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Ferri DM, Ayre M, Ariza Bareño L, Stedile M, DiGaudio AV, Fernandez Ugazio G, Kordon EC, Blackshear PJ, Urtreger A, Raimondi AR. TTP as Tumor Suppressor and Inflammatory Regulator in Oral Carcinogenesis. J Dent Res 2025:220345251316828. [PMID: 40077848 DOI: 10.1177/00220345251316828] [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: 03/14/2025] Open
Abstract
The stability of messenger RNA (mRNA) is controlled by proteins that bind to adenosine-uridine-rich sequences (AREs) in their 3' untranslated regions (3'UTR), known as AU-binding proteins. One of these proteins is tristetraprolin (TTP; encoded by Zfp36), which promotes degradation of mRNAs with AREs in their 3'UTR. TTP accelerates the decay of its target transcripts, many of which encode proinflammatory mediators that promote tumorigenesis. TTP underexpression has been reported in multiple cancer types. Oral squamous cell carcinoma is an aggressive disease characterized by high morbidity and few therapeutic options. The role of TTP has not been studied in oral epithelium homeostasis nor in its carcinogenesis. Herein, using tissue-specific TTP knockout mice (TTP-KO), we show that TTP expression is relevant for oral epithelium homeostasis. TTP-KO mice developed dysplastic lesions in the tongue along with inflammatory infiltrates in the connective tissue. Analysis of the inflammatory infiltrate revealed the presence of mast cells (MCs), CD45+ cells, and CD11b+ cells, with the MCs being the most abundant cell type and associated with cyclooxygenase-2 expression. Recruitment of MCs was dependent on tumor necrosis factor-α (TNFα) upon TTP ablation in the tongue. Although the infiltration of MCs was dependent on TNFα activity, this did not affect the development of tongue dysplasia. We analyzed the status of the NF-κB pathway, finding its activation. In addition, we demonstrate that K-ras activation combined with Zfp36 deletion leads to the rapid onset of the oral tongue phenotype and significantly reduces mouse survival. Our results support the notion that TTP expression protects against oral carcinogenesis, regulates the inflammatory infiltrate, and maintains the epithelial microenvironment, potentially serving as a barrier to tumorigenesis.
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Affiliation(s)
- D M Ferri
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE-UBA-CONICET), Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
| | - M Ayre
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE-UBA-CONICET), Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
| | - L Ariza Bareño
- Universidad de Buenos Aires, Instituto de Oncología Ángel H. Roffo, Área Investigación, Buenos Aires, Argentina
| | - M Stedile
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE-UBA-CONICET), Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
| | - A V DiGaudio
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE-UBA-CONICET), Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
| | - G Fernandez Ugazio
- Departamento de Patología, Hospital Zubizarreta, Buenos Aires, Argentina
| | - E C Kordon
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE-UBA-CONICET), Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Buenos Aires, Argentina
| | - P J Blackshear
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
- Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina, USA
| | - A Urtreger
- Universidad de Buenos Aires, Instituto de Oncología Ángel H. Roffo, Área Investigación, Buenos Aires, Argentina
| | - A R Raimondi
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE-UBA-CONICET), Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
- Universidad de Buenos Aires, Facultad de Odontología, Cátedra de Anatomía Patológica, Buenos Aires, Argentina
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2
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Pingping Z, Nan C, Yong T. Phytochemicals and their Nanoformulations for Overcoming Drug Resistance in Head and Neck Squamous Cell Carcinoma. Pharm Res 2025; 42:429-449. [PMID: 40032776 DOI: 10.1007/s11095-025-03836-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Accepted: 02/06/2025] [Indexed: 03/05/2025]
Abstract
BACKGROUND Drug resistance remains a significant challenge in the treatment of head and neck squamous cell carcinoma (HNSCC), leading to therapeutic failure and poor patient prognosis. Numerous mechanisms, including drug efflux pumps, altered tumor microenvironment (TME), and dysregulated cell death pathways, contribute to the development of resistance against conventional chemotherapeutic agents, immunotherapy, and targeted therapies. As resistance to traditional treatments continues to emerge, there is an urgent need for innovative therapeutic strategies to overcome these challenges. Phytochemicals are naturally occurring bioactive compounds and have demonstrated remarkable potential in targeting multiple resistance mechanisms simultaneously. METHOD This review comprehensively overviews the current understanding of drug resistance mechanisms in HNSCC and explores innovative strategies utilizing phytochemicals and their nanoformulations to overcome these resistance mechanisms, with a particular focus on recent developments and future perspectives in this field. RESULTS AND DISCUSSION Phytochemicals with anticancer properties include a wide range of herbal-derived molecules such as flavonoids, stilbenes, curcuminoids, alkaloids, traditional Chinese medicine, and others. These compounds can modulate ATP-binding cassette transporters, reverse epithelial-to-mesenchymal transition (EMT), target cancer stem cells (CSCs), and regulate various signaling pathways involved in drug resistance. The integration of phytochemicals into advanced nanoformulation systems has also shown a remarkable improvement in enhancing their bioavailability, stability, and targeted delivery to the TME, potentially improving their therapeutic efficacy. Furthermore, the combination of phytochemicals with conventional chemotherapeutic agents, targeted molecular therapy, and immune checkpoint inhibitors (ICIs) has exhibited synergistic effects, offering a promising approach to restoring drug sensitivity in resistant HNSCC cells. CONCLUSION Phytochemicals and their nanoformulations may improve response of HNSCC to therapy by alleviating drug resistance.
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Affiliation(s)
- Zhai Pingping
- Heilongjiang Academy of Chinese Medicine Sciences, Harbin, 150000, China
| | - Chen Nan
- Heilongjiang University of Chinese Medicine, Harbin, 150000, China
| | - Tang Yong
- Heilongjiang Academy of Chinese Medicine Sciences, Harbin, 150000, China.
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Veselá K, Kejík Z, Masařík M, Babula P, Dytrych P, Martásek P, Jakubek M. Curcumin: A Potential Weapon in the Prevention and Treatment of Head and Neck Cancer. ACS Pharmacol Transl Sci 2024; 7:3394-3418. [PMID: 39539276 PMCID: PMC11555516 DOI: 10.1021/acsptsci.4c00518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 09/27/2024] [Accepted: 10/03/2024] [Indexed: 11/16/2024]
Abstract
Head and neck cancers (HNC) are aggressive, difficult-to-treat tumors that can be caused by genetic factors but mainly by lifestyle or infection caused by the human papillomavirus. As the sixth most common malignancy, it presents a formidable therapeutic challenge with limited therapeutic modalities. Curcumin, a natural polyphenol, is appearing as a promising multitarget anticancer and antimetastatic agent. Numerous studies have shown that curcumin and its derivatives have the potential to affect signaling pathways (NF-κB, JAK/STAT, and EGFR) and molecular mechanisms that are crucial for the growth and migration of head and neck tumors. Furthermore, its ability to interact with the tumor microenvironment and trigger the immune system may significantly influence the organism's immune response to the tumor. Combining curcumin with conventional therapies such as chemotherapy or radiotherapy may improve the efficacy of treatment and reduce the side effects of treatment, thereby increasing its therapeutic potential. This review is a comprehensive overview that discusses both the benefits and limitations of curcumin and its therapeutic effects in the context of tumor biology, with an emphasis on molecular mechanisms in the context of HNC. This review also includes possibilities to improve the limiting properties of curcumin both in terms of the development of new derivatives, formulations, or combinations with conventional therapies that have potential as a new type of therapy for the treatment of HNC and subsequent use in clinical practice.
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Affiliation(s)
- Kateřina Veselá
- BIOCEV,
First Faculty of Medicine, Charles University, 252 50 Vestec, Czech Republic
- Department
of Paediatrics and Inherited Metabolic Disorders, First Faculty of
Medicine, Charles University and General
University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague 2, Czech Republic
| | - Zdeněk Kejík
- BIOCEV,
First Faculty of Medicine, Charles University, 252 50 Vestec, Czech Republic
- Department
of Paediatrics and Inherited Metabolic Disorders, First Faculty of
Medicine, Charles University and General
University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague 2, Czech Republic
| | - Michal Masařík
- BIOCEV,
First Faculty of Medicine, Charles University, 252 50 Vestec, Czech Republic
- Department
of Paediatrics and Inherited Metabolic Disorders, First Faculty of
Medicine, Charles University and General
University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague 2, Czech Republic
- Department
of Physiology, Faculty of Medicine, Masaryk
University, Kamenice 5, 625 00 Brno, Czech Republic
- Department
of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic
| | - Petr Babula
- Department
of Physiology, Faculty of Medicine, Masaryk
University, Kamenice 5, 625 00 Brno, Czech Republic
| | - Petr Dytrych
- First
Department of Surgery-Department of Abdominal, Thoracic Surgery and
Traumatology, First Faculty of Medicine, Charles University and General University Hospital, U Nemocnice 2, 121
08 Prague, Czech
Republic
| | - Pavel Martásek
- Department
of Paediatrics and Inherited Metabolic Disorders, First Faculty of
Medicine, Charles University and General
University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague 2, Czech Republic
| | - Milan Jakubek
- BIOCEV,
First Faculty of Medicine, Charles University, 252 50 Vestec, Czech Republic
- Department
of Paediatrics and Inherited Metabolic Disorders, First Faculty of
Medicine, Charles University and General
University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague 2, Czech Republic
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Mao W, Wang B, Huang R, Sun Z, Yan M, Dong P. Histone modifications in head and neck squamous cell carcinoma. Front Oncol 2024; 14:1427725. [PMID: 38983924 PMCID: PMC11231198 DOI: 10.3389/fonc.2024.1427725] [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: 05/04/2024] [Accepted: 06/10/2024] [Indexed: 07/11/2024] Open
Abstract
Head and neck cancer is the main cause of cancer death worldwide, with squamous cell carcinoma (HNSCC) being the second most frequent subtype. HNSCC poses significant health threats due to its high incidence and poor prognosis, underscoring the urgent need for advanced research. Histone modifications play a crucial role in the regulation of gene expression and influencing various biological processes. In the context of HNSCC, aberrant histone modifications are increasingly recognized as critical contributors to its development and pathologic progression. This review demonstrates the molecular mechanisms, by which histone modifications such as acetylation, methylation, phosphorylation, and ubiquitination, impact the pathogenesis of HNSCC. The dysregulation of histone-modifying enzymes, including histone acetyltransferases (HATs), histone deacetylases (HDACs), and histone methyltransferases (HMTs), is discussed for its role in altering chromatin structure and gene expression in HNSCC. Moreover, we will explore the potential of targeting histone modifications as a therapeutic strategy, highlighting current preclinical and clinical studies that investigate histone deacetylase inhibitors (HDIs) and other epigenetic drugs, referring to the completed and ongoing clinical trials on those medications.
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Affiliation(s)
- Wei Mao
- Department of Otolaryngology-Head and Neck Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Baoxin Wang
- Department of Otolaryngology-Head and Neck Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ruofei Huang
- Department of Otolaryngology-Head and Neck Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Zhenfeng Sun
- Department of Otolaryngology-Head and Neck Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Minzhu Yan
- Department of Otolaryngology-Head and Neck Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Pin Dong
- Department of Otolaryngology-Head and Neck Surgery, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Arora D, Ganapathy DM, Usman Pp AS, Ameya K, Sekar D, Kaliaperumal K. Expression analysis of nuclear factor kappa B (NF-κB) in oral squamous cell carcinoma. ORAL ONCOLOGY REPORTS 2024; 10:100481. [DOI: 10.1016/j.oor.2024.100481] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/17/2025]
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6
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Kostecki KL, Iida M, Crossman BE, Salgia R, Harari PM, Bruce JY, Wheeler DL. Immune Escape Strategies in Head and Neck Cancer: Evade, Resist, Inhibit, Recruit. Cancers (Basel) 2024; 16:312. [PMID: 38254801 PMCID: PMC10814769 DOI: 10.3390/cancers16020312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 01/08/2024] [Accepted: 01/09/2024] [Indexed: 01/24/2024] Open
Abstract
Head and neck cancers (HNCs) arise from the mucosal lining of the aerodigestive tract and are often associated with alcohol use, tobacco use, and/or human papillomavirus (HPV) infection. Over 600,000 new cases of HNC are diagnosed each year, making it the sixth most common cancer worldwide. Historically, treatments have included surgery, radiation, and chemotherapy, and while these treatments are still the backbone of current therapy, several immunotherapies have recently been approved by the Food and Drug Administration (FDA) for use in HNC. The role of the immune system in tumorigenesis and cancer progression has been explored since the early 20th century, eventually coalescing into the current three-phase model of cancer immunoediting. During each of the three phases-elimination, equilibrium, and escape-cancer cells develop and utilize multiple strategies to either reach or remain in the final phase, escape, at which point the tumor is able to grow and metastasize with little to no detrimental interference from the immune system. In this review, we summarize the many strategies used by HNC to escape the immune system, which include ways to evade immune detection, resist immune cell attacks, inhibit immune cell functions, and recruit pro-tumor immune cells.
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Affiliation(s)
- Kourtney L. Kostecki
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA; (K.L.K.); (M.I.); (B.E.C.)
| | - Mari Iida
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA; (K.L.K.); (M.I.); (B.E.C.)
| | - Bridget E. Crossman
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA; (K.L.K.); (M.I.); (B.E.C.)
| | - Ravi Salgia
- Department of Medical Oncology and Experimental Therapeutics, Comprehensive Cancer Center, City of Hope, Duarte, CA 91010, USA;
| | - Paul M. Harari
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA; (K.L.K.); (M.I.); (B.E.C.)
- University of Wisconsin Carbone Cancer Center, Madison, WI 53705, USA;
| | - Justine Y. Bruce
- University of Wisconsin Carbone Cancer Center, Madison, WI 53705, USA;
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Deric L. Wheeler
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA; (K.L.K.); (M.I.); (B.E.C.)
