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Ma L, Cong W, Zhang H, Zhang W, Zhan Y, Liu Y, Zhang J, Wang Z, Gao Y, Han B, Liu Y, Zhao L. Lidocaine Inhibits the Proliferation of Non-Small Cell Lung Cancer and Exerts Anti-Inflammatory Effects Through the TLR-9/MyD88/NF-κB Pathway. DNA Cell Biol 2025; 44:161-171. [PMID: 39874055 DOI: 10.1089/dna.2024.0207] [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] [Indexed: 01/30/2025] Open
Abstract
Lung cancer represents a significant global health burden, with non-small cell lung cancer (NSCLC) being the most common subtype. The current standard of care for NSCLC has limited efficacy, highlighting the necessity for innovative treatment options. Lidocaine, traditionally recognized as a local anesthetic, has emerged as a compound with potential antitumor and anti-inflammatory capabilities. This study was designed to explore the impact of lidocaine on NSCLC cell proliferation and inflammation, particularly focusing on the Toll-like receptor 9 (TLR)-9/MyD88/NF-κB signaling pathway. A nude mice model of NSCLC was employed, with animals receiving lidocaine at different concentrations. In vitro experiments on A549 cells involved exposure to lidocaine, followed by assessment of cell viability, cytokine expression, and TLR-9 levels using the 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay, enzyme-linked immunosorbent assay, and Quantitative Real-time polymerase chain reaction (qPCR). Protein levels were evaluated via Western blot analysis. Additionally, A549 cells were transfected with a TLR-9-overexpressing lentivirus to dissect the role of TLR-9 in lidocaine's mechanism of action. Treatment with lidocaine led to a significant reduction in tumor dimensions and a decrease in inflammatory marker expression in the NSCLC mouse model. In cellular assays, lidocaine effectively suppressed A549 cell proliferation and the expression of inflammatory cytokines. The overexpression of TLR-9 partially negated the suppressive effects of lidocaine, underscoring the significance of the TLR-9/MyD88/NF-κB pathway in mediating lidocaine's effects. Lidocaine's inhibitory effects on NSCLC cell proliferation and its anti-inflammatory mechanisms are mediated through the TLR-9/MyD88/NF-κB pathway. The study's results offer promising insights into the therapeutic potential of lidocaine in NSCLC and pave the way for future investigations into its application in cancer therapy.
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Affiliation(s)
- Lin Ma
- Department of Anesthesiology, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Weiliang Cong
- Department of Anesthesiology, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Hongwei Zhang
- Department of Anesthesiology, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Wenhua Zhang
- Department of Anesthesiology, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Yuru Zhan
- Department of Anesthesiology, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Yang Liu
- Department of Anesthesiology, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Junting Zhang
- Department of Anesthesiology, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Zhongqun Wang
- Department of Anesthesiology, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Yu Gao
- Department of Anesthesiology, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Bo Han
- Department of Anesthesiology, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Ying Liu
- Department of Anesthesiology, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
| | - Liang Zhao
- Department of Anesthesiology, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, China
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Binsi P, Parvathy U, Jeyakumari A, George Thomas N, Zynudheen A. Marine biopolymers in cosmetics. MARINE BIOPOLYMERS 2025:677-752. [DOI: 10.1016/b978-0-443-15606-9.00023-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Pessino G, Scotti C, Maggi M, Immuno-Hub Consortium. Hepatocellular Carcinoma: Old and Emerging Therapeutic Targets. Cancers (Basel) 2024; 16:901. [PMID: 38473265 DOI: 10.3390/cancers16050901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 02/16/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
Liver cancer, predominantly hepatocellular carcinoma (HCC), globally ranks sixth in incidence and third in cancer-related deaths. HCC risk factors include non-viral hepatitis, alcohol abuse, environmental exposures, and genetic factors. No specific genetic alterations are unequivocally linked to HCC tumorigenesis. Current standard therapies include surgical options, systemic chemotherapy, and kinase inhibitors, like sorafenib and regorafenib. Immunotherapy, targeting immune checkpoints, represents a promising avenue. FDA-approved checkpoint inhibitors, such as atezolizumab and pembrolizumab, show efficacy, and combination therapies enhance clinical responses. Despite this, the treatment of hepatocellular carcinoma (HCC) remains a challenge, as the complex tumor ecosystem and the immunosuppressive microenvironment associated with it hamper the efficacy of the available therapeutic approaches. This review explores current and advanced approaches to treat HCC, considering both known and new potential targets, especially derived from proteomic analysis, which is today considered as the most promising approach. Exploring novel strategies, this review discusses antibody drug conjugates (ADCs), chimeric antigen receptor T-cell therapy (CAR-T), and engineered antibodies. It then reports a systematic analysis of the main ligand/receptor pairs and molecular pathways reported to be overexpressed in tumor cells, highlighting their potential and limitations. Finally, it discusses TGFβ, one of the most promising targets of the HCC microenvironment.
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Affiliation(s)
- Greta Pessino
- Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Claudia Scotti
- Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Maristella Maggi
- Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Immuno-Hub Consortium
- Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
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Martin-Gallausiaux C, Salesse L, Garcia-Weber D, Marinelli L, Beguet-Crespel F, Brochard V, Le Gléau C, Jamet A, Doré J, Blottière HM, Arrieumerlou C, Lapaque N. Fusobacterium nucleatum promotes inflammatory and anti-apoptotic responses in colorectal cancer cells via ADP-heptose release and ALPK1/TIFA axis activation. Gut Microbes 2024; 16:2295384. [PMID: 38126163 PMCID: PMC10761154 DOI: 10.1080/19490976.2023.2295384] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 12/12/2023] [Indexed: 12/23/2023] Open
Abstract
The anaerobic bacterium Fusobacterium nucleatum is significantly associated with human colorectal cancer (CRC) and is considered a significant contributor to the disease. The mechanisms underlying the promotion of intestinal tumor formation by F. nucleatum have only been partially uncovered. Here, we showed that F. nucleatum releases a metabolite into the microenvironment that strongly activates NF-κB in intestinal epithelial cells via the ALPK1/TIFA/TRAF6 pathway. Furthermore, we showed that the released molecule had the biological characteristics of ADP-heptose. We observed that F. nucleatum induction of this pathway increased the expression of the inflammatory cytokine IL-8 and two anti-apoptotic genes known to be implicated in CRC, BIRC3 and TNFAIP3. Finally, it promoted the survival of CRC cells and reduced 5-fluorouracil chemosensitivity in vitro. Taken together, our results emphasize the importance of the ALPK1/TIFA pathway in Fusobacterium induced-CRC pathogenesis, and identify the role of ADP-H in this process.
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Affiliation(s)
| | - Laurène Salesse
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
| | | | - Ludovica Marinelli
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
| | | | - Vincent Brochard
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
| | - Camille Le Gléau
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
| | - Alexandre Jamet
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
| | - Joël Doré
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
- Université Paris-Saclay, INRAE, Metagenopolis, Jouy-en-Josas, France
| | - Hervé M. Blottière
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
- Université Paris-Saclay, INRAE, Metagenopolis, Jouy-en-Josas, France
| | | | - Nicolas Lapaque
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
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Liu CW, Peng HY, Siao AC, Tsuei YW, Lin YY, Shiah SG, Shih LJ, Yeh CC, Lee SW, Kao YH. Resistin stimulates PC-3 prostate cancer cell growth through stimulation of SOCS3 and SOCS5 genes. Exp Biol Med (Maywood) 2023; 248:1695-1707. [PMID: 37646261 PMCID: PMC10792425 DOI: 10.1177/15353702231191206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 05/08/2023] [Indexed: 09/01/2023] Open
Abstract
Resistin and suppressors of cytokine signaling (SOCSs) have been reported to regulate prostate cancer (PCa) cell proliferation and survival, respectively. Whether any of the SOCS molecules mediate the mitogenic effect of resistin on PCa cells is unknown. Using PC-3 human PCa cells, we found that resistin upregulates the expression of SOCS3 and SOCS5 mRNA, but not SOCS7 mRNA, in a dose- and time-dependent manner. The resistin-induced increases in SOCS3 and SOCS5 expression and cell proliferation were prevented by pretreatment with specific inhibitors of the TLR4, ERK, p38 MAPK, JNK, PI3K, and JAK2 proteins. However, pretreatment with a TLR2 inhibitor had no effect on resistin-mediated SOCS3 and SOCS5 expression. In addition, the effects of resistin on SOCS3, SOCS5, and SOCS7 mRNA levels were cell type-specific. Overexpression of either SOCS3 or SOCS5 enhanced further resistin-stimulated growth of PC-3 cells, whereas silencing SOCS3 or SOCS5 antagonized resistin-increased cell growth. Further PCa tissue analysis demonstrated higher levels of RETN, TLR4, SOCS3, and SOCS5 mRNAs in cancer tissues than benign prostate hyperplasia and indicated positive correlations among RETN, TLR4, and SOCS5. These data suggest that SOCS5, TLR4, and, to a lesser extent, SOCS3 can mediate the mitogenic effect of resistin on PC-3 PCa cells.
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Affiliation(s)
- Chi-Wei Liu
- Department of Life Sciences, National Central University, Taoyuan 320
- Department of Internal Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan 330
| | - Hsuan-Yu Peng
- National Institute of Cancer Research, National Health Research Institutes, Miaoli 350
| | - An-Ci Siao
- Department of Life Sciences, National Central University, Taoyuan 320
| | - Yi-Wei Tsuei
- Department of Emergency Medicine, Taoyuan Armed Forces General Hospital, Taoyuan 325
| | - Yen-Yue Lin
- Department of Life Sciences, National Central University, Taoyuan 320
- Department of Emergency Medicine, Taoyuan Armed Forces General Hospital, Taoyuan 325
| | - Shine-Gwo Shiah
- National Institute of Cancer Research, National Health Research Institutes, Miaoli 350
| | - Li-Jane Shih
- Medical Laboratory, Taoyuan Armed Forces General Hospital, Taoyuan 325
| | - Chien-Chih Yeh
- Division of Colon and Rectal Surgery, Department of Surgery, Taoyuan Armed Forces General Hospital, Taoyuan 325
| | - Shih-Wei Lee
- Department of Internal Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan 330
- Department of Nursing, Yuanpei University of Medical Technology, Hsinchu 300
| | - Yung-Hsi Kao
- Department of Life Sciences, National Central University, Taoyuan 320
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Liu Y, Li Y, Xie J. Traditional Chinese Medicine Strategy for Treating Major Depressive Disorder Based on a Famous Formulation-Baweixiaoyaosan. AN ACAD BRAS CIENC 2023; 95:e20220676. [PMID: 37255171 DOI: 10.1590/0001-3765202320220676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 12/13/2022] [Indexed: 06/01/2023] Open
Abstract
In this study, systematic pharmacological methods were used to reveal the potential pharmacological targets of baweixiaoyaosan in the treatment of major depressive disorder (MDD). We identified 133 potential active compounds through data mining and absorption, distribution, metabolism, and excretion evaluation systems. Then, the target of potential active compounds is predicted by a system model based on random forest and support vector machine methods. Next, construct herbal ingredient-target networks and target-disease networks for further analysis of multi-directional treatment methods. At the same time, we also performed gene ontology enrichment analysis, tissue location analysis, and pathway analysis on 76 potential targets. Finally, we conducted the Jun-Chen-Zuo-Shi compatibility analysis of the formula and scientifically explained the different functions of different herbs in the formula. In short, we found that the formula mainly exerts the effect of treating MDD through the four functional modules of inflammation inhibition, neuroprotection, monoamine neurotransmitter and liver. This research not only explores the mechanism of Traditional Chinese Medicine treatment of MDD from a multi-scale perspective, but also provides a reference for future research on BWXYS. It plays a role in promoting the widespread use of BWXYS.
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Affiliation(s)
- Yongwei Liu
- Dalian University of Technology, Chemical Engineering Institute, Linggong Road, 2, 116023 Dalian, Liaoning, China
| | - Yan Li
- Dalian University of Technology, Chemical Engineering Institute, Linggong Road, 2, 116023 Dalian, Liaoning, China
| | - Jing Xie
- Dalian University of Technology, Chemical Engineering Institute, Linggong Road, 2, 116023 Dalian, Liaoning, China
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Elahirad E, Gharagozlou MJ, Khosravi A, Sasani F. TLRs expression in canine mammary gland neoplasms: a pathological and molecular study. Vet Immunol Immunopathol 2023; 261:110611. [PMID: 37245345 DOI: 10.1016/j.vetimm.2023.110611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 05/11/2023] [Accepted: 05/13/2023] [Indexed: 05/30/2023]
Abstract
TLRs are a class of PRRs that play a vital role in innate immunity. TLRs are expressed on immune cells and mammary epithelial cells. They can promote tumor growth, angiogenesis, invasion, and viability signaling. The current study aimed to test the correlation between histologic types and grades of neoplasms and TLRs gene expression levels. Twenty-one tissue samples of canine mammary neoplasms were stained with H&E. Then, it evaluated histologic type and grade according to the methods of Goldschmidt et al. and Peña, respectively. We established real-time PCR quantification assays to measure the mRNA abundances of TLRs in normal and neoplastic mammary glands. Profile pattern of TLR 1, 2, 3, 4, 5, 6, and 9 genes expression in canine mammary glands performed in 21 samples of mammary gland neoplasms and three non-neoplastic mammary gland samples from normal dogs. TLR 3, 4, and 9 mRNA overexpression were detected. In addition, tubulopapillary carcinoma grade II, SCC grade III, and carcinoma mixed type grade II demonstrated the highest relative TLR-3, and 9 mRNA expression levels. Complex carcinoma grade I, ductal carcinoma grade II, and anaplastic carcinoma grade II showed the highest relative TLR4 mRNA expression level. Although histopathological characteristics of tumors, including histologic type, grade, and inflammation, influenced TLRs mRNA expression level, such correlation was insignificant (P > 0.05).
