI: 10.1016/j.canlet.2021.05.025] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 05/19/2021] [Accepted: 05/24/2021] [Indexed: 12/12/2022]
Abstract
This study reviews the molecular landscape of oral potentially malignant disorders (OPMD). We examine the impact of tumour heterogeneity, the spectrum of driver mutations (TP53, CDKN2A, TERT, NOTCH1, AJUBA, PIK3CA, CASP8) and gene transcription on tumour progression. We comment on how some of these mutations impact cellular senescence, field cancerization and cancer stem cells. We propose that OPMD can be monitored more closely and more dynamically through the use of liquid biopsies using an appropriate biomarker of transformation. We describe new gene interactions through the use of a systems biology approach and we highlight some of the first studies to identify functional genes using CRISPR-Cas9 technology. We believe that this information has translational implications for the use of re-purposed existing drugs and/or new drug development. Further, we argue that the use of digital technology encompassing clinical and laboratory-based data will create relevant datasets for machine learning/artificial intelligence. We believe that therapeutic intervention at an early molecular premalignant stage should be an important preventative strategy to inhibit the development of oral squamous cell carcinoma and that this approach is applicable to other aerodigestive tract cancers.
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Affiliation(s)
- S S Prime
- Centre for Immunology and Regenerative Medicine, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, E1 4NS, UK.
| | - N Cirillo
- Melbourne Dental School, University of Melbourne, 720 Swanson Street, Carlton, Melbourne, Victoria, 3053, Australia.
| | - S C Cheong
- Head and Neck Cancer Research Team, Cancer Research Malaysia, 1 Jalan SS12/1A, Subang Jaya, Selangor, Malaysia.
| | - M S Prime
- Roche Diagnostics Information Solutions, Hoffman-La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland.
| | - E K Parkinson
- Centre for Immunology and Regenerative Medicine, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, E1 4NS, UK.
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Notch Signaling and Human Papillomavirus-Associated Oral Tumorigenesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1287:105-122. [PMID: 33034029 DOI: 10.1007/978-3-030-55031-8_8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The NOTCH pathway is critical for the development of many cell types including the squamous epithelium lining of cutaneous and mucosal surfaces. In genetically engineered mouse models, Notch1 acts as one of the first steps to commit basal keratinocytes to terminally differentiate. Similarly, in human head and neck squamous cell cancers (HNSCCs), NOTCH1 is often lost consistent with its essential tumor-suppressive role for initiating keratinocyte differentiation. However, constitutive NOTCH1 activity in the epithelium results in expansion of the spinous keratinocyte layers and impaired terminal differentiation is consistent with the role of NOTCH1 as an oncogene in other cancers, especially in T-cell acute lymphoblastic leukemia. We have previously observed that NOTCH1 plays a dual role as both a tumor suppressor and oncogene, depending on the mutational context of the tumor. Namely, gain or loss or NOTCH1 activity promotes the development of human papillomavirus (HPV)-associated cancers. The additional HPV oncogenes likely disrupt the tumor-suppressive activities of NOTCH and enable the oncogenic pathways activated by NOTCH to promote tumor growth. In this review, we detail the role of NOTCH pathway in head and neck cancers with a focus on HPV-associated cancers.
