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Affiliation(s)
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Cited by Other Article(s) |
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1
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Kumar M, Jha AK. Exploring the potential of dietary factors and plant extracts as chemopreventive agents in oral squamous cell carcinoma treatment. FRONTIERS IN ORAL HEALTH 2023; 4:1246873. [PMID: 37859687 PMCID: PMC10582632 DOI: 10.3389/froh.2023.1246873] [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: 06/24/2023] [Accepted: 09/18/2023] [Indexed: 10/21/2023] Open
Abstract
Oral cancer, particularly oral squamous cell carcinoma (OSCC), is a prevalent malignancy having a significant fatality rate worldwide. Despite advancements in conventional treatment modalities, the overall survival rate for OSCC remains low. Therefore, there is a critical need to explore alternative therapeutic approaches that can improve patient outcomes. This review focuses on the potential of dietary factors and plant extracts as chemopreventive agents in treating oral cancer. These compounds possess diverse biological functions encompassing a range of attributes, such as antioxidative, anti-inflammatory, and anticancer capabilities. By targeting multiple cellular pathways involved in carcinogenesis, they possess the capacity to hinder tumor growth and development, promote programmed cell death, and impede the progression of oral cancer. Signaling pathways targeted by natural compounds that have been included in this review include Akt/mTOR/NF-κB signaling, Hippo-Tafazzin signaling pathway, notch signaling pathway, mitochondrial pathway, and Sonic Hedgehog pathway.
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Affiliation(s)
| | - Abhimanyu Kumar Jha
- Department of Biotechnology, Sharda School of Engineering and Technology, Sharda University, Greater Noida, India
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2
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Alam J, Huda MN, Tackett AJ, Miah S. Oncogenic signaling-mediated regulation of chromatin during tumorigenesis. Cancer Metastasis Rev 2023; 42:409-425. [PMID: 37147457 PMCID: PMC10348982 DOI: 10.1007/s10555-023-10104-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 04/05/2023] [Indexed: 05/07/2023]
Abstract
Signaling pathways play critical roles in executing and controlling important biological processes within cells. Cells/organisms trigger appropriate signal transduction pathways in order to turn on or off intracellular gene expression in response to environmental stimuli. An orchestrated regulation of different signaling pathways across different organs and tissues is the basis of many important biological functions. Presumably, any malfunctions or dysregulation of these signaling pathways contribute to the pathogenesis of disease, particularly cancer. In this review, we discuss how the dysregulation of signaling pathways (TGF-β signaling, Hippo signaling, Wnt signaling, Notch signaling, and PI3K-AKT signaling) modulates chromatin modifications to regulate the epigenome, thereby contributing to tumorigenesis and metastasis.
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Affiliation(s)
- Jahangir Alam
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Md Nazmul Huda
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Alan J Tackett
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Sayem Miah
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
- Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
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3
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Joshi P, Waghmare S. Molecular signaling in cancer stem cells of tongue squamous cell carcinoma: Therapeutic implications and challenges. World J Stem Cells 2023; 15:438-452. [PMID: 37342225 PMCID: PMC10277967 DOI: 10.4252/wjsc.v15.i5.438] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 02/21/2023] [Accepted: 04/07/2023] [Indexed: 05/26/2023] Open
Abstract
Head and neck squamous cell carcinoma is the seventh most common cancer worldwide with high mortality rates. Amongst oral cavity cancers, tongue carcinoma is a very common and aggressive oral cavity carcinoma. Despite the implementation of a multimodality treatment regime including surgical intervention, chemo-radiation as well as targeted therapy, tongue carcinoma shows a poor overall 5-year survival pattern, which is attributed to therapy resistance and recurrence of the disease. The presence of a rare population, i.e., cancer stem cells (CSCs) within the tumor, are involved in therapy resistance, recurrence, and distant metastasis that results in poor survival patterns. Therapeutic agents targeting CSCs have been in clinical trials, although they are unable to reach into therapy stage which is due to their failure in trials. A more detailed understanding of the CSCs is essential for identifying efficient targets. Molecular signaling pathways, which are differentially regulated in the CSCs, are one of the promising targets to manipulate the CSCs that would provide an improved outcome. In this review, we summarize the current understanding of molecular signaling associated with the maintenance and regulation of CSCs in tongue squamous cell carcinoma in order to emphasize the need of the hour to get a deeper understanding to unravel novel targets.
