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Liu J, Wei Z, Meng L, Wu L, Liu F, Sang M, Zhao L, Gu L, Shan B. CircJPH1 regulates the NF-κB/HERC5 axis to promote the malignant progression of esophageal squamous cell carcinoma through binding to XRCC6. Cell Signal 2024; 124:111403. [PMID: 39255925 DOI: 10.1016/j.cellsig.2024.111403] [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: 06/19/2024] [Revised: 09/02/2024] [Accepted: 09/07/2024] [Indexed: 09/12/2024]
Abstract
Esophageal squamous cell carcinoma (ESCC) is a prevalent and malignant cancer with an unknown pathogenesis and a poor prognosis; therefore, the identification of effective biomarkers and targets is crucial for its diagnosis and treatment. Circular (circ)RNAs are prominent functional biomarkers and therapeutic targets in various diseases, particularly cancer, due to their widespread expression and regulatory mechanisms. Our study aimed to investigate the therapeutic potential of circRNA for ESCC. We identified Hsa_circ_0137111 for the first time as one of the most significantly up-regulated genes in ESCC sequencing and named it circJPH1. The results of the present study demonstrated an enhanced expression of circJPH1 in ESCC tissues. Moreover, circJPH1-knockdown could significantly inhibit the proliferation, migration, and invasion of ESCC cells, while its overexpression promoted these characteristics. In addition, circJPH1 promoted ESCC cell tumor growth in vivo. For the first time, mass spectrometry and RNA pull-down analysis revealed the interaction of X-ray repair cross-complementary 6 (XRCC6) protein with circJPH1, thereby promoting its nuclear translocation. Consequently, the nuclear factor kappa-B (NF-κB) signaling pathway was activated, leading to an up-regulation of HECT and RLD domain containing E3 ubiquitin protein ligase 5 (HERC5), thereby promoting ESCC progression. In summary, the present study elucidated the regulatory impact of circJPH1 on ESCC progression in vitro and in vivo, thereby indicating its potential role in ESCC treatment.
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Affiliation(s)
- Jingjing Liu
- Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, China; Key Laboratory of Tumor Gene Diagnosis, Prevention and Therapy, Clinical Oncology Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province 050001, China
| | - Zishuan Wei
- Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, China; Key Laboratory of Tumor Gene Diagnosis, Prevention and Therapy, Clinical Oncology Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province 050001, China
| | - Lingjiao Meng
- Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, China; Key Laboratory of Tumor Gene Diagnosis, Prevention and Therapy, Clinical Oncology Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province 050001, China
| | - Lixia Wu
- Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, China; Key Laboratory of Tumor Gene Diagnosis, Prevention and Therapy, Clinical Oncology Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province 050001, China
| | - Fei Liu
- Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, China; Key Laboratory of Tumor Gene Diagnosis, Prevention and Therapy, Clinical Oncology Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province 050001, China
| | - Meixiang Sang
- Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, China
| | - Lianmei Zhao
- Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, China; Key Laboratory of Tumor Gene Diagnosis, Prevention and Therapy, Clinical Oncology Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province 050001, China
| | - Lina Gu
- Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, China; Key Laboratory of Tumor Gene Diagnosis, Prevention and Therapy, Clinical Oncology Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province 050001, China.
| | - Baoen Shan
- Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, China; Key Laboratory of Tumor Gene Diagnosis, Prevention and Therapy, Clinical Oncology Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province 050001, China.
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Meng F, Zhang X, Wang Y, Lin J, Tang Y, Zhang G, Qiu B, Zeng X, Liu W, He X. Hsa_circ_0021727 (circ-CD44) promotes ESCC progression by targeting miR-23b-5p to activate the TAB1/NFκB pathway. Cell Death Dis 2023; 14:9. [PMID: 36609391 PMCID: PMC9822936 DOI: 10.1038/s41419-022-05541-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 12/20/2022] [Accepted: 12/22/2022] [Indexed: 01/09/2023]
Abstract
Esophageal squamous cell carcinoma (ESCC) is characterized by high morbidity and mortality. Circular RNAs (circRNAs) play an important role in tumor progression. We discovered an aberrantly expressed circRNA (hsa_circ_0021727) in patients with ESCC. However, the mechanism of action of hsa_circ_0021727 in tumors is unclear. The present study aimed to investigate the biological role of hsa_circ_0021727 and its mechanism in ESCC progression. We screened for the expression of hsa_circ_0021727 in ESCC patients. Patients with ESCC with high expression of hsa_circ_0021727 had shorter survival than those with low expression. Hsa_circ_0021727 promoted the proliferation, invasion, and migration of ESCC cells. However, miR-23b-5p inhibited this ability of hsa_circ_0021727. MiR-23b-5p acts by targeting TAK1-binding protein 1 (TAB1). Upregulation of TAB1 can activate the nuclear factor kappa B (NFκB) pathway. Hsa_circ_0021727 promoted ESCC progression by activating TAB1/NFκB pathway by sponging miR-23b-5p. In addition, in vivo experiments also confirmed that hsa_circ_0021727 could promote the proliferation, invasion, and migration of ESCC cells. In short, hsa_circ_0021727 promotes ESCC progression by targeting miR-23b-5p to activate the TAB1/NFκB pathway. These findings might provide potential targets to treat ESCC.
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Affiliation(s)
- Fan Meng
- Digestive System Department, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Xiaokang Zhang
- Jiangxi Provincial Branch of China Clinical Medical Research Center for Geriatric Diseases, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Yanting Wang
- Department of Respiratory and Critical Illness Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Jie Lin
- Department of Respiratory and Critical Illness Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Yulin Tang
- Department of Respiratory and Critical Illness Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Guisheng Zhang
- Digestive System Department, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Binqiang Qiu
- Department of Respiratory and Critical Illness Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Xingdu Zeng
- Department of Respiratory and Critical Illness Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Weiyou Liu
- Jiangxi Provincial Branch of China Clinical Medical Research Center for Geriatric Diseases, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Department of Respiratory and Critical Illness Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Xin He
- Jiangxi Provincial Branch of China Clinical Medical Research Center for Geriatric Diseases, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China.
- Department of Respiratory and Critical Illness Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China.
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Younesian O, Sheikh Arabi M, Jafari SM, Joshaghani H. Long-Term Excessive Selenium Supplementation Affects Gene Expression in Esophageal Tissue of Rats. Biol Trace Elem Res 2022; 201:3387-3394. [PMID: 36319827 DOI: 10.1007/s12011-022-03413-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 09/02/2022] [Indexed: 04/17/2023]
Abstract
Esophageal cancer is one of the leading causes of cancer death and the seventh most prevalent cancer worldwide. Considering the positive association of high selenium with the prevalence of esophageal cancer, we have investigated the effect of high doses of selenium on gene expression in the normal esophageal tissue of rats. Twenty male rats were randomly divided into four groups: control group, group 2 mg Se/L, 10 mg Se/L, and 20 mg Se/L rats fed with a basal basic diet and 2, 10, and 20 mg Se/L as sodium selenite in drinking water, respectively, for 20 weeks. Serum malondialdehyde and glutathione peroxidase activity were measured. Moreover, the expression and concentration of the cyclin D1, cyclin E, KRAS, p53, NF-kB, TGF-β, and MGMT in the esophageal tissue were analyzed and compared between the four groups. In normal esophageal tissue, selenium supplementations (2, 10, and 20 mg Se/L) increased the mRNA levels of cyclin D1, P53, KRAS, NF-κB p65, and MGMT and decreased the mRNA level of TGFß1. The concentrations of cyclin D1 and MGMT were also significantly increased by selenium supplementations. Selenium supplementations had no significant effect on serum MDA but significantly increased GPX activity. The present study suggests that selenium supplementation (2, 10, and 20 mg Se/L) affects gene expression related to inflammation, Cell proliferation, and apoptosis in the normal esophageal tissue. However, there were no observed abnormalities other than reduced growth with supplementation of 20 mg/L as Na2SeO3 in rats.
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Affiliation(s)
- Ommolbanin Younesian
- Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Golestan Province, Iran
| | - Mehdi Sheikh Arabi
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Seyyed Mehdi Jafari
- Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Golestan Province, Iran
| | - Hamidreza Joshaghani
- Laboratory Sciences Research Center, Golestan University of Medical Sciences, 60 Kola, Road, Falsafi Building, Gorgan, Iran.