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Caliri AW, Tommasi S, Besaratinia A. Relationships among smoking, oxidative stress, inflammation, macromolecular damage, and cancer. MUTATION RESEARCH. REVIEWS IN MUTATION RESEARCH 2021; 787:108365. [PMID: 34083039 PMCID: PMC8287787 DOI: 10.1016/j.mrrev.2021.108365] [Citation(s) in RCA: 306] [Impact Index Per Article: 76.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 01/06/2021] [Accepted: 01/07/2021] [Indexed: 02/07/2023]
Abstract
Smoking is a major risk factor for a variety of diseases, including cancer and immune-mediated inflammatory diseases. Tobacco smoke contains a mixture of chemicals, including a host of reactive oxygen- and nitrogen species (ROS and RNS), among others, that can damage cellular and sub-cellular targets, such as lipids, proteins, and nucleic acids. A growing body of evidence supports a key role for smoking-induced ROS and the resulting oxidative stress in inflammation and carcinogenesis. This comprehensive and up-to-date review covers four interrelated topics, including 'smoking', 'oxidative stress', 'inflammation', and 'cancer'. The review discusses each of the four topics, while exploring the intersections among the topics by highlighting the macromolecular damage attributable to ROS. Specifically, oxidative damage to macromolecular targets, such as lipid peroxidation, post-translational modification of proteins, and DNA adduction, as well as enzymatic and non-enzymatic antioxidant defense mechanisms, and the multi-faceted repair pathways of oxidized lesions are described. Also discussed are the biological consequences of oxidative damage to macromolecules if they evade the defense mechanisms and/or are not repaired properly or in time. Emphasis is placed on the genetic- and epigenetic alterations that may lead to transcriptional deregulation of functionally-important genes and disruption of regulatory elements. Smoking-associated oxidative stress also activates the inflammatory response pathway, which triggers a cascade of events of which ROS production is an initial yet indispensable step. The release of ROS at the site of damage and inflammation helps combat foreign pathogens and restores the injured tissue, while simultaneously increasing the burden of oxidative stress. This creates a vicious cycle in which smoking-related oxidative stress causes inflammation, which in turn, results in further generation of ROS, and potentially increased oxidative damage to macromolecular targets that may lead to cancer initiation and/or progression.
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Affiliation(s)
- Andrew W Caliri
- Department of Preventive Medicine, USC Keck School of Medicine, University of Southern California, M/C 9603, Los Angeles, CA 90033, USA
| | - Stella Tommasi
- Department of Preventive Medicine, USC Keck School of Medicine, University of Southern California, M/C 9603, Los Angeles, CA 90033, USA
| | - Ahmad Besaratinia
- Department of Preventive Medicine, USC Keck School of Medicine, University of Southern California, M/C 9603, Los Angeles, CA 90033, USA.
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Enaka M, Nakanishi M, Muragaki Y. The Gain-of-Function Mutation p53R248W Suppresses Cell Proliferation and Invasion of Oral Squamous Cell Carcinoma through the Down-Regulation of Keratin 17. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 191:555-566. [PMID: 33307039 DOI: 10.1016/j.ajpath.2020.11.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 11/20/2020] [Accepted: 11/30/2020] [Indexed: 11/28/2022]
Abstract
Keratin 17 (KRT17) expression promotes the proliferation and invasion of oral squamous cell carcinoma (OSCC), and mutations in TP53 have been reported in 65% to 85% of OSCC cases. We studied the correlation between KRT17 expression and TP53 mutants. Ca9-22 cells, which exhibit low KRT17 expression, carried mutant p53 (p53R248W) and p53R248W knockdown promoted KRT17 expression. p53R248W knockdown in Ca9-22 cells promoted migration and invasion activity. In contrast, in HSC3 cells, which have p53 nonsense mutations and exhibit high KRT17 expression, the overexpression of p53R248W decreased KRT17 expression, cell size, proliferation, and migration and invasion activities. In addition, p53R248W significantly suppressed MMP2 mRNA expression and enzyme activity. Moreover, s.c. and orthotopic xenografts were generated from p53R248W- or p53R248Q-expressing HSC3 cells. Tumors formed from p53R248W-expressing HSC3 cells grew more slowly and had a lower Ki-67 index than those derived from the control or p53R248Q-expressing HSC3 cells. Finally, the survival rate of the mice inoculated with p53R248W-expressing HSC3 cells was significantly higher than that of the control mice. These results indicate that the p53R248W mutant suppresses proliferation and invasion activity through the suppression of KRT17 expression. We propose that OSCC with p53R248W-expressing cells may be classified as a new OSCC type that has a good prognosis.
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Affiliation(s)
- Mayu Enaka
- Department of Pathology, Wakayama Medical University School of Medicine, Wakayama, Japan
| | - Masako Nakanishi
- Department of Pathology, Wakayama Medical University School of Medicine, Wakayama, Japan
| | - Yasuteru Muragaki
- Department of Pathology, Wakayama Medical University School of Medicine, Wakayama, Japan.