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Affiliation(s)
- Priyanka Joshi
- Stem Cell Biology Group, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, India
| | - Sanjeev Waghmare
- Stem Cell Biology Group, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, India
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4
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Pongjantarasatian S, Nowwarote N, Rotchanakitamnuai V, Srirodjanakul W, Saehun R, Janebodin K, Manokawinchoke J, Fournier BPJ, Osathanon T. A γ-Secretase Inhibitor Attenuates Cell Cycle Progression and Invasion in Human Oral Squamous Cell Carcinoma: An In Vitro Study. Int J Mol Sci 2022; 23:8869. [PMID: 36012128 PMCID: PMC9408752 DOI: 10.3390/ijms23168869] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 08/06/2022] [Accepted: 08/08/2022] [Indexed: 12/13/2022] Open
Abstract
Notch signaling is associated with many human malignancies, including oral squamous cell carcinoma (OSCC). However, the exact function of Notch signaling in OSCC remains unclear. Here, we investigated the effect of Notch signaling inhibition using a γ-secretase inhibitor (DAPT) on OSCC behaviours in vitro. Bioinformatic analysis of public-available gene expression profiles revealed the dysregulation of the Notch signaling pathway in OSCC compared with normal tissues, indicating the role of Notch signaling in OSCC regulation. RNA sequencing analysis of DAPT-treated human OSCC cells revealed the dysregulation of genes related to cell cycle-related pathways. Blocking Notch signaling significantly inhibited cell proliferation. DAPT-induced G0/G1 cell cycle arrest induced cell apoptosis. Furthermore, cell migration and invasion were also reduced in DAPT-treated cells. These findings indicate that Notch signaling activation participates in OSCC regulation by promoting cell growth, cell cycle progression, cell migration, and invasion. These mechanisms could facilitate OSCC progression. These results imply the potential use of Notch signaling inhibitors as a candidate adjuvant treatment in OSCC patients.
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Affiliation(s)
- Sarai Pongjantarasatian
- Dental Stem Cell Biology Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
| | - Nunthawan Nowwarote
- Department of Oral Biology, Faculty of Dentistry, Universite Paris Cite, 75006 Paris, France
- Centre de Recherche des Cordeliers, INSERM UMRS 1138, Molecular Oral Pathophysiology, Universite Paris Cite, Sorbonne Universite, 75006 Paris, France
| | - Varumporn Rotchanakitamnuai
- Dental Stem Cell Biology Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
| | - Watcharee Srirodjanakul
- Dental Stem Cell Biology Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
| | - Ritmongkol Saehun
- Dental Stem Cell Biology Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
| | - Kajohnkiart Janebodin
- Department of Anatomy, Faculty of Dentistry, Mahidol University, Bangkok 10400, Thailand
| | - Jeeranan Manokawinchoke
- Dental Stem Cell Biology Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
- Department of Anatomy, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
| | - Benjamin P. J. Fournier
- Department of Oral Biology, Faculty of Dentistry, Universite Paris Cite, 75006 Paris, France
- Centre de Recherche des Cordeliers, INSERM UMRS 1138, Molecular Oral Pathophysiology, Universite Paris Cite, Sorbonne Universite, 75006 Paris, France
| | - Thanaphum Osathanon
- Dental Stem Cell Biology Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
- Department of Anatomy, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand
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5
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Maharati A, Zanguei AS, Khalili-Tanha G, Moghbeli M. MicroRNAs as the critical regulators of tyrosine kinase inhibitors resistance in lung tumor cells. Cell Commun Signal 2022; 20:27. [PMID: 35264191 PMCID: PMC8905758 DOI: 10.1186/s12964-022-00840-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/05/2022] [Indexed: 12/12/2022] Open
Abstract
Lung cancer is the second most common and the leading cause of cancer related deaths globally. Tyrosine Kinase Inhibitors (TKIs) are among the common therapeutic strategies in lung cancer patients, however the treatment process fails in a wide range of patients due to TKIs resistance. Given that the use of anti-cancer drugs can always have side effects on normal tissues, predicting the TKI responses can provide an efficient therapeutic strategy. Therefore, it is required to clarify the molecular mechanisms of TKIs resistance in lung cancer patients. MicroRNAs (miRNAs) are involved in regulation of various pathophysiological cellular processes. In the present review, we discussed the miRNAs that have been associated with TKIs responses in lung cancer. MiRNAs mainly exert their role on TKIs response through regulation of Tyrosine Kinase Receptors (TKRs) and down-stream signaling pathways. This review paves the way for introducing a panel of miRNAs for the prediction of TKIs responses in lung cancer patients.