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Gilbert S, Péant B, Mes-Masson AM, Saad F. IKKe Inhibitor Amlexanox Promotes Olaparib Sensitivity through the C/EBP-b-Mediated Transcription of Rad51 in Castrate-Resistant Prostate Cancer. Cancers (Basel) 2022; 14:cancers14153684. [PMID: 35954347 PMCID: PMC9367422 DOI: 10.3390/cancers14153684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Revised: 07/22/2022] [Accepted: 07/26/2022] [Indexed: 11/25/2022] Open
Abstract
Simple Summary Most men with advanced hormone-sensitive prostate cancer (HSPC) treated with androgen deprivation therapy will develop castrate resistant prostate cancer (CRPC), a lethal form of prostate cancer (PC). Our group has previously shown that IKKε expression is stronger in CRPC tumors and correlates with aggressive PC. Moreover, we have shown that IKKε depletion or inhibition (BX795, Amlexanox) decrease CRPC cell proliferation and tumor volume in an in vivo mouse model. We also demonstrate that IKKε inhibitors specifically target CRPC to induce a senescent phenotype as well as DNA damage and genomic instability. In this study, we demonstrated that IKKε depletion or inhibition block C/EBP-β recruitment on Rad51 promoter to decrease promoter activity. We have also shown that Amlexanox treatment sensitizes CRPC cells to Olaparib in vitro and in mouse models. Taken together, targeting IKKε with Amlexanox combined with Olaparib may lead to additional effective therapeutic strategies in the management of patients with CRPC. Abstract The progression of prostate cancer (PC) is often characterized by the development of castrate-resistant PC (CRPC). Patients with CRPC are treated with a variety of agents including new generation hormonal therapies or chemotherapy. However, as the cancer develops more resistance mechanisms, these drugs eventually become less effective and finding new therapeutic approaches is critical to improving patient outcomes. Previously, we have shown that IKKε depletion and IKKε inhibitors, BX795 and Amlexanox, decrease CRPC cell proliferation in vitro and in vivo and that IKKε inhibitors induce a senescence phenotype accompanied by increased DNA damage and genomic instability in CRPC cells. Here, we describe a new role for IKKε in DNA damage repair involving Rad51 and examine the therapeutic potential of Amlexanox combined with the PARP inhibitor Olaparib in CRPC cell lines. Combining Amlexanox with Olaparib decreased CRPC cell proliferation and enhanced DNA damage through the inhibition of Olaparib-induced Rad51 recruitment and expression in CRPC cells or IKKε-depleted PC-3 cells. We demonstrated that Rad51 promoter activity, measured by luciferase assay, was decreased with Amlexanox treatment or IKKε depletion and that Amlexanox treatment decreased the occupancy of transcription factor C/EBP-β on the Rad51 promoter. Our mouse model also showed that Amlexanox combined with Olaparib inhibited tumor growth of CRPC xenografts. Our study highlights a new role for IKKε in DNA damage repair through the regulation of Rad51 transcription and provides a rationale for the combination of Amlexanox and Olaparib in the treatment of patients with CRPC.
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Affiliation(s)
- Sophie Gilbert
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM) et Institut du Cancer de Montréal, Montréal, QC H2X 0A9, Canada; (S.G.); (B.P.); (F.S.)
| | - Benjamin Péant
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM) et Institut du Cancer de Montréal, Montréal, QC H2X 0A9, Canada; (S.G.); (B.P.); (F.S.)
| | - Anne-Marie Mes-Masson
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM) et Institut du Cancer de Montréal, Montréal, QC H2X 0A9, Canada; (S.G.); (B.P.); (F.S.)
- Department of Medicine, Université de Montréal, Montréal, QC H3C 3J7, Canada
- Correspondence: ; Tel.: +1-514-890-8000 (ext. 25496)
| | - Fred Saad
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM) et Institut du Cancer de Montréal, Montréal, QC H2X 0A9, Canada; (S.G.); (B.P.); (F.S.)
- Department of Surgery, Université de Montréal, Montréal, QC H3C 3J7, Canada
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Xiao QA, He Q, Li L, Song Y, Chen YR, Zeng J, Xia X. Role of IKKε in the Metabolic Diseases: Physiology, Pathophysiology, and Pharmacology. Front Pharmacol 2022; 13:888588. [PMID: 35662709 PMCID: PMC9162805 DOI: 10.3389/fphar.2022.888588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 04/19/2022] [Indexed: 11/13/2022] Open
Abstract
IKKε (inhibitor of nuclear factor kappa-B kinase ε) is a member of the noncanonical NF-κB pathway. It participates in the inflammatory response and innate immunity against bacteria. In recent decades, IKKε has been closely associated with metabolic regulation. Inhibition of the IKKε pathway can improve fat deposition in the liver, reduce subcutaneous fat inflammation, and improve liver gluconeogenesis in obesity. IKKε is expected to be a new therapeutic target for metabolic diseases such as nonalcoholic fatty liver disease, diabetes, and obesity. Herein, we summarize the structural characterization, physiological function, and pathological role of IKKε in metabolic diseases and small molecule inhibitors of IKKε.
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Affiliation(s)
- Qing-Ao Xiao
- Department of Endocrinology, The People's Hospital of China Three Gorges University/the First People's Hospital of Yichang, Yichang, China.,Third-grade Pharmacological Laboratory on Traditional Chinese MedicineState Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, China
| | - Qian He
- Department of Endocrinology, The People's Hospital of China Three Gorges University/the First People's Hospital of Yichang, Yichang, China.,National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Lun Li
- The Institute of Infection and Inflammation, China Three Gorges University, Yichang, China.,Department of Microbiology and Immunology, Medical College, China Three Gorges University, Yichang, China
| | - Yinhong Song
- The Institute of Infection and Inflammation, China Three Gorges University, Yichang, China.,Department of Microbiology and Immunology, Medical College, China Three Gorges University, Yichang, China
| | - Yue-Ran Chen
- Third-grade Pharmacological Laboratory on Traditional Chinese MedicineState Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, China.,Department of Physiology and Pathophysiology, Medical College, China Three Gorges University, Yichang, China
| | - Jun Zeng
- Department of Endocrinology, The People's Hospital of China Three Gorges University/the First People's Hospital of Yichang, Yichang, China
| | - Xuan Xia
- Third-grade Pharmacological Laboratory on Traditional Chinese MedicineState Administration of Traditional Chinese Medicine, China Three Gorges University, Yichang, China.,Department of Physiology and Pathophysiology, Medical College, China Three Gorges University, Yichang, China
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Danesh Pouya F, Rasmi Y, Nemati M. Signaling Pathways Involved in 5-FU Drug Resistance in Cancer. Cancer Invest 2022; 40:516-543. [PMID: 35320055 DOI: 10.1080/07357907.2022.2055050] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Anti-metabolite drugs prevent the synthesis of essential cell growth compounds. 5-fluorouracil is used as an anti-metabolic drug in various cancers in the first stage of treatment. Unfortunately, in some cancers, 5-fluorouracil has low effectiveness because of its drug resistance. Studies have shown that drug resistance to 5-fluorouracil is due to the activation of specific signaling pathways and increased expressions of enzymes involved in drug metabolites. However, when 5-fluorouracil is used in combination with other drugs, the sensitivity of cancer cells to 5-fluorouracil increases, and the effect of drug resistance is reversed. This study discusses how the function of 5-fluorouracil in JAK/STAT, Wnt, Notch, NF-κB, and hedgehogs in some cancers.
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Affiliation(s)
- Fahima Danesh Pouya
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Yousef Rasmi
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran.,Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Mohadeseh Nemati
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
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Das PK, Islam F, Smith RA, Lam AK. Therapeutic Strategies Against Cancer Stem Cells in Esophageal Carcinomas. Front Oncol 2021; 10:598957. [PMID: 33665161 PMCID: PMC7921694 DOI: 10.3389/fonc.2020.598957] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 12/29/2020] [Indexed: 12/24/2022] Open
Abstract
Cancer stem cells (CSCs) in esophageal cancer have a key role in tumor initiation, progression and therapy resistance. Novel therapeutic strategies to target CSCs are being tested, however, more in-depth research is necessary. Eradication of CSCs can result in successful therapeutic approaches against esophageal cancer. Recent evidence suggests that targeting signaling pathways, miRNA expression profiles and other properties of CSCs are important strategies for cancer therapy. Wnt/β-catenin, Notch, Hedgehog, Hippo and other pathways play crucial roles in proliferation, differentiation, and self-renewal of stem cells as well as of CSCs. All of these pathways have been implicated in the regulation of esophageal CSCs and are potential therapeutic targets. Interference with these pathways or their components using small molecules could have therapeutic benefits. Similarly, miRNAs are able to regulate gene expression in esophageal CSCs, so targeting self-renewal pathways with miRNA could be utilized to as a potential therapeutic option. Moreover, hypoxia plays critical roles in esophageal cancer metabolism, stem cell proliferation, maintaining aggressiveness and in regulating the metastatic potential of cancer cells, therefore, targeting hypoxia factors could also provide effective therapeutic modalities against esophageal CSCs. To conclude, additional study of CSCs in esophageal carcinoma could open promising therapeutic options in esophageal carcinomas by targeting hyper-activated signaling pathways, manipulating miRNA expression and hypoxia mechanisms in esophageal CSCs.