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11
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Krishnamurthy K, Lindsey AM, Estrada CA, Martinez CC, Cusnir M, Schwartz M, Sriganeshan V, Poppiti R. Title- Genomic landscape of squamous cell carcinoma- Different genetic pathways culminating in a common phenotype. Cancer Treat Res Commun 2020; 25:100238. [PMID: 33260028 DOI: 10.1016/j.ctarc.2020.100238] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 11/04/2020] [Accepted: 11/11/2020] [Indexed: 10/22/2022]
Abstract
INTRODUCTION Squamous cell carcinomas (SqCCs) are the most common solid tumors in humans and are found across multiple organ systems. Although, integrated analysis of genetic alterations divulge similarities between SqCCs from various body sites, certain genes appear to be more frequently mutated in a given SqCC. These subtle differences may hold the key to determining the differentiation characteristics and predicting aggressiveness of tumors. MATERIALS AND METHOD Fifty-four cases of SqCCs, in which the primary location of the tumor could be ascertained by clinical and radiological findings, were included in this study. Next generation sequencing data was analyzed for recurrent genetic abnormalities. RESULTS Genetic alterations were found in 219 genes in the 54 cases studied. TP53 mutations were found to be more frequent in pulmonary SqCCs (86.5%) as compared to non-pulmonary SqCCs (58.8%) (p<0.05). NOTCH gene family mutations and CREBBP mutations were limited to non-pulmonary SqCC (p<0.005) and were mutated in 41.2% and 17.6% cases. CONCLUSION A detailed comparative analysis of the genetic alterations identified by sequencing identified higher frequency of TP53 mutations in lung SqCCs as compared to non-pulmonary SqCCs. NOTCH and CREBPP mutations were found to be absent in lung and head and neck SqCCs and more frequent in SqCCs from other locations.
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Affiliation(s)
- Kritika Krishnamurthy
- A.M. Rywlin, MD Department of Pathology, Mount Sinai Medical Center, Miami Beach, FL 33140, United States.
| | - Allison M Lindsey
- Florida International University, Herbert Wertheim College of Medicine, Miami, FL 33199, United States
| | - Christie-Anne Estrada
- Florida International University, Herbert Wertheim College of Medicine, Miami, FL 33199, United States
| | - Camila C Martinez
- Florida International University, Herbert Wertheim College of Medicine, Miami, FL 33199, United States
| | - Mike Cusnir
- Department of Medical Oncology, Mount Sinai Medical Center, Miami Beach, FL 33140, United States
| | - Michael Schwartz
- Department of Medical Oncology, Mount Sinai Medical Center, Miami Beach, FL 33140, United States
| | - Vathany Sriganeshan
- A.M. Rywlin, MD Department of Pathology, Mount Sinai Medical Center, Miami Beach, FL 33140, United States; Florida International University, Herbert Wertheim College of Medicine, Miami, FL 33199, United States
| | - Robert Poppiti
- A.M. Rywlin, MD Department of Pathology, Mount Sinai Medical Center, Miami Beach, FL 33140, United States; Florida International University, Herbert Wertheim College of Medicine, Miami, FL 33199, United States
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12
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Ling Z, Cheng B, Tao X. Epithelial-to-mesenchymal transition in oral squamous cell carcinoma: Challenges and opportunities. Int J Cancer 2020; 148:1548-1561. [PMID: 33091960 DOI: 10.1002/ijc.33352] [Citation(s) in RCA: 126] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 10/08/2020] [Accepted: 10/12/2020] [Indexed: 02/06/2023]
Abstract
Oral squamous cell carcinoma (OSCC) is the most common malignancy representing 90% of all forms of oral cancer worldwide. Although great efforts have been made in the past decades, the 5-year survival rate of OSCC patients is no more than 60% due to tumor metastasis and subsequent recurrence. The metastasis from the primary site is due to a complex process known as epithelial-to-mesenchymal transition (EMT). During the EMT, epithelial cells gradually acquire the structural and functional characteristics of mesenchymal cells, leading to the upregulation of cell migration and the promotion of tumor cell dissemination. Therefore, EMT attracted broad attention due to its close relationship with cancer invasion and metastasis. Therefore, in the present review, an extensive description of the current research on OSCC and the role of EMT in this cancer type is provided, including diverse EMT markers, regulatory networks and crucial EMT-inducing transcription factors in OSCC. Moreover, a brief summary was made regarding the current application of EMT-correlated indexes in the prognostic analysis of OSCC patients, and the potential therapeutic approaches against OSCC and difficulties in the development of an effective anti-EMT treatment are discussed. Our aim is to provide novel insights to develop new strategies to combat OSCC by targeting EMT.