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Video Abstract
- Amirhosein Maharati
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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- Amir Sadra Zanguei
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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- Ghazaleh Khalili-Tanha
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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- Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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6
Kałafut J, Czerwonka A, Anameriç A, Przybyszewska-Podstawka A, Misiorek JO, Rivero-Müller A, Nees M. Shooting at Moving and Hidden Targets-Tumour Cell Plasticity and the Notch Signalling Pathway in Head and Neck Squamous Cell Carcinomas.
Cancers (Basel) 2021;
13:6219. [PMID:
34944837 PMCID:
PMC8699303 DOI:
10.3390/cancers13246219]
[Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/03/2021] [Accepted: 12/06/2021] [Indexed: 12/15/2022] Open
Abstract
Head and Neck Squamous Cell Carcinoma (HNSCC) is often aggressive, with poor response to current therapies in approximately 40-50% of the patients. Current therapies are restricted to operation and irradiation, often combined with a small number of standard-of-care chemotherapeutic drugs, preferentially for advanced tumour patients. Only very recently, newer targeted therapies have entered the clinics, including Cetuximab, which targets the EGF receptor (EGFR), and several immune checkpoint inhibitors targeting the immune receptor PD-1 and its ligand PD-L1. HNSCC tumour tissues are characterized by a high degree of intra-tumour heterogeneity (ITH), and non-genetic alterations that may affect both non-transformed cells, such as cancer-associated fibroblasts (CAFs), and transformed carcinoma cells. This very high degree of heterogeneity likely contributes to acquired drug resistance, tumour dormancy, relapse, and distant or lymph node metastasis. ITH, in turn, is likely promoted by pronounced tumour cell plasticity, which manifests in highly dynamic and reversible phenomena such as of partial or hybrid forms of epithelial-to-mesenchymal transition (EMT), and enhanced tumour stemness. Stemness and tumour cell plasticity are strongly promoted by Notch signalling, which remains poorly understood especially in HNSCC. Here, we aim to elucidate how Notch signal may act both as a tumour suppressor and proto-oncogenic, probably during different stages of tumour cell initiation and progression. Notch signalling also interacts with numerous other signalling pathways, that may also have a decisive impact on tumour cell plasticity, acquired radio/chemoresistance, and metastatic progression of HNSCC. We outline the current stage of research related to Notch signalling, and how this pathway may be intricately interconnected with other, druggable targets and signalling mechanisms in HNSCC.
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Affiliation(s)
- Joanna Kałafut
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, ul. Chodzki 1, 20-093 Lublin, Poland; (J.K.); (A.C.); (A.A.); (A.P.-P.); (A.R.-M.)
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- Arkadiusz Czerwonka
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, ul. Chodzki 1, 20-093 Lublin, Poland; (J.K.); (A.C.); (A.A.); (A.P.-P.); (A.R.-M.)
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- Alinda Anameriç
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, ul. Chodzki 1, 20-093 Lublin, Poland; (J.K.); (A.C.); (A.A.); (A.P.-P.); (A.R.-M.)
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- Alicja Przybyszewska-Podstawka
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, ul. Chodzki 1, 20-093 Lublin, Poland; (J.K.); (A.C.); (A.A.); (A.P.-P.); (A.R.-M.)
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- Julia O. Misiorek
- Department of Molecular Neurooncology, Institute of Bioorganic Chemistry Polish Academy of Sciences, ul. Noskowskiego 12/14, 61-704 Poznan, Poland;
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- Adolfo Rivero-Müller
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, ul. Chodzki 1, 20-093 Lublin, Poland; (J.K.); (A.C.); (A.A.); (A.P.-P.); (A.R.-M.)