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Affiliation(s)
- Plabon Kumar Das
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh
| | - Farhadul Islam
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh.,Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia
| | - Robert A Smith
- Centre for Genomics and Personalised Health, Genomics Research Centre, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology (QUT), Kelvin Grove, QLD, Australia.,Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, QLD, Australia
| | - Alfred K Lam
- Cancer Molecular Pathology, School of Medicine, Griffith University, Gold Coast, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
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8
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Morgan D, Garg M, Tergaonkar V, Tan SY, Sethi G. Pharmacological significance of the non-canonical NF-κB pathway in tumorigenesis. Biochim Biophys Acta Rev Cancer 2020; 1874:188449. [PMID: 33058996 DOI: 10.1016/j.bbcan.2020.188449] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 10/04/2020] [Accepted: 10/05/2020] [Indexed: 02/06/2023]
Abstract
The understanding of the impact of the non-canonical NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathway in several human diseases including autoimmune, inflammatory and cancers has been on the rise. This pathway induces the expression of several important genes involved in diverse biological processes. Though progress has been made in understanding the activation, regulation and biological functions of the non-canonical NF-κB signaling mechanism, no specific drug has been approved to target NF-κB inducing kinase (NIK), the key signaling molecule in this pathway. The inhibition of NIK can serve as a potential therapeutic strategy for various ailments, especially for the treatment of different types of human cancers. There are other targetable downstream molecules in this pathway as well. This review highlights the possible role of the non-canonical NF-κB pathway in normal physiology as well as in different cancers and discusses about various pharmacological strategies to modulate the activation of this pathway.
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Affiliation(s)
- Dhakshayini Morgan
- Laboratory of NF-κB Signaling, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, 138673, Singapore; Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, 119 074, Singapore
| | - Manoj Garg
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University, Uttar Pradesh, Noida 201313, India
| | - Vinay Tergaonkar
- Laboratory of NF-κB Signaling, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, 138673, Singapore; Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, 119 074, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
| | - Soo Yong Tan
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, 119 074, Singapore; Advanced Molecular Pathology Laboratory, Institute of Molecular and Cell Biology, 61 Biopolis Dr, 138673, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117 600, Singapore.
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Yin M, Wang X, Lu J. Advances in IKBKE as a potential target for cancer therapy. Cancer Med 2020; 9:247-258. [PMID: 31733040 PMCID: PMC6943080 DOI: 10.1002/cam4.2678] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Revised: 10/20/2019] [Accepted: 10/22/2019] [Indexed: 12/16/2022] Open
Abstract
IKBKE (inhibitor of nuclear factor kappa-B kinase subunit epsilon), a member of the nonclassical IKK family, plays an important role in the regulation of inflammatory reactions, activation and proliferation of immune cells, and metabolic diseases. Recent studies have demonstrated that IKBKE plays a crucial regulatory role in malignant tumor development. In recent years, IKBKE, an important oncoprotein in several kinds of tumors, has been widely found to regulate a variety of cytokines and signaling pathways. IKBKE promotes the growth, proliferation, invasion, and drug resistance of various cancers. This paper makes a detailed review that focuses on the recent discoveries of IKBKE in the malignant tumors, and puts forward that IKBKE is becoming an important therapeutic target for clinical treatment, which has been more and more realized.
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Affiliation(s)
- Min Yin
- Department of OncologyJinan Fifth People's HospitalJinanPR China
| | - Xin Wang
- Department of OncologyRenmin Hospital of Wuhan UniversityHubei ProvinceWuhanPR China
- Department of Radiation OncologyShandong Cancer Hospital Affiliated to Shandong UniversityShandong Academy of Medical ScienceJinanPR China
| | - Jie Lu
- Department of NeurosurgeryThe First Affiliated Hospital of Shandong First Medical UniversityJinanPR China
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10
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Dimitrakopoulos FID, Antonacopoulou AG, Kottorou AE, Panagopoulos N, Kalofonou F, Sampsonas F, Scopa C, Kalofonou M, Koutras A, Makatsoris T, Dougenis D, Papadaki H, Brock M, Kalofonos HP. Expression Of Intracellular Components of the NF-κB Alternative Pathway (NF-κB2, RelB, NIK and Bcl3) is Associated With Clinical Outcome of NSCLC Patients. Sci Rep 2019; 9:14299. [PMID: 31586084 PMCID: PMC6778110 DOI: 10.1038/s41598-019-50528-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 09/13/2019] [Indexed: 02/07/2023] Open
Abstract
A growing number of studies has shed light on the role of the NF-κΒ in non-small-cell lung cancer (NSCLC). To address the significance of major effectors of the NF-κΒ alternative pathway, we investigated the relationship between NF-κΒ2, RelB, NIK and Bcl3 expression (mRNA and protein) and the clinical outcome of NSCLC patients. NF-κΒ2, RelB, NIK and Bcl3 protein expression levels were assessed by immunohistochemistry in tissue samples from 151 NSCLC patients who had curative resection. mRNA levels were also evaluated in 69 patients using quantitative real-time PCR. Although all studied proteins were overexpressed in NSCLC (P < 0.001 for all), only RelB mRNA levels were strongly increased in cancerous specimens compared to tumor-adjacent non-neoplastic tissues (P = 0.009). Moreover, NF-κB2, RelB and Bcl3 expression was associated with overall survival (OS). In particular, cytoplasmic and mRNA expression of RelB was related to 5-year OS (P = 0.014 and P = 0.006, respectively). Multivariate analysis also showed that Bcl3 expression (nuclear and cytoplasmic) was associated with increased 5-year OS (P = 0.002 and P = 0.036, respectively). In addition, higher Bcl3 mRNA levels were associated with inferior OS in stages I & II and improved OS in stages III and IV after 5-year follow-up (P = 0.004 and P = 0.001, respectively). Furthermore, stage I patients with lower NF-κB2 mRNA levels had better 5-year survival in univariate and multivariate analysis (P = 0.031 and P = 0.028, respectively). Interestingly, RelB expression (cytoplasmic and mRNA) was inversely associated with relapse rates (P = 0.027 and P = 0.015, respectively), while low NIK cytoplasmic expression was associated with lower relapse rates (P = 0.019). Cytoplasmic NIK expression as well as NF-κB2/ Bcl3 detection was associated with lymph node infiltration (P = 0.039 and P = 0.014, respectively). The present study confirms the deregulation of the NF-κB alternative pathway in NSCLC and also demonstrates the importance of this pathway in prognosis, recurrence and infiltration of regional lymph nodes.
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Affiliation(s)
- Foteinos-Ioannis D Dimitrakopoulos
- Molecular Oncology Laboratory, Division of Oncology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Anna G Antonacopoulou
- Molecular Oncology Laboratory, Division of Oncology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Anastasia E Kottorou
- Molecular Oncology Laboratory, Division of Oncology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Nikolaos Panagopoulos
- Department of Cardiothoracic Surgery, Medical School, University of Patras, Patras, Greece
| | - Fotini Kalofonou
- Molecular Oncology Laboratory, Division of Oncology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Fotios Sampsonas
- Department of Respiratory Medicine, University Hospital of Patras, Patras, Greece
| | - Chrisoula Scopa
- Department of Pathology, Medical School, University of Patras, Patras, Greece
| | - Melpomeni Kalofonou
- Institute of Biomedical Engineering, Imperial College London, London, United Kingdom
| | - Angelos Koutras
- Molecular Oncology Laboratory, Division of Oncology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Thomas Makatsoris
- Molecular Oncology Laboratory, Division of Oncology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Dimitrios Dougenis
- Department of Cardiothoracic Surgery, Medical School, University of Patras, Patras, Greece
| | - Helen Papadaki
- Department of Anatomy, Medical School, University of Patras, Patras, Greece
| | - Malcolm Brock
- Division of Thoracic Surgery, Department of Surgery, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Haralabos P Kalofonos
- Molecular Oncology Laboratory, Division of Oncology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece.
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11
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Kim HY, Kim YM, Hong S. Astaxanthin suppresses the metastasis of colon cancer by inhibiting the MYC-mediated downregulation of microRNA-29a-3p and microRNA-200a. Sci Rep 2019; 9:9457. [PMID: 31263239 PMCID: PMC6603017 DOI: 10.1038/s41598-019-45924-3] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 06/19/2019] [Indexed: 12/19/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer, and is associated with a high percentage of cancer-related death globally. Furthermore, the success rate of therapeutic treatment for CRC patients mainly depends on the status of metastasis. Therefore, novel drugs or therapeutic techniques should be discovered for the treatment of metastatic CRC. In this study, we selected Astaxanthin (AXT), one of the most common carotenoids, as a novel metastasis inhibitor through high-throughput drug screening based on invadopodia staining, and confirmed the anti-migratory and anti-invasive activity of AXT. We demonstrated that AXT increases miR-29a-3p and miR-200a expression, and thereby suppresses the expression of MMP2 and ZEB1, respectively. As a result, AXT represses the epithelial-mesenchymal transition (EMT) of CRC cells. Through the mechanistic study, we identified that AXT shows anti-metastatic activity through the transcriptional repression of MYC transcription factor. Finally, we also confirmed that AXT suppresses the in vivo metastatic capacity of colon cancer cell using mouse model. Collectively, we uncovered the novel function of AXT in the inhibition of EMT and invadopodia formation, implicating the novel therapeutic potential for AXT in metastatic CRC patients.
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Affiliation(s)
- Hye-Youn Kim
- Laboratory of Cancer Cell Biology, Department of Biochemistry, Gachon University School of Medicine, Incheon, Republic of Korea
| | - Young-Mi Kim
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, Republic of Korea
| | - Suntaek Hong
- Laboratory of Cancer Cell Biology, Department of Biochemistry, Gachon University School of Medicine, Incheon, Republic of Korea. .,Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, Republic of Korea.