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Affiliation(s)
- Zihang Ling
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Bin Cheng
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
| | - Xiaoan Tao
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China
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13
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Isoform specific FBXW7 mediates NOTCH1 Abruptex mutation C1133Y deregulation in oral squamous cell carcinoma. Cell Death Dis 2020; 11:615. [PMID: 32792479 PMCID: PMC7426429 DOI: 10.1038/s41419-020-02873-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 08/03/2020] [Accepted: 08/04/2020] [Indexed: 11/29/2022]
Abstract
Our group previously identified that the NOTCH1 Abruptex domain contains the most mutations in Chinese OSCC patients, including a hotspot mutation (C1133Y). FBXW7 is an E3 ubiquitin ligase that regulates a network of proteins, including NOTCH1, via degradation. In this study, we first described the co-localization of isoform specific FBXW7-FBXW7β and NOTCH1C1133Y mutation in the same cytoplasmic sites. Gain- and loss-of-function assays were performed to examine the tumor suppressor role of FBXW7β in the proliferation and invasion of OSCC cells. The co-expression of NOTCH1C1133Y and FBXW7β significantly attenuated tumor growth. Meanwhile, FBXW7β reversed the oncogenic phenotype and the activation of the AKT/ERK/NFκB pathway induced by NOTCH1C1133Y mutation. FBXW7β downregulated the stability of NOTCH1C1133Y protein and promoted protein ubiquitination. This was the first time that we selected a NOTCH1 hotspot mutation detected in clinical samples and identified the function of FBXW7β that mediated NOTCH1 mutation degradation in OSCC. The newly identified interaction between FBXW7β and NOTCH1C1133Y protein provides new insights into the progression of OSCC, especially regarding Abruptex domain mutations, and represents a valuable target for OSCC therapy.
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14
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Li L, Xu Y, Wang Y, Liu M, Deng S, Yu X, Cong B, Wang W. Effects of Low Molecular Weight Fucoidan on the Proliferation and Apoptosis of Dysplastic Oral Keratinocyte and Oral Squamous Cell Carcinoma Cells. Nat Prod Commun 2020. [DOI: 10.1177/1934578x20921681] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors with high incidence, rapid progress, and high mortality. There are still some defects in the treatments of OSCC, which seriously affect the quality of patients’ life. Therefore, it is urgent to find a safer and more effective treatment for OSCC. Low molecular weight fucoidan (LMWF) has various biological activities, such as antitumor, anti-inflammatory, and antithrombotic, and has no obvious side effects, but the effect of LMWF on OSCC has not been reported. In this study, the effects of LMWF on dysplastic oral keratinocyte (DOK) and OSCC cells SCC-9 and SCC-25 were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry, TUNEL, colony formation, and wound healing assay, and the expression levels of Notch-1 and Jagged-1 treated with LMWF were detected by RT-qPCR. The results showed that LMWF could inhibit the proliferation and migration of DOK and SCC-9, and promote apoptosis. Low molecular weight fucoidan upregulated the expression of Notch-1 and Jagged-1 in DOK and SCC-9 cells. It indicated that LMWF might promote the apoptosis of DOK and SCC-9 by upregulating the Notch signal pathway, thereby inhibiting cell proliferation and playing an antitumor role. It provided theoretical basis to develop LMWF as a novel therapeutic drug for oral cancer.