- University of Wisconsin Carbone Cancer Center, Madison, WI 53705, USA;
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7
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Attiq A, Afzal S. Trinity of inflammation, innate immune cells and cross-talk of signalling pathways in tumour microenvironment. Front Pharmacol 2023; 14:1255727. [PMID: 37680708 PMCID: PMC10482416 DOI: 10.3389/fphar.2023.1255727] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Accepted: 08/08/2023] [Indexed: 09/09/2023] Open
Abstract
Unresolved inflammation is a pathological consequence of persistent inflammatory stimulus and perturbation in regulatory mechanisms. It increases the risk of tumour development and orchestrates all stages of tumorigenesis in selected organs. In certain cancers, inflammatory processes create the appropriate conditions for neoplastic transformation. While in other types, oncogenic changes pave the way for an inflammatory microenvironment that leads to tumour development. Of interest, hallmarks of tumour-promoting and cancer-associated inflammation are striking similar, sharing a complex network of stromal (fibroblasts and vascular cells) and inflammatory immune cells that collectively form the tumour microenvironment (TME). The cross-talks of signalling pathways initially developed to support homeostasis, change their role, and promote atypical proliferation, survival, angiogenesis, and subversion of adaptive immunity in TME. These transcriptional and regulatory pathways invariably contribute to cancer-promoting inflammation in chronic inflammatory disorders and foster "smouldering" inflammation in the microenvironment of various tumour types. Besides identifying common target sites of numerous cancer types, signalling programs and their cross-talks governing immune cells' plasticity and functional diversity can be used to develop new fate-mapping and lineage-tracing mechanisms. Here, we review the vital molecular mechanisms and pathways that establish the connection between inflammation and tumour development, progression, and metastasis. We also discussed the cross-talks between signalling pathways and devised strategies focusing on these interaction mechanisms to harness synthetic lethal drug combinations for targeted cancer therapy.
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Affiliation(s)
- Ali Attiq
- Discipline of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden, Penang, Malaysia
| | - Sheryar Afzal
- Department of Biomedical Sciences, Faculty of Veterinary Medicine, King Faisal University, Al Ahsa, Saudi Arabia
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Tran F, Lee E, Cuddapah S, Choi BH, Dai W. MicroRNA-Gene Interactions Impacted by Toxic Metal(oid)s during EMT and Carcinogenesis. Cancers (Basel) 2022; 14:5818. [PMID: 36497298 PMCID: PMC9741118 DOI: 10.3390/cancers14235818] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/21/2022] [Accepted: 11/22/2022] [Indexed: 11/29/2022] Open
Abstract
Chronic environmental exposure to toxic metal(loid)s significantly contributes to human cancer development and progression. It is estimated that approximately 90% of cancer deaths are a result of metastasis of malignant cells, which is initiated by epithelial-mesenchymal transition (EMT) during early carcinogenesis. EMT is regulated by many families of genes and microRNAs (miRNAs) that control signaling pathways for cell survival, death, and/or differentiation. Recent mechanistic studies have shown that toxic metal(loid)s alter the expression of miRNAs responsible for regulating the expression of genes involved in EMT. Altered miRNA expressions have the potential to be biomarkers for predicting survival and responses to treatment in cancers. Significantly, miRNAs can be developed as therapeutic targets for cancer patients in the clinic. In this mini review, we summarize key findings from recent studies that highlight chemical-miRNA-gene interactions leading to the perturbation of EMT after exposure to toxic metal(loid)s including arsenic, cadmium, nickel, and chromium.
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Affiliation(s)
| | | | | | - Byeong Hyeok Choi
- Division of Environmental Medicine, Department of Medicine, Grossman School of Medicine, New York University, New York, NY 10010, USA
| | - Wei Dai
- Division of Environmental Medicine, Department of Medicine, Grossman School of Medicine, New York University, New York, NY 10010, USA
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Seo E, Jang H, Kwon S, Kwon Y, Kim S, Lee S, Jeong AJ, Shin HM, Kim Y, Ma S, Kim H, Lee Y, Suh P, Ye S. Loss of phospholipase Cγ1 suppresses hepatocellular carcinogenesis through blockade of STAT3-mediated cancer development. Hepatol Commun 2022; 6:3234-3246. [PMID: 36153805 PMCID: PMC9592768 DOI: 10.1002/hep4.2077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 07/11/2022] [Accepted: 08/08/2022] [Indexed: 12/14/2022] Open
Abstract
Phospholipase C gamma 1 (PLCγ1) plays an oncogenic role in several cancers, alongside its usual physiological roles. Despite studies aimed at identifying the effect of PLCγ1 on tumors, the pathogenic role of PLCγ1 in the tumorigenesis and development of hepatocellular carcinoma (HCC) remains unknown. To investigate the function of PLCγ1 in HCC, we generated hepatocyte-specific PLCγ1 conditional knockout (PLCγ1f/f ; Alb-Cre) mice and induced HCC with diethylnitrosamine (DEN). Here, we identified that hepatocyte-specific PLCγ1 deletion effectively prevented DEN-induced HCC in mice. PLCγ1f/f ; Alb-Cre mice showed reduced tumor burden and tumor progression, as well as a decreased incidence of HCC and less marked proliferative and inflammatory responses. We also showed that oncogenic phenotypes such as repressed apoptosis, and promoted proliferation, cell cycle progression and migration, were induced by PLCγ1. In terms of molecular mechanism, PLCγ1 regulated the activation of signal transducer and activator of transcription 3 (STAT3) signaling. Moreover, PLCγ1 expression is elevated in human HCC and correlates with a poor prognosis in patients with HCC. Our results suggest that PLCγ1 promotes the pathogenic progression of HCC, and PLCγ1/STAT3 axis was identified as a potential therapeutic target pathway for HCC.
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Affiliation(s)
- Eun‐Bi Seo
- Department of Pharmacology and Biomedical SciencesSeoul National University College of MedicineSeoulRepublic of Korea
- Biomedical Science Project (BK21PLUS)Seoul National University College of MedicineSeoulRepublic of Korea
| | - Hyun‐Jun Jang
- School of Life SciencesUlsan National Institute of Science and TechnologyUlsanRepublic of Korea
| | - Sun‐Ho Kwon
- Department of Pharmacology and Biomedical SciencesSeoul National University College of MedicineSeoulRepublic of Korea
| | - Yong‐Jin Kwon
- Department of Pharmacology and Biomedical SciencesSeoul National University College of MedicineSeoulRepublic of Korea
- Biomedical Science Project (BK21PLUS)Seoul National University College of MedicineSeoulRepublic of Korea
| | - Seul‐Ki Kim
- Department of Pharmacology and Biomedical SciencesSeoul National University College of MedicineSeoulRepublic of Korea
| | - Song‐Hee Lee
- Department of Pharmacology and Biomedical SciencesSeoul National University College of MedicineSeoulRepublic of Korea
| | - Ae Jin Jeong
- Department of Pharmacology and Biomedical SciencesSeoul National University College of MedicineSeoulRepublic of Korea
| | - Hyun Mu Shin
- Wide River Institute of ImmunologySeoul National UniversityHongcheonRepublic of Korea
| | - Yong‐Nyun Kim
- Division of Translational ScienceNational Cancer CenterGoyangRepublic of Korea
| | - Stephanie Ma
- State Key Laboratory of Liver ResearchLi Ka Shing Faculty of Medicine, The University of Hong KongHong Kong
| | - Haeryoung Kim
- Department of PathologySeoul National University College of MedicineSeoulRepublic of Korea
| | - Yun‐Han Lee
- Department of Molecular MedicineKeimyung University School of MedicineDaeguRepublic of Korea
| | - Pann‐Ghill Suh
- School of Life SciencesUlsan National Institute of Science and TechnologyUlsanRepublic of Korea
- Korea Brain Research Institute (KBRI)DaeguRepublic of Korea
| | - Sang‐Kyu Ye
- Department of Pharmacology and Biomedical SciencesSeoul National University College of MedicineSeoulRepublic of Korea
- Biomedical Science Project (BK21PLUS)Seoul National University College of MedicineSeoulRepublic of Korea
- Wide River Institute of ImmunologySeoul National UniversityHongcheonRepublic of Korea
- Ischemic/Hypoxic Disease InstituteSeoul National University College of MedicineSeoulRepublic of Korea
- Neuro‐Immune Information Storage Network Research CenterSeoul National University College of MedicineSeoulRepublic of Korea
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Jeucken KCM, van Rooijen CCN, Kan YY, Kocken LA, Jongejan A, van Steen ACI, van Buul JD, Olsson HK, van Hamburg JP, Tas SW. Differential Contribution of NF-κB Signaling Pathways to CD4+ Memory T Cell Induced Activation of Endothelial Cells. Front Immunol 2022; 13:860327. [PMID: 35769477 PMCID: PMC9235360 DOI: 10.3389/fimmu.2022.860327] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 05/12/2022] [Indexed: 11/21/2022] Open
Abstract
Endothelial cells (ECs) are important contributors to inflammation in immune-mediated inflammatory diseases (IMIDs). In this study, we examined whether CD4+ memory T (Tm) cells can drive EC inflammatory responses. Human Tm cells produced ligands that induced inflammatory responses in human umbilical vein EC as exemplified by increased expression of inflammatory mediators including chemokines and adhesion molecules. NF-κB, a key regulator of EC activation, was induced by Tm cell ligands. We dissected the relative contribution of canonical and non-canonical NF-κB signaling to Tm induced EC responses using pharmacological small molecule inhibitors of IKKβ (iIKKβ) or NF-κB inducing kinase (iNIK). RNA sequencing revealed substantial overlap in IKKβ and NIK regulated genes (n=549) that were involved in inflammatory and immune responses, including cytokines (IL-1β, IL-6, GM-CSF) and chemokines (CXCL5, CXCL1). NIK regulated genes were more restricted, as 332 genes were uniquely affected by iNIK versus 749 genes by iIKKβ, the latter including genes involved in metabolism, proliferation and leukocyte adhesion (VCAM-1, ICAM-1). The functional importance of NIK and IKKβ in EC activation was confirmed by transendothelial migration assays with neutrophils, demonstrating stronger inhibitory effects of iIKKβ compared to iNIK. Importantly, iIKKβ – and to some extent iNIK - potentiated the effects of currently employed therapies for IMIDs, like JAK inhibitors and anti-IL-17 antibodies, on EC inflammatory responses. These data demonstrate that inhibition of NF-κB signaling results in modulation of Tm cell-induced EC responses and highlight the potential of small molecule NF-κB inhibitors as a novel treatment strategy to target EC inflammatory responses in IMIDs.
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Affiliation(s)
- Kim C. M. Jeucken
- Department of Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
| | - Charlotte C. N. van Rooijen
- Department of Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
| | - Yik Y. Kan
- Department of Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
| | - Lotte A. Kocken
- Department of Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
| | - Aldo Jongejan
- Department of Epidemiology and Data Science, Bioinformatics Laboratory, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Abraham C. I. van Steen
- Molecular Cell Biology Lab at Dept. Molecular Hematology, Sanquin Research and Landsteiner Laboratory, Amsterdam, Netherlands
| | - Jaap D. van Buul
- Molecular Cell Biology Lab at Dept. Molecular Hematology, Sanquin Research and Landsteiner Laboratory, Amsterdam, Netherlands
- Leeuwenhoek Centre for Advanced Microscopy (LCAM), Section Molecular Cytology, Swammerdam Institute for Life Sciences (SILS), University of Amsterdam, Amsterdam, Netherlands
| | - Henric K. Olsson
- Translational Science and Experimental Medicine, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Jan Piet van Hamburg
- Department of Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
| | - Sander W. Tas
- Department of Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
- *Correspondence: Sander W. Tas,
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Vageli DP, Doukas PG, Siametis A, Judson BL. Targeting STAT3 prevents bile reflux-induced oncogenic molecular events linked to hypopharyngeal carcinogenesis. J Cell Mol Med 2021; 26:75-87. [PMID: 34850540 PMCID: PMC8742186 DOI: 10.1111/jcmm.17011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 10/04/2021] [Accepted: 10/06/2021] [Indexed: 12/26/2022] Open
Abstract
The signal transducer and activator of transcription 3 (STAT3) oncogene is a transcription factor with a central role in head and neck cancer. Hypopharyngeal cells (HCs) exposed to acidic bile present aberrant activation of STAT3, possibly contributing to its oncogenic effect. We hypothesized that STAT3 contributes substantially to the bile reflux‐induced molecular oncogenic profile, which can be suppressed by STAT3 silencing or pharmacological inhibition. To explore our hypothesis, we targeted the STAT3 pathway, by knocking down STAT3 (STAT3 siRNA), and inhibiting STAT3 phosphorylation (Nifuroxazide) or dimerization (SI3‐201; STA‐21), in acidic bile (pH 4.0)‐exposed human HCs. Immunofluorescence, luciferase assay, Western blot, enzyme‐linked immunosorbent assay and qPCR analyses revealed that STAT3 knockdown or pharmacologic inhibition significantly suppressed acidic bile‐induced STAT3 activation and its transcriptional activity, Bcl‐2 overexpression, transcriptional activation of IL6, TNF‐α, BCL2, EGFR, STAT3, RELA(p65), REL and WNT5A, and cell survival. Our novel findings document the important role of STAT3 in bile reflux‐related molecular oncogenic events, which can be dramatically prevented by STAT3 silencing. STA‐21, SI3‐201 or Nifuroxazide effectively inhibited STAT3 and cancer‐related inflammatory phenotype, encouraging their single or combined application in preventive or therapeutic strategies of bile reflux‐related hypopharyngeal carcinogenesis.
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Affiliation(s)
- Dimitra P Vageli
- The Yale Larynx Laboratory, Department of Surgery (Otolaryngology), Yale School of Medicine, New Haven, Connecticut, USA
| | - Panagiotis G Doukas
- The Yale Larynx Laboratory, Department of Surgery (Otolaryngology), Yale School of Medicine, New Haven, Connecticut, USA
| | - Athanasios Siametis
- The Yale Larynx Laboratory, Department of Surgery (Otolaryngology), Yale School of Medicine, New Haven, Connecticut, USA
| | - Benjamin L Judson
- The Yale Larynx Laboratory, Department of Surgery (Otolaryngology), Yale School of Medicine, New Haven, Connecticut, USA
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12
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Overview of Candida albicans and Human Papillomavirus (HPV) Infection Agents and their Biomolecular Mechanisms in Promoting Oral Cancer in Pediatric Patients. BIOMED RESEARCH INTERNATIONAL 2021; 2021:7312611. [PMID: 34765678 PMCID: PMC8577934 DOI: 10.1155/2021/7312611] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 10/16/2021] [Indexed: 12/28/2022]
Abstract
Oral carcinoma represents one of the most common malignancies worldwide. Oral squamous cell carcinomas (OSCCs) account over 90% of all oral malignant tumors and are characterized by high mortality in the advanced stages. Early diagnosis is often a challenge for its ambiguous appearance in early stages. Mucosal infection by the human papillomavirus (HPV) is responsible for a growing number of malignancies, particularly cervical cancer and oropharyngeal carcinomas. In addition, Candida albicans (C. albicans), which is the principal fungi involved in the oral cancer development, may induce carcinogenesis through several mechanisms, mainly promoting inflammation. Medical knowledge and research on adolescent/pediatric patients' management and prevention are in continuous evolution. Besides, microbiota can play an important role in maintaining oral health and therefore all human health. The aim of this review is to evaluate epidemiological and pathophysiological characteristics of the several biochemical pathways involved during HPV and C. albicans infections in pediatric dentistry.