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- Matthias Nees
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, ul. Chodzki 1, 20-093 Lublin, Poland; (J.K.); (A.C.); (A.A.); (A.P.-P.); (A.R.-M.)
- Western Finland Cancer Centre (FICAN West), Institute of Biomedicine, University of Turku, 20101 Turku, Finland
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7
Wang X, Chen Q. FERMT1 knockdown inhibits oral squamous cell carcinoma cell epithelial-mesenchymal transition by inactivating the PI3K/AKT signaling pathway.
BMC Oral Health 2021;
21:598. [PMID:
34814915 PMCID:
PMC8609848 DOI:
10.1186/s12903-021-01955-9]
[Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 11/02/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND
The metastasis of oral cancer is one of the main causes of death. However, the mechanisms underlying oral cancer metastasis have not been completely elucidated. Fermitin family member 1 (FERMT1) plays an -oncogene role in many cancers; however, the role of FERMT1 in oral squamous cell cancer (OSCC) remains unclear.
METHODS
In this study, OSCC cells were treated with 5 ng/ml recombinant human Transforming growth factor-β1 (TGF-β1) protein. FERMT1 expression was measured in OSCC cell lines by RT-qPCR and western blotting. The effect of FERMT1 knockdown on the migration and invasion of OSCC cells was evaluated by Transwell assay. The epithelial-mesenchymal transition (EMT) and PI3K/AKT signaling pathway-related mRNA expression and protein levels were assessed by RT-qPCR and western blotting.
RESULTS
We found that FERMT1 expression was elevated in TGF-β1-induced OSCC cell lines, and knockdown of FERMT1 inhibited the migration and invasion in TGF-β1-induced OSCC cells. FERMT1 silencing inhibited vimentin, N-cadherin, matrix metalloproteinase 9 (MMP-9) expression and promoted E-cadherin expression, suggesting that FERMT1 silencing inhibited EMT in TGF-β1-induced OSCC cells. Furthermore, FERMT1 silencing inactivated the PI3K/AKT signaling pathway in TGF-β1-induced OSCC cells. Activation of the PI3K/AKT signaling pathway reversed the effect of FERMT1 silencing on OSCC cell migration, invasion, and EMT.
CONCLUSIONS
FERMT1 silencing inhibits the migration, invasion, and EMT of OSCC cells via inactivation of the PI3K/AKT signaling pathway, suggesting that FERMT1 is a novel and potential therapeutic target for anti-metastatic strategies for OSCC.
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Affiliation(s)
- Xiao Wang
- Department of Stomatology, The First Affiliated Hospital, Guangxi University of Science and Technology, Liuzhou, 545006, China.,Medical College, Medical Experimental Center, Guangxi University of Science and Technology, Building D, 257 Liushi Road, Yufeng District, Liuzhou, 545006, China
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- Qianqian Chen
- Medical College, Medical Experimental Center, Guangxi University of Science and Technology, Building D, 257 Liushi Road, Yufeng District, Liuzhou, 545006, China.
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8
Patni AP, Harishankar MK, Joseph JP, Sreeshma B, Jayaraj R, Devi A. Comprehending the crosstalk between Notch, Wnt and Hedgehog signaling pathways in oral squamous cell carcinoma - clinical implications.
Cell Oncol (Dordr) 2021;
44:473-494. [PMID:
33704672 DOI:
10.1007/s13402-021-00591-3]
[Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 01/17/2021] [Accepted: 01/19/2021] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND
Oral squamous cell carcinoma (OSCC) is a malignant oral cavity neoplasm that affects many people, especially in developing countries. Despite several advances that have been made in diagnosis and treatment, the morbidity and mortality rates due to OSCC remain high. Accumulating evidence indicates that aberrant activation of cellular signaling pathways, such as the Notch, Wnt and Hedgehog pathways, occurs during the development and metastasis of OSCC. In this review, we have articulated the roles of the Notch, Wnt and Hedgehog signaling pathways in OSCC and their crosstalk during tumor development and progression. We have also examined possible interactions and associations between these pathways and treatment regimens that could be employed to effectively tackle OSCC and/or prevent its recurrence.