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Affiliation(s)
- Lulu Li
- School of Stomatology of Qingdao University, Shandong, China
| | - Yingjie Xu
- Department of Oral Medicine, Qingdao Stomatological Hospital, Shandong, China
| | - Yixue Wang
- School of Stomatology of Nanjing Medical University, Jiangsu, China
| | - Mengjia Liu
- School of Stomatology of Qingdao University, Shandong, China
| | - Songsong Deng
- School of Stomatology of Qingdao University, Shandong, China
| | - Xixi Yu
- Department of Oral Medicine, Qingdao Stomatological Hospital, Shandong, China
| | - Beibei Cong
- Department of Oral Medicine, Qingdao Stomatological Hospital, Shandong, China
| | - Wanchun Wang
- Department of Oral Medicine, Qingdao Stomatological Hospital, Shandong, China
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15
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Hsu PJ, Yan K, Shi H, Izumchenko E, Agrawal N. Molecular biology of oral cavity squamous cell carcinoma. Oral Oncol 2020; 102:104552. [PMID: 31918173 DOI: 10.1016/j.oraloncology.2019.104552] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 07/30/2019] [Accepted: 12/21/2019] [Indexed: 12/23/2022]
Abstract
Oral cavity squamous cell carcinoma (OCSCC) is a heterogeneous and complex disease that arises due to dysfunction of multiple molecular signaling pathways. Recent advances in high-throughput genetic sequencing technologies coupled with innovative analytical techniques have begun to characterize the molecular determinants driving OCSCC. An understanding of the key molecular signaling networks underlying the initiation and progression of is essential for informing treatment of the disease. In this chapter, we discuss recent findings of key genes altered in OCSCC and potential treatments targeting these genes.
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Affiliation(s)
- Phillip J Hsu
- Medical Scientist Training Program, The University of Chicago, Chicago, IL 60637, USA
| | - Kenneth Yan
- Section of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Chicago Medicine, Chicago, IL 60637, USA
| | - Hailing Shi
- Department of Chemistry and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA
| | - Evgeny Izumchenko
- Section of Hematology Oncology, Department of Medicine, University of Chicago Medicine, Chicago, IL 60637, USA
| | - Nishant Agrawal
- Section of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Chicago Medicine, Chicago, IL 60637, USA.
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16
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Mitsiadis TA. Emerging Trends and Promises in Orofacial Cancers. Front Physiol 2019; 10:679. [PMID: 31191362 PMCID: PMC6549536 DOI: 10.3389/fphys.2019.00679] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 05/13/2019] [Indexed: 12/11/2022] Open
Affiliation(s)
- Thimios A Mitsiadis
- Orofacial Development and Regeneration, Institute of Oral Biology, Centre for Dental Medicine, University of Zurich, Zurich, Switzerland
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17
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Porcheri C, Meisel CT, Mitsiadis T. Multifactorial Contribution of Notch Signaling in Head and Neck Squamous Cell Carcinoma. Int J Mol Sci 2019; 20:E1520. [PMID: 30917608 PMCID: PMC6471940 DOI: 10.3390/ijms20061520] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 03/21/2019] [Accepted: 03/22/2019] [Indexed: 12/20/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) defines a group of solid tumors originating from the mucosa of the upper aerodigestive tract, pharynx, larynx, mouth, and nasal cavity. It has a metastatic evolution and poor prognosis and is the sixth most common cancer in the world, with 600,000 new cases reported every year. HNSCC heterogeneity and complexity is reflected in a multistep progression, involving crosstalk between several molecular pathways. The Notch pathway is associated with major events supporting cancerogenic evolution: cell proliferation, self-renewal, angiogenesis, and preservation of a pro-oncogenic microenvironment. Additionally, Notch is pivotal in tumor development and plays a dual role acting as both oncogene and tumor suppressor. In this review, we summarize the role of the Notch pathway in HNSCC, with a special focus on its compelling role in major events of tumor initiation and growth.
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Affiliation(s)
- Cristina Porcheri
- University of Zurich, Institute of Oral Biology, Plattenstrasse 11, CH-8032 Zurich, Switzerland.
| | - Christian Thomas Meisel
- University of Zurich, Institute of Oral Biology, Plattenstrasse 11, CH-8032 Zurich, Switzerland.
| | - Thimios Mitsiadis
- University of Zurich, Institute of Oral Biology, Plattenstrasse 11, CH-8032 Zurich, Switzerland.