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13
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Vageli DP, Doukas SG, Doukas PG, Judson BL. Bile reflux and hypopharyngeal cancer (Review). Oncol Rep 2021; 46:244. [PMID: 34558652 PMCID: PMC8485019 DOI: 10.3892/or.2021.8195] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 08/24/2021] [Indexed: 12/26/2022] Open
Abstract
Laryngopharyngeal reflux, a variant of gastroesophageal reflux disease, has been considered a risk factor in the development of hypopharyngeal cancer. Bile acids are frequently present in the gastroesophageal refluxate and their effect has been associated with inflammatory and neoplastic changes in the upper aerodigestive tract. Recent in vitro and in vivo studies have provided direct evidence of the role of acidic bile refluxate in hypopharyngeal carcinogenesis and documented the crucial role of NF-κB as a key mediator of early oncogenic molecular events in this process and also suggested a contribution of STAT3. Acidic bile can cause premalignant changes and invasive squamous cell cancer in the affected hypopharynx accompanied by DNA damage, elevated p53 expression and oncogenic mRNA and microRNA alterations, previously linked to head and neck cancer. Weakly acidic bile can also increase the risk for hypopharyngeal carcinogenesis by inducing DNA damage, exerting anti-apoptotic effects and causing precancerous lesions. The most important findings that strongly support bile reflux as an independent risk factor for hypopharyngeal cancer are presented in the current review and the underlying mechanisms are provided.
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Affiliation(s)
- Dimitra P Vageli
- The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT 06510, USA
| | - Sotirios G Doukas
- The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT 06510, USA
| | - Panagiotis G Doukas
- The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT 06510, USA
| | - Benjamin L Judson
- The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT 06510, USA
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14
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A Robust and Highly Precise Alternative against the Proliferation of Intestinal Carcinoma and Human Hepatocellular Carcinoma Cells Based on Lanthanum Strontium Manganite Nanoparticles. MATERIALS 2021; 14:ma14174979. [PMID: 34501078 PMCID: PMC8433762 DOI: 10.3390/ma14174979] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/16/2021] [Accepted: 08/25/2021] [Indexed: 01/09/2023]
Abstract
In this report, lanthanum strontium manganite at different Sr2+ ion concentrations, as well as Gd3+ or Sm3+ ion substituted La0.5-YMYSr0.5MnO3 (M = Gd and Sm, y = 0.2), have been purposefully tailored using a sol gel auto-combustion approach. XRD profiles confirmed the formation of a monoclinic perovskite phase. FE-SEM analysis displayed a spherical-like structure of the La0.8Sr0.2MnO3 and La0.3Gd0.2Sr0.2MnO3 samples. The particle size of the LSM samples was found to decrease with increased Sr2+ ion concentration. For the first time, different LSM concentrations were inspected for their cytotoxic activity against CACO-2 (intestinal carcinoma cells) and HepG-2 (human hepatocellular carcinoma cells). The cell viability for CACO-2 and HepG-2 was assayed and seen to decrease depending on the Sr2+ ion concentration. Half maximal inhibitory concentration IC50 of CACO-2 cell and HepG-2 cell inhibition was connected with Sr2+ ion ratio. Low IC50 was noticable at low Sr2+ ion content. Such results were correlated to the particle size and the morphology. Indeed, the IC50 of CACO-2 cell inhibition by LSM at a strontium content of 0.2 was 5.63 ± 0.42 µg/mL, and the value increased with increased Sr2+ ion concentration by up to 0.8 to be = 25 ± 2.7 µg/mL. Meanwhile, the IC50 of HepG-2 cell inhibition by LSM at a strontium content of 0.2 was 6.73 ± 0.4 µg/mL, and the value increased with increased Sr2+ ion concentration by up to 0.8 to be 31± 3.1 µg/mL. All LSM samples at different conditions were tested as antimicrobial agents towards fungi, Gram positive bacteria, and Gram negative bacteria. For instance, all LSM samples were found to be active towards Gram negative bacteria Escherichia coli, whereas some samples have presumed antimicrobial effect towards Gram negative bacteria Proteus vulgaris. Such results confirmed that LSM samples possessed cytotoxicity against CACO-2 and HepG-2 cells, and they could be considered to play a substantial role in pharmaceutical and therapeutic applications.
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15
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Yu N, Wu MJ, Liu JX, Zheng CH, Xu Y. Correntropy-Based Hypergraph Regularized NMF for Clustering and Feature Selection on Multi-Cancer Integrated Data. IEEE TRANSACTIONS ON CYBERNETICS 2021; 51:3952-3963. [PMID: 32603306 DOI: 10.1109/tcyb.2020.3000799] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Non-negative matrix factorization (NMF) has become one of the most powerful methods for clustering and feature selection. However, the performance of the traditional NMF method severely degrades when the data contain noises and outliers or the manifold structure of the data is not taken into account. In this article, a novel method called correntropy-based hypergraph regularized NMF (CHNMF) is proposed to solve the above problem. Specifically, we use the correntropy instead of the Euclidean norm in the loss term of CHNMF, which will improve the robustness of the algorithm. And the hypergraph regularization term is also applied to the objective function, which can explore the high-order geometric information in more sample points. Then, the half-quadratic (HQ) optimization technique is adopted to solve the complex optimization problem of CHNMF. Finally, extensive experimental results on multi-cancer integrated data indicate that the proposed CHNMF method is superior to other state-of-the-art methods for clustering and feature selection.
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16
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Doukas PG, Vageli DP, Sasaki CT, Judson BL. Pepsin Promotes Activation of Epidermal Growth Factor Receptor and Downstream Oncogenic Pathways, at Slightly Acidic and Neutral pH, in Exposed Hypopharyngeal Cells. Int J Mol Sci 2021; 22:ijms22084275. [PMID: 33924087 PMCID: PMC8074291 DOI: 10.3390/ijms22084275] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/16/2021] [Accepted: 04/17/2021] [Indexed: 02/07/2023] Open
Abstract
Pepsin refluxate is considered a risk factor for laryngopharyngeal carcinogenesis. Non-acidic pepsin was previously linked to an inflammatory and tumorigenic effect on laryngopharyngeal cells in vitro. Yet there is no clear evidence of the pepsin-effect on a specific oncogenic pathway and the importance of pH in this process. We hypothesized that less acidic pepsin triggers the activation of a specific oncogenic factor and related-signalling pathway. To explore the pepsin-effect in vitro, we performed intermittent exposure of 15 min, once per day, for a 5-day period, of human hypopharyngeal primary cells (HCs) to pepsin (1 mg/mL), at a weakly acidic pH of 5.0, a slightly acidic pH of 6.0, and a neutral pH of 7.0. We have documented that the extracellular environment at pH 6.0, and particularly pH 7.0, vs. pH 5.0, promotes the pepsin-effect on HCs, causing increased internalized pepsin and cell viability, a pronounced activation of EGFR accompanied by NF-κB and STAT3 activation, and a significant upregulation of EGFR, AKT1, mTOR, IL1β, TNF-α, RELA(p65), BCL-2, IL6 and STAT3. We herein provide new evidence of the pepsin-effect on oncogenic EGFR activation and its related-signaling pathway at neutral and slightly acidic pH in HCs, opening a window to further explore the prevention and therapeutic approach of laryngopharyngeal reflux disease.
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17
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Zafar E, Maqbool MF, Iqbal A, Maryam A, Shakir HA, Irfan M, Khan M, Li Y, Ma T. A comprehensive review on anticancer mechanism of bazedoxifene. Biotechnol Appl Biochem 2021; 69:767-782. [PMID: 33759222 DOI: 10.1002/bab.2150] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 03/08/2021] [Indexed: 12/24/2022]
Abstract
Cancer is counted as a second leading cause of death among nontransmissible diseases. Identification of novel anticancer drugs is therefore necessary for the effective treatment of cancer. Conventional drug discovery is time consuming and expensive process. Unlike conventional drug discovery, drug repositioning offers a novel strategy for urgent drug discovery since it is a cost-effective and faster process. Bazedoxifene (BZA) is a synthetic selective estrogen receptor modulator, approved by the United States Food and Drug Administration for the treatment of osteoporosis in postmenopausal women. BZA is now being studied for its anticancer activity in various cancers including breast cancer, liver cancer, pancreatic cancer, colon cancer, head and neck cancer, medulloblastoma, brain cancer, and gastrointestinal cancer. Studies have reported that BZA is effective in reducing cancer progression through multiple mechanisms. BZA could effectively inhibit STAT3, PI3K/AKT, and MAPK signaling pathways and induce apoptosis. In addition to its anticancer activity as monotherapy, BZA has been shown to enhance the chemotherapeutic efficacy of clinical drugs such as paclitaxel, cisplatin, palbociclib, and oxaliplatin in multiple neoplasms. This review mainly focused on the anticancer activity, cellular targets, and anticancer mechanism of BZA, which may help the further design and conduct of research and repositioning it for oncological clinic trials.
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Affiliation(s)
- Erum Zafar
- Department of Zoology, University of the Punjab, Quaid-e-Azam Campus, Lahore, Pakistan
| | | | - Asia Iqbal
- Department of Wild Life and Ecology, University of Veternary and Animal Sciences, Ravi Campus, Patoki, Pakistan
| | - Amara Maryam
- Department of Zoology, University of the Punjab, Quaid-e-Azam Campus, Lahore, Pakistan
| | - Hafiz Abdullah Shakir
- Department of Zoology, University of the Punjab, Quaid-e-Azam Campus, Lahore, Pakistan
| | - Muhammad Irfan
- Department of Biotechnology, University of Sargodha, Sargodha, Pakistan
| | - Muhammad Khan
- Department of Zoology, University of the Punjab, Quaid-e-Azam Campus, Lahore, Pakistan
| | - Yongming Li
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, People's Republic of China
| | - Tonghui Ma
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, People's Republic of China
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18
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Correlations between serum cetuximab and EGFR-related markers, and skin disorders in head and neck cancer patients. Cancer Chemother Pharmacol 2021; 87:555-565. [PMID: 33462734 DOI: 10.1007/s00280-020-04228-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 12/29/2020] [Indexed: 12/12/2022]
Abstract
PURPOSE Cetuximab inhibits epidermal growth factor receptor (EGFR) signaling in cancer and skin cells, thereby inducing anti-cancer effects and skin disorders. The present study aimed to evaluate the relationships between serum cetuximab and EGFR-related markers, and adverse effects in head and neck cancer patients. METHODS Thirty-four head and neck cancer patients receiving weekly intravenous cetuximab were enrolled. Serum cetuximab levels were determined just before dosing. Blood samples for determination of serum EGFR-related markers including soluble epidermal growth factor receptor (sEGFR) and interleukin-6 (IL-6) were obtained. The severities of skin disorders, their medications, and hypomagnesemia treatment were also assessed. RESULTS Serum levels of cetuximab and sEGFR were negatively and positively correlated with that of IL-6, respectively. The serum cetuximab level was twofold higher in the patients with a grade 2-3 skin rash than with a grade 0-1 rash. The serum cetuximab cutoff value related to severe skin rash was 71 μg/mL (sensitivity, 59%; and specificity, 94%). The use of a strong topical corticosteroid for skin rash was also associated with a higher serum cetuximab level. Serum levels of sEGFR and IL-6 had no correlations with the skin disorder severities or their medications. Hypomagnesemia treatment using intravenous magnesium sulfate was not related to serum cetuximab and EGFR-related markers. CONCLUSIONS Head and neck cancer patients with a higher serum IL-6 level tended to have a lower serum cetuximab level. Serum cetuximab had positive correlations to skin rash severity and its medication in the study population.
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19
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Aggarwal N, Yadav J, Thakur K, Bibban R, Chhokar A, Tripathi T, Bhat A, Singh T, Jadli M, Singh U, Kashyap MK, Bharti AC. Human Papillomavirus Infection in Head and Neck Squamous Cell Carcinomas: Transcriptional Triggers and Changed Disease Patterns. Front Cell Infect Microbiol 2020. [PMID: 33344262 DOI: 10.3389/fcimb.2020.537650,] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of cancers. Collectively, HNSCC ranks sixth in incidence rate worldwide. Apart from classical risk factors like tobacco and alcohol, infection of human papillomavirus (HPV) is emerging as a discrete risk factor for HNSCC. HPV-positive HNSCC represent a distinct group of diseases that differ in their clinical presentation. These lesions are well-differentiated, occur at an early age, and have better prognosis. Epidemiological studies have demonstrated a specific increase in the proportions of the HPV-positive HNSCC. HPV-positive and HPV-negative HNSCC lesions display different disease progression and clinical response. For tumorigenic-transformation, HPV essentially requires a permissive cellular environment and host cell factors for induction of viral transcription. As the spectrum of host factors is independent of HPV infection at the time of viral entry, presumably entry of HPV only selects host cells that are permissive to establishment of HPV infection. Growing evidence suggest that HPV plays a more active role in a subset of HNSCC, where they are transcriptionally-active. A variety of factors provide a favorable environment for HPV to become transcriptionally-active. The most notable are the set of transcription factors that have direct binding sites on the viral genome. As HPV does not have its own transcription machinery, it is fully dependent on host transcription factors to complete the life cycle. Here, we review and evaluate the current evidence on level of a subset of host transcription factors that influence viral genome, directly or indirectly, in HNSCC. Since many of these transcription factors can independently promote carcinogenesis, the composition of HPV permissive transcription factors in a tumor can serve as a surrogate marker of a separate molecularly-distinct class of HNSCC lesions including those cases, where HPV could not get a chance to infect but may manifest better prognosis.
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Affiliation(s)
- Nikita Aggarwal
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Joni Yadav
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Kulbhushan Thakur
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Rakhi Bibban
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Arun Chhokar
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Tanya Tripathi
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Anjali Bhat
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Tejveer Singh
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Mohit Jadli
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Ujala Singh
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Manoj K Kashyap
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India.,Amity Medical School, Stem Cell Institute, Amity University Haryana, Amity Education Valley Panchgaon, Gurugram, India
| | - Alok C Bharti
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
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20
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Aggarwal N, Yadav J, Thakur K, Bibban R, Chhokar A, Tripathi T, Bhat A, Singh T, Jadli M, Singh U, Kashyap MK, Bharti AC. Human Papillomavirus Infection in Head and Neck Squamous Cell Carcinomas: Transcriptional Triggers and Changed Disease Patterns. Front Cell Infect Microbiol 2020; 10:537650. [PMID: 33344262 PMCID: PMC7738612 DOI: 10.3389/fcimb.2020.537650] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 11/02/2020] [Indexed: 02/05/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of cancers. Collectively, HNSCC ranks sixth in incidence rate worldwide. Apart from classical risk factors like tobacco and alcohol, infection of human papillomavirus (HPV) is emerging as a discrete risk factor for HNSCC. HPV-positive HNSCC represent a distinct group of diseases that differ in their clinical presentation. These lesions are well-differentiated, occur at an early age, and have better prognosis. Epidemiological studies have demonstrated a specific increase in the proportions of the HPV-positive HNSCC. HPV-positive and HPV-negative HNSCC lesions display different disease progression and clinical response. For tumorigenic-transformation, HPV essentially requires a permissive cellular environment and host cell factors for induction of viral transcription. As the spectrum of host factors is independent of HPV infection at the time of viral entry, presumably entry of HPV only selects host cells that are permissive to establishment of HPV infection. Growing evidence suggest that HPV plays a more active role in a subset of HNSCC, where they are transcriptionally-active. A variety of factors provide a favorable environment for HPV to become transcriptionally-active. The most notable are the set of transcription factors that have direct binding sites on the viral genome. As HPV does not have its own transcription machinery, it is fully dependent on host transcription factors to complete the life cycle. Here, we review and evaluate the current evidence on level of a subset of host transcription factors that influence viral genome, directly or indirectly, in HNSCC. Since many of these transcription factors can independently promote carcinogenesis, the composition of HPV permissive transcription factors in a tumor can serve as a surrogate marker of a separate molecularly-distinct class of HNSCC lesions including those cases, where HPV could not get a chance to infect but may manifest better prognosis.