CONCLUSIONS
Activation of the Notch signaling pathway upregulates the expression of several genes, including c-Myc, β-catenin, NF-κB and Shh. Associations between the Notch signaling pathway and other pathways have been shown to enhance OSCC tumor aggressiveness. Crosstalk between these pathways supports the maintenance of cancer stem cells (CSCs) and regulates OSCC cell motility. Thus, application of compounds that block these pathways may be a valid strategy to treat OSCC. Such compounds have already been employed in other types of cancer and could be repurposed for OSCC.
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Affiliation(s)
- Anjali P Patni
- Stem Cell Biology Laboratory, Department of Genetic Engineering, School of Bioengineering, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Kanchipuram, Kattankulathur, Chennai, Tamil Nadu, 603203, India
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- M K Harishankar
- Stem Cell Biology Laboratory, Department of Genetic Engineering, School of Bioengineering, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Kanchipuram, Kattankulathur, Chennai, Tamil Nadu, 603203, India
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- Joel P Joseph
- Stem Cell Biology Laboratory, Department of Genetic Engineering, School of Bioengineering, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Kanchipuram, Kattankulathur, Chennai, Tamil Nadu, 603203, India
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- Bhuvanadas Sreeshma
- Stem Cell Biology Laboratory, Department of Genetic Engineering, School of Bioengineering, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Kanchipuram, Kattankulathur, Chennai, Tamil Nadu, 603203, India
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- Rama Jayaraj
- College of Human and Human Sciences, Charles Darwin University, Ellangowan Drive, Darwin, Northern Territory, 0909, Australia
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- Arikketh Devi
- Stem Cell Biology Laboratory, Department of Genetic Engineering, School of Bioengineering, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Kanchipuram, Kattankulathur, Chennai, Tamil Nadu, 603203, India.
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9
Context Matters: NOTCH Signatures and Pathway in Cancer Progression and Metastasis.
Cells 2021;
10:cells10010094. [PMID:
33430387 PMCID:
PMC7827494 DOI:
10.3390/cells10010094]
[Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/23/2020] [Accepted: 12/30/2020] [Indexed: 02/06/2023] Open
Abstract
The Notch signaling pathway is a critical player in embryogenesis but also plays various roles in tumorigenesis, with both tumor suppressor and oncogenic activities. Mutations, deletions, amplifications, or over-expression of Notch receptors, ligands, and a growing list of downstream Notch-activated genes have by now been described for most human cancer types. Yet, it often remains unclear what may be the functional impact of these changes for tumor biology, initiation, and progression, for cancer therapy, and for personalized medicine. Emerging data indicate that Notch signaling can also contribute to increased aggressive properties such as invasion, tumor heterogeneity, angiogenesis, or tumor cell dormancy within solid cancer tissues; especially in epithelial cancers, which are in the center of this review. Notch further supports the “stemness” of cancer cells and helps define the stem cell niche for their long-term survival, by integrating the interaction between cancer cells and the cells of the tumor microenvironment (TME). The complexity of Notch crosstalk with other signaling pathways and its roles in cell fate and trans-differentiation processes such as epithelial-to-mesenchymal transition (EMT) point to this pathway as a decisive player that may tip the balance between tumor suppression and promotion, differentiation and invasion. Here we not only review the literature, but also explore genomic databases with a specific focus on Notch signatures, and how they relate to different stages in tumor development. Altered Notch signaling hereby plays a key role for tumor cell survival and coping with a broad spectrum of vital issues, contributing to failed therapies, poor patient outcome, and loss of lives.
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10
Jonckheere S, Adams J, De Groote D, Campbell K, Berx G, Goossens S. Epithelial-Mesenchymal Transition (EMT) as a Therapeutic Target.
Cells Tissues Organs 2021;
211:157-182. [PMID:
33401271 DOI:
10.1159/000512218]
[Citation(s) in RCA: 90] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 10/11/2020] [Indexed: 11/19/2022] Open
Abstract
Metastasis is the spread of cancer cells from the primary tumour to distant sites and organs throughout the body. It is the primary cause of cancer morbidity and mortality, and is estimated to account for 90% of cancer-related deaths. During the initial steps of the metastatic cascade, epithelial cancer cells undergo an epithelial-mesenchymal transition (EMT), and as a result become migratory and invasive mesenchymal-like cells while acquiring cancer stem cell properties and therapy resistance. As EMT is involved in such a broad range of processes associated with malignant transformation, it has become an increasingly interesting target for the development of novel therapeutic strategies. Anti-EMT therapeutic strategies could potentially not only prevent the invasion and dissemination of cancer cells, and as such prevent the formation of metastatic lesions, but also attenuate cancer stemness and increase the effectiveness of more classical chemotherapeutics. In this review, we give an overview about the pros and cons of therapies targeting EMT and discuss some already existing candidate drug targets and high-throughput screening tools to identify novel anti-EMT compounds.