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18
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Tommasi S, Caliri AW, Caceres A, Moreno DE, Li M, Chen Y, Siegmund KD, Besaratinia A. Deregulation of Biologically Significant Genes and Associated Molecular Pathways in the Oral Epithelium of Electronic Cigarette Users. Int J Mol Sci 2019; 20:E738. [PMID: 30744164 PMCID: PMC6386888 DOI: 10.3390/ijms20030738] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 02/06/2019] [Accepted: 02/07/2019] [Indexed: 12/15/2022] Open
Abstract
We have investigated the regulation of genes and associated molecular pathways, genome-wide, in oral cells of electronic cigarette (e-cigs) users and cigarette smokers as compared to non-smokers. Interrogation of the oral transcriptome by RNA-sequencing (RNA-seq) analysis showed significant number of aberrantly expressed transcripts in both e-cig users (vapers) and smokers relative to non-smokers; however, smokers had ~50% more differentially expressed transcripts than vapers (1726 versus 1152). Whereas the deregulated transcripts in smokers were predominately from protein-coding genes (79% versus 53% in vapers), nearly 28% of the aberrantly expressed transcripts in vapers (versus 8% in smokers) belonged to regulatory non-coding RNAs, including long intergenic non-coding, antisense, small nucleolar and misc RNA (P < 0.0001). Molecular pathway and functional network analyses revealed that "cancer" was the top disease associated with the deregulated genes in both e-cig users and smokers (~62% versus 79%). Examination of the canonical pathways and networks modulated in either e-cig users or smokers identified the "Wnt/Ca⁺ pathway" in vapers and the "integrin signaling pathway" in smokers as the most affected pathways. Amongst the overlapping functional pathways impacted in both e-cig users and smokers, the "Rho family GTPases signaling pathway" was the top disrupted pathway, although the number of affected targets was three times higher in smokers than vapers. In conclusion, we observed deregulation of critically important genes and associated molecular pathways in the oral epithelium of vapers that bears both resemblances and differences with that of smokers. Our findings have significant implications for public health and tobacco regulatory science.
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Affiliation(s)
- Stella Tommasi
- Department of Preventive Medicine, USC Keck School of Medicine, University of Southern California, M/C 9603, Los Angeles, CA 90033, USA.
| | - Andrew W Caliri
- Department of Preventive Medicine, USC Keck School of Medicine, University of Southern California, M/C 9603, Los Angeles, CA 90033, USA.
| | - Amanda Caceres
- Department of Preventive Medicine, USC Keck School of Medicine, University of Southern California, M/C 9603, Los Angeles, CA 90033, USA.
| | - Debra E Moreno
- Department of Preventive Medicine, USC Keck School of Medicine, University of Southern California, M/C 9603, Los Angeles, CA 90033, USA.
| | - Meng Li
- USC Libraries Bioinformatics Service, University of Southern California, NML 203, M/C 9130, Los Angeles, CA 90089, USA.
| | - Yibu Chen
- USC Libraries Bioinformatics Service, University of Southern California, NML 203, M/C 9130, Los Angeles, CA 90089, USA.
| | - Kimberly D Siegmund
- Department of Preventive Medicine, USC Keck School of Medicine, University of Southern California, M/C 9603, Los Angeles, CA 90033, USA.
| | - Ahmad Besaratinia
- Department of Preventive Medicine, USC Keck School of Medicine, University of Southern California, M/C 9603, Los Angeles, CA 90033, USA.