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Affiliation(s)
- Nikita Aggarwal
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Joni Yadav
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Kulbhushan Thakur
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Rakhi Bibban
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Arun Chhokar
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Tanya Tripathi
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Anjali Bhat
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Tejveer Singh
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Mohit Jadli
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Ujala Singh
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Manoj K. Kashyap
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
- Amity Medical School, Stem Cell Institute, Amity University Haryana, Amity Education Valley Panchgaon, Gurugram, India
| | - Alok C. Bharti
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
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21
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Sohn MS, Kang M, Kang SM, Bae S. Downregulation of APRIN expression increases cancer cell proliferation via an interleukin-6/STAT3/cyclin D axis. Oncol Lett 2020; 21:55. [PMID: 33281966 PMCID: PMC7709549 DOI: 10.3892/ol.2020.12317] [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: 05/28/2020] [Accepted: 10/28/2020] [Indexed: 12/20/2022] Open
Abstract
APRIN is a putative tumor suppressor whose expression is low in a variety of cancer cells. While decreased expression of APRIN leads to increased cell proliferation, unfavorable diagnosis or metastases in various cancer types, there is limited knowledge on the cellular mechanism of APRIN in cellular responses. The effect of APRIN depletion on cancer cell proliferation was examined in the present study, and the IL-6/STAT3/cyclin D axis was identified as a novel regulatory mechanism. Stable depletion of APRIN in cancer cells resulted in increased cell proliferation. Cytokine array analysis of the cells revealed that downregulation of APRIN induced secretion of interleukin-6 (IL-6) with corresponding activation of STAT3, a downstream intracellular mediator. Levels of cyclin D1 were increased in cells with APRIN depletion and cyclin D1 expression was associated with increased STAT3 binding on cyclin D1 promoter sequence; assessed by chromatin immunoprecipitation assay. The addition of an IL-6 neutralizing antibody P620 to the cell culture attenuated STAT3 activation and cyclin D1 expression in APRIN-depleted cells with corresponding decrease in cell proliferation. These experiments suggest that APRIN regulates cancer cell proliferation via an IL-6/STAT3/cyclin D axis and that targeting this axis in APRIN-associated cancer might provide a novel therapeutic approach.
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Affiliation(s)
- Min-Shik Sohn
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences (KIRAMS), Nowon-Gu, Seoul 139-706, Republic of Korea.,Graduate School of Life Sciences, Korea University, Inchonro, Seongbuk-Gu, Seoul 139-706, Republic of Korea
| | - Miae Kang
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences (KIRAMS), Nowon-Gu, Seoul 139-706, Republic of Korea
| | - Seong-Man Kang
- Graduate School of Life Sciences, Korea University, Inchonro, Seongbuk-Gu, Seoul 139-706, Republic of Korea
| | - Sangwoo Bae
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences (KIRAMS), Nowon-Gu, Seoul 139-706, Republic of Korea
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22
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Morgan EL, Chen Z, Van Waes C. Regulation of NFκB Signalling by Ubiquitination: A Potential Therapeutic Target in Head and Neck Squamous Cell Carcinoma? Cancers (Basel) 2020; 12:E2877. [PMID: 33036368 PMCID: PMC7601648 DOI: 10.3390/cancers12102877] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 09/22/2020] [Accepted: 09/29/2020] [Indexed: 02/08/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with over 600,000 cases per year. The primary causes for HNSCC include smoking and alcohol consumption, with an increasing number of cases attributed to infection with Human Papillomavirus (HPV). The treatment options for HNSCC currently include surgery, radiotherapy, and/or platinum-based chemotherapeutics. Cetuximab (targeting EGFR) and Pembrolizumab (targeting PD-1) have been approved for advanced stage, recurrent, and/or metastatic HNSCC. Despite these advances, whilst HPV+ HNSCC has a 3-year overall survival (OS) rate of around 80%, the 3-year OS for HPV- HNSCC is still around 55%. Aberrant signal activation of transcription factor NFκB plays an important role in the pathogenesis and therapeutic resistance of HNSCC. As an important mediator of inflammatory signalling and the immune response to pathogens, the NFκB pathway is tightly regulated to prevent chronic inflammation, a key driver of tumorigenesis. Here, we discuss how NFκB signalling is regulated by the ubiquitin pathway and how this pathway is deregulated in HNSCC. Finally, we discuss the current strategies available to target the ubiquitin pathway and how this may offer a potential therapeutic benefit in HNSCC.
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Affiliation(s)
- Ethan L. Morgan
- Tumor Biology Section, Head and Neck Surgery Branch, National Institute of Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA;
| | - Zhong Chen
- Tumor Biology Section, Head and Neck Surgery Branch, National Institute of Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA;
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Morgan EL, Macdonald A. Manipulation of JAK/STAT Signalling by High-Risk HPVs: Potential Therapeutic Targets for HPV-Associated Malignancies. Viruses 2020; 12:E977. [PMID: 32899142 PMCID: PMC7552066 DOI: 10.3390/v12090977] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 08/28/2020] [Accepted: 08/30/2020] [Indexed: 12/14/2022] Open
Abstract
Human papillomaviruses (HPVs) are small, DNA viruses that cause around 5% of all cancers in humans, including almost all cervical cancer cases and a significant proportion of anogenital and oral cancers. The HPV oncoproteins E5, E6 and E7 manipulate cellular signalling pathways to evade the immune response and promote virus persistence. The Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway has emerged as a key mediator in a wide range of important biological signalling pathways, including cell proliferation, cell survival and the immune response. While STAT1 and STAT2 primarily drive immune signalling initiated by interferons, STAT3 and STAT5 have widely been linked to the survival and proliferative potential of a number of cancers. As such, the inhibition of STAT3 and STAT5 may offer a therapeutic benefit in HPV-associated cancers. In this review, we will discuss how HPV manipulates JAK/STAT signalling to evade the immune system and promote cell proliferation, enabling viral persistence and driving cancer development. We also discuss approaches to inhibit the JAK/STAT pathway and how these could potentially be used in the treatment of HPV-associated disease.
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Affiliation(s)
- Ethan L. Morgan
- Tumour Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA
| | - Andrew Macdonald
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, West Yorkshire, UK
- Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, West Yorkshire, UK
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Doukas SG, Doukas PG, Sasaki CT, Vageli D. The in vivo preventive and therapeutic properties of curcumin in bile reflux-related oncogenesis of the hypopharynx. J Cell Mol Med 2020; 24:10311-10321. [PMID: 32691972 PMCID: PMC7521262 DOI: 10.1111/jcmm.15640] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 06/21/2020] [Accepted: 06/25/2020] [Indexed: 02/06/2023] Open
Abstract
Bile at strongly acidic pH exerts a carcinogenic effect on the hypopharynx, based upon recent pre‐clinical studies that support its role as an independent risk factor. We recently demonstrated in vitro that curcumin can prevent oncogenic profile of bile in human hypopharyngeal cells, by inhibiting NF‐κB. We hypothesize that topically applied curcumin to the hypopharynx can similarly block early oncogenic molecular events of bile, by inhibiting NF‐κB and consequently altering the expression of genes with oncogenic function. Using Mus musculus (C57Bl/6J), we topically applied curcumin (250 μmol/L; three times per day; 10 days) to the hypopharynx, 15 minutes before, 15 minutes after or in combination with bile acids (pH 3.0). Immunohistochemical analysis and qPCR revealed that topically applied curcumin either before, after or in combination with acidic bile exposure significantly suppressed its induced NF‐κB activation in regenerating epithelial cells, and overexpression of Rela, Bcl2, Egfr, Stat3, Wnt5a, Tnf, Il6, Ptgs2. Akt1 was particularly inhibited by curcumin when applied simultaneously with bile. We provide novel evidence into the preventive and therapeutic properties of topically applied curcumin in acidic bile‐induced early oncogenic molecular events in hypopharyngeal mucosa, by inhibiting NF‐κB, and shaping future translational development of effective targeted therapies using topical non‐pharmacologic inhibitors of NF‐κB.
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Affiliation(s)
- Sotirios G Doukas
- The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT, USA
| | - Panagiotis G Doukas
- The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT, USA
| | - Clarence T Sasaki
- The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT, USA
| | - Dimitra Vageli
- The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT, USA
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Borgato GB, Borges GA, Souza AP, Squarize CH, Castilho RM. Loss of PTEN sensitizes head and neck squamous cell carcinoma to 5-AZA-2'-deoxycytidine. Oral Surg Oral Med Oral Pathol Oral Radiol 2020; 130:181-190. [PMID: 32546428 DOI: 10.1016/j.oooo.2020.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 03/23/2020] [Accepted: 05/03/2020] [Indexed: 11/25/2022]
Abstract
OBJECTIVE Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer associated with poor survival. Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene involved in the maintenance of stem cells. DNA methylation is a known epigenetic modification involved in tumor progression. In this study, we investigated the effect of the DNA demethylation agent 5-AZA-2'-deoxycytidine (5-AZA) over HNSCC and its population of cancer stem cells (CSCs) presenting dysfunctional PTEN. STUDY DESIGN The effects of 5-AZA on HNSCC were evaluated by using WSU-HN13 cells. CSC was assessed by sphere-forming assays, along with the endogenous levels of aldehyde dehydrogenase. The clonogenic potential of tumors was evaluated, along with the protein expression of mTOR signaling and the identification of nuclear factor-κB (NF-κB) and epithelial-mesenchymal transition (EMT)-associated genes, using real-time polymerase chain reaction (PCR). RESULTS We observed that loss of PTEN enhances tumor biologic behavior, including colony- and tumor sphere-forming abilities. We also found that 5-AZA has an inhibitory effect over the CSCs and molecular markers associated with the NF-κB and EMT pathways. CONCLUSIONS Our findings suggest that the stratification of treatment of HNSCC based on PTEN status may identify a subset of patients who can benefit from the coadministration of 5-AZA.
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Affiliation(s)
- Gabriell Bonifacio Borgato
- Department of Oral Biology, School of Dentistry, State University of Campinas, Piracicaba, São Paulo, Brazil; Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA
| | - Gabriel Alvares Borges
- Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA; Laboratory of Oral Histopathology, Health Sciences Faculty, University of Brasilia, Brasilia, Brazil
| | - Ana Paula Souza
- Department of Oral Biology, School of Dentistry, State University of Campinas, Piracicaba, São Paulo, Brazil
| | - Cristiane Helena Squarize
- Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA
| | - Rogerio Moraes Castilho
- Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
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Pisani P, Airoldi M, Allais A, Aluffi Valletti P, Battista M, Benazzo M, Briatore R, Cacciola S, Cocuzza S, Colombo A, Conti B, Costanzo A, della Vecchia L, Denaro N, Fantozzi C, Galizia D, Garzaro M, Genta I, Iasi GA, Krengli M, Landolfo V, Lanza GV, Magnano M, Mancuso M, Maroldi R, Masini L, Merlano MC, Piemonte M, Pisani S, Prina-Mello A, Prioglio L, Rugiu MG, Scasso F, Serra A, Valente G, Zannetti M, Zigliani A. Metastatic disease in head & neck oncology. ACTA OTORHINOLARYNGOLOGICA ITALICA : ORGANO UFFICIALE DELLA SOCIETA ITALIANA DI OTORINOLARINGOLOGIA E CHIRURGIA CERVICO-FACCIALE 2020; 40:S1-S86. [PMID: 32469009 PMCID: PMC7263073 DOI: 10.14639/0392-100x-suppl.1-40-2020] [Citation(s) in RCA: 105] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The head and neck district represents one of the most frequent sites of cancer, and the percentage of metastases is very high in both loco-regional and distant areas. Prognosis refers to several factors: a) stage of disease; b) loco-regional relapses; c) distant metastasis. At diagnosis, distant metastases of head and neck cancers are present in about 10% of cases with an additional 20-30% developing metastases during the course of their disease. Diagnosis of distant metastases is associated with unfavorable prognosis, with a median survival of about 10 months. The aim of the present review is to provide an update on distant metastasis in head and neck oncology. Recent achievements in molecular profiling, interaction between neoplastic tissue and the tumor microenvironment, oligometastatic disease concepts, and the role of immunotherapy have all deeply changed the therapeutic approach and disease control. Firstly, we approach topics such as natural history, epidemiology of distant metastases and relevant pathological and radiological aspects. Focus is then placed on the most relevant clinical aspects; particular attention is reserved to tumours with distant metastasis and positive for EBV and HPV, and the oligometastatic concept. A substantial part of the review is dedicated to different therapeutic approaches. We highlight the role of immunotherapy and the potential effects of innovative technologies. Lastly, we present ethical and clinical perspectives related to frailty in oncological patients and emerging difficulties in sustainable socio-economical governance.