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12
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Shaverdashvili K, Padlo J, Weinblatt D, Jia Y, Jiang W, Rao D, Laczkó D, Whelan KA, Lynch JP, Muir AB, Katz JP. KLF4 activates NFκB signaling and esophageal epithelial inflammation via the Rho-related GTP-binding protein RHOF. PLoS One 2019; 14:e0215746. [PMID: 30998758 PMCID: PMC6472825 DOI: 10.1371/journal.pone.0215746] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 04/08/2019] [Indexed: 12/12/2022] Open
Abstract
Understanding the regulatory mechanisms within esophageal epithelia is essential to gain insight into the pathogenesis of esophageal diseases, which are among the leading causes of morbidity and mortality throughout the world. The zinc-finger transcription factor Krüppel-like factor (KLF4) is implicated in a large number of cellular processes, such as proliferation, differentiation, and inflammation in esophageal epithelia. In murine esophageal epithelia, Klf4 overexpression causes chronic inflammation which is mediated by activation of NFκB signaling downstream of KLF4, and this esophageal inflammation produces epithelial hyperplasia and subsequent esophageal squamous cell cancer. Yet, while NFκB activation clearly promotes esophageal inflammation, the mechanisms by which NFκB signaling is activated in esophageal diseases are not well understood. Here, we demonstrate that the Rho-related GTP-binding protein RHOF is activated by KLF4 in esophageal keratinocytes, leading to the induction of NFκB signaling. Moreover, RHOF is required for NFκB activation by KLF4 in esophageal keratinocytes and is also important for esophageal keratinocyte proliferation and migration. Finally, we find that RHOF is upregulated in eosinophilic esophagitis, an important esophageal inflammatory disease in humans. Thus, RHOF activation of NFκB in esophageal keratinocytes provides a potentially important and clinically-relevant mechanism for esophageal inflammation and inflammation-mediated esophageal squamous cell cancer.
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Affiliation(s)
- Khvaramze Shaverdashvili
- Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
| | - Jennie Padlo
- Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
| | - Daniel Weinblatt
- Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
| | - Yang Jia
- Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
| | - Wenpeng Jiang
- Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
| | - Divya Rao
- Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
| | - Dorottya Laczkó
- Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
| | - Kelly A. Whelan
- Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
| | - John P. Lynch
- Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
| | - Amanda B. Muir
- Division of Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, United States of America
| | - Jonathan P. Katz
- Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
- * E-mail:
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13
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Gayed DT, Wodeyar J, Wang ZX, Wei X, Yao YY, Chen XX, Du Z, Chen JC. Prognostic values of inhibitory κB kinases mRNA expression in human gastric cancer. Biosci Rep 2019; 39:BSR20180617. [PMID: 30487159 PMCID: PMC6331671 DOI: 10.1042/bsr20180617] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 10/18/2018] [Accepted: 11/02/2018] [Indexed: 12/12/2022] Open
Abstract
Background: Inhibitory κB kinases (IKKs) play a key role in modulating proinflammatory and growth stimulating signals through their regulation of the nuclear factor κB (NF-κB) cascade. Therefore, the level of expression of IKKs represents a viable prognostic predictor with regard to various pathological processes. The prognostic value of IKKs expression in gastric cancer remains unclear. Methods: We used the 'Kaplan-Meier plotter' (KM plotter) online database, to explore the predictive prognostic value of individual IKKs members' mRNA expression to overall survival (OS) in different clinical data including pathological staging, histology, and therapies employed. Results: Our results revealed that a higher mRNA expression of inhibitor of NF-κB kinase subunit α (IKKα) was correlated to better OS, whereas higher mRNA expression of IKKβ, inhibitor of NF-κB kinase subunit γ (IKKγ), inhibitor of NF-κB kinase subunit ε (IKKε), and suppressor of IKKε (SIKE) were generally correlated to unfavorable OS in gastric cancer. Increased mRNA expression of IKKε also showed better outcomes in stage IV gastric cancer. Further a correlation between elevated levels of mRNA expression of both IKKε and SIKE was found to have favorable OS in diffuse type gastric cancer. It was also revealed that high expression of SIKE had favorable OS when treated with other adjuvant therapies, while worse OS when treated only with 5FU therapy. Conclusion: Our results suggest that mRNA expression of individual IKKs and SIKE are associated with unique prognostic significance and may act as valuable prognostic biomarkers and potential targets for future therapeutic interventions in gastric cancer.
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Affiliation(s)
- David Timothy Gayed
- School of the First Clinical Medical Sciences, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, China
| | | | - Zi-Xiang Wang
- School of the First Clinical Medical Sciences, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, China
| | - Xiang Wei
- School of the First Clinical Medical Sciences, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, China
| | - Yi-Yi Yao
- School of the First Clinical Medical Sciences, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, China
| | - Xiao-Xi Chen
- Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhou Du
- Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ji-Cai Chen
- Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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14
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Tu Y, Tan F, Zhou J, Pan J. Pristimerin targeting NF-κB pathway inhibits proliferation, migration, and invasion in esophageal squamous cell carcinoma cells. Cell Biochem Funct 2018; 36:228-240. [PMID: 29781107 DOI: 10.1002/cbf.3335] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 04/23/2018] [Indexed: 12/20/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of cancer-related death with poor prognosis in China. Identifying novel targeted therapies in ESCC is urgently needed. The aberrant activation of NF-κB signalling pathway is critical for prognosis and recurrence of ESCC, which make it a potential target in the treatment of ESCC. Here, we found that pristimerin inhibited ESCC cell proliferation, migration, invasion, induced cell apoptosis, and eliminated cancer stem-like cells (CSCs). It also showed a synergistic effect on ESCC when combined with 5-fluorouracil (5-FU). Moreover, pristimerin potently inhibited the growth of ESCC xenograft in nude mice. The anti-ESCC effects of pristimerin were demonstrated to be associated with the inhibition of NF-κB pathway by suppressing tumour necrosis factor α (TNFα)-induced IκBα phosphorylation, p65 translocation, and NF-κB-dependent gene expression. This study provides an evidence for the development of pristimerin to be a new therapeutic agent for ESCC. SIGNIFICANCE OF THE STUDY Although several approaches including surgery, chemotherapy, and radiotherapy had been applied in the treatment of ESCC, more effective targeted chemotherapies are required to increase the survival rates of patients. This study suggested that inhibiting NF-κB signalling pathway could be an effective approach for the treatment of ESCC. Pristimerin, a potent NF-κB inhibitor, exerted potent anti-ESCC effects both in vitro and in vivo, which may be a promising therapeutic agent for ESCC.
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Affiliation(s)
- Yuanqing Tu
- Jinan University Institute of Tumor Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China
| | - Fuxing Tan
- Jinan University Institute of Tumor Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China
| | - Jingfeng Zhou
- Jinan University Institute of Tumor Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China
| | - Jingxuan Pan
- Jinan University Institute of Tumor Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China
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15
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Wang J, Zhang Z, Che Y, Yuan Z, Lu Z, Li Y, Wan J, Sun H, Chen Z, Pu J, He J. Rabdocoestin B exhibits antitumor activity by inducing G2/M phase arrest and apoptosis in esophageal squamous cell carcinoma. Cancer Chemother Pharmacol 2018; 81:469-481. [PMID: 29308536 DOI: 10.1007/s00280-017-3507-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2017] [Accepted: 12/19/2017] [Indexed: 12/20/2022]
Abstract
PURPOSE Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive squamous cell carcinomas and is generally resistant to chemotherapy. In the present study, the cytotoxic activity of Rabdocoestin B (Rabd-B) against ESCC and the underlying mechanisms were investigated. METHODS The inhibitory effect of Rabd-B on KYSE30 and KYSE450 was evaluated by Cell Counting Kit-8 (CCK8) and colony formation assays in vitro. The cell cycle distribution and apoptosis of cells treated with Rabd-B were determined by flow cytometry. The mechanisms underlying the effects of Rabd-B were systematically examined by Western blot. The in vivo anti-tumor ability of Rabd-B was measured in mouse xenograft models and cisplatin (DDP) was used as positive control. RESULTS Rabd-B efficiently induced G2/M phase arrest in ESCC cells by upregulating the Chk1/Chk2-Cdc25C axis to inhibit the G2→M transition facilitated by Cdc2/Cyclin B1. Furthermore, Rabd-B suppressed ATM/ATR phosphorylation, thereby inhibiting BRCA1-mediated DNA repair, which resulted in mitotic catastrophe and induced cell apoptosis. Rabd-B also decreased the activity of the Akt and NF-κB survival signaling pathways and ultimately initiated the caspase-9-dependent intrinsic apoptotic pathway in ESCC cells. The apoptosis induced by Rabd-B could be partially reversed by a caspase-9-specific inhibitor (Z-LEHD-FMK) and a pan-caspase inhibitor (Z-VAD-FMK). Moreover, Rabd-B effectively suppressed tumor growth in mouse xenografts which was comparable to that of DDP without significant injuries to the mice. CONCLUSION Taken together, these findings indicate that Rabd-B is a promising precursor compound that may be useful as a treatment for ESCC and thus warrants further investigation.