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19
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Torabi K, Erola P, Alvarez-Mora MI, Díaz-Gay M, Ferrer Q, Castells A, Castellví-Bel S, Milà M, Lozano JJ, Miró R, Ried T, Ponsa I, Camps J. Quantitative analysis of somatically acquired and constitutive uniparental disomy in gastrointestinal cancers. Int J Cancer 2018; 144:513-524. [PMID: 30350313 PMCID: PMC6635747 DOI: 10.1002/ijc.31936] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 08/31/2018] [Accepted: 10/02/2018] [Indexed: 12/20/2022]
Abstract
Somatically acquired uniparental disomies (aUPDs) are frequent events in solid tumors and have been associated with cancer‐related genes. Studies assessing their functional consequences across several cancer types are therefore necessary. Here, we aimed at integrating aUPD profiles with the mutational status of cancer‐related genes in a tumor‐type specific manner. Using TCGA datasets for 1,032 gastrointestinal cancers, including colon (COAD), rectum (READ), stomach (STAD), esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), we show a non‐random distribution of aUPD, suggesting the existence of a cancer‐specific landscape of aUPD events. Our analysis indicates that aUPD acts as a “second hit” in Knudson's model in order to achieve biallelic inactivation of tumor suppressor genes. In particular, APC, ARID1A and NOTCH1 were recurrently inactivated by the presence of homozygous mutation as a consequence of aUPD in COAD and READ, STAD and ESCC, respectively. Furthermore, while TP53 showed inactivation caused by aUPD at chromosome arm 17p across all tumor types, copy number losses at this genomic position were also frequent. By experimental and computationally inferring genome ploidy, we demonstrate that an increased number of aUPD events, both affecting the whole chromosome or segments of it, were present in highly aneuploid genomes compared to near‐diploid tumors. Finally, the presence of mosaic UPD was detected at a higher frequency in DNA extracted from peripheral blood lymphocytes of patients with colorectal cancer compared to healthy individuals. In summary, our study defines specific profiles of aUPD in gastrointestinal cancers and provides unequivocal evidence of their relevance in cancer. What's new? Somatically acquired uniparental disomies (aUPDs), in which two copies of a chromosome originate from the same parent, have been documented in various human cancers. Here, the authors examined the frequency of aUPDs in different gastrointestinal cancer types. Events involving aUPDs were found to occur at high incidence in gastrointestinal cancers and at increased frequency particularly in highly aneuploid genomes. The data also reveal a nonrandom distribution of aUPDs, with evidence of biallelic inactivation of tumor suppressor genes and activation of oncogenes in a tumor type‐specific manner. The findings suggest that aUPDs are functionally relevant in gastrointestinal malignancies.
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Affiliation(s)
- Keyvan Torabi
- Gastrointestinal and Pancreatic Oncology Group, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Catalonia, Spain.,Unitat de Biologia Cel·lular i Genètica Mèdica, Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Catalonia, Spain
| | - Pau Erola
- Bioinformatics Unit, CIBEREHD, Barcelona, Catalonia, Spain.,Roslin Institute, University of Edinburgh, Midlothian, Scotland, United Kingdom
| | - Maria Isabel Alvarez-Mora
- Biochemistry and Molecular Genetics Department, Hospital Clínic, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Catalonia, Spain
| | - Marcos Díaz-Gay
- Gastrointestinal and Pancreatic Oncology Group, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Catalonia, Spain
| | - Queralt Ferrer
- Gastrointestinal and Pancreatic Oncology Group, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Catalonia, Spain
| | - Antoni Castells
- Gastrointestinal and Pancreatic Oncology Group, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Catalonia, Spain
| | - Sergi Castellví-Bel
- Gastrointestinal and Pancreatic Oncology Group, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Catalonia, Spain
| | - Montserrat Milà
- Biochemistry and Molecular Genetics Department, Hospital Clínic, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Catalonia, Spain
| | | | - Rosa Miró
- Unitat de Biologia Cel·lular i Genètica Mèdica, Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Catalonia, Spain.,Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Catalonia, Spain
| | - Thomas Ried
- Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Immaculada Ponsa
- Unitat de Biologia Cel·lular i Genètica Mèdica, Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Catalonia, Spain.,Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Catalonia, Spain
| | - Jordi Camps
- Gastrointestinal and Pancreatic Oncology Group, Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Catalonia, Spain.,Unitat de Biologia Cel·lular i Genètica Mèdica, Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Catalonia, Spain
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20