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Affiliation(s)
- Paolo Pisani
- ENT Unit, ASL AT, “Cardinal Massaja” Hospital, Asti, Italy
| | - Mario Airoldi
- Medical Oncology, Città della Salute e della Scienza, Torino, Italy
| | | | - Paolo Aluffi Valletti
- SCDU Otorinolaringoiatria, AOU Maggiore della Carità di Novara, Università del Piemonte Orientale, Italy
| | | | - Marco Benazzo
- SC Otorinolaringoiatria, Fondazione IRCCS Policlinico “S. Matteo”, Università di Pavia, Italy
| | | | | | - Salvatore Cocuzza
- Department of Medical, Surgical and Advanced Technologies “G.F. Ingrassia”, University of Catania, Italy
| | - Andrea Colombo
- ENT Unit, ASL AT, “Cardinal Massaja” Hospital, Asti, Italy
| | - Bice Conti
- Department of Drug Sciences, University of Pavia, Italy
- Polymerix S.r.L., Pavia, Italy
| | | | - Laura della Vecchia
- Unit of Otorhinolaryngology General Hospital “Macchi”, ASST dei Settelaghi, Varese, Italy
| | - Nerina Denaro
- Oncology Department A.O.S. Croce & Carle, Cuneo, Italy
| | | | - Danilo Galizia
- Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo,Italy
| | - Massimiliano Garzaro
- SCDU Otorinolaringoiatria, AOU Maggiore della Carità di Novara, Università del Piemonte Orientale, Italy
| | - Ida Genta
- Department of Drug Sciences, University of Pavia, Italy
- Polymerix S.r.L., Pavia, Italy
| | | | - Marco Krengli
- Dipartimento Medico Specialistico ed Oncologico, SC Radioterapia Oncologica, AOU Maggiore della Carità, Novara, Italy
- Dipartimento di Medicina Traslazionale, Università del Piemonte Orientale, Novara, Italy
| | | | - Giovanni Vittorio Lanza
- S.O.C. Chirurgia Toracica, Azienda Ospedaliera Nazionale “SS. Antonio e Biagio e Cesare Arrigo”, Alessandria, Italy
| | | | - Maurizio Mancuso
- S.O.C. Chirurgia Toracica, Azienda Ospedaliera Nazionale “SS. Antonio e Biagio e Cesare Arrigo”, Alessandria, Italy
| | - Roberto Maroldi
- Department of Radiology, University of Brescia, ASST Spedali Civili Brescia, Italy
| | - Laura Masini
- Dipartimento Medico Specialistico ed Oncologico, SC Radioterapia Oncologica, AOU Maggiore della Carità, Novara, Italy
| | - Marco Carlo Merlano
- Oncology Department A.O.S. Croce & Carle, Cuneo, Italy
- Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo,Italy
| | - Marco Piemonte
- ENT Unit, University Hospital “Santa Maria della Misericordia”, Udine, Italy
| | - Silvia Pisani
- Immunology and Transplantation Laboratory Fondazione IRCCS Policlinico “S. Matteo”, Pavia, Italy
| | - Adriele Prina-Mello
- LBCAM, Department of Clinical Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin 8, Ireland
- Centre for Research on Adaptive Nanostructures and Nanodevices (CRANN), Trinity College Dublin, Dublin 2, Ireland
| | - Luca Prioglio
- Department of Otorhinolaryngology, ASL 3 “Genovese”, “Padre Antero Micone” Hospital, Genoa, Italy
| | | | - Felice Scasso
- Department of Otorhinolaryngology, ASL 3 “Genovese”, “Padre Antero Micone” Hospital, Genoa, Italy
| | - Agostino Serra
- University of Catania, Italy
- G.B. Morgagni Foundation, Catania, Italy
| | - Guido Valente
- Dipartimento di Medicina Traslazionale, Università del Piemonte Orientale, Novara, Italy
| | - Micol Zannetti
- Dipartimento di Medicina Traslazionale, Università del Piemonte Orientale, Novara, Italy
| | - Angelo Zigliani
- Department of Radiology, University of Brescia, ASST Spedali Civili Brescia, Italy
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Cheng CY, Yeh CC. Adaptive immunoregulation of luteolin and chlorogenic acid in lipopolysaccharide-induced interleukin-10 expression. Tzu Chi Med J 2020; 32:186-192. [PMID: 32269953 PMCID: PMC7137375 DOI: 10.4103/tcmj.tcmj_23_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 03/01/2019] [Accepted: 04/11/2019] [Indexed: 12/27/2022] Open
Abstract
Objective To investigate the mechanism of the adaptive effect of two compounds in Lonicerae japonica flos (LJF), luteolin (LUT) and chlorogenic acid (CGA), on the expression of interleukin (IL) IL-10 and IL-6. Materials and Methods RAW264.7 cells receiving lipopolysaccharide (LPS) were pretreated with CGA and LJF. The expression of pro-inflammatory cytokines and IL-10 was evaluated by reverse transcription-polymerase chain reaction. Moreover, the concentrations of IL-10 and IL-6 were measured by enzyme-linked immunosorbent assay in the culture medium obtained 24 h after LPS treatment. Nuclear extracts of RAW264.7 cells, pretreated with CGA or LUT and LPS, were prepared after 6 h, and C/EBPβ and C/EBPδ were measured by Western blotting. Nuclear factor-κB (NF-κB) activity was measured by electrophoretic mobility shift assay. The phosphorylated form of IκB, ERK1/2, p38, JNK, and IκB, ERK2, p38, or JNK were also measured by Western blotting. Results CGA enhanced the LPS-induced expression of IL-10 and IL-6, and increased NF-κB, Sp1, C/EBPβ and δ. The effect of CGA is interfered with Lut by suppressing the phosphorylation of IκB and p38, and NF-κB activity. In the event, IL-6 was suppressed and IL-10 was not influenced. Conclusion LUT and CGA, which are abundant in LJF that is one of the ingredients in Gingyo-san, have adaptive immunoregulative effect on the expression of IL-10.
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Affiliation(s)
- Chu-Yen Cheng
- Department of Chinese Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, Taiwan
| | - Chia-Chou Yeh
- Department of Chinese Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, Taiwan
- School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan
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Mohan CD, Rangappa S, Preetham HD, Chandra Nayaka S, Gupta VK, Basappa S, Sethi G, Rangappa KS. Targeting STAT3 signaling pathway in cancer by agents derived from Mother Nature. Semin Cancer Biol 2020; 80:157-182. [DOI: 10.1016/j.semcancer.2020.03.016] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 03/23/2020] [Accepted: 03/28/2020] [Indexed: 02/07/2023]
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Borges GÁ, Elias ST, Araujo TSD, Souza PM, Nascimento-Filho CHV, Castilho RM, Squarize CH, Magalhães PDO, Guerra ENS. Asparaginase induces selective dose- and time-dependent cytotoxicity, apoptosis, and reduction of NFκB expression in oral cancer cells. Clin Exp Pharmacol Physiol 2020; 47:857-866. [PMID: 31943292 DOI: 10.1111/1440-1681.13256] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 11/19/2019] [Accepted: 01/08/2020] [Indexed: 01/10/2023]
Abstract
Asparaginase is fundamental to the treatment of haematological malignancies. However, little has been studied on the effects that asparaginase could exert on solid tumours. Thus, this study aimed to evaluate the effects of asparaginase on an oral carcinoma cell line. The cytotoxicity of asparaginase in SCC-9 (tongue squamous cell carcinoma) and HaCaT (human keratinocyte) cell lines was evaluated with MTT cell viability assay. The cells were treated with asparaginase at 0.04, 0.16, 0.63, 1.0, 1.5, 2.5, and 5.0 IU/mL. Dose-response curves and IC50 values were obtained and the Tumour Selectivity Index (TSI) was calculated. The effect of asparaginase on procaspase-3 and nuclear factor κB (NFκB) expression was evaluated with western blot because it was reported that the overexpression of NFκB has been shown to contribute to tumour cell survival, proliferation, and migration. Caspase 3/7 staining was performed to identify cell death using flow cytometry. Effective asparaginase concentrations were lower for SCC-9 cells when compared to HaCaT cells. The cytotoxicity results at 48 and 72 hours were significantly different for SCC-9 cells. The TSI indicated that asparaginase was selective for the tumour cells. A decrease in procaspase-3 and NFκB protein levels was observed in SCC-9 cells. Furthermore, asparaginase resulted in significant apoptosis after 48 and 72 hours. Based on these results, asparaginase was cytotoxic in a dose- and time-dependent manner, induces apoptosis, and reduces NFκB expression in oral cancer cells. These results encourage further studies on the effectiveness of this enzyme as a treatment for solid tumours, especially head and neck cancer.
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Affiliation(s)
- Gabriel Álvares Borges
- Laboratory of Oral Histopathology, Faculty of Health Sciences, University of Brasilia, Brasilia, Brazil.,Epithelial Biology Laboratory, Department of Periodontics and Oral Medicine, Division of Oral Pathology Oral Radiology and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Silvia Taveira Elias
- Laboratory of Oral Histopathology, Faculty of Health Sciences, University of Brasilia, Brasilia, Brazil
| | - Tassiana Souza De Araujo
- Laboratory of Oral Histopathology, Faculty of Health Sciences, University of Brasilia, Brasilia, Brazil
| | - Paula Monteiro Souza
- Natural Products Laboratory, Faculty of Health Sciences, University of Brasilia, Brasilia, Brazil
| | - Carlos Henrique Viesi Nascimento-Filho
- Epithelial Biology Laboratory, Department of Periodontics and Oral Medicine, Division of Oral Pathology Oral Radiology and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Rogerio M Castilho
- Epithelial Biology Laboratory, Department of Periodontics and Oral Medicine, Division of Oral Pathology Oral Radiology and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Cristiane H Squarize
- Epithelial Biology Laboratory, Department of Periodontics and Oral Medicine, Division of Oral Pathology Oral Radiology and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | | | - Eliete Neves Silva Guerra
- Laboratory of Oral Histopathology, Faculty of Health Sciences, University of Brasilia, Brasilia, Brazil.,Epithelial Biology Laboratory, Department of Periodontics and Oral Medicine, Division of Oral Pathology Oral Radiology and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA
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Temporal characteristics of NF-κB inhibition in blocking bile-induced oncogenic molecular events in hypopharyngeal cells. Oncotarget 2019; 10:3339-3351. [PMID: 31164956 PMCID: PMC6534360 DOI: 10.18632/oncotarget.26917] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Accepted: 04/21/2019] [Indexed: 12/16/2022] Open
Abstract
Biliary esophageal reflux at acidic pH is considered a risk factor in laryngopharyngeal cancer. We previously showed the key role NF-κB in mediating acidic bile-induced pre-neoplastic events in hypopharyngeal cells, and that co-administration of specific NF-κB inhibitor, BAY 11-7082, together with acidic bile, can effectively prevent its related oncogenic molecular effects. We hypothesize that the addition of BAY 11-7082 (10μM) either before or after application of acidic bile (400μM conjugated bile acids; pH 4.0), is capable of comparably blocking acidic bile-induced oncogenic molecular phenotypes in murine hypopharyngeal primary cells. We performed immunofluorescence, luciferase assay, western blot and qPCR analysis, demonstrating that 15-min of pre- or post-application of BAY 11-7082 effectively inhibits acidic bile-induced NF-κB activation, transcriptional activation of RELA(p65), STAT3, EGFR, IL-6, bcl-2, WNT5A, "upregulation" of "oncomirs" miR-21, miR-155, miR-192 and "downregulation" of "tumor suppressor" miR-34a, miR-375, miR-451a. Our observations support the understanding that acidic bile-induced deregulation of anti-apoptotic or oncogenic factors, bcl-2, STAT3, EGFR, IL-6, WNT5A, miR-21, miR-155, miR-375, is highly NF-κB-dependent, showing that even post-application of inhibitor can suppress their deregulation. In conclusion, application of specific NF-κB inhibitor, has the capability of adequately blocking the early oncogenic molecular events produced by acidic bile whether it is applied pre or post exposure. In addition to therapeutic implications these findings provide a window of observation into the complex kinetics characterizing the mechanistic link between acidic bile and early neoplasia. Although BAY 11-7082 itself may not be suitable for clinical use, the application of other NF-κB inhibitors merits exploration.
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31
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Mercau ME, Calanni JS, Aranda ML, Caldareri LJ, Rosenstein RE, Repetto EM, Cymeryng CB. Melatonin prevents early pituitary dysfunction induced by sucrose-rich diets. J Pineal Res 2019; 66:e12545. [PMID: 30586198 DOI: 10.1111/jpi.12545] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 12/11/2018] [Accepted: 12/18/2018] [Indexed: 12/14/2022]
Abstract
While physiological levels of glucocorticoids are required to ensure proper functions of the body, consistently high levels may engender several deleterious consequences. We have previously shown an increase in the activity of the hypothalamic-pituitary-adrenal (HPA) axis in rats fed sucrose-rich diets (SRD). The main goal of this study was to analyze the processes involved in the modulation of the pituitary production of ACTH by SRD, and to test melatonin as a possible therapeutic agent for the prevention of the HPA axis dysfunction. Male Wistar rats were fed standard chow and either SRD (30% sucrose in the drinking water) or plain water for three weeks. Melatonin was administered as subcutaneous pellets. Results showed that SRD treatment induced an increase in systemic ACTH and corticosterone levels and a decrease in melatonin levels. In the pituitary gland, we also detected an increase in the expression levels of proopiomelanocortin (POMC) that was accompanied by increased levels of: lipoperoxides, nitro-tyrosine modified proteins, catalase, heme oxygenase-1, interleukin-1β mRNA, and by an increase in the tissue number of inflammatory cells (F4/80 and Iba-1 positive cells). Melatonin treatment prevented all these systemic and pituitary changes as well as the increase in POMC expression induced by incubation of AtT-20 corticotrophs with conditioned media obtained from stimulated macrophages. In conclusion, stimulation of POMC/ACTH production in rats fed a SRD could involve the generation of oxidative stress and inflammation in the pituitary gland. Melatonin treatment prevented these effects and normalized the activity of the HPA axis.
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Affiliation(s)
- María Elisa Mercau
- Facultad de Medicina, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Juan Salvador Calanni
- Facultad de Medicina, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Marcos Luis Aranda
- Facultad de Medicina, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Lilian Julia Caldareri
- Facultad de Medicina, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Ruth Estela Rosenstein
- Facultad de Medicina, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Universidad de Buenos Aires, Buenos Aires, Argentina
- Facultad de Medicina, Departamento de Bioquímica Humana, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Esteban Martin Repetto
- Facultad de Medicina, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Universidad de Buenos Aires, Buenos Aires, Argentina
- Facultad de Farmacia y Bioquímica, Departamento de Bioquímica Clínica, Cátedra Bioquímica Clínica I, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Cora Beatriz Cymeryng
- Facultad de Medicina, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Universidad de Buenos Aires, Buenos Aires, Argentina
- Facultad de Medicina, Departamento de Bioquímica Humana, Universidad de Buenos Aires, Buenos Aires, Argentina
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Moeinian M, Abdolghaffari AH, Nikfar S, Momtaz S, Abdollahi M. Effects of alpha lipoic acid and its derivative "andrographolid-lipoic acid-1" on ulcerative colitis: A systematic review with meta-analysis of animal studies. J Cell Biochem 2018; 120:4766-4782. [PMID: 30362597 DOI: 10.1002/jcb.27807] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 09/12/2018] [Indexed: 12/25/2022]
Abstract
We aimed to review and meta-analyze the inflammatory and oxidative factors following alpha lipoic acid (ALA) and its derivative "andrographolid-lipoic acid-1" (AL-1) in ulcerative colitis (UC). ALA plays an important role in scavenging intracellular radicals and inflammatory elements. AL-1 is found in herbal medicines with potent anti-inflammatory properties. Data were collected from the Google Scholar, PubMed, Scopus, Evidence-based medicine/clinical trials, and Cochrane library database until 2017, which finally resulted in 22 animal studies (70 rats and 162 mice). The beneficial effects of ALA or AL-1 on the most important parameters of UC were reviewed; also, studies were considered separately in mice and rats. Administration of ALA and AL-1 significantly reduced the tumor necrosis factor-α level compared with the controls, while data were not noteworthy in the meta-analysis (mean differences = -18.57 [95% CI = -42.65 to 5.51], P = 0.13). In spite of insignificant decrease in meta-analysis outcomes (differences = 6.92 [95% CI = -39.33 to 53.16], P = 0.77), a significant reduction in myeloperoxidase activity was shown following ALA or AL-1 treatment compared with the controls. Despite significant differences in each study, we had to exclude some studies to homogenize data for meta-analyzing as they showed insignificant results. Interleukin 6, cyclooxygenase-2, glutathione, malondialdehyde, superoxide dismutase, histopathological score, macroscopic and microscopic scores, disease activity index, body weight change, and colon length were also reviewed. Most studies have emphasized on significant positive effects of ALA and AL-1. Comprehensive clinical trials are obligatory to determine the precious position of ALA or AL-1 in the management of UC.