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Affiliation(s)
- Elnaz Elahirad
- Department of Pathology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
| | | | - Alireza Khosravi
- Mycology Research Center, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Farhang Sasani
- Department of Pathology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
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Han J, Geng L, Lu C, Zhou J, Li Y, Ming T, Zhang Z, Su X. Analyzing the mechanism by which oyster peptides target IL-2 in melanoma cell apoptosis based on RNA-seq and m6A-seq. Food Funct 2023; 14:2362-2373. [PMID: 36779260 DOI: 10.1039/d2fo03672j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
Melanoma is a kind of skin cancer with high malignancy and strong proliferation and invasion abilities. Chemotherapy drugs in the clinic have the disadvantages of high price and high toxicity. Peptides are natural active ingredients that have many functions and are safe and effective. Previous studies have shown that oysters are rich in protein and have antitumor effects. In this study, a high-throughput strategy combined with MALDI TOF/TOF-MS and molecular docking was developed to screen peptides with antitumor functions from oyster hydrolysate. Three dominant peptides were predicted to have similar functions to IL-2 via molecular docking. Then, the activity of the peptides was confirmed in B16 cells, and we found that the three peptides increased the apoptosis of B16 cells. Furthermore, via RNA-seq and m6A-seq of B16 cells treated with the peptides, we found that ILADSAPR downregulates the expression of Pcna, Tlr4, and Ncbp2 and upregulates the expression of Bax, Bad, Pak4, Rasa2, Cct6, and Gbp2. ILADSAPR inhibited B16 cell proliferation and promoted cell apoptosis by regulating the expression of these genes. In addition, the result of metabolic pathway analysis also proved this point. This study provides a preliminary reference for antitumor research on oyster peptides.
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Affiliation(s)
- Jiaojiao Han
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China. .,School of Marine Science, Ningbo University, Ningbo, China
| | - Lingxin Geng
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China. .,School of Marine Science, Ningbo University, Ningbo, China
| | - Chenyang Lu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China. .,School of Marine Science, Ningbo University, Ningbo, China
| | - Jun Zhou
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China. .,School of Marine Science, Ningbo University, Ningbo, China
| | - Ye Li
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China. .,School of Marine Science, Ningbo University, Ningbo, China
| | - Tinghong Ming
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China. .,School of Marine Science, Ningbo University, Ningbo, China
| | - Zhen Zhang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China. .,School of Marine Science, Ningbo University, Ningbo, China
| | - Xiurong Su
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, China. .,School of Marine Science, Ningbo University, Ningbo, China
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Ying J, Zhou H, Wang Z, You Q, Chen J, Lu H, Zhang J. Aspirin increases chemosensitivity of colorectal cancer cells and inhibits the expression of toll-like receptor 4. Cancer Cell Int 2023; 23:6. [PMID: 36647071 PMCID: PMC9843993 DOI: 10.1186/s12935-023-02847-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 01/02/2023] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Chemotherapy resistance is an important bottleneck affecting the efficacy of chemotherapy in colon cancer. Therefore, improving the chemotherapy sensitivity of colorectal cancer cells is of great significance for improving the prognosis of patients with colon cancer. METHODS CCK-8 assay was employed to examine the cell viability of colorectal cancer cell lines. Realtime-PCR and western blot were used to explore toll-like receptor 4 (TLR4) expression in colorectal cancer cell lines. The functions of TLR4 in the stemness of the colorectal cancer cell lines were analyzed by infecting cells with lentivirus containing TLR4 siRNA. RESULTS We found that aspirin could effectively enhance the chemosensitivity of CT26 and HCT116 colorectal cancer cell lines. Aspirin can also inhibit the stemness of colorectal cancer cell including inhibiting the number of clone formation and reducing the volume and number of cell spheres and inducing the down-regulation of stemness-related genes. Besides that, aspirin also lead to down-regulation of TLR4 expression in colorectal cancer cells. The TLR4 positive colorectal cancer cells demonstrated a higher chemotherapy resistance potential than TLR4 negative colorectal cancer cells. In addition, the stemness of TLR4 positive colorectal cancer cells is stronger than TLR4 negative colorectal cancer cells. CONCLUSION The results of our study indicate that aspirin increases chemosensitivity of colorectal cancer cells and inhibits the expression of toll-like receptor 4.
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Affiliation(s)
- Jun Ying
- grid.73113.370000 0004 0369 1660Division of Colorectal Surgery, Department of Surgery, Second Affiliated Hospital of Naval Medical University, 415 Fengyang Road, Shanghai, 200003 China
| | - Haiyang Zhou
- grid.73113.370000 0004 0369 1660Division of Colorectal Surgery, Department of Surgery, Second Affiliated Hospital of Naval Medical University, 415 Fengyang Road, Shanghai, 200003 China
| | - Zhiguo Wang
- grid.73113.370000 0004 0369 1660Division of Colorectal Surgery, Department of Surgery, Second Affiliated Hospital of Naval Medical University, 415 Fengyang Road, Shanghai, 200003 China
| | - Qing You
- grid.73113.370000 0004 0369 1660Department of Gastrointestinal Surgery, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Junnan Chen
- grid.73113.370000 0004 0369 1660Division of Colorectal Surgery, Department of Surgery, Second Affiliated Hospital of Naval Medical University, 415 Fengyang Road, Shanghai, 200003 China
| | - Hao Lu
- grid.73113.370000 0004 0369 1660Division of Colorectal Surgery, Department of Surgery, Second Affiliated Hospital of Naval Medical University, 415 Fengyang Road, Shanghai, 200003 China
| | - Jian Zhang
- grid.73113.370000 0004 0369 1660Division of Colorectal Surgery, Department of Surgery, Second Affiliated Hospital of Naval Medical University, 415 Fengyang Road, Shanghai, 200003 China
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Wang Q, Sun Z, Xia W, Sun L, Du Y, Zhang Y, Jia Z. Role of USP13 in physiology and diseases. Front Mol Biosci 2022; 9:977122. [PMID: 36188217 PMCID: PMC9515447 DOI: 10.3389/fmolb.2022.977122] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 08/23/2022] [Indexed: 11/13/2022] Open
Abstract
Ubiquitin specific protease (USP)-13 is a deubiquitinase that removes ubiquitin from substrates to prevent protein degradation by the proteasome. Currently, the roles of USP13 in physiology and pathology have been reported. In physiology, USP13 is highly associated with cell cycle regulation, DNA damage repair, myoblast differentiation, quality control of the endoplasmic reticulum, and autophagy. In pathology, it has been reported that USP13 is important in the pathogenesis of infection, inflammation, idiopathic pulmonary fibrosis (IPF), neurodegenerative diseases, and cancers. This mini-review summarizes the most recent advances in USP13 studies involving its pathophysiological roles in different conditions and provides new insights into the prevention and treatment of relevant diseases, as well as further research on USP13.
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Affiliation(s)
- Qian Wang
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Zhenzhen Sun
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Weiwei Xia
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Le Sun
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Yang Du
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Yue Zhang
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
- *Correspondence: Yue Zhang, ; Zhanjun Jia,
| | - Zhanjun Jia
- Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, China
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
- *Correspondence: Yue Zhang, ; Zhanjun Jia,
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Eroğlu Güneş C, Seçer Çelik F, Seçme M, Elmas L, Dodurga Y, Kurar E. Glycoside oleandrin downregulates toll-like receptor pathway genes and associated miRNAs in human melanoma cells. Gene X 2022; 843:146805. [PMID: 35964872 DOI: 10.1016/j.gene.2022.146805] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 07/29/2022] [Accepted: 08/06/2022] [Indexed: 12/01/2022] Open
Abstract
Melanoma accounts for the majority of skin cancer-related deaths. Nerium oleander is a plant known to be toxic and consumed due to the cardiac glycosides it contains. Oleandrin is a cardiac glycoside obtained from of N. oleander. Beside capable of inhibiting proliferation and metastasis of cancer cells, cardiac glycoside derivative compounds cause cardiovascular side effects. Because of cardiovascular toxicity of clinically used cardiac glycosides, it is necessary to investigate cardiac glycoside derivative compounds capable of inhibiting proliferation and metastasis of cancer cells. It is known that oleandrin has anticarcinogenic effects in other cancers. Previous studies have shown that toll-like receptors (TLRs) and their related microRNAs (miRNAs) are associated with cancer. Therefore, aim was to investigate the effect of oleandrin on genes and miRNAs associated with TLRs in A375 melanoma cells in this study. The effects of oleandrin on cell viability, cytokines, apoptosis were evaluated using XTT, ELISA and TUNEL analyses, respectively. The effect of oleandrin on expression of TLR genes and 5 associated miRNAs in A375 cells has been determined by qRT-PCR. In addition, the levels of MyD88, TLR2 and TLR4 proteins were analyzed by western blot method. ELISA indicated that oleandrin treatment (47 nM at 48 h) reduced the level of proinflammatory cytokine IFNG. TUNEL analysis showed that apoptosis rate was significantly increased in the oleandrin dose group. According to qRT-PCR results, there was a significant decrease in IRAK1, IRAK4, MyD88, TLR2-TLR7 and TRAF3 expressions in the oleandrin treated group compared to the control (untreated cell). Also, a significant decrease in TLR4 protein expression has been observed. In addition, oleandrin significantly downregulated the levels of hsa-miRNA-146a-5p and hsa-miRNA-21-5p. In conclusion, it has been observed that oleandrin has an effect on TLR pathway-related genes and miRNAs in melanoma cells. We show that TLRs pathways and hsa-miR-146a-5p and hsa-miR-21-5p can participate in the oleandrin molecular mechanism of action.
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Affiliation(s)
- Canan Eroğlu Güneş
- Department of Medical Biology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey.
| | - Fatma Seçer Çelik
- Department of Molecular Biology and Genetics, Konya Food and Agriculture University, Konya, Turkey
| | - Mücahit Seçme
- Department of Medical Biology, Faculty of Medicine, Ordu University, Ordu, Turkey
| | - Levent Elmas
- Department of Medical Biology, Faculty of Medicine, Bakırçay University, Izmir, Turkey
| | - Yavuz Dodurga
- Department of Medical Biology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - Ercan Kurar
- Department of Medical Biology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
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12
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Man SM, Jenkins BJ. Context-dependent functions of pattern recognition receptors in cancer. Nat Rev Cancer 2022; 22:397-413. [PMID: 35355007 DOI: 10.1038/s41568-022-00462-5] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/01/2022] [Indexed: 02/07/2023]
Abstract
The immune system plays a critical role in shaping all facets of cancer, from the early initiation stage through to metastatic disease and resistance to therapy. Our understanding of the importance of the adaptive arm of the immune system in antitumour immunity has led to the implementation of immunotherapy with immune checkpoint inhibitors in numerous cancers, albeit with differing efficacy. By contrast, the clinical utility of innate immunity in cancer has not been exploited, despite dysregulated innate immunity being a feature of at least one-third of all cancers associated with tumour-promoting chronic inflammation. The past two decades have seen innate immune pattern recognition receptors (PRRs) emerge as critical regulators of the immune response to microbial infection and host tissue damage. More recently, it has become apparent that in many cancer types, PRRs play a central role in modulating a vast array of tumour-inhibiting and tumour-promoting cellular responses both in immune cells within the tumour microenvironment and directly in cancer cells. Herein, we provide a comprehensive overview of the fast-evolving field of PRRs in cancer, and discuss the potential to target PRRs for drug development and biomarker discovery in a wide range of oncology settings.
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Affiliation(s)
- Si Ming Man
- Division of Immunity, Inflammation and Infection, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Brendan J Jenkins
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
- Department of Molecular and Translational Science, School of Clinical Sciences, Monash University, Clayton, VIC, Australia.
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13
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Kithsiri Wijeratne EM, Xu YM, Liu MX, Inacio MC, Brooks AD, Tewary P, Sayers TJ, Gunatilaka AAL. Ring A/B-Modified 17β-Hydroxywithanolide Analogues as Antiproliferative Agents for Prostate Cancer and Potentiators of Immunotherapy for Renal Carcinoma and Melanoma. JOURNAL OF NATURAL PRODUCTS 2021; 84:3029-3038. [PMID: 34851111 DOI: 10.1021/acs.jnatprod.1c00724] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Physachenolide C (1) is a 17β-hydroxywithanolide natural product with a unique anticancer potential, as it exhibits potent and selective in vitro antiproliferative activity against prostate cancer (PC) cells and promotes TRAIL-induced apoptosis of renal carcinoma (RC) and poly I:C-induced apoptosis of melanoma cells. To explore the effect of ring A/B modifications of physachenolide C (1) on these biological activities, 23 of its natural and semisynthetic analogues were evaluated. Analogues 4-23 were prepared by chemical transformations of a readily accessible compound, physachenolide D (2). Compound 1 and its analogues 2-23 were evaluated for their antiproliferative activity against PC (LNCaP and 22Rv1), RC (ACHN), and melanoma (M14 and SK-MEL-28) cell lines and normal human foreskin fibroblast (HFF) cells. Most of the active analogues had selective and potent activity in reducing cell number for PC cell lines, some showing selectivity for androgen-independent and enzalutamide-resistant 22Rv1 cells compared to androgen-dependent LNCaP cells. Analogues with IC50s below 5.0 μM against ACHN cells, when tested in the presence of TRAIL, showed a significantly increased ability to reduce cell number, and those analogues active against the M14 and SK-MEL-28 cell lines exhibited enhanced activity when combined with poly I:C. These data provide additional structure-activity relationship information for 17β-hydroxywithanolides and suggest that selective activities of some analogues may be exploited to develop natural products-based tumor-specific agents for cancer chemotherapy.