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Karagianni F, Kataki A, Koniaris E, Karamagkiolas S, Derventzi A, Giotakis E, Konstandoulakis M, Zografos G, Giotakis I. Distinctive expression profiles of Caveolin-1 and Notch-1 protein in patients with nasal polyps or sinonasal inverted papillomas. Pathol Res Pract 2018; 214:2004-2010. [PMID: 30297114 DOI: 10.1016/j.prp.2018.09.029] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 09/02/2018] [Accepted: 09/28/2018] [Indexed: 01/13/2023]
Abstract
BACKGROUND Nasal polyposis (NP) and sinonasal inverted papillomas (SIP) are considered benign lesions capable of recurrence or malignant transformation although not with the same prevalence. Since fluctuations of Caveolin-1 and Notch-1 proteins expression have been reported in many pathologies, the current study aimed to investigate their involvement in the epithelial transformation observed in SIPs compared to NP. METHODS Immunohistochemical expression of Caveolin-1 and Notch-1 proteins was assessed in 104 patients with sinonasal lesions (45 NP, 45 SIP and 14 NP with SIP), semiquantively (percentage times intensity). Proteins expression profiles were evaluated statistically for their correlation with patients demographic and clinicopathological variables (grade of dysplasia, inflammation, recurrence) as well as with markers of proliferation (Ki67) and apoptosis (7-AAD) as determined by flow cytometry analysis. RESULTS SIP lesions presented increased Caveolin-1 immunopositivity compared to NP (62.2%, vs 40.9%; p = 0.045). Cytoplasmic staining was observed only in epithelium's basal and suprabasal layers. Caveolin-1 positivity was not related to Ki67 expression, apoptosis, inflammation or dysplasia, eventhough 81.8% of highly immunopositive lesions were dysplastic (p = 0.03). Also, smokers presented significantly increased immunopositivy (p = 0.03). In contrast SIP lesions presented reduced Notch-1 expression compared to NP (68.9% vs 100%; p < 0.001). Dysplastic lesions presented low Notch-1 immunopositivity (p < 0.001). Enhancement of Notch-1 gene expression was also associated with inflammation. CONCLUSIONS The herein presented data suggest that the expression profiles of Caveolin-1 and Notch-1 proteins in sinonasal pathologies are distinctive and that could be explored as potential targets for the development of alternative therapeutic approaches.
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Affiliation(s)
- Fani Karagianni
- 1st Department of Propaedeutic Surgery, Hippocration Hospital, Athens Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Agapi Kataki
- 1st Department of Propaedeutic Surgery, Hippocration Hospital, Athens Medical School, National and Kapodistrian University of Athens, Athens, Greece.
| | - Eythymios Koniaris
- Department of Pathology-Anatomy, Hippocration Hospital of Athens, Athens Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Sotirios Karamagkiolas
- 1st Department of Otolaryngology, Hippocration Hospital of Athens, Athens Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Anastasia Derventzi
- 1st Department of Propaedeutic Surgery, Hippocration Hospital, Athens Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Evangelos Giotakis
- 1st Department of Otolaryngology, Hippocration Hospital of Athens, Athens Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Manousos Konstandoulakis
- 1st Department of Propaedeutic Surgery, Hippocration Hospital, Athens Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - George Zografos
- 1st Department of Propaedeutic Surgery, Hippocration Hospital, Athens Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Ioannis Giotakis
- 2nd Otolaryngology Department, 'Attikon' University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
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Nowwarote N, Osathanon T. Dysregulation of Notch signaling related genes in oral lichen planus. Asian Pac J Trop Biomed 2017. [DOI: 10.1016/j.apjtb.2017.07.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
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Kumar A, Sarode SC, Sarode GS, Majumdar B, Patil S, Sharma NK. Beyond gene dictation in oral squamous cell carcinoma progression and its therapeutic implications. TRANSLATIONAL RESEARCH IN ORAL ONCOLOGY 2017. [DOI: 10.1177/2057178x17701463] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Ajay Kumar
- Cancer and Translational Research Lab, Dr D.Y. Patil Biotechnology and Bioinformatics Institute, Dr D.Y. Patil Vidyapeeth, Pune, Maharashtra, India
| | - Sachin C Sarode
- Department of Oral Pathology, Dr D.Y. Patil Dental College and Research, Pimpri, Pune, Maharashtra, India
| | - Gargi S Sarode
- Department of Oral Pathology, Dr D.Y. Patil Dental College and Research, Pimpri, Pune, Maharashtra, India
| | - Barnali Majumdar
- Department of Oral Pathology and Microbiology, Bhojia Dental College and Hospital, Baddi, Himachal Pradesh, India
| | - Shankargouda Patil
- Department of Maxillofacial Surgery and Diagnostic Sciences, Division of Oral Pathology, College of Dentistry, Jazan University, Jazan, Saudi Arabia
| | - Nilesh Kumar Sharma
- Cancer and Translational Research Lab, Dr D.Y. Patil Biotechnology and Bioinformatics Institute, Dr D.Y. Patil Vidyapeeth, Pune, Maharashtra, India
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