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Affiliation(s)
- Mahsa Moeinian
- Toxicology and Diseases Group, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Hossein Abdolghaffari
- Toxicology and Diseases Group, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.,Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran.,Gastrointestinal Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Shekoufeh Nikfar
- Toxicology and Diseases Group, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.,Department of Pharmacoeconomics and Pharmaceutical Administration, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeideh Momtaz
- Toxicology and Diseases Group, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.,Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran
| | - Mohammad Abdollahi
- Toxicology and Diseases Group, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.,Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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Lesinski GB, Nannapaneni S, Griffith CC, Patel M, Chen W, Chen Z, Ahmed R, Wieland A, Shin DM, Chen ZG, Saba NF. Interleukin-6/STAT3 Signaling is Prominent and Associated with Reduced Overall Survival in p16 Negative Oropharyngeal Squamous Cell Carcinoma. Head Neck Pathol 2018; 13:304-312. [PMID: 30191505 PMCID: PMC6684688 DOI: 10.1007/s12105-018-0962-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 09/03/2018] [Indexed: 12/20/2022]
Abstract
This study addresses the hypothesis that IL-6/STAT3 signaling is of clinical relevance in oropharyngeal squamous cell carcinoma (OPSCC). We evaluated relationships between key components of this pathway in tumors from a unique cohort of n = 59 fully annotated, treatment-naïve patients with OPSCC. The multiplex Opal platform was utilized for immunofluorescence (IF) analysis of tissues to detect IL-6 and phosphorylated STAT3 (pSTAT3), taking into consideration its nuclear versus cytoplasmic localization. Abundant staining for both IL-6 and pSTAT3 was evident in tumor-rich regions of each specimen. IL-6 correlated with cytoplasmic pSTAT3 but not nuclear or total pSTAT3 in this cohort of OPSCC tumors, regardless of p16 status (r = 0.682, p < 0.0001). There was a significant association between increased total pSTAT3, nuclear pSTAT3, cytoplasmic pSTAT3 and IL-6 in p16 negative tumors. Our data indicate STAT3 phosphorylation was a key feature in p16-negative OPSCC tumors. When IL-6 data was stratified by median expression in tumors, there was no association with overall survival. In contrast, both total and nuclear pSTAT3 were significant predictors of poor overall and disease free survival. This strong inverse relationship with overall survival was present in p16 negative tumors for both total and nuclear pSTAT3, but not in p16 positive OPSCC tumors. Together these data indicate that activation of the STAT3 signaling pathway is a marker of p16 negative tumors and relevant to OPSCC prognosis and a potential target for treatment of this more aggressive OPSCC sub-population.
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Affiliation(s)
- Gregory B. Lesinski
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, 1365 Clifton Rd., NE, Atlanta, GA 30322 USA
| | - Sreenivas Nannapaneni
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, 1365 Clifton Rd., NE, Atlanta, GA 30322 USA
| | | | - Mihir Patel
- Department of Otolaryngology, Emory University School of Medicine, Atlanta, USA
| | - Wanqi Chen
- Biostatistics and Bioinformatics, Winship Cancer Institute of Emory University, Atlanta, USA
| | - Zhengjia Chen
- Biostatistics and Bioinformatics, Winship Cancer Institute of Emory University, Atlanta, USA
| | - Rafi Ahmed
- Emory Vaccine Center, Emory University, Atlanta, USA
| | | | - Dong M. Shin
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, 1365 Clifton Rd., NE, Atlanta, GA 30322 USA
| | - Zhuo G. Chen
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, 1365 Clifton Rd., NE, Atlanta, GA 30322 USA
| | - Nabil F. Saba
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, 1365 Clifton Rd., NE, Atlanta, GA 30322 USA
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Small-molecule compounds targeting the STAT3 DNA-binding domain suppress survival of cisplatin-resistant human ovarian cancer cells by inducing apoptosis. Eur J Med Chem 2018; 157:887-897. [DOI: 10.1016/j.ejmech.2018.08.037] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 06/19/2018] [Accepted: 08/12/2018] [Indexed: 12/24/2022]
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Chernova T, Murphy FA, Galavotti S, Sun XM, Powley IR, Grosso S, Schinwald A, Zacarias-Cabeza J, Dudek KM, Dinsdale D, Le Quesne J, Bennett J, Nakas A, Greaves P, Poland CA, Donaldson K, Bushell M, Willis AE, MacFarlane M. Long-Fiber Carbon Nanotubes Replicate Asbestos-Induced Mesothelioma with Disruption of the Tumor Suppressor Gene Cdkn2a (Ink4a/Arf). Curr Biol 2018; 27:3302-3314.e6. [PMID: 29112861 PMCID: PMC5681354 DOI: 10.1016/j.cub.2017.09.007] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Revised: 07/18/2017] [Accepted: 09/05/2017] [Indexed: 02/07/2023]
Abstract
Mesothelioma is a fatal tumor of the pleura and is strongly associated with asbestos exposure. The molecular mechanisms underlying the long latency period of mesothelioma and driving carcinogenesis are unknown. Moreover, late diagnosis means that mesothelioma research is commonly focused on end-stage disease. Although disruption of the CDKN2A (INK4A/ARF) locus has been reported in end-stage disease, information is lacking on the status of this key tumor suppressor gene in pleural lesions preceding mesothelioma. Manufactured carbon nanotubes (CNTs) are similar to asbestos in terms of their fibrous shape and biopersistent properties and thus may pose an asbestos-like inhalation hazard. Here we show that instillation of either long CNTs or long asbestos fibers into the pleural cavity of mice induces mesothelioma that exhibits common key pro-oncogenic molecular events throughout the latency period of disease progression. Sustained activation of pro-oncogenic signaling pathways, increased proliferation, and oxidative DNA damage form a common molecular signature of long-CNT- and long-asbestos-fiber-induced pathology. We show that hypermethylation of p16/Ink4a and p19/Arf in CNT- and asbestos-induced inflammatory lesions precedes mesothelioma; this results in silencing of Cdkn2a (Ink4a/Arf) and loss of p16 and p19 protein, consistent with epigenetic alterations playing a gatekeeper role in cancer. In end-stage mesothelioma, silencing of p16/Ink4a is sustained and deletion of p19/Arf is detected, recapitulating human disease. This study addresses the long-standing question of which early molecular changes drive carcinogenesis during the long latency period of mesothelioma development and shows that CNT and asbestos pose a similar health hazard.
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Affiliation(s)
- Tatyana Chernova
- Medical Research Council Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK
| | - Fiona A Murphy
- Medical Research Council Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK
| | - Sara Galavotti
- Medical Research Council Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK
| | - Xiao-Ming Sun
- Medical Research Council Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK
| | - Ian R Powley
- Medical Research Council Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK
| | - Stefano Grosso
- Medical Research Council Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK
| | - Anja Schinwald
- Medical Research Council/University of Edinburgh, Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK
| | - Joaquin Zacarias-Cabeza
- Medical Research Council Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK
| | - Kate M Dudek
- Medical Research Council Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK
| | - David Dinsdale
- Medical Research Council Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK
| | - John Le Quesne
- Medical Research Council Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK; University Hospitals of Leicester NHS Trust, Glenfield Hospital, Leicester LE3 9QP, UK
| | - Jonathan Bennett
- University Hospitals of Leicester NHS Trust, Glenfield Hospital, Leicester LE3 9QP, UK
| | - Apostolos Nakas
- University Hospitals of Leicester NHS Trust, Glenfield Hospital, Leicester LE3 9QP, UK
| | - Peter Greaves
- Department of Cancer Studies, University of Leicester, Leicester LE2 7LX, UK
| | - Craig A Poland
- Medical Research Council/University of Edinburgh, Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK
| | - Ken Donaldson
- Medical Research Council/University of Edinburgh, Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK
| | - Martin Bushell
- Medical Research Council Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK.
| | - Anne E Willis
- Medical Research Council Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK.
| | - Marion MacFarlane
- Medical Research Council Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK.
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Vageli DP, Doukas SG, Spock T, Sasaki CT. Curcumin prevents the bile reflux-induced NF-κB-related mRNA oncogenic phenotype, in human hypopharyngeal cells. J Cell Mol Med 2018; 22:4209-4220. [PMID: 29911313 PMCID: PMC6111812 DOI: 10.1111/jcmm.13701] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 04/25/2018] [Indexed: 12/21/2022] Open
Abstract
The presence of bile is not an uncommon finding in acidic oesophageal and extra‐oesophageal refluxate, possibly affecting the hypopharyngeal mucosa and leading to neoplastic events. We recently demonstrated that acidic bile (pH ≤ 4.0) can induce NF‐κB activation and oncogenic mRNA phenotype in normal hypopharyngeal cells and generate premalignant changes in treated hypopharyngeal mucosa. We hypothesize that curcumin, a dietary inhibitor of NF‐κB, may effectively inhibit the acidic bile‐induced cancer‐related mRNA phenotype, in treated human hypopharyngeal primary cells (HHPC), supporting its potential preventive use in vivo. Luciferase assay, immunofluorescence, Western blot, qPCR and PCR microarray analysis were used to explore the effect of curcumin in HHPC exposed to bile (400 μmol/L) at acidic and neutral pH. Curcumin successfully inhibited the acidic bile‐induced NF‐κB signalling pathway (25% of analysed genes), and overexpression of NF‐κB transcriptional factors, c‐REL, RELA(p65), anti‐apoptotic bcl‐2, oncogenic TNF‐α, EGFR, STAT3, WNT5A, ΔNp63 and cancer‐related IL‐6. Curcumin effectively reduced bile‐induced bcl‐2 overexpression at both acidic and neutral pH. Our novel findings suggest that, similar to pharmacologic NF‐κB inhibitor, BAY 11‐7082, curcumin can suppress acidic bile‐induced oncogenic mRNA phenotype in hypopharyngeal cells, encouraging its future in vivo pre‐clinical and clinical explorations in prevention of bile reflux‐related pre‐neoplastic events mediated by NF‐κB.
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Affiliation(s)
- Dimitra P Vageli
- Department of Surgery, The Yale Larynx Laboratory, Yale School of Medicine, New Haven, CT, USA
| | - Sotirios G Doukas
- Department of Surgery, The Yale Larynx Laboratory, Yale School of Medicine, New Haven, CT, USA
| | - Todd Spock
- Department of Surgery, The Yale Larynx Laboratory, Yale School of Medicine, New Haven, CT, USA
| | - Clarence T Sasaki
- Department of Surgery, The Yale Larynx Laboratory, Yale School of Medicine, New Haven, CT, USA
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Cottin SC, Turcotte S, Douville P, Meyer F, Bairati I. Predictors of circulating INTERLEUKIN-6 levels in head and neck cancer patients. CANCERS OF THE HEAD & NECK 2018; 3. [PMID: 29951282 PMCID: PMC6017994 DOI: 10.1186/s41199-018-0029-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Background Circulating interleukin-6 (IL-6) improves outcome prediction for second primary cancer (SPC) in head and neck cancer (HNC) patients. This study aimed to identify factors associated with IL-6 serum levels in HNC patients. Methods This study was conducted as part of a phase III chemoprevention trial. IL-6 was measured using chemiluminescent immunometric assay on pretreatment serum sample obtained from 527 stage I-II HNC patients. Patients’ lifestyle habits, sociodemographic, medical and tumor characteristics were evaluated before radiation therapy (RT). Factors independently associated with IL-6 levels before RT were identified using multiple linear regression. Results The median IL-6 serum level was 3.1 ng/L. In the multivariate analysis, eight factors were significantly associated (p < 0.05) with IL-6: age, gender, marital status, body mass index, tobacco consumption, comorbidities, Karnofsky Performance Status and HNC site. Smoking duration and lifetime pack-years were positively associated with IL-6 serum levels in a dose-response relationship (p-value for trend ≤0.03). Conclusions Circulating IL-6 is a strong predictor of the occurrence of SPC in HNC patients. We identified eight factors independently associated with serum IL-6 levels in 527 stage I-II HNC patients. The dose-response relationship between lifetime smoking and IL-6 serum levels suggested a causal role of tobacco exposure on IL-6 production. Further studies are needed to establish whether the effect of tobacco exposure on SPC could be partly mediated by IL-6, a pro-inflammatory cytokine.