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Affiliation(s)
- Sven Jonckheere
- Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
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- Jamie Adams
- Department of Biomedical Science, The University of Sheffield, Sheffield, United Kingdom
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- Dominic De Groote
- Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium
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- Kyra Campbell
- Department of Biomedical Science, The University of Sheffield, Sheffield, United Kingdom
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- Geert Berx
- Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
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- Steven Goossens
- Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium, .,Department of Diagnostic Sciences, Ghent University, Ghent, Belgium,
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11
Núñez-Acurio D, Bravo D, Aguayo F. Epstein-Barr Virus-Oral Bacterial Link in the Development of Oral Squamous Cell Carcinoma.
Pathogens 2020;
9:E1059. [PMID:
33352891 PMCID:
PMC7765927 DOI:
10.3390/pathogens9121059]
[Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 12/11/2020] [Accepted: 12/16/2020] [Indexed: 12/18/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer. Its development has been associated with diverse factors such as tobacco smoking and alcohol consumption. In addition, it has been suggested that microorganisms are risk factors for oral carcinogenesis. Epstein-Barr virus (EBV), which establishes lifelong persistent infections and is intermittently shed in the saliva, has been associated with several lymphomas and carcinomas that arise in the oral cavity. In particular, it has been detected in a subset of OSCCs. Moreover, its presence in patients with periodontitis has also been described. Porphyromonas gingivalis (P. gingivalis) is an oral bacterium in the development of periodontal diseases. As a keystone pathogen of periodontitis, P. gingivalis is known not only to damage local periodontal tissues but also to evade the host immune system and eventually affect systemic health. Persistent exposure to P. gingivalis promotes tumorigenic properties of oral epithelial cells, suggesting that chronic P. gingivalis infection is a potential risk factor for OSCC. Given that the oral cavity serves as the main site where EBV and P. gingivalis are harbored, and because of their oncogenic potential, we review here the current information about the participation of these microorganisms in oral carcinogenesis, describe the mechanisms by which EBV and P. gingivalis independently or synergistically can collaborate, and propose a model of interaction between both microorganisms.
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Affiliation(s)
- Daniela Núñez-Acurio
- Laboratory of Oral Microbiology, Faculty of Dentistry, University of Chile, Santiago 8380492, Chile;
- Laboratory of Oncovirology, Virology Program, Faculty of Medicine, Institute of Biomedical Sciences (ICBM), University of Chile, Santiago 8380000, Chile
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- Denisse Bravo
- Laboratory of Oral Microbiology, Faculty of Dentistry, University of Chile, Santiago 8380492, Chile;
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, University of Chile, Santiago 8380000, Chile
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- Francisco Aguayo
- Laboratory of Oncovirology, Virology Program, Faculty of Medicine, Institute of Biomedical Sciences (ICBM), University of Chile, Santiago 8380000, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, University of Chile, Santiago 8380000, Chile
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12
Shah PA, Huang C, Li Q, Kazi SA, Byers LA, Wang J, Johnson FM, Frederick MJ. NOTCH1 Signaling in Head and Neck Squamous Cell Carcinoma.