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Affiliation(s)
- E M Kithsiri Wijeratne
- Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona, 250 E. Valencia Road, Tucson, Arizona 85706, United States
| | - Ya-Ming Xu
- Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona, 250 E. Valencia Road, Tucson, Arizona 85706, United States
| | - Manping X Liu
- Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona, 250 E. Valencia Road, Tucson, Arizona 85706, United States
| | - Marielle C Inacio
- Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona, 250 E. Valencia Road, Tucson, Arizona 85706, United States
| | - Alan D Brooks
- Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, United States
- Cancer and Inflammation Program, National Cancer Institute-Frederick, Frederick, Maryland 21702, United States
| | - Poonam Tewary
- Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, United States
- Cancer and Inflammation Program, National Cancer Institute-Frederick, Frederick, Maryland 21702, United States
| | - Thomas J Sayers
- Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, United States
- Cancer and Inflammation Program, National Cancer Institute-Frederick, Frederick, Maryland 21702, United States
| | - A A Leslie Gunatilaka
- Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona, 250 E. Valencia Road, Tucson, Arizona 85706, United States
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Vanajothi R, Srikanth N, Vijayakumar R, Palanisamy M, Bhavaniramya S, Premkumar K. HPV-mediated Cervical Cancer: A Systematic review on Immunological Basis, Molecular Biology and Immune evasion mechanisms. Curr Drug Targets 2021; 23:782-801. [PMID: 34939539 DOI: 10.2174/1389450123666211221160632] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 07/26/2021] [Accepted: 07/28/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Human papillomavirus (HPV), one of the most frequently transmitted viruses globally, causing several malignancies including cervical cancer. AIM Owing to their unique pathogenicity HPV viruses can persist in the host organism for a longer duration than other virus types, to complete their lifecycle. During its association with the host, HPV causes various pathological conditions affecting the immune system by evading the host immune- mechanisms leading to the progression of various diseases, including cancer. METHOD To date, ~ 150 serotypes were identified, and certain high-risk HPV types are known to be associated with genital warts and cervical cancer. As of now, two prophylactic vaccines are in use for the treatment of HPV infection, however, no effective antiviral drug is available for HPV-associated disease/infections. Numerous clinical and laboratory studies are being investigated to formulate an effective and specific vaccine again HPV infections and associated diseases. RESULT As the immunological basis of HPV infection and associated disease progress persist indistinctly, deeper insights on immune evasion mechanism and molecular biology of disease would aid in developing an effective vaccine. CONCLUSION Thus this review focuses, aiming a systematic review on the immunological aspects of HPV-associated cervical cancer by uncovering immune evasion strategies adapted by HPV.
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Affiliation(s)
- Ramar Vanajothi
- Department of Biomedical Science, Bharathidasan University, Tiruchirappalli-620024. India
| | - Natarajan Srikanth
- Department of Integrative Biology, Vellore Institute of Technology, Vellore. India
| | - Rajendran Vijayakumar
- Department of Biology, College of Science in Zulfi, Majmaah University, Majmaah 11952. Saudi Arabia
| | - Manikandan Palanisamy
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah 11952. Saudi Arabia
| | - Sundaresan Bhavaniramya
- College of Food and Dairy Technology, Tamil Nadu Veterinary and Animal Sciences, University, Chennai-600052, Tamil Nadu. India
| | - Kumpati Premkumar
- Department of Biomedical Science, Bharathidasan University, Tiruchirappalli-620024. India
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15
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Brunty S, Clower L, Mitchell B, Fleshman T, Zgheib NB, Santanam N. Peritoneal Modulators of Endometriosis-Associated Ovarian Cancer. Front Oncol 2021; 11:793297. [PMID: 34900746 PMCID: PMC8655857 DOI: 10.3389/fonc.2021.793297] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 11/04/2021] [Indexed: 12/13/2022] Open
Abstract
Ovarian cancer is the 4th largest cause of cancer death in women. Approximately 10-15% of women of childbearing age suffer from endometriosis. Endometriosis is defined by the growth and presence of endometrial tissue (lesions) outside of the uterus. The women with endometriosis also have an increased presence of peritoneal fluid (PF) that comprises of inflammatory cells, growth factors, cytokines/chemokines, etc. Epidemiological studies have shown that >3% of women with endometriosis develop ovarian cancer (low-grade serous or endometrioid types). Our hypothesis is that the PF from women with endometriosis induces transformative changes in the ovarian cells, leading to ovarian cancer development. PF from women with and without endometriosis was collected after IRB approval and patient consent. IOSE (human normal ovarian epithelial cells) and TOV-21G cells (human ovarian clear cell carcinoma cell line) were treated with various volumes of PF (no endometriosis or endometriosis) for 48 or 96 h and proliferation measured. Expression levels of epigenetic regulators and FoxP3, an inflammatory tumor suppressor, were determined. A Human Cancer Inflammation and Immunity Crosstalk RT2 Profiler PCR array was used to measure changes in cancer related genes in treated cells. Results showed increased growth of TOV-21G cells treated with PF from women with endometriosis versus without endometriosis and compared to IOSE cells. Endo PF treatment induced EZH2, H3K27me3, and FoxP3. The RT2 PCR array of TOV-21G cells treated with endo PF showed upregulation of various inflammatory genes (TLRs, Myd88, etc.). These studies indicate that PF from women with endometriosis can both proliferate and transform ovarian cells and hence this microenvironment plays a major mechanistic role in the progression of endometriosis to ovarian cancer.
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Affiliation(s)
- Sarah Brunty
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Lauren Clower
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Brenda Mitchell
- Department of Obstetrics & Gynecology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Taylor Fleshman
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Nadim Bou Zgheib
- Department of Obstetrics & Gynecology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Nalini Santanam
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
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16
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Farooq M, Batool M, Kim MS, Choi S. Toll-Like Receptors as a Therapeutic Target in the Era of Immunotherapies. Front Cell Dev Biol 2021; 9:756315. [PMID: 34671606 PMCID: PMC8522911 DOI: 10.3389/fcell.2021.756315] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 09/13/2021] [Indexed: 12/29/2022] Open
Abstract
Toll-like receptors (TLRs) are the pattern recognition receptors, which are activated by foreign and host molecules in order to initiate the immune response. They play a crucial role in the regulation of innate immunity, and several studies have shown their importance in bacterial, viral, and fungal infections, autoimmune diseases, and cancers. The consensus view from an immunological perspective is that TLR agonists can serve either as a possible therapeutic agent or as a vaccine adjuvant toward cancers or infectious diseases and that TLR inhibitors may be a promising approach to the treatment of autoimmune diseases, some cancers, bacterial, and viral infections. These notions are based on the fact that TLR agonists stimulate the secretion of proinflammatory cytokines and in general, the development of proinflammatory responses. Some of the TLR-based inhibitory agents have shown to be efficacious in preclinical models and have now entered clinical trials. Therefore, TLRs seem to hold the potential to serve as a perfect target in the era of immunotherapies. We offer a perspective on TLR-based therapeutics that sheds light on their usefulness and on combination therapies. We also highlight various therapeutics that are in the discovery phase or in clinical trials.
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Affiliation(s)
- Mariya Farooq
- Department of Molecular Science and Technology, Ajou University, Suwon, South Korea
| | - Maria Batool
- Department of Molecular Science and Technology, Ajou University, Suwon, South Korea
- S&K Therapeutics, Suwon, South Korea
| | - Moon Suk Kim
- Department of Molecular Science and Technology, Ajou University, Suwon, South Korea
| | - Sangdun Choi
- Department of Molecular Science and Technology, Ajou University, Suwon, South Korea
- S&K Therapeutics, Suwon, South Korea
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17
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da Cruz LLP, de Souza PO, Dal Prá M, Falchetti M, de Abreu AM, Azambuja JH, Bertoni APS, Paz AHR, Araújo AB, Visioli F, Fazolo T, da Silva GG, Worm PV, Wink MR, Zanotto-Filho A, Braganhol E. TLR4 expression and functionality are downregulated in glioblastoma cells and in tumor-associated macrophages: A new mechanism of immune evasion? Biochim Biophys Acta Mol Basis Dis 2021; 1867:166155. [PMID: 33932524 DOI: 10.1016/j.bbadis.2021.166155] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 03/30/2021] [Accepted: 04/22/2021] [Indexed: 02/08/2023]
Abstract
Glioblastoma (GB) is the most common and aggressive form of primary brain tumor, in which the presence of an inflammatory environment, composed mainly by tumor-associated macrophages (TAMs), is related to its progression and development of chemoresistance. Toll-Like Receptors (TLRs) are key components of the innate immune system and their expression in both tumor and immune-associated cells may impact the cell communication in the tumor microenvironment (TME), further modeling cancer growth and response to therapy. Here, we investigated the participation of TLR4-mediated signaling as a mechanism of induced-immune escape in GB. Initially, bioinformatics analysis of public datasets revealed that TLR4 expression is lower in GB tumors when compared to astrocytomas (AST), and in a subset of TAMs. Further, we confirmed that TLR4 expression is downregulated in chemoresistant GB, as well as in macrophages co-cultured with GB cells. Additionally, TLR4 function is impaired in those cells even following stimulation with LPS, an agonist of TLR4. Finally, experiments performed in a cohort of clinical primary and metastatic brain tumors indicated that the immunostaining of TLR4 and CD45 are inversely proportional, and confirmed the low TLR4 expression in GBs. Interestingly, the cytoplasmic/nuclear pattern of TLR4 staining in cancer tissues suggests additional roles of this receptor in carcinogenesis. Overall, our data suggest the downregulation of TLR4 expression and activity as a strategy for GB-associated immune escape. Additional studies are necessary to better understand TLR4 signaling in TME in order to improve the benefits of immunotherapy based on TLR signaling.
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Affiliation(s)
- L L P da Cruz
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil
| | - P O de Souza
- Programa de Pós-Graduação em Biociências, UFCSPA, Porto Alegre, RS, Brazil
| | - M Dal Prá
- Programa de Pós-Graduação em Biociências, UFCSPA, Porto Alegre, RS, Brazil
| | - M Falchetti
- Programa de Pós-Graduação em Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil
| | - A M de Abreu
- Programa de Pós-Graduação em Biociências, UFCSPA, Porto Alegre, RS, Brazil
| | - J H Azambuja
- Programa de Pós-Graduação em Biociências, UFCSPA, Porto Alegre, RS, Brazil
| | - A P S Bertoni
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil
| | - A H R Paz
- Departamento de Morfologia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - A B Araújo
- Centro de Processamento Celular, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil
| | - F Visioli
- Faculdade de Odontologia, UFRGS, Porto Alegre, RS, Brazil
| | - T Fazolo
- Hospital Moinhos de Vento, Porto Alegre, RS, Brazil
| | - G G da Silva
- Hospital São José, Irmandade Santa Casa de Misericórdia de Porto Alegre (ISCMPA), Porto Alegre, RS, Brazil
| | - P V Worm
- Hospital São José, Irmandade Santa Casa de Misericórdia de Porto Alegre (ISCMPA), Porto Alegre, RS, Brazil; Departamento de Cirurgia, UFCSPA, Porto Alegre, RS, Brazil
| | - M R Wink
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Biociências, UFCSPA, Porto Alegre, RS, Brazil
| | - A Zanotto-Filho
- Programa de Pós-Graduação em Farmacologia, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil
| | - E Braganhol
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Biociências, UFCSPA, Porto Alegre, RS, Brazil; Instituto de Cardiologia do Rio Grande do Sul/Fundação Universitária do Instituto de Cardiologia (IC-FUC), Porto Alegre, RS, Brazil.
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18
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Shende P, Sharma P. Current Status and Emerging Trend of Nanoshuttle in Biological Applications. Curr Pharm Des 2021; 27:105-114. [PMID: 32660398 DOI: 10.2174/1381612826666200713170356] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 06/12/2020] [Indexed: 11/22/2022]
Abstract
Nanoshuttles are unique structures that resemble double-headed arrows or a nanorod with sharp tips for better penetration into the tumor cells, reduction of toxicity and minimization of off-targeting effect. These biologically- inspired multimetallic or bimetallic nano swimmers are capable of transporting cargoes from one end to another via self-propulsion in an efficient manner. Encapsulation with pH- and heat-sensitive polymers allows nanoshuttles to release cargos at the targeted site in a controlled fashion. This review article focuses on the methods of preparation and characterization of nanoshuttles with applications in the field of antineoplastic, antibacterial, erectile dysfunction, electrochemical biosensing, anticounterfeiting, on-demand and targeted delivery system for imaging as well as cell ablation therapy. Magnetic nanoshuttles exhibit modified optical properties for utilization in diagnostic imaging for sensitive and early diagnosis of diseases. Smart drug delivery is achieved when nanoshuttles are combined with nanomotors to exhibit distinctive, rapid and unidirectional movement in the bloodstream. Cost-effective synthesis of nanoshuttles will extend their applications in the commercial sectors by overcoming the limitations like scale-up and regulatory approval. In the near future, nanoshuttles will diversify in the fields of energy conversion, energy storage, 3D printing, stem cell fabrication and theranostics.