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Affiliation(s)
- Jingnan Wang
- Department of Thoracic Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China
| | - Zhirong Zhang
- Department of Thoracic Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China
| | - Yun Che
- Department of Thoracic Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China
| | - Zuyang Yuan
- Department of Thoracic Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China
| | - Zhiliang Lu
- Department of Thoracic Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China
| | - Yuan Li
- Department of Thoracic Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China
| | - Jun Wan
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, People's Republic of China
| | - Handong Sun
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, People's Republic of China
| | - Zhaoli Chen
- Department of Thoracic Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China.
| | - Jianxin Pu
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, People's Republic of China.
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China.
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16
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Abstract
Inhibitor of kappa B kinase epsilon (IKKε) and TANK-binding kinase 1 (TBK1) are non-canonical IKKs. IKKε and TBK1 share the kinase domain and are similar in their ability to activate the nuclear factor-kappa B signaling pathway. IKKε and TBK1 are overexpressed through multiple mechanisms in various human cancers. However, the expression of IKKε and TBK1 in gastric cancer and their role in prognosis have not been studied. To investigate overexpression of the IKKε and TBK1 proteins in gastric cancer and their relationship with clinicopathologic factors, we performed immunohistochemical staining using a tissue microarray. Tissue microarray samples were obtained from 1,107 gastric cancer patients who underwent R0 gastrectomy with extensive lymph node dissection and adjuvant chemotherapy. We identified expression of IKKε in 150 (13.6%) and TBK1 in 38 (3.4%) gastric cancers. Furthermore, co-expression of IKKε and TBK1 was identified in 1.5% of cases. Co-expression of IKKε and TBK1 was associated with differentiated intestinal histology and earlier T stage. In a multivariate binary logistic regression model, intestinal histologic type by Lauren classification and early AJCC stage were significant predictors for expression of IKKε and TBK1 proteins in gastric cancer. Changes in IKKε and TBK1 expression may be involved in the development of intestinal-type gastric cancer. The overexpression of IKKε and TBK1 should be considered in selected patients with intestinal-type gastric cancer. In conclusion, this is the first large-scale study investigating the relationships between expression of IKKε and TBK1 and clinicopathologic features of gastric cancer. The role of IKKε and TBK1 in intestinal-type gastric cancer pathogenesis should be elucidated by further investigation.
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17
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Merga YJ, O'Hara A, Burkitt MD, Duckworth CA, Probert CS, Campbell BJ, Pritchard DM. Importance of the alternative NF-κB activation pathway in inflammation-associated gastrointestinal carcinogenesis. Am J Physiol Gastrointest Liver Physiol 2016; 310:G1081-90. [PMID: 27102559 DOI: 10.1152/ajpgi.00026.2016] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 04/17/2016] [Indexed: 02/07/2023]
Abstract
Chronic inflammation is a common factor in the development of many gastrointestinal malignancies. Examples include inflammatory bowel disease predisposing to colorectal cancer, Barrett's esophagus as a precursor of esophageal adenocarcinoma, and Helicobacter pylori-induced gastric cancer. The classical activation pathway of NF-κB signaling has been identified as regulating several sporadic and inflammation-associated gastrointestinal tract malignancies. Emerging evidence suggests that the alternative NF-κB signaling pathway also exerts a distinct influence on these processes. This review brings together current knowledge of the role of the alternative NF-κB signaling pathway in the gastrointestinal tract, with a particular emphasis on inflammation-associated cancer development.
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Affiliation(s)
- Yvette J Merga
- Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Adrian O'Hara
- Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Michael D Burkitt
- Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Carrie A Duckworth
- Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Christopher S Probert
- Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Barry J Campbell
- Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - D Mark Pritchard
- Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
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18
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Zeng W, Li H, Chen Y, Lv H, Liu L, Ran J, Sun X, Bieerkehazhi S, Liu Y, Li X, Lai W, Watibieke J, Dawulietihan M, Li X, Li H. Survivin activates NF‑κB p65 via the IKKβ promoter in esophageal squamous cell carcinoma. Mol Med Rep 2015; 13:1869-80. [PMID: 26718331 DOI: 10.3892/mmr.2015.4737] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 12/02/2015] [Indexed: 11/06/2022] Open
Abstract
Survivin and transcription factor p65 (NF‑κB p65) participate in the progression of esophageal squamous cell carcinoma (ESCC). However, the mechanism of NF‑κB p65 activation in ESCC remains to be elucidated. The aim of the present study was to investigate the role of survivin in the activation of NF‑κB p65 in ESCC. The expression levels of survivin, NF‑κB p65, inhibitor of nuclear factor κB kinase subunit α (IKKα) and inhibitor of nuclear factor κB kinase subunit β (IKKβ) were detected in ESCC tissue samples. Eca109 and KYSE150 cells were cultured and survivin activity was modulated via transfection with an overexpression plasmid, a small hairpin RNA plasmid and a specific inhibitor. Quantitative reverse transcription-polymerase chain reaction and western blotting assays were conducted to assess the effects of survivin on the expression levels of IKKα, IKKβ and NF‑κB p65. Cell cycle and apoptosis assays were conducted to detect surviving-dependent cellular behavior changes. In addition, the luciferase reporter gene assay and chromatin immunoprecipitation assay were conducted to determine the genomic sites responsible for surviving-induced activation of NF‑κB p65. The present study demonstrated that the expression of survivin is positively correlated with IKKα and IKKβ in ESCC tissues. Survivin affected the mRNA and protein expression levels of IKKα, IKKβ, and NF‑κB p65 in Eca109 and KYSE150 cells. Furthermore, survivin increased the transcriptional activity of the IKKβ promoter and bound to the IKKβ promoter region in the Eca109 cells. Downregulation of survivin arrested the cell cycle at the G2/M phase and induced apoptosis. Results of the present study suggest that survivin activates NF‑κB p65 in Eca109 cells via binding to the IKKβ promoter region and upregulating IKKβ promoter transcriptional activity. Survivin overexpression activates NF‑κB p65, which is important in the acquisition and maintenance of the oncogenic characteristics of ESCC.
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Affiliation(s)
- Wei Zeng
- Department of Labour Hygiene and Sanitary Science, College of Public Health, Xinjiang Medical University, Ürümqi, Xinjiang Uyghur Autonomous Region 830011, P.R. China
| | - Hui Li
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Xinjiang Medical University, Ürümqi, Xinjiang Uyghur Autonomous Region 830011, P.R. China
| | - Yan Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Xinjiang Medical University, Ürümqi, Xinjiang Uyghur Autonomous Region 830011, P.R. China
| | - Hongbo Lv
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Xinjiang Medical University, Ürümqi, Xinjiang Uyghur Autonomous Region 830011, P.R. China
| | - Ling Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Xinjiang Medical University, Ürümqi, Xinjiang Uyghur Autonomous Region 830011, P.R. China
| | - Jihua Ran
- Clinical Laboratory Diagnosis Center of PLA, General Hospital of Lanzhou Command, Ürümqi, Xinjiang Uyghur Autonomous Region 830000, P.R. China
| | - Xiaohong Sun
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Xinjiang Medical University, Ürümqi, Xinjiang Uyghur Autonomous Region 830011, P.R. China
| | - Shayahati Bieerkehazhi
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Xinjiang Medical University, Ürümqi, Xinjiang Uyghur Autonomous Region 830011, P.R. China
| | - Yining Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Xinjiang Medical University, Ürümqi, Xinjiang Uyghur Autonomous Region 830011, P.R. China
| | - Xiaomiao Li
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Xinjiang Medical University, Ürümqi, Xinjiang Uyghur Autonomous Region 830011, P.R. China
| | - Wenting Lai
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Xinjiang Medical University, Ürümqi, Xinjiang Uyghur Autonomous Region 830011, P.R. China
| | - Jibieke Watibieke
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Xinjiang Medical University, Ürümqi, Xinjiang Uyghur Autonomous Region 830011, P.R. China
| | - Meiliwuerti Dawulietihan
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Xinjiang Medical University, Ürümqi, Xinjiang Uyghur Autonomous Region 830011, P.R. China
| | - Xiumei Li
- Morphology Center, School of Basic Medicine, Xinjiang Medical University, Ürümqi, Xinjiang Uyghur Autonomous Region 830011, P.R. China
| | - Huiwu Li
- Cancer Institute, The Affiliated Cancer Hospital of Xinjiang Medical University, Ürümqi, Xinjiang Uyghur Autonomous Region 830011, P.R. China
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19
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Multiple Mechanisms of Anti-Cancer Effects Exerted by Astaxanthin. Mar Drugs 2015; 13:4310-30. [PMID: 26184238 PMCID: PMC4515619 DOI: 10.3390/md13074310] [Citation(s) in RCA: 112] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Revised: 07/06/2015] [Accepted: 07/07/2015] [Indexed: 12/21/2022] Open
Abstract
Astaxanthin (ATX) is a xanthophyll carotenoid which has been approved by the United States Food and Drug Administration (USFDA) as food colorant in animal and fish feed. It is widely found in algae and aquatic animals and has powerful anti-oxidative activity. Previous studies have revealed that ATX, with its anti-oxidative property, is beneficial as a therapeutic agent for various diseases without any side effects or toxicity. In addition, ATX also shows preclinical anti-tumor efficacy both in vivo and in vitro in various cancer models. Several researches have deciphered that ATX exerts its anti-proliferative, anti-apoptosis and anti-invasion influence via different molecules and pathways including signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and peroxisome proliferator-activated receptor gamma (PPARγ). Hence, ATX shows great promise as chemotherapeutic agents in cancer. Here, we review the rapidly advancing field of ATX in cancer therapy as well as some molecular targets of ATX.