Cells 2020;
9:cells9122677. [PMID:
33322834 PMCID:
PMC7764697 DOI:
10.3390/cells9122677]
[Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 12/04/2020] [Accepted: 12/08/2020] [Indexed: 12/12/2022] Open
Abstract
Biomarker-driven targeted therapies are lacking for head and neck squamous cell carcinoma (HNSCC), which is common and lethal. Efforts to develop such therapies are hindered by a genomic landscape dominated by the loss of tumor suppressor function, including NOTCH1 that is frequently mutated in HNSCC. Clearer understanding of NOTCH1 signaling in HNSCCs is crucial to clinically targeting this pathway. Structural characterization of NOTCH1 mutations in HNSCC demonstrates that most are predicted to cause loss of function, in agreement with NOTCH1's role as a tumor suppressor in this cancer. Experimental manipulation of NOTCH1 signaling in HNSCC cell lines harboring either mutant or wild-type NOTCH1 further supports a tumor suppressor function. Additionally, the loss of NOTCH1 signaling can drive HNSCC tumorigenesis and clinical aggressiveness. Our recent data suggest that NOTCH1 controls genes involved in early differentiation that could have different phenotypic consequences depending on the cancer's genetic background, including acquisition of pseudo-stem cell-like properties. The presence of NOTCH1 mutations may predict response to treatment with an immune checkpoint or phosphatidylinositol 3-kinase inhibitors. The latter is being tested in a clinical trial, and if validated, it may lead to the development of the first biomarker-driven targeted therapy for HNSCC.
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Affiliation(s)
- Pooja A. Shah
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (P.A.S.); (L.A.B.)
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- Chenfei Huang
- Bobby R. Alford Department of Otolaryngology, Baylor College of Medicine, Houston, TX 77030, USA; (C.H.); (M.J.F.)
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- Qiuli Li
- Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China;
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- Sawad A. Kazi
- School of Natural Sciences, University of Texas, Austin, TX 78712, USA;
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- Lauren A. Byers
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (P.A.S.); (L.A.B.)
- The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA;
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- Jing Wang
- The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA;
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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- Faye M. Johnson
- Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (P.A.S.); (L.A.B.)
- The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA;
- Correspondence: ; Tel.: +1-713–792-6363; Fax: +1-713-792-1220
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- Mitchell J. Frederick
- Bobby R. Alford Department of Otolaryngology, Baylor College of Medicine, Houston, TX 77030, USA; (C.H.); (M.J.F.)
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13
He K, Zhu ZB, Shu R, Hong A. LncRNA NEAT1 mediates progression of oral squamous cell carcinoma via VEGF-A and Notch signaling pathway.
World J Surg Oncol 2020;
18:261. [PMID:
33023572 PMCID:
PMC7542398 DOI:
10.1186/s12957-020-02028-x]
[Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 09/10/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND
lncRNAs and VEGF have been shown to have close connections with oral squamous cell carcinoma (OSCC). We explored the interaction between lncRNA NEAT1 and VEGF-A in OSCC.
METHODS
RT-qPCR was implemented to measure levels of lncRNA NEAT1 and VEGF-A in OSCC cell lines and normal cell lines. Cell functions then were checked after regulating the expressions of lncRNA NEAT1 and VEGF-A separately. Cell viabilities were examined with CCK-8 and apoptosis rate was checked with flow cytometry. Meanwhile, EMT-related genes E-cadherin, N-cadherin, Vimentin, and Snail and Notch signaling genes Notch1, Notch2, and Jagged were evaluated by RT-qPCR. IMR-1 was applied for impeding Notch signaling pathway. Later, cell viabilities, apoptosis, and EMT were assessed.
RESULTS
Expressions of lncRNA NEAT1 and VEGF-A were both increased significantly in OSCC cell lines especially in TSCC1 cell line. Suppression of lncNRA NEAT1 was associated with lower cell viabilities and EMT and higher apoptosis rate in the TSCC1 cell line. Meanwhile, knockdown of VEGF-A significantly repressed cell viabilities and EMT in the TSCC1 cell line. Magnifying functions of inhibited lncRNA NEAT1 Notch signaling pathway was obviously activated with overexpressions of lncRNA NEAT1 and VEGF-A. Adding IMR-1 significantly downregulated cell viabilities and EMT and sharply increased apoptosis in the context of lncRNA NEAT1 and VEGF-A overexpression.
CONCLUSION
LncRNA NEAT1 may upregulate proliferation and EMT and repress apoptosis through activating VEGF-A and Notch signaling pathway in vitro, suggesting an underlying regulatory factor in OSCC. Nevertheless, further research is necessary to gain a greater understanding of lncRNA NEAT1 and connections with VEGF-A in vivo and in clinical study.