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Affiliation(s)
- Pravin Shende
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM'S NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai, India
| | - Pragya Sharma
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM'S NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai, India
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19
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Flis E, Barber G, Nulty C, Keogh B, McGuirk P, Anand A, O’Sullivan J, Quante M, Creagh EM. Identification of TLR2 Signalling Mechanisms Which Contribute to Barrett's and Oesophageal Adenocarcinoma Disease Progression. Cancers (Basel) 2021; 13:cancers13092065. [PMID: 33922955 PMCID: PMC8123271 DOI: 10.3390/cancers13092065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 04/14/2021] [Accepted: 04/22/2021] [Indexed: 11/30/2022] Open
Abstract
Simple Summary Oesophageal adenocarcinoma (EAC) is a common type of oesophageal cancer with a rapidly rising incidence. Risk factors such as reflux, smoking, obesity and Barrett’s oesophagus cause chronic irritation and inflammation in the oesophagus. A receptor that causes inflammation, called Toll-like receptor 2 (TLR2), is expressed at higher levels in oesophageal cells from patients with Barrett’s and EAC, compared to disease-free patients. This study aimed to identify mechanisms involved in TLR2-mediated inflammation in oesophageal cells; and to assess whether TLR2 represents a therapeutic target to limit EAC development. Findings reveal that TLR2 activation in Barrett’s organoids and oesophageal cancer cells amplifies inflammation and promotes cancer development by causing the secretion of several inflammatory factors, most notably the nuclear protein, HMGB1. We demonstrate that TLR2 neutralisation efficiently blocks the inflammatory effects of TLR2 in these systems, revealing the therapeutic potential of TLR2 targeting to limit oesophageal disease and cancer progression. Abstract Chronic inflammation plays an important role in the pathogenesis of oesophageal adenocarcinoma (EAC) and its only known precursor, Barrett’s oesophagus (BE). Recent studies have shown that oesophageal TLR2 levels increase from normal epithelium towards EAC. TLR2 signalling is therefore likely to be important during EAC development and progression, which requires an inflammatory microenvironment. Here, we show that, in response to TLR2 stimulation, BE organoids and early-stage EAC cells secrete pro-inflammatory cytokines and chemokines which recruit macrophages to the tumour site. Factors secreted from TLR2-stimulated EAC cells are shown to subsequently activate TLR2 on naïve macrophages, priming them for inflammasome activation and inducing their differentiation to an M2/TAM-like phenotype. We identify the endogenous TLR2 ligand, HMGB1, as the factor secreted from EAC cells responsible for the observed TLR2-mediated effects on macrophages. Our results indicate that HMGB1 signalling between EAC cells and macrophages creates an inflammatory tumour microenvironment to facilitate EAC progression. In addition to identifying HMGB1 as a potential target for early-stage EAC treatment, our data suggest that blocking TLR2 signalling represents a mechanism to limit HMGB1 release, inflammatory cell infiltration and inflammation during EAC progression.
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Affiliation(s)
- Ewelina Flis
- School of Biochemistry and Immunology, Trinity Biomedical Science Institute (TBSI), Trinity College Dublin, D02 R590 Dublin, Ireland; (E.F.); (G.B.); (C.N.); (B.K.); (P.M.)
| | - Gillian Barber
- School of Biochemistry and Immunology, Trinity Biomedical Science Institute (TBSI), Trinity College Dublin, D02 R590 Dublin, Ireland; (E.F.); (G.B.); (C.N.); (B.K.); (P.M.)
| | - Ciara Nulty
- School of Biochemistry and Immunology, Trinity Biomedical Science Institute (TBSI), Trinity College Dublin, D02 R590 Dublin, Ireland; (E.F.); (G.B.); (C.N.); (B.K.); (P.M.)
| | - Brian Keogh
- School of Biochemistry and Immunology, Trinity Biomedical Science Institute (TBSI), Trinity College Dublin, D02 R590 Dublin, Ireland; (E.F.); (G.B.); (C.N.); (B.K.); (P.M.)
| | - Peter McGuirk
- School of Biochemistry and Immunology, Trinity Biomedical Science Institute (TBSI), Trinity College Dublin, D02 R590 Dublin, Ireland; (E.F.); (G.B.); (C.N.); (B.K.); (P.M.)
| | - Akanksha Anand
- Department of Internal Medicine, Technical University of Munich, D-80333 Munich, Germany; (A.A.); (M.Q.)
| | - Jacintha O’Sullivan
- Department of Surgery, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St. James’s Hospital, D08 W9RT Dublin, Ireland;
| | - Michael Quante
- Department of Internal Medicine, Technical University of Munich, D-80333 Munich, Germany; (A.A.); (M.Q.)
| | - Emma M. Creagh
- School of Biochemistry and Immunology, Trinity Biomedical Science Institute (TBSI), Trinity College Dublin, D02 R590 Dublin, Ireland; (E.F.); (G.B.); (C.N.); (B.K.); (P.M.)
- Correspondence: ; Tel.: +353-1-8962539
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20
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Bates M, Spillane CD, Gallagher MF, McCann A, Martin C, Blackshields G, Keegan H, Gubbins L, Brooks R, Brooks D, Selemidis S, O’Toole S, O’Leary JJ. The role of the MAD2-TLR4-MyD88 axis in paclitaxel resistance in ovarian cancer. PLoS One 2020; 15:e0243715. [PMID: 33370338 PMCID: PMC7769460 DOI: 10.1371/journal.pone.0243715] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 11/25/2020] [Indexed: 01/29/2023] Open
Abstract
Despite the use of front-line anticancer drugs such as paclitaxel for ovarian cancer treatment, mortality rates have remained almost unchanged for the past three decades and the majority of patients will develop recurrent chemoresistant disease which remains largely untreatable. Overcoming chemoresistance or preventing its onset in the first instance remains one of the major challenges for ovarian cancer research. In this study, we demonstrate a key link between senescence and inflammation and how this complex network involving the biomarkers MAD2, TLR4 and MyD88 drives paclitaxel resistance in ovarian cancer. This was investigated using siRNA knockdown of MAD2, TLR4 and MyD88 in two ovarian cancer cell lines, A2780 and SKOV-3 cells and overexpression of MyD88 in A2780 cells. Interestingly, siRNA knockdown of MAD2 led to a significant increase in TLR4 gene expression, this was coupled with the development of a highly paclitaxel-resistant cell phenotype. Additionally, siRNA knockdown of MAD2 or TLR4 in the serous ovarian cell model OVCAR-3 resulted in a significant increase in TLR4 or MAD2 expression respectively. Microarray analysis of SKOV-3 cells following knockdown of TLR4 or MAD2 highlighted a number of significantly altered biological processes including EMT, complement, coagulation, proliferation and survival, ECM remodelling, olfactory receptor signalling, ErbB signalling, DNA packaging, Insulin-like growth factor signalling, ion transport and alteration of components of the cytoskeleton. Cross comparison of the microarray data sets identified 7 overlapping genes including MMP13, ACTBL2, AMTN, PLXDC2, LYZL1, CCBE1 and CKS2. These results demonstrate an important link between these biomarkers, which to our knowledge has never before been shown in ovarian cancer. In the future, we hope that triaging patients into alterative treatment groups based on the expression of these three biomarkers or therapeutic targeting of the mechanisms they are involved in will lead to improvements in patient outcome and prevent the development of chemoresistance.
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Affiliation(s)
- Mark Bates
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland
- Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland
- Trinity St James’s Cancer Institute, Dublin, Ireland
- Department of Obstetrics and Gynaecology, Trinity College Dublin, Dublin, Ireland
- * E-mail:
| | - Cathy D. Spillane
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland
- Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland
- Trinity St James’s Cancer Institute, Dublin, Ireland
| | - Michael F. Gallagher
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland
- Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland
- Trinity St James’s Cancer Institute, Dublin, Ireland
| | - Amanda McCann
- College of Health Sciences, University College Dublin, Belfield, Dublin, Ireland
| | - Cara Martin
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland
- Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland
- Trinity St James’s Cancer Institute, Dublin, Ireland
- Department of Pathology, Coombe Women & Infants University Hospital, Dublin, Ireland
| | - Gordon Blackshields
- Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland
- Trinity St James’s Cancer Institute, Dublin, Ireland
- Department of Pathology, Coombe Women & Infants University Hospital, Dublin, Ireland
| | - Helen Keegan
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland
- Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland
- Trinity St James’s Cancer Institute, Dublin, Ireland
- Department of Pathology, Coombe Women & Infants University Hospital, Dublin, Ireland
| | - Luke Gubbins
- College of Health Sciences, University College Dublin, Belfield, Dublin, Ireland
| | - Robert Brooks
- School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia
| | - Doug Brooks
- School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia
| | - Stavros Selemidis
- School of Health and Biomedical Sciences, Royal Melbourne Institute of Technology, Bundoora, Australia
| | - Sharon O’Toole
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland
- Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland
- Trinity St James’s Cancer Institute, Dublin, Ireland
- Department of Obstetrics and Gynaecology, Trinity College Dublin, Dublin, Ireland
| | - John J. O’Leary
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland
- Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland
- Trinity St James’s Cancer Institute, Dublin, Ireland
- Department of Pathology, Coombe Women & Infants University Hospital, Dublin, Ireland
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21
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Modulation of Immune Infiltration of Ovarian Cancer Tumor Microenvironment by Specific Subpopulations of Fibroblasts. Cancers (Basel) 2020; 12:cancers12113184. [PMID: 33138184 PMCID: PMC7692816 DOI: 10.3390/cancers12113184] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 10/20/2020] [Accepted: 10/24/2020] [Indexed: 12/15/2022] Open
Abstract
Tumor immune infiltration plays a key role in the progression of solid tumors, including ovarian cancer, and immunotherapies are rapidly emerging as effective treatment modalities. However, the role of cancer-associated fibroblasts (CAFs), a predominant stromal constituent, in determining the tumor-immune microenvironment and modulating efficacy of immunotherapies remains poorly understood. We have conducted an extensive bioinformatic analysis of our and other publicly available ovarian cancer datasets (GSE137237, GSE132289 and GSE71340), to determine the correlation of fibroblast subtypes within the tumor microenvironment (TME) with the characteristics of tumor-immune infiltration. We identified (1) four functional modules of CAFs in ovarian cancer that are associated with the TME and metastasis of ovarian cancer, (2) immune-suppressive function of the collagen 1,3,5-expressing CAFs in primary ovarian cancer and omental metastases, and (3) consistent positive correlations between the functional modules of CAFs with anti-immune response genes and negative correlation with pro-immune response genes. Our study identifies a specific fibroblast subtype, fibroblast functional module (FFM)2, in the ovarian cancer tumor microenvironment that can potentially modulate a tumor-promoting immune microenvironment, which may be detrimental toward the effectiveness of ovarian cancer immunotherapies.
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22
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Gao S, Chen T, Li L, Liu X, Liu Y, Zhao J, Lu Q, Zeng Z, Xu Q, Huang D, Tu K. Hypoxia-Inducible Ubiquitin Specific Peptidase 13 Contributes to Tumor Growth and Metastasis via Enhancing the Toll-Like Receptor 4/Myeloid Differentiation Primary Response Gene 88/Nuclear Factor-κB Pathway in Hepatocellular Carcinoma. Front Cell Dev Biol 2020; 8:587389. [PMID: 33195243 PMCID: PMC7604352 DOI: 10.3389/fcell.2020.587389] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 09/24/2020] [Indexed: 12/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. The activation of the toll-like receptor 4/myeloid differentiation primary response gene 88/nuclear factor-κB (TLR4/MyD88/NF-κB) pathway contributes to the development and progression of HCC. The ubiquitin-proteasome system regulates TLR4 expression. However, whether ubiquitin specific peptidase 13 (USP13) stabilizes TLR4 and facilitates HCC progression remains unclear. Here, quantitative real-time PCR (qRT-PCR) and immunohistochemistry analysis revealed that USP13 expression in HCC tissues was higher than in non-tumor liver tissues. Moreover, the elevated expression of USP13 was detected in HCC cells (SK-HEP-1, HepG2, Huh7, and Hep3B) compared to LO2 cells. Interestingly, the positive staining of USP13 was closely correlated with tumor size ≥ 5 cm and advanced tumor stage and conferred to significantly lower survival of HCC patients. Next, USP13 knockdown prominently reduced the proliferation, epithelial-mesenchymal transition (EMT), migration, and invasion of Hep3B and Huh7 cells, while USP13 overexpression enhanced these biological behaviors of HepG2 and LO2 cells. The silencing of USP13 significantly restrained the growth and lung metastasis of HCC cells in vivo. Mechanistically, the USP13 depletion markedly inhibited the TLR4/MyD88/NF-κB pathway in HCC cells. USP13 interacted with TLR4 and inhibited the ubiquitin-mediated degradation of TLR4. Significantly, TLR4 re-expression remarkably reversed the effects of USP13 knockdown on HCC cells. USP13 expression was markedly upregulated in HCC cells under hypoxia conditions. Notably, USP13 knockdown repressed hypoxia-induced activation of the TLR4/MyD88/NF-κB pathway in HCC cells. In conclusion, our study uncovered that hypoxia-induced USP13 facilitated HCC progression via enhancing TLR4 deubiquitination and subsequently activating the TLR4/MyD88/NF-κB pathway.
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Affiliation(s)
- Shan Gao
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), Hangzhou, China
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Tianxiang Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Lijie Li
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), Hangzhou, China
| | - Xin Liu
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), Hangzhou, China
| | - Yang Liu
- The Medical College of Qingdao University, Qingdao, China
| | - Junjun Zhao
- Graduate Department, Bengbu Medical College, Bengbu, China
| | - Qiliang Lu
- Graduate Department, Bengbu Medical College, Bengbu, China
| | - Zhi Zeng
- Graduate Department, Bengbu Medical College, Bengbu, China
| | - Qiuran Xu
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), Hangzhou, China
| | - Dongsheng Huang
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital (People’s Hospital of Hangzhou Medical College), Hangzhou, China
| | - Kangsheng Tu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
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23
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TAK-242 Attenuates Crush Injury Induced Acute Kidney Injury through Inhibiting TLR4/NF-κB Signaling Pathways in Rats. Prehosp Disaster Med 2020; 35:619-628. [PMID: 32967743 DOI: 10.1017/s1049023x20001132] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND To investigate if toll-like receptor (TLR) 4/nuclear factor-kappa B (NF-κB) signaling pathways mediated crush injury induced acute kidney injury (AKI) in rats, and if TAK-242 (a specific inhibitor of TLR4) attenuates the injury through inhibiting the signaling pathways. METHODS This study was divided into two parts: (1) Establish the crush injury model: 50 rats were randomly divided into control group and four crush injury groups (n = 10/group). Crush injury groups were given 3kg pressure for eight hours and were sacrificed at the time points of 0h, 6h, 12h, and 24h after relieving pressure. And (2) Select the most obvious injury group (12h group) for drug intervention group. Thirty rats were randomly divided into control group, 12h group, and 12h+TAK-242 group (n = 10/group). Two parts detection were as follows: pathological changes of kidney tissues were observed in Haematoxylin and Eosin (HE) staining. Serum creatinine, blood urea nitrogen (BUN), myoglobin (Mb), and blood potassium were examined by automatic biochemical analysis instrument. Interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunosorbent assay (ELISA). The TLR4 messenger ribonucleic acid (mRNA), TLR4, and P65 were detected by real-time polymerase chain reaction (PCR), western blot, immunohistochemistry staining. RESULTS Compared with the control group, kidney tissues were damaged in crush injury groups, and most obvious in the 12h group. The level of serum creatinine, BUN, Mb, blood potassium, IL-6, TNF-α, and TLR4mRNA were increased in the crush injury groups and significantly increased in the 12h group (P <.05). The TLR4 and P65 were significantly increased in the 12h group (P <.05). Compared with the 12h group, kidney tissue damage was significantly reduced in the TAK-242 group (P <.05). The level of serum creatinine, BUN, Mb, blood potassium, IL-6, TNF-α, TLR4mRNA, TLR4, and P65 in the TAK-242 group were significantly reduced (P <.05). CONCLUSION The present findings conclude that TLR4/NF-κB signaling pathways mediated crush injury induced AKI in rats, and TAK-242 attenuates the injury through inhibiting the signaling pathways.