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Affiliation(s)
- Sylvine Carrondo Cottin
- Centre de recherche sur le cancer, Université Laval, 6, rue McMahon, 1899-2, Quebec City, QC G1R 2J6, Canada.,Centre de recherche du CHU de Québec - Université Laval, Quebec City, QC, Canada
| | - Stéphane Turcotte
- Centre de recherche sur le cancer, Université Laval, 6, rue McMahon, 1899-2, Quebec City, QC G1R 2J6, Canada.,Centre de recherche du CHU de Québec - Université Laval, Quebec City, QC, Canada
| | - Pierre Douville
- Centre de recherche sur le cancer, Université Laval, 6, rue McMahon, 1899-2, Quebec City, QC G1R 2J6, Canada.,Centre de recherche du CHU de Québec - Université Laval, Quebec City, QC, Canada
| | - François Meyer
- Centre de recherche sur le cancer, Université Laval, 6, rue McMahon, 1899-2, Quebec City, QC G1R 2J6, Canada.,Centre de recherche du CHU de Québec - Université Laval, Quebec City, QC, Canada
| | - Isabelle Bairati
- Centre de recherche sur le cancer, Université Laval, 6, rue McMahon, 1899-2, Quebec City, QC G1R 2J6, Canada.,Centre de recherche du CHU de Québec - Université Laval, Quebec City, QC, Canada
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Lim YC, Quek H, Offenhäuser C, Fazry S, Boyd A, Lavin M, Roberts T, Day B. ATM inhibition prevents interleukin-6 from contributing to the proliferation of glioblastoma cells after ionizing radiation. J Neurooncol 2018; 138:509-518. [DOI: 10.1007/s11060-018-2838-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 02/10/2018] [Indexed: 12/24/2022]
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Doukas SG, Vageli DP, Sasaki CT. NF-κB inhibition reverses acidic bile-induced miR-21, miR-155, miR-192, miR-34a, miR-375 and miR-451a deregulations in human hypopharyngeal cells. J Cell Mol Med 2018. [PMID: 29516639 PMCID: PMC5908126 DOI: 10.1111/jcmm.13591] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
We previously demonstrated that acidic bile activates NF-κB, deregulating the expression of oncogenic miRNA markers, in pre-malignant murine laryngopharyngeal mucosa. Here, we hypothesize that the in vitro exposure of human hypopharyngeal cells to acidic bile deregulates cancer-related miRNA markers that can be reversed by BAY 11-7082, a pharmacologic NF-κB inhibitor. We repetitively exposed normal human hypopharyngeal primary cells and human hypopharyngeal keratinocytes to bile fluid (400 μmol/L), at pH 4.0 and 7.0, with/without BAY 11-7082 (20 μmol/L). We centred our study on the transcriptional activation of oncogenic miR-21, miR-155, miR-192, miR-34a, miR-375, miR-451a and NF-κB-related genes, previously linked to acidic bile-induced pre-neoplastic events. Our novel findings in vitro are consistent with our hypothesis demonstrating that BAY 11-7082 significantly reverses the acidic bile-induced oncogenic miRNA phenotype, in normal hypopharyngeal cells. BAY 11-7082 strongly inhibits the acidic bile-induced up-regulation of miR-192 and down-regulation of miR-451a and significantly decreases the miR-21/375 ratios, previously related to poor prognosis in hypopharyngeal cancer. This is the first in vitro report that NF-κB inhibition reverses acidic bile-induced miR-21, miR-155, miR-192, miR-34a, miR-375 and miR-451a deregulations in normal human hypopharyngeal cells, suggesting that acidic bile-induced events are directly or indirectly dependent on NF-κB signalling.
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Affiliation(s)
- Sotirios G Doukas
- The Yale Larynx laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT, USA
| | - Dimitra P Vageli
- The Yale Larynx laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT, USA
| | - Clarence T Sasaki
- The Yale Larynx laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT, USA
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40
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Almeida LO, Neto MPC, Sousa LO, Tannous MA, Curti C, Leopoldino AM. SET oncoprotein accumulation regulates transcription through DNA demethylation and histone hypoacetylation. Oncotarget 2018; 8:26802-26818. [PMID: 28460463 PMCID: PMC5432298 DOI: 10.18632/oncotarget.15818] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 02/20/2017] [Indexed: 01/23/2023] Open
Abstract
Epigenetic modifications are essential in the control of normal cellular processes and cancer development. DNA methylation and histone acetylation are major epigenetic modifications involved in gene transcription and abnormal events driving the oncogenic process. SET protein accumulates in many cancer types, including head and neck squamous cell carcinoma (HNSCC); SET is a member of the INHAT complex that inhibits gene transcription associating with histones and preventing their acetylation. We explored how SET protein accumulation impacts on the regulation of gene expression, focusing on DNA methylation and histone acetylation. DNA methylation profile of 24 tumour suppressors evidenced that SET accumulation decreased DNA methylation in association with loss of 5-methylcytidine, formation of 5-hydroxymethylcytosine and increased TET1 levels, indicating an active DNA demethylation mechanism. However, the expression of some suppressor genes was lowered in cells with high SET levels, suggesting that loss of methylation is not the main mechanism modulating gene expression. SET accumulation also downregulated the expression of 32 genes of a panel of 84 transcription factors, and SET directly interacted with chromatin at the promoter of the downregulated genes, decreasing histone acetylation. Gene expression analysis after cell treatment with 5-aza-2′-deoxycytidine (5-AZA) and Trichostatin A (TSA) revealed that histone acetylation reversed transcription repression promoted by SET. These results suggest a new function for SET in the regulation of chromatin dynamics. In addition, TSA diminished both SET protein levels and SET capability to bind to gene promoter, suggesting that administration of epigenetic modifier agents could be efficient to reverse SET phenotype in cancer.
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Affiliation(s)
- Luciana O Almeida
- Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.,Department of Genetics and Evolution, Federal University of São Carlos, São Carlos, SP, Brazil
| | - Marinaldo P C Neto
- Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Lucas O Sousa
- Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Maryna A Tannous
- Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Carlos Curti
- Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Andreia M Leopoldino
- Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.,CEPID-FAPESP, Center for Cell Based Therapy, Hemotherapy Center of Ribeirão Preto, Ribeirão Preto, SP, Brazil
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Nazari F, Pearson AT, Nör JE, Jackson TL. A mathematical model for IL-6-mediated, stem cell driven tumor growth and targeted treatment. PLoS Comput Biol 2018; 14:e1005920. [PMID: 29351275 PMCID: PMC5792033 DOI: 10.1371/journal.pcbi.1005920] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Revised: 01/31/2018] [Accepted: 12/10/2017] [Indexed: 12/20/2022] Open
Abstract
Targeting key regulators of the cancer stem cell phenotype to overcome their critical influence on tumor growth is a promising new strategy for cancer treatment. Here we present a modeling framework that operates at both the cellular and molecular levels, for investigating IL-6 mediated, cancer stem cell driven tumor growth and targeted treatment with anti-IL6 antibodies. Our immediate goal is to quantify the influence of IL-6 on cancer stem cell self-renewal and survival, and to characterize the subsequent impact on tumor growth dynamics. By including the molecular details of IL-6 binding, we are able to quantify the temporal changes in fractional occupancies of bound receptors and their influence on tumor volume. There is a strong correlation between the model output and experimental data for primary tumor xenografts. We also used the model to predict tumor response to administration of the humanized IL-6R monoclonal antibody, tocilizumab (TCZ), and we found that as little as 1mg/kg of TCZ administered weekly for 7 weeks is sufficient to result in tumor reduction and a sustained deceleration of tumor growth. A small population of cancer stem cells that share many of the biological characteristics of normal adult stem cells are believed to initiate and sustain tumor growth for a wide variety of malignancies. Growth and survival of these cancer stem cells is highly influenced by tumor micro-environmental factors and molecular signaling initiated by cytokines and growth factors. This work focuses on quantifying the influence of IL-6, a pleiotropic cytokine secreted by a variety of cell types, on cancer stem cell self-renewal and survival. We present a mathematical model for IL-6 mediated, cancer stem cell driven tumor growth that operates at the following levels: (1) the molecular level—capturing cell surface dynamics of receptor-ligand binding and receptor activation that lead to intra-cellular signal transduction cascades; and (2) the cellular level—describing tumor growth, cellular composition, and response to treatments targeted against IL-6.
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Affiliation(s)
- Fereshteh Nazari
- Simon A. Levin Mathematical, Computational, and Modeling Sciences Center, School of Human Evolution and Social Change, Arizona State University, Tempe, Arizona, United States of America
| | - Alexander T. Pearson
- Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Cancer Center, Ann Arbor, Michigan, United States of America
| | - Jacques Eduardo Nör
- Departments of Cardiology, Restorative Sciences, and Endontics, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Trachette L. Jackson
- Department of Mathematics, University of Michigan, Ann Arbor, Michigan, United States of America
- * E-mail:
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Inhibition of NF- κB prevents the acidic bile-induced oncogenic mRNA phenotype, in human hypopharyngeal cells. Oncotarget 2017; 9:5876-5891. [PMID: 29464041 PMCID: PMC5814181 DOI: 10.18632/oncotarget.23143] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 11/01/2017] [Indexed: 12/03/2022] Open
Abstract
Bile-containing gastro-duodenal reflux has been clinically considered an independent risk factor in hypopharyngeal carcinogenesis. We recently showed that the chronic effect of acidic bile, at pH 4.0, selectively induces NF-κB activation and accelerates the transcriptional levels of genes, linked to head and neck cancer, in normal hypopharyngeal epithelial cells. Here, we hypothesize that NF-κB inhibition is capable of preventing the acidic bile-induced and cancer-related mRNA phenotype, in treated normal human hypopharyngeal cells. In this setting we used BAY 11-7082, a specific and well documented pharmacologic inhibitor of NF-κB, and we observed that BAY 11-7082 effectively inhibits the acidic bile-induced gene expression profiling of the NF-κB signaling pathway (down-regulation of 72 out of 84 analyzed genes). NF-κB inhibition significantly prevents the acidic bile-induced transcriptional activation of NF-κB transcriptional factors, RELA (p65) and c-REL, as well as genes related to and commonly found in established HNSCC cell lines. These include anti-apoptotic bcl-2, oncogenic STAT3, EGFR, ∆Np63, TNF-α and WNT5A, as well as cytokines IL-1β and IL-6. Our findings are consistent with our hypothesis demonstrating that NF-κB inhibition effectively prevents the acidic bile-induced cancer-related mRNA phenotype in normal human hypopharyngeal epithelial cells supporting an understanding that NF-κB may be a critical link between acidic bile and early preneoplastic events in this setting.
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4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol} (TIMBD) suppresses HIV1-gp120 mediated production of IL6 and IL8 but not CCL5. Sci Rep 2017; 7:8129. [PMID: 28811543 PMCID: PMC5557832 DOI: 10.1038/s41598-017-08332-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 07/07/2017] [Indexed: 12/28/2022] Open
Abstract
Human immunodeficiency virus (HIV) has been associated with inflammatory effects that may potentially result in neurodegenerative changes and a number of newer chemotherapeutic agents are being tested to ameliorate these effects. In this study, we investigated the anti-neuroinflammatory activity of a novel resveratrol analog 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol} (TIMBD) against HIV1-gp120 induced neuroinflammation in SVG astrocytes. SVG astrocytic cells were pretreated with TIMBD or resveratrol (RES) and then transfected with a plasmid encoding HIV1-gp120. The mRNA and protein expression levels of proinflammatory cytokines IL6, IL8 and CCL5 were determined. Protein expression levels of NF-κB, AP1, p-STAT3, p-AKT, p-IKKs and p-p38 MAPK were also determined. TIMBD inhibited gp120-induced RNA and protein expression levels of IL6 and IL8, but not that of CCL5 in SVG astrocytes. Moreover, TIMBD attenuated gp120-induced phosphorylation of cJUN, cFOS, STAT3, p38-MAPK, AKT and IKKs, and the nuclear translocation of NF-κB p-65 subunit whereas RES mostly affected NF-κB protein expression levels. Our results suggest that TIMBD exerts anti-inflammatory effects better than that of RES in SVG astrocytes in vitro. These effects seem to be regulated by AP1, STAT-3 and NF-κB signaling pathways. TIMBD may thus have a potential of being a novel agent for treating HIV1-gp120-mediated neuroinflammatory diseases.
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Pfeffer SR, Fan M, Du Z, Yang CH, Pfeffer LM. Unphosphorylated STAT3 regulates the antiproliferative, antiviral, and gene-inducing actions of type I interferons. Biochem Biophys Res Commun 2017. [PMID: 28642132 DOI: 10.1016/j.bbrc.2017.06.111] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Type I interferon (IFNα/β) induces antiviral and antiproliferative responses in cells through the induction of IFN-stimulated genes (ISGs). Although the roles of IFN-activated STAT1 and STAT2 in the IFN response are well described, the function of STAT3 is poorly characterized. We investigated the role of STAT3 in the biological response to IFNα/β in mouse embryonic fibroblasts (MEFs) with a germ line deletion of STAT3. These STAT3 knockout (STAT3-KO) MEFs were reconstituted with STAT3 or the F705-STAT3 mutant (unphosphorylated STAT3) where the canonical Y705 tyrosine phosphorylation site was mutated. We show that both STAT3 and unphosphorylated STAT3 expression enhance the sensitivity of MEFs to the antiviral, antiproliferative and gene-inducing actions of IFN. By chromatin immunoprecipitation assays, unphosphorylated STAT3 appears to bind, albeit weakly, to select gene promoters to enhance their expression. These results suggest that unphosphorylated STAT3 plays an important role in the IFN response pathway.
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Affiliation(s)
- Susan R Pfeffer
- Department of Pathology and Laboratory Medicine, and Center for Cancer Research, University of Tennessee Health Science Center and Memphis, TN 38163, USA
| | - Meiyun Fan
- Department of Pathology and Laboratory Medicine, and Center for Cancer Research, University of Tennessee Health Science Center and Memphis, TN 38163, USA
| | - Ziyun Du
- Department of Pathology and Laboratory Medicine, and Center for Cancer Research, University of Tennessee Health Science Center and Memphis, TN 38163, USA
| | - Chuan He Yang
- Department of Pathology and Laboratory Medicine, and Center for Cancer Research, University of Tennessee Health Science Center and Memphis, TN 38163, USA
| | - Lawrence M Pfeffer
- Department of Pathology and Laboratory Medicine, and Center for Cancer Research, University of Tennessee Health Science Center and Memphis, TN 38163, USA.
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Dasari C, Yaghnam DP, Walther R, Ummanni R. Tumor protein D52 (isoform 3) contributes to prostate cancer cell growth via targeting nuclear factor-κB transactivation in LNCaP cells. Tumour Biol 2017; 39:1010428317698382. [PMID: 28466782 DOI: 10.1177/1010428317698382] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Our previous study showed that TPD52 overexpression could increase migration and proliferation of LNCaP cells contributing to the development of prostate cancer. However, mechanism of TPD52 in prostate cancer initiation and progression remains elusive. In this study, we investigated the possible underlying mechanism of TPD52 in prostate cancer progression. In LNCaP cells, TPD52 expression was altered by transfecting with either EGFP-TPD52 or specific short hairpin RNA. Overexpression of TPD52 protected LNCaP cells from apoptosis through elevated anti-apoptotic proteins XIAP, Bcl-2, and Cyclin D1, whereas Bax was downregulated. Mechanistically, we found that TPD52 confers transactivation of nuclear factor-κB, thereby enhancing its target gene expression in LNCaP cells. TPD52 promotes LNCaP cell invasion probably via increased matrix metalloproteinase 9 expression and its activity while tissue inhibitor of metalloproteinase expression is significantly downregulated. Notably, TPD52 might be involved in cell adhesion, promoting tumor metastasis by inducing loss of E-cadherin, expression of vimentin and vascular cell adhesion molecule, and additionally activation of focal adhesion kinase. Furthermore, TPD52 directly interacts with nuclear factor-κB p65 (RelA) and promotes accumulation of phosphorylated nuclear factor-κB (p65)S536 that is directly linked with nuclear factor-κB transactivation. Indeed, depletion of TPD52 or inhibition of nuclear factor-κB in TPD52-positive cells inhibited secretion of tumor-related cytokines and contributes to the activation of STAT3, nuclear factor-κB, and Akt. Interestingly, in TPD52 overexpressing LNCaP cells, nuclear factor-κB inhibition prevented the autocrine/paracrine activation of STAT3. TPD52 activates STAT3 through ascertaining a cross talk between the nuclear factor-κB and the STAT3 signaling systems. Collectively, these results reveal mechanism by which TPD52 is associated with prostate cancer progression and highlight the approach for therapeutic targeting of TPD52 in prostate cancer.