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20
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Bauer D, Redmon N, Mazzio E, Taka E, Reuben JS, Day A, Sadrud-Din S, Flores-Rozas H, Soliman KFA, Darling-Reed S. Diallyl disulfide inhibits TNFα induced CCL2 release through MAPK/ERK and NF-Kappa-B signaling. Cytokine 2015; 75:117-26. [PMID: 26100848 DOI: 10.1016/j.cyto.2014.12.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Revised: 08/16/2014] [Accepted: 12/05/2014] [Indexed: 01/08/2023]
Abstract
TNFα receptors are constitutively overexpressed in tumor cells, correlating to sustain elevated NFκB and monocyte chemotactic protein-1 (MCP-1/CCL2) expression. The elevation of CCL2 evokes aggressive forms of malignant tumors marked by tumor associated macrophage (TAM) recruitment, cell proliferation, invasion and angiogenesis. Previously, we have shown that the organo-sulfur compound diallyl disulfide (DADS) found in garlic (Allium sativum) attenuates TNFα induced CCL2 production in MDA-MB-231 cells. In the current study, we explored the signaling pathways responsible for DADS suppressive effect on TNFα mediated CCL2 release using PCR Arrays, RT-PCR and western blots. The data in this study show that TNFα initiates a rise in NFκB mRNA, which is not reversed by DADS. However, TNFα induced heightened expression of IKKε and phosphorylated ERK. The expression of these proteins corresponds to increased CCL2 release that can be attenuated by DADS. CCL2 induction by TNFα was also lessened by inhibitors of p38 (SB202190) and MEK (U0126) but not JNK (SP 600125), all of which were suppressed by DADS. In conclusion, the obtained results indicate that DADS down regulates TNFα invoked CCL2 production primarily through reduction of IKKε and phosphorylated-ERK, thereby impairing MAPK/ERK, and NFκB pathway signaling. Future research will be required to evaluate the effects of DADS on the function and expression of TNFα surface receptors.
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Affiliation(s)
- D Bauer
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
| | - N Redmon
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
| | - E Mazzio
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
| | - E Taka
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
| | - J S Reuben
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
| | - A Day
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
| | - S Sadrud-Din
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
| | - H Flores-Rozas
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
| | - K F A Soliman
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
| | - S Darling-Reed
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
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Gambhir S, Vyas D, Hollis M, Aekka A, Vyas A. Nuclear factor kappa B role in inflammation associated gastrointestinal malignancies. World J Gastroenterol 2015; 21:3174-3183. [PMID: 25805923 PMCID: PMC4363746 DOI: 10.3748/wjg.v21.i11.3174] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2014] [Accepted: 02/12/2015] [Indexed: 02/06/2023] Open
Abstract
Nuclear factor kappa B (NF-κB) has an established role in the regulation of innate immunity and inflammation. NF-κB is also involved in critical mechanisms connecting inflammation and cancer development. Recent investigations suggest that the NF-κB signaling cascade may be the central mediator of gastrointestinal malignancies including esophageal, gastric and colorectal cancers. This review will explore NF-κB’s function in inflammation-associated gastrointestinal malignancies, highlighting its oncogenic contribution to each step of carcinogenesis. NF-κB’s role in the inflammation-to-carcinoma sequence in gastrointestinal malignancies warrants stronger emphasis upon targeting this pathway in achieving greater therapeutic efficacy.
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Guzman ML, Allan JN. Concise review: Leukemia stem cells in personalized medicine. Stem Cells 2015; 32:844-51. [PMID: 24214290 DOI: 10.1002/stem.1597] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Accepted: 10/21/2013] [Indexed: 12/14/2022]
Abstract
Despite increased comprehension of acute myelogenous leukemia (AML) pathogenesis, current treatment strategies have done little to improve upon standard induction chemotherapy to induce long-term remissions. Since the identification of the leukemic stem cell, efforts have been placed on identifying therapeutically actionable pathways that distinguish this increasingly important cellular compartment. With the advent of increased genome sequencing efforts and phenotypic characterization, opportunities for personalized treatment strategies are rapidly emerging. In this review, we highlight recent advances in the understanding of leukemic stem cell biology and their potential for translation into clinically relevant therapeutics. NF-kappa B activation, Bcl-2 expression, oxidative and metabolic state, and epigenetic modifications all bear their own clinical implications. With advancements in genetic, epigenetic, and metabolic profiling, personalized strategies may be feasible in the near future to improve outcomes for AML patients.
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Affiliation(s)
- Monica L Guzman
- Division of Hematology/Medical Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, New York, USA
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23
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Zhang Y, Meng Z, Zhang M, Tan J, Tian W, He X, Fu Q, Xu K, He Q, Zhu M, Li X, Zhang G, He Y, Jia Q, Zhang J, Wang S, Song X. Immunohistochemical evaluation of midkine and nuclear factor-kappa B as diagnostic biomarkers for papillary thyroid cancer and synchronous metastasis. Life Sci 2014; 118:39-45. [PMID: 25283079 DOI: 10.1016/j.lfs.2014.09.025] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2014] [Revised: 09/18/2014] [Accepted: 09/19/2014] [Indexed: 01/09/2023]
Abstract
AIMS Midkine (MK) is a multifunctional cytokine identified to be a promising cancer biomarker. Nuclear factor-kappa B (NF-κB) is an important transcription factor that plays a pivotal role in tumorigenesis. We aimed to investigate values of MK and NF-κB as markers for diagnosis and synchronous metastasis prediction in papillary thyroid cancer (PTC). MAIN METHODS 76 cases of PTC and 70 cases of multi-nodular goiter (MNG) were retrieved. The PTC group was further divided into subgroup 1 (16 cases with synchronous metastases) and subgroup 2 (60 cases without metastases). A retrospective review of demographic and clinical information was performed. Immunohistochemistry of MK, NF-κB p65 and Ki-67 was performed on paraffin-embedded specimens and results were quantified. Diagnostic values of the parameters were conducted by receiver operating characteristic (ROC) curves. Protein levels of MK and NF-κB p65 were then confirmed by Western blot. KEY FINDINGS Immunoreactivities of MK, NF-κB p65 and Ki-67 were significantly higher in the PTC group than in the MNG group with good differential diagnostic capabilities. Moreover, immunoreactivities of all three parameters were significantly higher in subgroup 1 than in subgroup 2 with good synchronous metastasis predictive efficacies. Western blot showed that MK and NF-κB p65 protein levels in lesions from subgroup 1 were significantly higher than those from subgroup 2, both of which were significantly higher than in MNG lesions. SIGNIFICANCE We discovered that MK and NF-κB immunohistochemistries can potentially be used for differential diagnosis between PTC and MNG, and for prediction of synchronous metastases.
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Affiliation(s)
- Yujie Zhang
- Department of Pathology, Tianjin Medical University General Hospital, Tianjin, PR China
| | - Zhaowei Meng
- Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin, PR China.
| | - Mingfang Zhang
- Department of Pathology, Tianjin First Center Hospital, Tianjin, PR China
| | - Jian Tan
- Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin, PR China.
| | - Weijun Tian
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, PR China
| | - Xianghui He
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, PR China
| | - Qiang Fu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, PR China
| | - Ke Xu
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenviroment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, PR China
| | - Qing He
- Department of Endocrinology, Tianjin Medical University General Hospital, Tianjin, PR China
| | - Mei Zhu
- Department of Endocrinology, Tianjin Medical University General Hospital, Tianjin, PR China
| | - Xue Li
- Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin, PR China
| | - Guizhi Zhang
- Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin, PR China
| | - Yajing He
- Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin, PR China
| | - Qiang Jia
- Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin, PR China
| | - Jianping Zhang
- Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin, PR China
| | - Sheng Wang
- Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin, PR China
| | - Xinghua Song
- Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin, PR China; Department of Nuclear Medicine, Second Affiliated Hospital of Zhejiang Medical University, Hangzhou, PR China
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In vitro 3D colon tumor penetrability of SRJ09, a new anti-cancer andrographolide analog. Invest New Drugs 2014; 32:806-14. [DOI: 10.1007/s10637-014-0105-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Accepted: 04/15/2014] [Indexed: 01/13/2023]
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Pang XL, Cui XB, Li S, Jin J, Liang WH, Li F, Chen YZ. Clinical significance of expression of PKCα and NF-κB p50/p65 in esophageal squamous cell carcinoma in Kazakh patients. Shijie Huaren Xiaohua Zazhi 2014; 22:227-232. [DOI: 10.11569/wcjd.v22.i2.227] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze the expression of protein kinase Cα (PKCα) and nuclear factor-kappa B (NF-κB) p50/p65 proteins in esophageal squamous cell carcinoma (ESCC) in Kazakh patients and to analyze their clinical significance.