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24
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Beilmann-Lehtonen I, Böckelman C, Mustonen H, Koskensalo S, Hagström J, Haglund C. The prognostic role of tissue TLR2 and TLR4 in colorectal cancer. Virchows Arch 2020; 477:705-715. [PMID: 32424768 PMCID: PMC7581516 DOI: 10.1007/s00428-020-02833-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 04/17/2020] [Accepted: 04/28/2020] [Indexed: 12/22/2022]
Abstract
Colorectal cancer (CRC), the second most common cancer globally, resulted in 881,000 deaths in 2018. Toll-like receptors (TLRs) are crucial to detecting pathogen invasion and inducing the host’s immune response. This study aimed to explore the prognostic value of TLR2 and TLR4 tumor expressions in colorectal cancer patients. We studied the immunohistochemical expressions of TLR2 and TLR4 using tissue microarray specimens from 825 patients undergoing surgery in the Department of Surgery, Helsinki University Hospital, between 1982 and 2002. We assessed the relationships between TLR2 and TLR4 expressions and clinicopathological variables and patient survival. We generated survival curves using the Kaplan-Meier method, determining significance with the log-rank test. Among patients with lymph node–positive disease and no distant metastases (Dukes C), a strong TLR2 immunoactivity associated with a better prognosis (p < 0.001). Among patients with local Dukes B disease, a strong TLR4 immunoactivity associated with a worse disease-specific survival (DSS; p = 0.017). In the multivariate survival analysis, moderate TLR4 immunoactivity compared with strong TLR4 immunoactivity (hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.49–0.89, p = 0.007) served as an independent prognostic factor. In the multivariate analysis for the Dukes subgroups, moderate TLR2 immunoactivity (HR 2.63, 95% CI 1.56–4.44, p < 0.001) compared with strong TLR2 immunoactivity served as an independent negative prognostic factor in the Dukes C subgroup. TLR2 and TLR4 might be new prognostic factors to indicate which CRC patients require adjuvant therapy and which could spare from an unnecessary follow-up, but further investigations are needed.
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Affiliation(s)
- Ines Beilmann-Lehtonen
- Department of Surgery, University of Helsinki and Helsinki University Hospital HUS, Haartmaninkatu 4, PO Box 440, FIN-00029, Helsinki, Finland.
| | - Camilla Böckelman
- Department of Surgery, University of Helsinki and Helsinki University Hospital HUS, Haartmaninkatu 4, PO Box 440, FIN-00029, Helsinki, Finland.,Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Harri Mustonen
- Department of Surgery, University of Helsinki and Helsinki University Hospital HUS, Haartmaninkatu 4, PO Box 440, FIN-00029, Helsinki, Finland
| | - Selja Koskensalo
- Department of Surgery, University of Helsinki and Helsinki University Hospital HUS, Haartmaninkatu 4, PO Box 440, FIN-00029, Helsinki, Finland
| | - Jaana Hagström
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Caj Haglund
- Department of Surgery, University of Helsinki and Helsinki University Hospital HUS, Haartmaninkatu 4, PO Box 440, FIN-00029, Helsinki, Finland.,Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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25
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Mohamed FEZA, Hammad S, Luong TV, Dewidar B, Al-Jehani R, Davies N, Dooley S, Jalan R. Expression of TLR-2 in hepatocellular carcinoma is associated with tumour proliferation, angiogenesis and Caspase-3 expression. Pathol Res Pract 2020; 216:152980. [PMID: 32703481 DOI: 10.1016/j.prp.2020.152980] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Revised: 03/25/2020] [Accepted: 04/13/2020] [Indexed: 02/07/2023]
Abstract
AIMS Unlike other Toll-like receptors (TLRs), the role of toll like receptor 2 (TLR-2) in the pathogenesis of chronic liver disease and hepatocellular carcinoma (HCC) is not well studied. We, therefore, set out to investigate the expression of TLR-2 in different chronic liver disease states along with other markers of cell death, cellular proliferation and tissue vascularisation METHODS AND RESULTS: Immunohistochemistry was performed on liver tissue microarrays comprising hepatitis, cirrhosis and HCC patient samples using antibodies against TLR-2, Ki-67, Caspase-3 and VEGF. This was done in order to characterise receptor expression and translocation, apoptosis, cell proliferation and vascularisation. Cytoplasmic TLR-2 expression was found to be weak in 5/8 normal liver cases, 10/19 hepatitis cases and 8/21 cirrhosis patients. Moderate to strong TLR-2 expression was observed in some cases of hepatitis and cirrhosis. Both, nuclear and cytoplasmic TLR-2 expression was present in HCC with weak intensity in 11/41 cases, and moderate to strong staining in 19/41 cases. Eleven HCC cases were TLR-2 negative. Surprisingly, both cytoplasmic and nuclear TLR-2 expression in HCC were found to significantly correlate with proliferative index (r = 0.24 and 0.37), Caspase-3 expression (r = 0.27 and 0.38) and vascularisation (r = 0.56 and 0.23). Further, nuclear TLR-2 localisation was predominant in HCC, whereas cytoplasmic expression was more prevalent in hepatitis and cirrhosis. Functionally, treatment of HUH7 HCC cells with a TLR-2 agonist induced the expression of cellular proliferation and vascularisation markers CD34 and VEGF. CONCLUSIONS Our results demonstrate a positive correlation between the expression of TLR-2 and other markers of proliferation and vascularisation in HCC which suggests a possible role for TLR-2 in HCC pathogenesis.
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Affiliation(s)
- Fatma El-Zahraa Ammar Mohamed
- Molecular Hepatology Section, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Pathology, Faculty of Medicine, Minia University, Minia, Egypt.
| | - Seddik Hammad
- Molecular Hepatology Section, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Forensic Medicine and Veterinary Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
| | - Tu Vinh Luong
- Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London, UK
| | - Bedair Dewidar
- Molecular Hepatology Section, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Rajai Al-Jehani
- Institute for Liver and Digestive Health, Royal Free London NHS Foundation Trust, London, UK
| | - Nathan Davies
- UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Steven Dooley
- Molecular Hepatology Section, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Rajiv Jalan
- UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
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26
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Li J, Alvero AB, Nuti S, Tedja R, Roberts CM, Pitruzzello M, Li Y, Xiao Q, Zhang S, Gan Y, Wu X, Mor G, Yin G. CBX7 binds the E-box to inhibit TWIST-1 function and inhibit tumorigenicity and metastatic potential. Oncogene 2020; 39:3965-3979. [PMID: 32205869 PMCID: PMC8343988 DOI: 10.1038/s41388-020-1269-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 03/05/2020] [Accepted: 03/11/2020] [Indexed: 12/16/2022]
Abstract
Deaths from ovarian cancer usually occur when patients succumb to overwhelmingly numerous and widespread micrometastasis. Whereas epithelial-mesenchymal transition is required for epithelial ovarian cancer cells to acquire metastatic potential, the cellular phenotype at secondary sites and the mechanisms required for the establishment of metastatic tumors are not fully determined. Using in vitro and in vivo models we show that secondary epithelial ovarian cancer cells (sEOC) do not fully reacquire the molecular signature of the primary epithelial ovarian cancer cells from which they are derived. Despite displaying an epithelial morphology, sEOC maintains a high expression of the mesenchymal effector, TWIST-1. TWIST-1 is however transcriptionally nonfunctional in these cells as it is precluded from binding its E-box by the PcG protein, CBX7. Deletion of CBX7 in sEOC was sufficient to reactivate TWIST-1-induced transcription, prompt mesenchymal transformation, and enhanced tumorigenicity in vivo. This regulation allows secondary tumors to achieve an epithelial morphology while conferring the advantage of prompt reversal to a mesenchymal phenotype upon perturbation of CBX7. We also describe a subclassification of ovarian tumors based on CBX7 and TWIST-1 expression, which predicts clinical outcomes and patient prognosis.
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Affiliation(s)
- Juanni Li
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China
| | - Ayesha B Alvero
- Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Sudhakar Nuti
- Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Roslyn Tedja
- Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Cai M Roberts
- Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Mary Pitruzzello
- Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Yimin Li
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China
| | - Qing Xiao
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China
| | - Sai Zhang
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China
| | - Yaqi Gan
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China
| | - Xiaoying Wu
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China
| | - Gil Mor
- Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, USA.
| | - Gang Yin
- Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China.
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27
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Moncrieffe MC, Bollschweiler D, Li B, Penczek PA, Hopkins L, Bryant CE, Klenerman D, Gay NJ. MyD88 Death-Domain Oligomerization Determines Myddosome Architecture: Implications for Toll-like Receptor Signaling. Structure 2020; 28:281-289.e3. [PMID: 31995744 PMCID: PMC7054835 DOI: 10.1016/j.str.2020.01.003] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 11/26/2019] [Accepted: 01/07/2020] [Indexed: 01/12/2023]
Abstract
Toll-like receptors (TLRs) are pivotal in triggering the innate immune response to pathogen infection. Ligand binding induces receptor dimerization which facilitates the recruitment of other post-receptor signal transducers into a complex signalosome, the Myddosome. Central to this process is Myeloid differentiation primary response 88 (MyD88), which is required by almost all TLRs, and signaling is thought to proceed via the stepwise, sequential assembly of individual components. Here, we show that the death domains of human MyD88 spontaneously and reversibly associate to form helical filaments in vitro. A 3.1-Å cryoelectron microscopy structure reveals that the architecture of the filament is identical to that of the 6:4 MyD88-IRAK4-IRAK2 hetero-oligomeric Myddosome. Additionally, the death domain of IRAK4 interacts with the filaments to reconstitute the non-stoichiometric 6:4 MyD88-IRAK4 complex. Together, these data suggest that intracellularly, the MyD88 scaffold may be pre-formed and poised for recruitment of IRAKs on receptor activation and TIR engagement.
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Affiliation(s)
| | | | - Bing Li
- Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK
| | - Pawel A Penczek
- Department of Biochemistry & Molecular Biology, The University of Texas, McGovern Medical School, Houston, TX 77030, USA
| | - Lee Hopkins
- Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK
| | - Clare E Bryant
- Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK
| | - David Klenerman
- Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK
| | - Nicholas J Gay
- Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK
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28
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Toll-Like Receptors Signaling in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1223:81-97. [PMID: 32030686 DOI: 10.1007/978-3-030-35582-1_5] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The involvement of inflammation in cancer progression is well-established. The immune system can play both tumor-promoting and -suppressive roles, and efforts to harness the immune system to help fight tumor growth are at the forefront of research. Of particular importance is the inflammatory profile at the site of the tumor, with respect to both the leukocyte population numbers, the phenotype of these cells, as well as the contribution of the tumor cells themselves. In this regard, the pro-inflammatory effects of pattern recognition receptor expression and activation in the tumor microenvironment have emerged as a relevant issue both for therapy and to understand tumor development.Pattern recognition receptors (PRRs) were originally recognized as components of immune cells, particularly innate immune cells, as detectors of pathogens. PRR signaling in immune cells activates them, inducing robust antimicrobial responses. In particular, toll-like receptors (TLRs) constitute a family of membrane-bound PRRs which can recognize pathogen-associated molecular patterns (PAMPs) carried by bacteria, virus, and fungi. In addition, PRRs can recognize products generated by stressed cells or damaged tissues, namely damage-associated molecular patterns or DAMPS. Taking into account the role of the immune system in fighting tumors together with the presence of immune cells in the microenvironment of different types of tumors, strategies to activate immune cells via PRR ligands have been envisioned as an anticancer therapeutic approach.In the last decades, it has been determined that PRRs are present and functional on nonimmune cells and that their activation in these cells contributes to the inflammation in the tumor microenvironment. Both tumor-promoting and antitumor effects have been observed when tumor cell PRRs are activated. This argues against nonspecific activation of PRR ligands in the tumor microenvironment as a therapeutic approach. Therefore, the use of PRR ligands for anticancer therapy might benefit from strategies that specifically deliver these ligands to immune cells, thus avoiding tumor cells in some settings. This review focuses on these aspects of TLR signaling in the tumor microenvironment.