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Affiliation(s)
- Chandrashekhar Dasari
- 1 Center for Chemical Biology, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad, India.,2 Centre for Academy of Scientific & Innovative Research, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad, India
| | - Dattu Prasad Yaghnam
- 1 Center for Chemical Biology, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad, India
| | - Reinhard Walther
- 3 Department of Medical Biochemistry and Molecular Biology, Ernst Moritz Arndt University of Greifswald, Greifswald, Germany
| | - Ramesh Ummanni
- 1 Center for Chemical Biology, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad, India
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Verma G, Vishnoi K, Tyagi A, Jadli M, Singh T, Goel A, Sharma A, Agarwal K, Prasad SC, Pandey D, Sharma S, Mehrotra R, Singh SM, Bharti AC. Characterization of key transcription factors as molecular signatures of HPV-positive and HPV-negative oral cancers. Cancer Med 2017; 6:591-604. [PMID: 28155253 PMCID: PMC5345654 DOI: 10.1002/cam4.983] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2016] [Revised: 09/29/2016] [Accepted: 11/07/2016] [Indexed: 12/12/2022] Open
Abstract
Prior studies established constitutively active AP-1, NF-κB, and STAT3 signaling in oral cancer. Differential expression/activation of specific members of these transcription factors has been documented in HPV-positive oral lesions that respond better to therapy. We performed a comprehensive analysis of differentially expressed, transcriptionally active members of these pivotal signaling mediators to develop specific signatures of HPV-positive and HPV-negative oral lesions by immunohistochemical method that is applicable in low-resource settings. We examined a total of 31 prospective and 30 formalin-fixed, paraffin-embedded tissues from treatment-naïve, histopathologically and clinically confirmed cases diagnosed as oral or oropharyngeal squamous cell carcinoma (OSCC/OPSCC). Following determination of their HPV status by GP5 + /GP6 + PCR, the sequential sections of the tissues were evaluated for expression of JunB, JunD, c-Fos, p50, p65, STAT3, and pSTAT3(Y705), along with two key regulatory proteins pEGFR and p16 by IHC. Independent analysis of JunB and p65 showed direct correlation with HPV positivity, whereas STAT3 and pSTAT3 were inversely correlated. A combined analysis of transcription factors revealed a more restrictive combination, characterized by the presence of AP-1 and NF-κB lacking involvement of STAT3 that strongly correlated with HPV-positive tumors. Presence of STAT3/pSTAT3 with NF-κB irrespective of the presence or absence of AP-1 members was present in HPV-negative lesions. Expression of pSTAT3 strongly correlated with all the AP-1/NF-κB members (except JunD), its upstream activator pEGFRY1092 , and HPV infection-related negative regulator p16. Overall, we show a simple combination of AP-1, NF-κB, and STAT3 members' expression that may serve as molecular signature of HPV-positive lesions or more broadly the tumors that show better prognosis.
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Affiliation(s)
- Gaurav Verma
- Division of Molecular OncologyInstitute of Cytology & Preventive Oncology (ICMR)NoidaUttar PradeshIndia
- School of BiotechnologyBanaras Hindu UniversityVaranasiUttar PradeshIndia
- Molecular Oncology LaboratoryDepartment of ZoologyUniversity of DelhiDelhiIndia
| | - Kanchan Vishnoi
- Division of Molecular OncologyInstitute of Cytology & Preventive Oncology (ICMR)NoidaUttar PradeshIndia
- School of BiotechnologyBanaras Hindu UniversityVaranasiUttar PradeshIndia
- Molecular Oncology LaboratoryDepartment of ZoologyUniversity of DelhiDelhiIndia
| | - Abhishek Tyagi
- Division of Molecular OncologyInstitute of Cytology & Preventive Oncology (ICMR)NoidaUttar PradeshIndia
| | - Mohit Jadli
- Molecular Oncology LaboratoryDepartment of ZoologyUniversity of DelhiDelhiIndia
| | - Tejveer Singh
- Molecular Oncology LaboratoryDepartment of ZoologyUniversity of DelhiDelhiIndia
| | - Ankit Goel
- Subharti Dental CollegeMeerutUttar PradeshIndia
| | | | | | - Subhash Chandra Prasad
- Division of Molecular OncologyInstitute of Cytology & Preventive Oncology (ICMR)NoidaUttar PradeshIndia
| | - Durgatosh Pandey
- Department of OncosurgeryDr. Bheem Rao Ambedkar Institute‐Rotary Cancer HospitalAll India Institute Of Medical SciencesNew DelhiIndia
| | - Shashi Sharma
- Division of Molecular OncologyInstitute of Cytology & Preventive Oncology (ICMR)NoidaUttar PradeshIndia
| | - Ravi Mehrotra
- Division of Molecular OncologyInstitute of Cytology & Preventive Oncology (ICMR)NoidaUttar PradeshIndia
| | | | - Alok Chandra Bharti
- Division of Molecular OncologyInstitute of Cytology & Preventive Oncology (ICMR)NoidaUttar PradeshIndia
- Molecular Oncology LaboratoryDepartment of ZoologyUniversity of DelhiDelhiIndia
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Vageli DP, Prasad ML, Sasaki CT. Gastro-duodenal fluid induced nuclear factor-κappaB activation and early pre-malignant alterations in murine hypopharyngeal mucosa. Oncotarget 2016; 7:5892-908. [PMID: 26745676 PMCID: PMC4868729 DOI: 10.18632/oncotarget.6824] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Accepted: 12/24/2015] [Indexed: 01/01/2023] Open
Abstract
We recently described the role of gastro-duodenal fluids (GDFs) in generating changes consistent with hypopharyngeal neoplasia through activation of NF-κB pathway, using an in vitro model of human hypopharyngeal normal keratinocytes. Here, we further provide evidence that gastro-duodenal reflux is a risk factor for early pre-malignant alterations in hypopharyngeal mucosa (HM) related to an activated NF-κB oncogenic pathway, using both an in vitro and a novel in vivo model of C57Bl/6J mice. Histological, immunohistochemical and automated quantitative analysis documents significant NF-κB activation and early pre-malignant alterations in HM topically exposed to GDFs, compared to acid alone and other controls. Early pre-malignant histologic lesions exhibited increased Ki67, CK14 and ΔNp63, cell proliferation markers, changes of cell adhesion molecules, E-Cadherin and β-catenin, and STAT3 activation. The in vivo effect of NF-κB activation is positively correlated with p-STAT3, Ki67, CK14 or β-catenin expression, while GDFs induce significant transcriptional activation of RELA(p65), bcl-2, TNF-α, STAT3, EGFR and wnt5A, in vivo. Our in vivo model demonstrates selectively activated NF-κB in response to topically administrated GDFs, leading to early pre-malignant events in HM.
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Affiliation(s)
- Dimitra P Vageli
- Department of Surgery,Yale Larynx Laboratory Section of Otolaryngology, Yale School of Medicine, New Haven, CT, USA
| | - Manju L Prasad
- Pathology and of Surgery (Otolaryngology), Yale School of Medicine, New Haven, CT, USA
| | - Clarence T Sasaki
- Department of Surgery,Yale Larynx Laboratory Section of Otolaryngology, Yale School of Medicine, New Haven, CT, USA
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Sasaki CT, Toman J, Vageli D. The In Vitro Effect of Acidic-Pepsin on Nuclear Factor KappaB Activation and Its Related Oncogenic Effect on Normal Human Hypopharyngeal Cells. PLoS One 2016; 11:e0168269. [PMID: 27973541 PMCID: PMC5156414 DOI: 10.1371/journal.pone.0168269] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Accepted: 11/29/2016] [Indexed: 12/20/2022] Open
Abstract
Background Extra-esophageal carcinogenesis has been widely discussed in relation to the chronic effects of laryngopharyngeal reflux and most prominently with pepsin historically central to this discussion. With refluxate known to include gastric (pepsin) and duodenal (bile) fluids, we recently demonstrated the mechanistic role of NF-κB in mediating the preneoplastic effects of acidic-bile. However, the role of pepsin in promoting hypopharyngeal premalignant events remains historically unclear. Here, we investigate the in vitro effect of acidic-pepsin on the NF-κB oncogenic pathway to better define its potential role in hypopharyngeal neoplasia. Methods Human hypopharyngeal primary cells (HHPC) and keratinocytes (HHK) were repetitively exposed to physiologic pepsin concentrations (0.1 mg/ml) at pH 4.0, 5.0 and 7.0. Cellular localization of phospho-NF-κB and bcl-2 was determined using immunofluorescence and western blotting. NF-κB transcriptional activity was tested by luc reporter and qPCR. Analysis of DNA content of pepsin treated HHK and HHPC was performed using Fluorescence-activated-cell sorting assay. To explore a possible dose related effect, pepsin concentration was reduced from 0.1 to 0.05 and 0.01 mg/ml. Results At physiologic concentration, acidic-pepsin (0.1 mg/ml at pH 4.0) is lethal to most normal hypopharyngeal cells. However, in surviving cells, no NF-κB transcriptional activity is noted. Acidic-pepsin fails to activate the NF-κB or bcl-2, TNF-α, EGFR, STAT3, and wnt5α but increases the Tp53 mRNAs, in both HHPC and HHK. Weakly acidic-pepsin (pH 5.0) and neutral-pepsin (pH 7.0) induce mild activation of NF-κB with increase in TNF-α mRNAs, without oncogenic transcriptional activity. Lower concentrations of pepsin at varying pH do not produce NF-κB activity or transcriptional activation of the analyzed genes. Conclusion Our findings in vitro do not support the role of acidic-pepsin in NF-κB related hypopharyngeal carcinogenesis.
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Affiliation(s)
- Clarence T. Sasaki
- The Yale Larynx laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT, United States of America
- * E-mail:
| | - Julia Toman
- The Yale Larynx laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT, United States of America
| | - Dimitra Vageli
- The Yale Larynx laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT, United States of America
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Genomic amplification of Fanconi anemia complementation group A (FancA) in head and neck squamous cell carcinoma (HNSCC): Cellular mechanisms of radioresistance and clinical relevance. Cancer Lett 2016; 386:87-99. [PMID: 27867017 DOI: 10.1016/j.canlet.2016.11.014] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Revised: 10/25/2016] [Accepted: 11/10/2016] [Indexed: 01/06/2023]
Abstract
Radio (chemo) therapy is a crucial treatment modality for head and neck squamous cell carcinoma (HNSCC), but relapse is frequent, and the underlying mechanisms remain largely elusive. Therefore, novel biomarkers are urgently needed. Previously, we identified gains on 16q23-24 to be associated with amplification of the Fanconi anemia A (FancA) gene and to correlate with reduced progression-free survival after radiotherapy. Here, we analyzed the effects of FancA on radiation sensitivity in vitro, characterized the underlying mechanisms, and evaluated their clinical relevance. Silencing of FancA expression in HNSCC cell lines with genomic gains on 16q23-24 resulted in significantly impaired clonogenic survival upon irradiation. Conversely, overexpression of FancA in immortalized keratinocytes conferred increased survival accompanied by improved DNA repair, reduced accumulation of chromosomal translocations, but no hyperactivation of the FA/BRCA-pathway. Downregulation of interferon signaling as identified by microarray analyses, enforced irradiation-induced senescence, and elevated production of the senescence-associated secretory phenotype (SASP) appeared to be candidate mechanisms contributing to FancA-mediated radioresistance. Data of the TCGA HNSCC cohort confirmed the association of gains on 16q24.3 with FancA overexpression and impaired overall survival. Importantly, transcriptomic alterations similar to those observed upon FancA overexpression in vitro strengthened the clinical relevance. Overall, FancA amplification and overexpression appear to be crucial for radiotherapeutic failure in HNSCC.
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50
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Binder Gallimidi A, Fischman S, Revach B, Bulvik R, Maliutina A, Rubinstein AM, Nussbaum G, Elkin M. Periodontal pathogens Porphyromonas gingivalis and Fusobacterium nucleatum promote tumor progression in an oral-specific chemical carcinogenesis model. Oncotarget 2016; 6:22613-23. [PMID: 26158901 PMCID: PMC4673186 DOI: 10.18632/oncotarget.4209] [Citation(s) in RCA: 295] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Accepted: 05/26/2015] [Indexed: 02/06/2023] Open
Abstract
Oral squamous cell carcinoma (OSCC) is a lethal disease whose incidence is increasing. Epidemiologic studies demonstrate an association between periodontitis and oral cancer, and periodontal pathogens are implicated in the pathogenesis of numerous disorders, including rheumatoid arthritis, cardiovascular diseases, diabetes and gastrointestinal malignancies. Nevertheless, a causal role for periodontal pathogens in OSCC has not been shown, partly due to the lack of an appropriate animal model. Here, utilizing a newly-established murine model of periodontitis-associated oral tumorigenesis, we report that chronic bacterial infection promotes OSCC, and that augmented signaling along the IL-6-STAT3 axis underlies this effect. Our results indicate that periodontal pathogens P. gingivalis and F. nucleatum stimulate tumorigenesis via direct interaction with oral epithelial cells through Toll-like receptors. Furthermore, oral pathogens stimulate human OSCC proliferation and induce expression of key molecules implicated in tumorigenesis. To the best of our knowledge, these findings represent the first demonstration of a mechanistic role for oral bacteria in chemically induced OSCC tumorigenesis. These results are highly relevant for the design of effective prevention and treatment strategies for OSCC.
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Affiliation(s)
- Adi Binder Gallimidi
- Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.,Institute of Dental Sciences, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem, Israel
| | - Stuart Fischman
- Institute of Dental Sciences, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem, Israel
| | - Brurya Revach
- Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Raanan Bulvik
- Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Alina Maliutina
- Institute of Dental Sciences, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem, Israel
| | - Ariel M Rubinstein
- Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Gabriel Nussbaum
- Institute of Dental Sciences, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem, Israel
| | - Michael Elkin
- Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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