METHODS: Immunohistochemistry was used to detect the expression of PKCα and NF-κB p50/p65 in 50 ESCC specimens and matched tumor-adjacent normal tissues.
RESULTS: The positive rates of PKCα and NF-κB p50/p65 proteins in ESCC were significantly higher than those in adjacent normal tissues (PKCα: 46.0% vs 8.0%; p50: 82.0% vs 48.0%; p65: 56.0% vs 36.0%, P = 1.9 × 10-5, 3.7 × 10-4 and 0.045, respectively). The expression of PKCα protein was closely correlated with ESCC differentiation (P = 0.030), p50 expression was correlated with metastasis (P = 0.042), and p65 expression was significantly correlated with differentiation and invasion (P = 0.015 and 0.042, respectively). PKCα expression had a positive correlation with p50 and p65 expression in ESCC (p50: r = 0.435, P = 4.5 × 10-6; p65: r = 0.626, P = 1 × 10-6).
CONCLUSION: The interaction of PKCα with NF-κB signal pathway may be involved in the invasion and metastasis of ESCC in Kazakh patients.
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Elevated expression patterns and tight correlation of the PLCE1 and NF-κB signaling in Kazakh patients with esophageal carcinoma. Med Oncol 2013; 31:791. [DOI: 10.1007/s12032-013-0791-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2013] [Accepted: 11/25/2013] [Indexed: 10/25/2022]
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Umar M, Upadhyay R, Kumar S, Ghoshal UC, Mittal B. Association of common polymorphisms in TNFA, NFkB1 and NFKBIA with risk and prognosis of esophageal squamous cell carcinoma. PLoS One 2013; 8:e81999. [PMID: 24324738 PMCID: PMC3852749 DOI: 10.1371/journal.pone.0081999] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Accepted: 10/19/2013] [Indexed: 12/30/2022] Open
Abstract
Background Tumour necrosis factor-alpha (TNF-α) and nuclear factor of kappa light chain gene enhancer in activated B cells (NF-κB) play critical role in carcinogenesis processes like tumour initiation, proliferation, migration and invasion. Single nucleotide polymorphisms in TNF-α, NF-κB and its inhibitor IκB genes were shown to be associated with susceptibility and prognosis of several cancers; however, their role in esophageal squamous cell carcinoma (ESCC) is not well recognised. Therefore, in present study, we aimed to investigate association of common polymorphisms in TNFA, NFkB1 and NFKBIA with risk and prognosis of ESCC in northern Indian population. Methods We genotyped 290 ESCC patients (including 162 followed up cases) and 311 mean age, gender and ethnicity matched controls for TNFA -308G>A, NFkB1 -94ATTG ins/del and NFKBIA (-826C>T and 3’UTRA>G) polymorphisms using PCR alone or followed by RFLP and TaqMan assay. Results TNFA-308GA genotype was associated with increased risk of ESCC specifically in females and in patients with regional lymph node involvement, while, NFKBIA -826CT+TT genotype conferred decreased risk of ESCC in females. Haplotypes of NFKBIA -826C>T and 3’UTRA>G polymorphisms, C-826G3’UTR and T-826A3’UTR, were associated with reduced risk of ESCC. No independent role of NFkB1 -94ATTG ins/del polymorphism in susceptibility of ESCC was found. Multi-dimensionality reduction analysis showed three factor model TNFA-308, NFKBIA-826, NFKBIA 3’UTR as better predictor for risk of ESCC. Furthermore, combined risk genotype analysis of all studied polymorphisms showed increased risk of ESCC in patients with 1-3 risk genotype compared to ‘0’ risk genotype. Survival analysis did not show any significant prognostic effect of studied polymorphisms. However, in stepwise multivariate analysis, metastasis was found to be independent prognostic predictor of ESCC patients. Conclusion TNFA-308 and NFKBIA (-826C>T and 3’UTRA>G) polymorphisms may play role in susceptibility but not in prognosis of ESCC patients in northern Indian population.
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Affiliation(s)
- Meenakshi Umar
- Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Rohit Upadhyay
- Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Shaleen Kumar
- Department of Radiotherapy, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Uday Chand Ghoshal
- Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Balraj Mittal
- Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
- * E-mail:
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Lin C, Song L, Gong H, Liu A, Lin X, Wu J, Li M, Li J. Nkx2-8 Downregulation Promotes Angiogenesis and Activates NF-κB in Esophageal Cancer. Cancer Res 2013; 73:3638-48. [DOI: 10.1158/0008-5472.can-12-4028] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Verhelst K, Verstrepen L, Carpentier I, Beyaert R. IκB kinase ε (IKKε): a therapeutic target in inflammation and cancer. Biochem Pharmacol 2013; 85:873-80. [PMID: 23333767 PMCID: PMC7111187 DOI: 10.1016/j.bcp.2013.01.007] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2012] [Revised: 01/04/2013] [Accepted: 01/11/2013] [Indexed: 01/10/2023]
Abstract
The innate immune system forms our first line of defense against invading pathogens and relies for a major part on the activation of two transcription factors, NF-κB and IRF3. Signaling pathways that activate these transcription factors are intertwined at the level of the canonical IκB kinases (IKKα, IKKβ) and non-canonical IKK-related kinases (IKKε, TBK1). Recently, significant progress has been made in understanding the function and mechanism of action of IKKε in immune signaling. In addition, IKKε impacts on cell proliferation and transformation, and is thereby also classified as an oncogene. Studies with IKKε knockout mice have illustrated a key role for IKKε in inflammatory and metabolic diseases. In this review we will highlight the mechanisms by which IKKε impacts on signaling pathways involved in disease development and discuss its potential as a novel therapeutic target.
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Affiliation(s)
- Kelly Verhelst
- Department for Molecular Biomedical Research, Unit of Molecular Signal Transduction in Inflammation, VIB, Zwijnaarde (Ghent), Belgium
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Gong H, Song L, Lin C, Liu A, Lin X, Wu J, Li M, Li J. Downregulation of miR-138 sustains NF-κB activation and promotes lipid raft formation in esophageal squamous cell carcinoma. Clin Cancer Res 2013; 19:1083-93. [PMID: 23319823 DOI: 10.1158/1078-0432.ccr-12-3169] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Constitutive activation of NF-κB signaling plays vital roles in esophageal squamous cell carcinoma (ESCC) progression. The aim of this study was to evaluate the effect of miR-138 on NF-κB activation and ESCC progression. EXPERIMENTAL DESIGN Expression of miR-138 in ESCC cell lines, ESCC tissues, and 205 archived ESSC specimens was determined using real-time PCR analysis. Anchorage-independent growth, chicken chorioallantoic membrane, Transwell matrix invasion and Annexin V-binding assays, and a xenograft tumor model were used to determine the role of miR-138 in ESCC progression. The effect of miR-138 on NF-κB activation was investigated using IKK in vitro kinase, electrophoretic mobility shift, lipid raft isolation, and luciferase reporter assays. RESULTS miR-138 was downregulated and inversely correlated with tumor progression and patient survival in ESCCs. Downregulation of miR-138 enhanced, whereas upregulation of miR-138 reduced, the aggressive phenotype of ESCC cells both in vitro and in vivo. Silencing miR-138 promoted K63-linked polyubiquitination of the NF-κB signaling intermediaries TRAF2 and RIP1 and sustained NF-κB activation. Furthermore, downregulation of miR-138 induced lipid raft formation via upregulating multiple components of lipid rafts, including FLOT1, FLOT2, and caveolin-1. Importantly, the in vitro analysis was consistent with a significant inverse correlation between miR-138 expression and NF-κB hyperactivation in a cohort of human ESCC specimens. CONCLUSION Our results show that miR-138 functions as a tumor-suppressive miRNA and that downregulation of miR-138 contributes to constitutive NF-κB activation and ESCC progression.