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29
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Lupi LA, Delella FK, Cucielo MS, Romagnoli GG, Kaneno R, Nunes IDS, Domeniconi RF, Martinez M, Martinez FE, Fávaro WJ, Chuffa LGDA. P-MAPA and Interleukin-12 Reduce Cell Migration/Invasion and Attenuate the Toll-Like Receptor-Mediated Inflammatory Response in Ovarian Cancer SKOV-3 Cells: A Preliminary Study. Molecules 2019; 25:E5. [PMID: 31861351 PMCID: PMC6982916 DOI: 10.3390/molecules25010005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 11/28/2019] [Accepted: 12/09/2019] [Indexed: 12/29/2022] Open
Abstract
Immunotherapies have emerged as promising complementary treatments for ovarian cancer (OC), but its effective and direct role on OC cells is unclear. This study examined the combinatory effects of the protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride, known as P-MAPA, and the human recombinant interleukin-12 (hrIL-12) on cell migration/invasion, apoptosis, toll-like receptor (TLR)-mediated inflammation, and cytokine/chemokine profile in human OC cell line SKOV-3. P-MAPA and IL-12 showed cancer cell toxicity under low doses after 48 h. Although apoptosis/necrosis and the cell cycle were unchanged by the treatments, P-MAPA enhanced the sensitivity to paclitaxel (PTX) and P-MAPA associated with IL-12 significantly reduced the migratory potential and invasion capacity of SKOV-3 cells. P-MAPA therapy reduced TLR2 immunostaining and the myeloid differentiation factor 88 (MyD88), but not the TLR4 levels. Moreover, the combination of P-MAPA with IL-12 attenuated the levels of MyD88, interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-kB p65). The IL-12 levels were increased and P-MAPA stimulated the secretion of cytokines IL-3, IL-9, IL-10, and chemokines MDC/CCL22 and, regulated on activation, normal T cells expressed and secreted (RANTES)/CCL5. Conversely, combination therapy reduced the levels of IL-3, IL-9, IL-10, MDC/CCL22, and RANTES/CCL5. Collectively, P-MAPA and IL-12 reduce cell dynamics and effectively target the TLR-related downstream molecules, eliciting a protective effect against chemoresistance. P-MAPA also stimulates the secretion of anti-inflammatory molecules, possibly having an immune response in the OC microenvironment.
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Affiliation(s)
- Luiz Antonio Lupi
- Department of Anatomy, UNESP-São Paulo State University, Institute of Biosciences, Botucatu, 18618-689 São Paulo, Brazil; (L.A.L.); (M.S.C.); (R.F.D.); (F.E.M.)
| | - Flávia Karina Delella
- Department of Morphology, UNESP-São Paulo State University, Institute of Biosciences, Botucatu, 18618-689 São Paulo, Brazil;
| | - Maira Smaniotto Cucielo
- Department of Anatomy, UNESP-São Paulo State University, Institute of Biosciences, Botucatu, 18618-689 São Paulo, Brazil; (L.A.L.); (M.S.C.); (R.F.D.); (F.E.M.)
| | - Graziela Gorete Romagnoli
- Department of Microbiology and Immunology, UNESP-São Paulo State University, Institute of Biosciences, Botucatu, 18618-689 São Paulo, Brazil; (G.G.R.); (R.K.)
| | - Ramon Kaneno
- Department of Microbiology and Immunology, UNESP-São Paulo State University, Institute of Biosciences, Botucatu, 18618-689 São Paulo, Brazil; (G.G.R.); (R.K.)
| | | | - Raquel Fantin Domeniconi
- Department of Anatomy, UNESP-São Paulo State University, Institute of Biosciences, Botucatu, 18618-689 São Paulo, Brazil; (L.A.L.); (M.S.C.); (R.F.D.); (F.E.M.)
| | - Marcelo Martinez
- Department of Morphology and Pathology, Federal University of São Carlos, 13565-905 São Paulo, Brazil;
| | - Francisco Eduardo Martinez
- Department of Anatomy, UNESP-São Paulo State University, Institute of Biosciences, Botucatu, 18618-689 São Paulo, Brazil; (L.A.L.); (M.S.C.); (R.F.D.); (F.E.M.)
| | - Wagner José Fávaro
- Department of Structural and Functional Biology, UNICAMP-University of Campinas, Campinas, 13083-970 São Paulo, Brazil;
| | - Luiz Gustavo de Almeida Chuffa
- Department of Anatomy, UNESP-São Paulo State University, Institute of Biosciences, Botucatu, 18618-689 São Paulo, Brazil; (L.A.L.); (M.S.C.); (R.F.D.); (F.E.M.)
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30
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Rajagopalan D, Tirado-Magallanes R, Bhatia SS, Teo WS, Sian S, Hora S, Lee KK, Zhang Y, Jadhav SP, Wu Y, Gan YH, Karnani N, Benoukraf T, Jha S. TIP60 represses activation of endogenous retroviral elements. Nucleic Acids Res 2019; 46:9456-9470. [PMID: 30053221 PMCID: PMC6182167 DOI: 10.1093/nar/gky659] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2018] [Accepted: 07/11/2018] [Indexed: 01/09/2023] Open
Abstract
TIP60 is a lysine acetyltransferase and is known to be a haplo-insufficient tumor suppressor. TIP60 downregulation is an early event in tumorigenesis which has been observed in several cancer types including breast and colorectal cancers. However, the mechanism by which it regulates tumor progression is not well understood. In this study, we identified the role of TIP60 in the silencing of endogenous retroviral elements (ERVs). TIP60-mediated silencing of ERVs is dependent on BRD4. TIP60 and BRD4 positively regulate the expression of enzymes, SUV39H1 and SETDB1 and thereby, the global H3K9 trimethylation (H3K9me3) level. In colorectal cancer, we found that the loss of TIP60 de-represses retrotransposon elements genome-wide, which in turn activate the cellular response to pathogens, mediated by STING, culminating in an induction of Interferon Regulatory Factor 7 (IRF7) and associated inflammatory response. In summary, this study has identified a unique mechanism of ERV regulation in cancer cells mediated by TIP60 and BRD4 through regulation of histone H3 K9 trimethylation, and a new tumor suppressive role of TIP60 in vivo.
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Affiliation(s)
- Deepa Rajagopalan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | | | | | - Wen Shiun Teo
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599
| | - Stephanie Sian
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599
| | - Shainan Hora
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Kwok Kin Lee
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599
| | - Yanzhou Zhang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599
| | - Shweta Pradip Jadhav
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599
| | - Yonghui Wu
- Singapore Institute for Clinical Sciences, A* STAR, Singapore
| | - Yunn-Hwen Gan
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Neerja Karnani
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Singapore Institute for Clinical Sciences, A* STAR, Singapore
| | - Touati Benoukraf
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599
| | - Sudhakar Jha
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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31
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Zanini D, Manfredi LH, Pelinson LP, Pimentel VC, Cardoso AM, Carmo Araújo Gonçalves VD, Santos CBD, Gutierres JM, Morsch VM, Leal DBR, Schetinger MRC. ADA activity is decreased in lymphocytes from patients with advanced stage of lung cancer. Med Oncol 2019; 36:78. [PMID: 31375946 DOI: 10.1007/s12032-019-1301-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 07/23/2019] [Indexed: 01/23/2023]
Abstract
Cigarette smoking is directly associated with lung cancer. Non-small cell lung carcinoma (NSCLC) represents approximately 80% from all types of lung cancer. This latter is hard to diagnose and to treat due to the lack of symptoms in early stages of the disease. The aim of this study was to evaluate ADA activity and the expression of P2X7, A1, and A2A receptors and in lymphocytes. In addition, the profile of pro-inflammatory and anti-inflammatory cytokines serum levels of patients with lung cancer in advanced stage was evaluated. Patients (n = 13) previously treated for lung cancer at stage IV (UICC) with chemotherapy had their blood collected. Cancer patients showed a decrease in ADA activity and an increase in A1 receptor expression in lymphocytes when compared to the control group. Moreover, patients exhibited an increase in IL-6 and TNF-α, while IL-17 and INF-ϒ serum levels were lower in patients with lung cancer. The decreased ADA activity and the increase in A1 receptor expression may contribute to adenosine pro-tumor effects by increasing IL-6 and TNF-α and decreasing IL-17 and INF-γ serum levels. Our data show an indirect evidence that purinergic signaling may have a role in promoting a profile of cytokines levels that favors tumor progression.
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Affiliation(s)
- Daniela Zanini
- Medical School, Federal University of Fronteira Sul, Chapecó, Santa Catarina, Brazil. .,Molecular biochemistry and biology, Federal University of Santa Maria, Santa Maria, 97105-900, Rio Grande do Sul, Brazil.
| | | | - Luana Paula Pelinson
- Molecular biochemistry and biology, Federal University of Santa Maria, Santa Maria, 97105-900, Rio Grande do Sul, Brazil
| | - Victor Camera Pimentel
- Molecular biochemistry and biology, Federal University of Santa Maria, Santa Maria, 97105-900, Rio Grande do Sul, Brazil
| | - Andréia Machado Cardoso
- Medical School, Federal University of Fronteira Sul, Chapecó, Santa Catarina, Brazil.,Molecular biochemistry and biology, Federal University of Santa Maria, Santa Maria, 97105-900, Rio Grande do Sul, Brazil
| | | | - Cláudia Bertoncelli Dos Santos
- Molecular biochemistry and biology, Federal University of Santa Maria, Santa Maria, 97105-900, Rio Grande do Sul, Brazil
| | - Jessié Martins Gutierres
- Molecular biochemistry and biology, Federal University of Santa Maria, Santa Maria, 97105-900, Rio Grande do Sul, Brazil
| | - Vera Maria Morsch
- Molecular biochemistry and biology, Federal University of Santa Maria, Santa Maria, 97105-900, Rio Grande do Sul, Brazil
| | - Daniela Bitencourt Rosa Leal
- Molecular biochemistry and biology, Federal University of Santa Maria, Santa Maria, 97105-900, Rio Grande do Sul, Brazil
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32
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Zhu Y, Zhang H, Zhang G, Shi Y, Huang J. Co-expression of CD44/MyD88 is a poor prognostic factor in advanced epithelial ovarian cancer. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:91. [PMID: 31019941 DOI: 10.21037/atm.2019.01.28] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Background Cluster of differentiation 44 (CD44)/myeloid differentiation factor 88 (MyD88) is the molecular characterization of EOC stem cells. An important characteristic of CD44+/MyD88+ epithelial ovarian cancer (EOC) cells, which differentiate them from the CD44-/MyD88- EOC cells, is the presence of a functional TLR4-MyD88-NFkB pathway. The aim of our study is to investigate the clinical significance of CD44/MyD88 co-expression in EOC. Methods A total of 138 specimens of ovarian tissues was detected CD44 and MyD88 expression by immunocytochemistry, including EOC (N=108), borderline tumors (N=10), benign cysts (N=10) and normal ovarian tissue (N=10). The association of CD44/MyD88 co-expression with clinicopathological factors and outcomes was analyzed. Results The expression of CD44 was showed distinct difference in EOC (53 of 108, 49.1%), in borderline tumors (3 of 10, 30.0%), in benign cysts (2 of 10, 20.0%) and normal ovarian (2 of 10, 20.0%). A total of 41 (38.0%) cancers showed a combined expression of CD44/MyD88. The expression of CD44 and MyD88 had definitely correlativity (r=0.21, P=0.026). CD44/MyD88 co-expression was associated with tumor progression, metastasis, and recurrence in advanced EOC, and an independent prognostic factor for disease-free survival and overall survival. Conclusions CD44/MyD88 co-expression has been shown to contribute to EOC progression and outcome directly and has a promising as a therapeutic target in EOC.
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Affiliation(s)
- Yi Zhu
- Department of Gynaecologic Oncology, Sichuan Cancer Hospital & Institute, Cancer Hospital Affiliated to School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China.,Department of Ultrasound, Sichuan Cancer Hospital & Institute, Cancer Hospital Affiliated to School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China
| | - Hongtao Zhang
- Department of Obstetrics and Gynecology, Sichuan Jinxin Women and Children's Hospital, Chengdu 610000, China
| | - Guonan Zhang
- Department of Gynaecologic Oncology, Sichuan Cancer Hospital & Institute, Cancer Hospital Affiliated to School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China
| | - Yu Shi
- Department of Gynaecologic Oncology, Sichuan Cancer Hospital & Institute, Cancer Hospital Affiliated to School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China
| | - Jianming Huang
- Department of Gynaecologic Oncology, Sichuan Cancer Hospital & Institute, Cancer Hospital Affiliated to School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China.,Department of Biochemistry & Molecular Biology, Sichuan Cancer Hospital & Institute, Cancer Hospital Affiliated to School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China
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33
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Zhou S, Du R, Wang Z, Shen W, Gao R, Jiang S, Fang Y, Shi Y, Chang A, Liu L, Liu C, Li N, Xiang R. TLR4 increases the stemness and is highly expressed in relapsed human hepatocellular carcinoma. Cancer Med 2019; 8:2325-2337. [PMID: 30957973 PMCID: PMC6536932 DOI: 10.1002/cam4.2070] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2018] [Revised: 02/10/2019] [Accepted: 02/13/2019] [Indexed: 12/12/2022] Open
Abstract
Toll‐like receptor 4 (TLR4) plays an essential role in cancer progress. Here, we find that the expression of TLR4 in relapsed human hepatocellular carcinoma (HCC) clinical samples is higher than that in the non‐relapsed ones, which leads us to explore the role of TLR4 in cancer stemness. We reported that TLR4‐AKT signaling pathway was activated by lipopolysaccharides (LPS) in HCC cell lines to enhance the cancer stemness capacity, which was reflected by the increased percentage of CD133+CD49f+ population and side population, enhanced sphere formation, and the upregulation of stemness marker gene‐SOX2. Downregulation of SOX2 attenuated the enhanced HCC stemness induced by LPS, indicating SOX2 as a downstream mediator of LPS‐TLR4 signaling. The role of LPS‐TLR4 signaling in inducing HCC stemness was further confirmed by tumor xenograft experiment in vivo. Taken together, our findings provide a novel therapeutic target to prevent the recurrence of HCC.