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Affiliation(s)
- Ke He
- Department of Stomatology, Chengdu Seventh People's Hospital, Chengdu, Sichuan, 610015, China
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- Zhi-Bin Zhu
- Department of Stomatology, Chengdu Seventh People's Hospital, Chengdu, Sichuan, 610015, China
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- Rui Shu
- Department of Orthodontics and Pediatric Dentistry, West China School of Stomatology State Key Laboratory of Oral Diseases, Sichuan University, Chengdu, 610041, China.
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- Ai Hong
- Department of Stomatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510000, China
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14
Zhang Y, Cai H, Liao Y, Zhu Y, Wang F, Hou J. Activation of PGK1 under hypoxic conditions promotes glycolysis and increases stem cell‑like properties and the epithelial‑mesenchymal transition in oral squamous cell carcinoma cells via the AKT signalling pathway.
Int J Oncol 2020;
57:743-755. [PMID:
32705252 PMCID:
PMC7384853 DOI:
10.3892/ijo.2020.5083]
[Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 04/22/2020] [Indexed: 12/16/2022] Open
Abstract
Although it has been previously documented that a hypoxic environment can promote glycolysis and the malignant progression of oral squamous cell carcinoma (OSCC) cells, the specific underlying mechanism remains unclear. Phosphoglycerate kinase 1 (PGK1) has been previously reported to serve an important role in tumor metabolism. The aim of the present study was to investigate the effects of hypoxia and PGK1 on glycolysis, stem cell-like properties and epithelial-mesenchymal transition (EMT) in OSCC cells. Cell Counting Kit-8 assays were performed to examine tumor cell viability under hypoxic conditions. Sphere formation, immunohistochemistry, western blotting, Transwell assays and mouse xenograft studies were performed to assess the biological effects of PGK1. Under hypoxic conditions, phosphoglycerate PGK1 expression was found to be upregulated, which resulted in the potentiation of stem cell-like properties and enhancement of EMT. However, PGK1 knockdown reversed hypoxia-mediated glycolysis, stem cell-like properties, EMT in addition to inhibiting OSCC cell invasion and migration. PGK1 knockdown also inhibited tumour growth, whilst the overexpression of PGK1 was demonstrated to promote tumour growth in mouse xenograft models in vivo. Downstream, activation of the AKT signalling pathway reversed the series of changes induced by PGK1 knockdown. PGK1 expression was found to be upregulated in human OSCC tissues, which was associated with the pathological differentiation of tumours and lymph node metastasis. To conclude, results from the present study demonstrate that hypoxia can increase PGK1 expression, resulting in the promotion of glycolysis, enhancing stem cell-like properties and EMT by activating AKT signalling in OSCC.
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Affiliation(s)
- Yadong Zhang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510055, P.R. China
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- Hongshi Cai
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510055, P.R. China
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- Yan Liao
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510055, P.R. China
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- Yue Zhu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510055, P.R. China
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- Fang Wang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510055, P.R. China
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- Jinsong Hou
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510055, P.R. China
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15
A "NOTCH" Deeper into the Epithelial-To-Mesenchymal Transition (EMT) Program in Breast Cancer.
Genes (Basel) 2019;
10:genes10120961. [PMID:
31766724 PMCID:
PMC6947643 DOI:
10.3390/genes10120961]
[Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 11/14/2019] [Accepted: 11/18/2019] [Indexed: 12/20/2022] Open
Abstract
Notch signaling is a primitive signaling pathway having various roles in the normal origin and development of each multicellular organisms. Therefore, any aberration in the pathway will inevitably lead to deadly outcomes such as cancer. It has now been more than two decades since Notch was acknowledged as an oncogene in mouse mammary tumor virus-infected mice. Since that discovery, activated Notch signaling and consequent up-regulation of tumor-promoting Notch target genes have been observed in human breast cancer. Moreover, consistent over-expression of Notch ligands and receptors has been shown to correlate with poor prognosis in human breast cancer. Notch regulates a number of key processes during breast carcinogenesis, of which, one key phenomenon is epithelial-mesenchymal transition (EMT). EMT is a key process for large-scale cell movement during morphogenesis at the time of embryonic development. Cancer cells aided by transcription factors usurp this developmental program to execute the multi-step process of tumorigenesis and metastasis. In this review, we recapitulate recent progress in breast cancer research that has provided new perceptions into the molecular mechanisms behind Notch-mediated EMT regulation during breast tumorigenesis.
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