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MESH Headings
- 3' Untranslated Regions/genetics
- Animals
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Blotting, Western
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/mortality
- Carcinoma, Squamous Cell/pathology
- Caveolin 1/genetics
- Caveolin 1/metabolism
- Chickens
- Chorioallantoic Membrane/metabolism
- Chorioallantoic Membrane/pathology
- DNA Primers/chemistry
- Electrophoretic Mobility Shift Assay
- Esophageal Neoplasms/genetics
- Esophageal Neoplasms/mortality
- Esophageal Neoplasms/pathology
- Esophagus/metabolism
- Esophagus/pathology
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Humans
- Immunoenzyme Techniques
- Luciferases/metabolism
- Membrane Microdomains/metabolism
- Membrane Microdomains/pathology
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- MicroRNAs/genetics
- NF-kappa B/genetics
- NF-kappa B/metabolism
- Oligonucleotide Array Sequence Analysis
- Polyubiquitin/metabolism
- RNA, Messenger/genetics
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
- Survival Rate
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Hui Gong
- State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China
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Almanaa TN, Geusz ME, Jamasbi RJ. Effects of curcumin on stem-like cells in human esophageal squamous carcinoma cell lines. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2012; 12:195. [PMID: 23095512 PMCID: PMC3528437 DOI: 10.1186/1472-6882-12-195] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2012] [Accepted: 10/15/2012] [Indexed: 01/06/2023]
Abstract
Background Many cancers contain cell subpopulations that display characteristics of stem cells. Because these cancer stem cells (CSCs) appear to provide resistance to chemo-radiation therapy, development of therapeutic agents that target CSCs is essential. Curcumin is a phytochemical agent that is currently used in clinical trials to test its effectiveness against cancer. However, the effect of curcumin on CSCs is not well established. The current study evaluated curcumin-induced cell death in six cancer cell lines derived from human esophageal squamous cell carcinomas. Moreover, these cell lines and the ones established from cells that survived curcumin treatments were characterized. Methods Cell loss was assayed after TE-1, TE-8, KY-5, KY-10, YES-1, and YES-2 cells were exposed to 20–80 μM curcumin for 30 hrs. Cell lines surviving 40 or 60 μM curcumin were established from these six original lines. The stem cell markers aldehyde dehydrogenase-1A1 (ALDH1A1) and CD44 as well as NF-κB were used to compare CSC-like subpopulations within and among the original lines as well as the curcumin-surviving lines. YES-2 was tested for tumorsphere-forming capabilities. Finally, the surviving lines were treated with 40 and 60 μM curcumin to determine whether their sensitivity was different from the original lines. Results The cell loss after curcumin treatment increased in a dose-dependent manner in all cell lines. The percentage of cells remaining after 60 μM curcumin treatment varied from 10.9% to 36.3% across the six lines. The cell lines were heterogeneous with respect to ALDH1A1, NF-κB and CD44 expression. KY-5 and YES-1 were the least sensitive and had the highest number of stem-like cells whereas TE-1 had the lowest. The curcumin-surviving lines showed a significant loss in the high staining ALDH1A1 and CD44 cell populations. Tumorspheres formed from YES-2 but were small and rare in the YES-2 surviving line. The curcumin-surviving lines showed a small but significant decrease in sensitivity to curcumin when compared with the original lines. Conclusion Our results suggest that curcumin not only eliminates cancer cells but also targets CSCs. Therefore, curcumin may be an effective compound for treating esophageal and possibly other cancers in which CSCs can cause tumor recurrence.
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Song L, Gong H, Lin C, Wang C, Liu L, Wu J, Li M, Li J. Flotillin-1 promotes tumor necrosis factor-α receptor signaling and activation of NF-κB in esophageal squamous cell carcinoma cells. Gastroenterology 2012; 143:995-1005.e12. [PMID: 22732732 DOI: 10.1053/j.gastro.2012.06.033] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2011] [Revised: 06/05/2012] [Accepted: 06/07/2012] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS The flotillin family of proteins, including flotillin-1 (FLOT1 or Reggie-2), are lipid raft proteins that initiate receptor kinase signaling and are up-regulated in several tumor types. We investigated the role of FLOT1 signaling and activation of the transcription factor nuclear factor (NF)-κB in esophageal squamous cell carcinoma (ESCC) cells. METHODS We used immunoblot and immunochemical analyses to determine levels of the lipid raft-associated protein FLOT1 in ESCC cell lines and 432 ESSC samples from patients; primary normal esophageal epithelial cells and matched adjacent nontumor tissues were used as controls. We determined the ability of FLOT1 to activate NF-κB using kinase, electrophoretic mobility shift, and luciferase reporter assays. We measured the effects of FLOT1 overexpression and knockdown with short hairpin RNAs in ESCC cell lines using colony formation, anchorage-independent growth, chicken chorioallantoic membrane, transwell matrix penetration, and Annexin V-binding assays. We analyzed growth of ESCC xenograft tumors in nude mice. RESULTS Levels of FLOT1 were increased in ESCC cell lines and samples from patients, compared with controls; protein levels correlated with disease stage and survival time. Overexpression of FLOT1 in Kyse30 and Kyse510 ESCC cell lines increased proliferation, anchorage-independent growth, and invasive activity and protected them from apoptosis. FLOT1-transduced ESCC cells formed larger tumors in nude mice than control cells (transduced with only the vector). FLOT1 facilitated recruitment of the tumor necrosis factor-α receptor to lipid rafts; promoted K63-linked polyubiquitination of the signaling intermediaries tumor necrosis factor receptor associated factor 2, receptor interacting protein, and NEMO; and sustained the activation of NF-κB. Levels of FLOT1 correlated with activation of NF-κB in ESCC samples from patients. CONCLUSIONS The lipid raft protein FLOT1 is up-regulated in ESCC cell lines and samples from patients and promotes ESCC cell proliferation and tumor growth in mice. FLOT1 activates tumor necrosis factor-α receptor signaling and sustains activation of NF-κB in ESCC cells.
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Affiliation(s)
- Libing Song
- State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China
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NSCLC and the alternative pathway of NF-κB: uncovering an unknown relation. Virchows Arch 2012; 460:515-23. [PMID: 22562129 DOI: 10.1007/s00428-012-1230-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2012] [Accepted: 03/23/2012] [Indexed: 02/01/2023]
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. Although our knowledge on the pathobiology of the disease has increased in the last decades, the prognosis of lung cancer patients has hardly changed. Many signaling pathways are implicated in lung carcinogenesis, but the role of the alternative pathway of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in lung cancer pathogenesis and progression has not been investigated. The aim of our study was to investigate the role of this pathway in non-small cell lung cancer (NSCLC) patients. NF-κB2 and RelB protein expression was retrospectively assessed by immunohistochemistry in tissue samples from 109 NSCLC patients. RelB and NF-κB2 protein levels differed between tumors and adjacent nonneoplastic lung parenchyma. Cytoplasmic immunoreactivity of NF-κB2 and RelB was correlated with tumor stage (p = 0.03 and p = 0.016, respectively). In addition, cytoplasmic NF-κB2 levels were related to tumor grade (p = 0.046). Expression of RelB in the cytoplasm was tumor histologic type-specific, with squamous cell carcinomas having the highest protein levels. Nuclear expression of RelB and NF-κB2 differed between tumor and nonneoplastic tissues, possibly indicating activation of the alternative pathway of NF-κB in cancer cells. Moreover, lymph node metastasis was related to nuclear NF-κB2 expression in tumor cells. The deregulation of the alternative NF-κB pathway in NSCLC could play a role in the development and progression of the disease.
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Kuo SH, Weng WH, Chen ZH, Hsu PN, Wu MS, Lin CW, Jeng HJ, Yeh KH, Tsai HJ, Chen LT, Cheng AL. Establishment of a novel MALT lymphoma cell line, ma-1, from a patient with t(14;18)(q32;q21)-positive Helicobacter Pylori-Independent Gastric MALT Lymphoma. Genes Chromosomes Cancer 2011; 50:908-21. [PMID: 21837708 DOI: 10.1002/gcc.20910] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2011] [Accepted: 06/27/2011] [Indexed: 01/27/2023] Open
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TETREAULT MARIE, WANG MEI, YANG YIZENG, TRAVIS JENNA, YU QIAN, KLEIN–SZANTO ANDRESJ, KATZ JONATHANP. Klf4 overexpression activates epithelial cytokines and inflammation-mediated esophageal squamous cell cancer in mice. Gastroenterology 2010; 139:2124-2134.e9. [PMID: 20816834 PMCID: PMC3457785 DOI: 10.1053/j.gastro.2010.08.048] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2010] [Revised: 08/03/2010] [Accepted: 08/27/2010] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS Esophageal squamous cell cancer accounts for more than 90% of cases of esophageal cancers. Its pathogenesis involves chronic epithelial irritation, although the factors involved in the inflammatory process and the mechanisms of carcinogenesis are unknown. We sought to develop a mouse model of this cancer. METHODS We used the ED-L2 promoter of Epstein-Barr virus to overexpress the transcriptional regulator Krüppel-like factor 4 (Klf4) in esophageal epithelia of mice; we used mouse primary esophageal keratinocytes to examine the mechanisms by which KLF4 induces cytokine production. RESULTS KLF4 was an epithelial-specific mediator of inflammation; we developed a new mouse model of esophageal squamous dysplasia and inflammation-mediated squamous cell cancer. KLF4 activated a number of proinflammatory cytokines, including TNF-α, CXCL5, G-CSF and IL-1α, within keratinocytes in an NF-κB-dependent manner. KLF4 was not detected in proliferating or cancer cells, indicating a non-cell autonomous effect of KLF4 on proliferation and carcinogenesis. CONCLUSIONS KLF4 has distinct functions in carcinogenesis; upregulation of Klf4 specifically in esophageal epithelial cells induces inflammation. This mouse model might be used to determine the molecular mechanisms of esophageal squamous cell cancer and inflammation-mediated carcinogenesis.
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Affiliation(s)
- MARIE–PIER TETREAULT
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
| | - MEI–LUN WANG
- Division of Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - YIZENG YANG
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
| | - JENNA TRAVIS
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
| | - QIAN–CHUN YU
- University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
| | | | - JONATHAN P. KATZ
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
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