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Affiliation(s)
- Shuang Zhou
- School of Medicine, Nankai University, Tianjin, China
| | - Renle Du
- School of Medicine, Nankai University, Tianjin, China
| | - Zhenglu Wang
- Biobank of Tianjin First Center Hospital, Tianjin, China
| | - Wenzhi Shen
- School of Medicine, Nankai University, Tianjin, China
| | - Ruifang Gao
- School of Medicine, Nankai University, Tianjin, China
| | - Shan Jiang
- School of Medicine, Nankai University, Tianjin, China
| | - Yan Fang
- School of Medicine, Nankai University, Tianjin, China
| | - Yuzhi Shi
- School of Medicine, Nankai University, Tianjin, China
| | - Antao Chang
- School of Medicine, Nankai University, Tianjin, China
| | - Lei Liu
- Biobank of Tianjin First Center Hospital, Tianjin, China
| | - Chenghu Liu
- School of Medicine, Nankai University, Tianjin, China
| | - Na Li
- School of Medicine, Nankai University, Tianjin, China.,Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Tianjin, China.,The 2011 Project Collaborative Innovation Center for Biological Therapy, Nankai University, Tianjin, China
| | - Rong Xiang
- School of Medicine, Nankai University, Tianjin, China.,Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Tianjin, China.,The 2011 Project Collaborative Innovation Center for Biological Therapy, Nankai University, Tianjin, China
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34
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Tan J, Sun T, Shen J, Zhu H, Gong Y, Zhu H, Wu G. FAM46C inhibits lipopolysaccharides-induced myocardial dysfunction via downregulating cellular adhesion molecules and inhibiting apoptosis. Life Sci 2019; 229:1-12. [PMID: 30910647 DOI: 10.1016/j.lfs.2019.03.048] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 03/19/2019] [Accepted: 03/20/2019] [Indexed: 10/27/2022]
Abstract
AIMS Sepsis is a syndrome of inflammatory response induced by infection. Cellular adhesion molecules may involve in sepsis-induced myocardial dysfunction (SIMD) which is a major predictor of morbidity and mortality of sepsis. Here we studied the role of FAM46C in AC16 cells and c57 mice with lipopolysaccharides (LPS) treatment. MAIN METHODS Real-time PCR and western blot were used to detect the expression level of relative genes and protein. Cell proliferation and apoptosis were evaluated. KEY FINDINGS Interestingly, negative correlation between Toll-like receptor 4 (TLR4) and FAM46C in sepsis was observed. The overexpression of FAM46C reduced the apoptosis induced by LPS in AC16 cells. Inhibition of apoptosis contributed by FAM46C was mediated by adhesion molecule via blocking p38 and ERK/MAPK signaling pathway. Moreover, overexpression of Fam46c and inhibition of TLR4 by TAK-242 could attenuate apoptosis induced by LPS in vivo. SIGNIFICANCE FAM46C played an important role in SIMD via inhibiting LPS-induced myocardial dysfunction by downregulating cellular adhesion molecules and inhibiting apoptosis. It was the first time to explore the role of FAM46C in SIMD in this study.
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Affiliation(s)
- Jiaying Tan
- Department of Critical Care Medicine, Huashan Hospital, Fudan University, No. 12 Middle Urumqi Road, Shanghai, PR China
| | - Tao Sun
- Department of Cardiology, Huashan Hospital, Fudan University, No. 12 Middle Urumqi Road, Shanghai, PR China
| | - Jun Shen
- Department of Critical Care Medicine, Huashan Hospital, Fudan University, No. 12 Middle Urumqi Road, Shanghai, PR China
| | - Huigeng Zhu
- Department of Critical Care Medicine, Huashan Hospital, Fudan University, No. 12 Middle Urumqi Road, Shanghai, PR China
| | - Ye Gong
- Department of Critical Care Medicine, Huashan Hospital, Fudan University, No. 12 Middle Urumqi Road, Shanghai, PR China
| | - Hechen Zhu
- Department of Critical Care Medicine, Huashan Hospital, Fudan University, No. 12 Middle Urumqi Road, Shanghai, PR China
| | - Gang Wu
- Department of Critical Care Medicine, Huashan Hospital, Fudan University, No. 12 Middle Urumqi Road, Shanghai, PR China.
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35
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Human Toll-Like Receptor 4 (hTLR4): Structural and functional dynamics in cancer. Int J Biol Macromol 2019; 122:425-451. [DOI: 10.1016/j.ijbiomac.2018.10.142] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 10/10/2018] [Accepted: 10/18/2018] [Indexed: 12/23/2022]
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36
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Long T, Liu Z, Zhou X, Yu S, Tian H, Bao Y. Identification of differentially expressed genes and enriched pathways in lung cancer using bioinformatics analysis. Mol Med Rep 2019; 19:2029-2040. [PMID: 30664219 PMCID: PMC6390056 DOI: 10.3892/mmr.2019.9878] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Accepted: 10/16/2018] [Indexed: 12/24/2022] Open
Abstract
Lung cancer is the leading cause of cancer‑associated mortality worldwide. The aim of the present study was to identify the differentially expressed genes (DEGs) and enriched pathways in lung cancer by bioinformatics analysis, and to provide potential targets for diagnosis and treatment. Valid microarray data of 31 pairs of lung cancer tissues and matched normal samples (GSE19804) were obtained from the Gene Expression Omnibus database. Significance analysis of the gene expression profile was used to identify DEGs between cancer tissues and normal tissues, and a total of 1,970 DEGs, which were significantly enriched in biological processes, were screened. Through the Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, 77 KEGG pathways associated with lung cancer were identified, among which the Toll‑like receptor pathway was observed to be important. Protein‑protein interaction network analysis extracted 1,770 nodes and 10,667 edges, and identified 10 genes with key roles in lung cancer with highest degrees, hub centrality and betweenness. Additionally, the module analysis of protein‑protein interactions revealed that 'chemokine signaling pathway', 'cell cycle' and 'pathways in cancer' had a close association with lung cancer. In conclusion, the identified DEGs, particularly the hub genes, strengthen the understanding of the development and progression of lung cancer, and certain genes (including advanced glycosylation end‑product specific receptor and epidermal growth factor receptor) may be used as candidate target molecules to diagnose, monitor and treat lung cancer.
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Affiliation(s)
- Tingting Long
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Zijing Liu
- Department of Clinical Medicine, Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Xing Zhou
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Shuang Yu
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Hui Tian
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Yixi Bao
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
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Gao C, Qiao T, Zhang B, Yuan S, Zhuang X, Luo Y. TLR9 signaling activation at different stages in colorectal cancer and NF-kappaB expression. Onco Targets Ther 2018; 11:5963-5971. [PMID: 30271180 PMCID: PMC6151094 DOI: 10.2147/ott.s174274] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background The relationship of inflammation and tumor is becoming more and more important in the study on the pathogenesis of colorectal cancer. The role of TLR9-mediated immune inflammation reaction in the process is not currently clear. The purpose of the study was to discuss the correlation of TLR9 signal activation with tumor progression by detecting the expression of TLR9 and its downstream molecule NF-kappaB in colorectal cancer tissues at different stages. Methods TLR9 expression in colorectal cancer tissues was detected by immunohistochemical streptavidin-perosidase method and Western blot. Results The result showed that the high expression of TLR9 was correlated with tumor poorly differentiation, invasion and liver metastasis, the abnomal increasing levels of CEA in blood. With the signal activation, the levels of TLR9 protein raised more in advanced colorectal cancer than in early colorectal cancer. Afterward, we found that the activation of specific expression of TLR9 signal was related to histologic origin. TLR9-C expression displayed in both advanced cancer and para-carcinoma tissues, and TLR9-R protein was predominat in partial sigmoid and rectal cancer tissues. With the differential expression of TLR9, the levels of its downstream molecule NF-kappaB protein increased in colon cancer tissues and decreased in rectal cancer tissues. Conclusion The results confirmed that TLR9 signaling activation participated in the clinical process of colorectal cancer and influenced NF-kappaB expression.
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Affiliation(s)
- Caixia Gao
- Department of Oncology, Jinshan Hospital of Fudan University, Shanghai, People's Republic of China,
| | - Tiankui Qiao
- Department of Oncology, Jinshan Hospital of Fudan University, Shanghai, People's Republic of China,
| | - Bin Zhang
- Department of Oncology, Jinshan Hospital of Fudan University, Shanghai, People's Republic of China,
| | - Sujuan Yuan
- Department of Oncology, Jinshan Hospital of Fudan University, Shanghai, People's Republic of China,
| | - Xibing Zhuang
- Department of Oncology, Jinshan Hospital of Fudan University, Shanghai, People's Republic of China,
| | - Youjun Luo
- Department of Oncology, Jinshan Hospital of Fudan University, Shanghai, People's Republic of China,
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38
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Choi CH, Kang TH, Song JS, Kim YS, Chung EJ, Ylaya K, Kim S, Koh SS, Chung JY, Kim JH, Hewitt SM. Elevated expression of pancreatic adenocarcinoma upregulated factor (PAUF) is associated with poor prognosis and chemoresistance in epithelial ovarian cancer. Sci Rep 2018; 8:12161. [PMID: 30111860 PMCID: PMC6093878 DOI: 10.1038/s41598-018-30582-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 07/23/2018] [Indexed: 12/11/2022] Open
Abstract
Pancreatic adenocarcinoma upregulated factor (PAUF) is a ligand of toll-like receptors (TLRs) and has been reported to be involved in pancreatic tumor development. However, the significance of PAUF expression in epithelial ovarian cancer remains unclear. We aimed to investigate the possible clinical significance of PAUF in epithelial ovarian cancer. We examined the link between PAUF and TLR4 in ovarian cancer cell lines. Recombinant PAUF induced cell activation and proliferation in ovarian cancer cell lines, whereas PAUF knockdown inhibited these properties. Subsequently, we assessed PAUF and TLR4 expression by immunohistochemistry on tissue microarray of 408 ovarian samples ranging from normal to metastatic. PAUF expression positively correlated with TLR4 expression. Overexpression of PAUF was associated with high-grade tumor (p = 0.014) and chemoresistant tumor (p = 0.017). Similarly, high expression of TLR4 correlated with advanced tumor stage (p = 0.002) and chemoresistant tumor (p = 0.001). Multivariate analysis indicated that PAUFhigh, TLR4high, and PAUFhigh/TLR4high expression are independent prognostic factor for progression-free survival, while TLR4high and PAUFhigh/TLR4high expression were independent prognostic factors for overall survival. Our results suggest that PAUF has a role in ovarian cancer progression and is a potential prognostic marker and novel chemotherapeutic target for ovarian cancer.
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Affiliation(s)
- Chel Hun Choi
- Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.,Departments of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea
| | - Tae Heung Kang
- Department of Immunology, College of Medicine, Konkuk University, Chungju, 27478, Republic of Korea
| | - Joon Seon Song
- Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.,Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
| | - Young Seob Kim
- Department of Immunology, College of Medicine, Konkuk University, Chungju, 27478, Republic of Korea
| | - Eun Joo Chung
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD, 20892, USA
| | - Kris Ylaya
- Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Seokho Kim
- Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea
| | - Sang Seok Koh
- Department of Biological Sciences, Dong-A University, Busan, 49315, Republic of Korea
| | - Joon-Yong Chung
- Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Jae-Hoon Kim
- Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, 06273, Republic of Korea.
| | - Stephen M Hewitt
- Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
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Alt EU, Barabadi Z, Pfnür A, Ochoa JE, Daneshimehr F, Lang LM, Lin D, Braun SE, Chandrasekar B, Izadpanah R. TRAF3IP2, a novel therapeutic target in glioblastoma multiforme. Oncotarget 2018; 9:29772-29788. [PMID: 30038719 PMCID: PMC6049871 DOI: 10.18632/oncotarget.25710] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 06/13/2018] [Indexed: 11/25/2022] Open
Abstract
Glioblastoma multiforme (glioblastoma) remains one of the deadliest cancers. Pro-inflammatory and pro-tumorigenic mediators present in tumor microenvironment (TME) facilitate communication between tumor cells and adjacent non-malignant cells, resulting in glioblastoma growth. Since a majority of these mediators are products of NF-κB- and/or AP-1-responsive genes, and as TRAF3 Interacting Protein 2 (TRAF3IP2) is an upstream regulator of both transcription factors, we hypothesized that targeting TRAF3IP2 blunts tumor growth by inhibiting NF-κB and pro-inflammatory/pro-tumorigenic mediators. Our in vitro data demonstrate that similar to primary glioblastoma tumor tissues, malignant glioblastoma cell lines (U87 and U118) express high levels of TRAF3IP2. Silencing TRAF3IP2 expression inhibits basal and inducible NF-κB activation, induction of pro-inflammatory mediators, clusters of genes involved in cell cycle progression and angiogenesis, and formation of spheroids. Additionally, silencing TRAF3IP2 significantly increases apoptosis. In vivo studies indicate TRAF3IP2-silenced U87 cells formed smaller tumors. Additionally, treating existing tumors formed by wild type U87 cells with lentiviral TRAF3IP2 shRNA markedly regresses their size. Analysis of residual tumors revealed reduced expression of pro-inflammatory/pro-tumorigenic/pro-angiogenic mediators and kinesins. In contrast, the expression of IL-10, an anti-inflammatory cytokine, was increased. Together, these novel data indicate that TRAF3IP2 is a master regulator of malignant signaling in glioblastoma, and its targeting modulates the TME and inhibits tumor growth by suppressing the expression of mediators involved in inflammation, angiogenesis, growth, and malignant transformation. Our data identify TRAF3IP2 as a potential therapeutic target in glioblastoma growth and dissemination.
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Affiliation(s)
- Eckhard U Alt
- Applied Stem Cell Laboratory, Medicine/Heart and Vascular Institute, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
| | - Zahra Barabadi
- Applied Stem Cell Laboratory, Medicine/Heart and Vascular Institute, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
| | - Andreas Pfnür
- Applied Stem Cell Laboratory, Medicine/Heart and Vascular Institute, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
| | - Joana E Ochoa
- Department of Surgery, Tulane University Health Science Center, New Orleans, Louisiana, USA
| | - Fatemeh Daneshimehr
- Applied Stem Cell Laboratory, Medicine/Heart and Vascular Institute, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
| | - Lea M Lang
- Applied Stem Cell Laboratory, Medicine/Heart and Vascular Institute, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
| | - Dong Lin
- Applied Stem Cell Laboratory, Medicine/Heart and Vascular Institute, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
| | - Stephen E Braun
- Division of Regenerative Medicine, Tulane National Primate Research Center, Covington, Louisiana, USA
| | - Bysani Chandrasekar
- Department of Medicine, University of Missouri School of Medicine and Harry S. Truman Veterans Memorial Hospital, Columbia, Missouri, USA
| | - Reza Izadpanah
- Applied Stem Cell Laboratory, Medicine/Heart and Vascular Institute, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.,Department of Surgery, Tulane University Health Science Center, New Orleans, Louisiana, USA
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Evaluation of the detection of Toll-like receptors (TLRs) in cancer development and progression in patients with colorectal cancer. PLoS One 2018; 13:e0197327. [PMID: 29883450 PMCID: PMC5993256 DOI: 10.1371/journal.pone.0197327] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Accepted: 04/29/2018] [Indexed: 12/22/2022] Open
Abstract
Background Toll-like receptors (TLRs) play essential role in innate and acquired immunity, are expressed in various cell types, and are associated with altered susceptibility to many diseases, and cancers. The aim of this study was to investigate TLR2 (-196 to-174del), TLR4 (Asp299Gly and Thr399Ile) and TLR9 (T1237C and T1486C) gene polymorphisms at risk of colorectal cancer (CRC) development and progression. Methods Peripheral blood was obtained from 397 patients with adjuvant (stage II/III, n = 202) and metastatic (n = 195) CRC. Moreover, blood samples from 50 healthy volunteers and 40 patients with adenomatous polyps were also included as control groups. DNA from patients and controls was analyzed using PCR and PCR-RFLP for genotyping functional polymorphism within TLR2, TLR4 and TLR9 genotypes. Results TLR2–196 to-174del/del genotype was detected in 76.6% of the patients and was significantly higher that the controls groups (p<0.001). TLR4 Asp299Gly, TLR4 Thr399Ile, TLR9 T1237C and T1486C homozygous genotypes were detected in 70.5%, 70.5%, 61.5% and 61.5% of the patients respectively, and were also significantly higher than that in the control groups (p<0.001). All polymorphisms detected were also significantly associated with the metastatic disease (p<0.001) leading to shorter overall survival (p<0.001); whereas, TLR4 Asp299Gly and Thr399Ile polymorphisms were significantly associated with KRAS mutations. Conclusions The detection of higher frequencies of the TLR2, TLR4 and/or TLR9 polymorphisms in CRC patients compared with the control groups highlight the role of these polymorphism in CRC development and cancer progression.
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Ou T, Lilly M, Jiang W. The Pathologic Role of Toll-Like Receptor 4 in Prostate Cancer. Front Immunol 2018; 9:1188. [PMID: 29928275 PMCID: PMC5998742 DOI: 10.3389/fimmu.2018.01188] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 05/14/2018] [Indexed: 01/01/2023] Open
Abstract
Toll-like receptor (TLR) 4 is expressed on normal and malignant prostate epithelial cells. The TLR4 and its downstream signaling pathways mediate innate immune responses in the host against invading pathogens. However, multiple lines of evidence shows that TLR4 expression is increased in prostate tissues from prostate cancer patients, and altered TLR4 signals may promote cancer development, as well as antitumor effects. In this review, we have summarized key features of the TLR4 signaling pathway and its associated immune responses and focused on the pathologic role of TLR4 in prostate carcinogenesis and tumor progression.
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Affiliation(s)
- Tongwen Ou
- Department of Urology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Michael Lilly
- Division of Hematology and Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC, United States
| | - Wei Jiang
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
- Division of Infectious Diseases, Department of Medicine, Medical University of South Carolina, Charleston, SC, United States
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Serpin Facilitates Tumor-Suppressive Cell Competition by Blocking Toll-Mediated Yki Activation in Drosophila. Curr Biol 2018; 28:1756-1767.e6. [DOI: 10.1016/j.cub.2018.04.022] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 03/06/2018] [Accepted: 04/05/2018] [Indexed: 11/23/2022]
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Sisti F, Wang S, Brandt SL, Glosson-Byers N, Mayo LD, Son YM, Sturgeon S, Filgueiras L, Jancar S, Wong H, Dela Cruz CS, Andrews N, Alves-Filho JC, Cunha FQ, Serezani CH. Nuclear PTEN enhances the maturation of a microRNA regulon to limit MyD88-dependent susceptibility to sepsis. Sci Signal 2018; 11:11/528/eaai9085. [PMID: 29717063 DOI: 10.1126/scisignal.aai9085] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Sepsis-induced organ damage is caused by systemic inflammatory response syndrome (SIRS), which results in substantial comorbidities. Therefore, it is of medical importance to identify molecular brakes that can be exploited to dampen inflammation and prevent the development of SIRS. We investigated the role of phosphatase and tensin homolog (PTEN) in suppressing SIRS, increasing microbial clearance, and preventing lung damage. Septic patients and mice with sepsis exhibited increased PTEN expression in leukocytes. Myeloid-specific Pten deletion in an animal model of sepsis increased bacterial loads and cytokine production, which depended on enhanced myeloid differentiation primary response gene 88 (MyD88) abundance and resulted in mortality. PTEN-mediated induction of the microRNAs (miRNAs) miR125b and miR203b reduced the abundance of MyD88. Loss- and gain-of-function assays demonstrated that PTEN induced miRNA production by associating with and facilitating the nuclear localization of Drosha-Dgcr8, part of the miRNA-processing complex. Reconstitution of PTEN-deficient mouse embryonic fibroblasts with a mutant form of PTEN that does not localize to the nucleus resulted in retention of Drosha-Dgcr8 in the cytoplasm and impaired production of mature miRNAs. Thus, we identified a regulatory pathway involving nuclear PTEN-mediated miRNA generation that limits the production of MyD88 and thereby limits sepsis-associated mortality.
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Affiliation(s)
- Flavia Sisti
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Soujuan Wang
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Stephanie L Brandt
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.,Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Nicole Glosson-Byers
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Lindsey D Mayo
- Herman B Wells Center for Pediatric Research, Departments of Pediatrics and Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Young Min Son
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Sarah Sturgeon
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Luciano Filgueiras
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.,Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil
| | - Sonia Jancar
- Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil
| | - Hector Wong
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA
| | - Charles S Dela Cruz
- Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Nathaniel Andrews
- Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Jose Carlos Alves-Filho
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, Brazil
| | - Fernando Q Cunha
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, Brazil
| | - C Henrique Serezani
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. .,Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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Kim KH, Park SH, Do KH, Kim J, Choi KU, Moon Y. NSAID-activated gene 1 mediates pro-inflammatory signaling activation and paclitaxel chemoresistance in type I human epithelial ovarian cancer stem-like cells. Oncotarget 2018; 7:72148-72166. [PMID: 27708225 PMCID: PMC5342151 DOI: 10.18632/oncotarget.12355] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 09/20/2016] [Indexed: 12/30/2022] Open
Abstract
Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy in developed countries. Chronic endogenous sterile pro-inflammatory responses are strongly linked to EOC progression and chemoresistance to anti-cancer therapeutics. In the present study, the activity of epithelial NF-κB, a key pro-inflammatory transcription factor, was enhanced with the progress of EOC. This result was mechanistically linked with an increased expression of NSAID-Activated Gene 1 (NAG-1) in MyD88-positive type I EOC stem-like cells, compared with that in MyD88-negative type II EOC cells. Elevated NAG-1 as a potent biomarker of poor prognosis in the ovarian cancer was positively associated with the levels of NF-κB activation, chemokines and stemness markers in type I EOC cells. In terms of signal transduction, NAG-1-activated SMAD-linked and non-canonical TGFβ-activated kinase 1 (TAK-1)-activated pathways contributed to NF-κB activation and the subsequent induction of some chemokines and cancer stemness markers. In addition to effects on NF-κB-dependent gene regulation, NAG-1 was involved in expression of EGF receptor and subsequent activation of EGF receptor-linked signaling. The present study also provided evidences for links between NAG-1-linked signaling and chemoresistance in ovarian cancer cells. NAG-1 and pro-inflammatory NF-κB were positively associated with resistance to paclitaxel in MyD88-positive type I EOC cells. Mechanistically, this chemoresistance occurred due to enhanced activation of the SMAD-4- and non-SMAD-TAK-1-linked pathways. All of the present data suggested NAG-1 protein as a crucial mediator of EOC progression and resistance to the standard first-line chemotherapy against EOC, particularly in MyD88-positive ovarian cancer stem-like cells.
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Affiliation(s)
- Ki-Hyung Kim
- Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan, South Korea.,Biomedical Research Institute and Pusan Cancer Center, Pusan National University Hospital, Busan, South Korea.,Department of Obstetrics and Gynecology, Pusan National University School of Medicine, Busan, South Korea
| | - Seong-Hwan Park
- Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan, South Korea.,Research Institute for Basic Sciences, Pusan National University, Busan, South Korea
| | - Kee Hun Do
- Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan, South Korea.,Research Institute for Basic Sciences, Pusan National University, Busan, South Korea
| | - Juil Kim
- Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan, South Korea.,Research Institute for Basic Sciences, Pusan National University, Busan, South Korea
| | - Kyung Un Choi
- Biomedical Research Institute and Pusan Cancer Center, Pusan National University Hospital, Busan, South Korea.,Department of Pathology, Pusan National University School of Medicine, Busan, South Korea
| | - Yuseok Moon
- Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan, South Korea.,Biomedical Research Institute and Pusan Cancer Center, Pusan National University Hospital, Busan, South Korea.,Research Institute for Basic Sciences, Pusan National University, Busan, South Korea
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Hsp90 Inhibition Reduces TLR5 Surface Expression and NF- κB Activation in Human Myeloid Leukemia THP-1 Cells. BIOMED RESEARCH INTERNATIONAL 2018; 2018:4319369. [PMID: 29651431 PMCID: PMC5832108 DOI: 10.1155/2018/4319369] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 01/07/2018] [Accepted: 01/17/2018] [Indexed: 01/19/2023]
Abstract
Tumors highly express active heat shock protein 90 (Hsp90), which is involved in tumor survival and progression. Enhanced Toll-like receptor (TLR) 5 expression and signaling were reported to be associated with acute myeloid leukemia. In the present study, we investigated the possible modulatory effects of Hsp90 inhibitors on TLR5 expression and signaling in the human myeloid leukemia cell line THP-1. Cells were pretreated with various concentrations of the Hsp90 inhibitor geldanamycin (GA) or the Hsp70 inhibitor VER155008, followed by stimulation with bacterial flagellin. Flagellin-induced nuclear factor-κB (NF-κB) activation was significantly reduced by treatment with GA or VER155008. To elucidate the underlying mechanism of this effect, mRNA and cell surface expression of TLR5 was examined. TLR5 mRNA expression was enhanced by both GA and VER155008, whereas cell surface expression of TLR5 was reduced by three different Hsp90 inhibitors, including GA, 17-(allylamino)-17-demethoxygeldanamycin, and radicicol, and an Hsp70 inhibitor. The inhibitory effect of Hsp90 inhibitors was much higher than that of Hsp70 inhibitor. Our results suggest that Hsp90 inhibitors suppress TLR5 surface expression and activation of NF-κB in THP-1 cells in response to TLR5 ligand, and these inhibitory effects may be associated with the possible mechanisms by which Hsp90 inhibitors suppress myeloid leukemia.
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de Almeida Chuffa LG, de Moura Ferreira G, Lupi LA, da Silva Nunes I, Fávaro WJ. P-MAPA immunotherapy potentiates the effect of cisplatin on serous ovarian carcinoma through targeting TLR4 signaling. J Ovarian Res 2018; 11:8. [PMID: 29343281 PMCID: PMC5773141 DOI: 10.1186/s13048-018-0380-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Accepted: 01/11/2018] [Indexed: 01/16/2023] Open
Abstract
Background Toll-like receptors (TLRs) are transmembrane proteins expressed on the surface of ovarian cancer (OC) and immune cells. Identifying the specific roles of the TLR-mediated signaling pathways in OC cells is important to guide new treatments. Because immunotherapies have emerged as the adjuvant treatment for patients with OC, we investigated the effect of a promising immunotherapeutic strategy based on protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride (P-MAPA) combined with cisplatin (CIS) on the TLR2 and TLR4 signaling pathways via myeloid differentiation factor 88 (MyD88) and TLR-associated activator of interferon (TRIF) in an in vivo model of OC. Methods Tumors were chemically induced by a single injection of 100 μg of 7,12-dimethylbenz(a)anthracene (DMBA) directly under the left ovarian bursa in Fischer 344 rats. After the rats developed serous papillary OC, they were given P-MAPA, CIS or the combination P-MAPA+CIS as therapies. To understand the effects of the treatments, we assessed the tumor size, histopathology, and the TLR2- and TLR4-mediated inflammatory responses. Results Although CIS therapy was more effective than P-MAPA in reducing the tumor size, P-MAPA immunotherapy significantly increased the expressions of TLR2 and TLR4. More importantly, the combination of P-MAPA with CIS showed a greater survival rate compared to CIS alone, and exhibited a significant reduction in tumor volume compared to P-MAPA alone. The combination therapy also promoted the increase in the levels of the following OC-related proteins: TLR4, MyD88, TRIF, inhibitor of phosphorylated NF-kB alpha (p-IkBα), and nuclear factor kappa B (NF-kB p65) in both cytoplasmic and nuclear sites. While P-MAPA had no apparent effect on tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6, it seems to increase interferon-γ (IFN-γ), which may induce the Thelper (Th1)-mediated immune response. Conclusion Collectively, our results suggest that P-MAPA immunotherapy combined with cisplatin could be considered an important therapeutic strategy against OC cells based on signaling pathways activated by TLR4.
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Affiliation(s)
- Luiz Gustavo de Almeida Chuffa
- Department of Anatomy, São Paulo State University (Unesp), Institute of Biosciences, Rubião Júnior, s/n, P.O Box: 18618-970, Botucatu, SP, 510, Brazil.
| | - Grazielle de Moura Ferreira
- Department of Anatomy, São Paulo State University (Unesp), Institute of Biosciences, Rubião Júnior, s/n, P.O Box: 18618-970, Botucatu, SP, 510, Brazil
| | - Luiz Antonio Lupi
- Department of Anatomy, São Paulo State University (Unesp), Institute of Biosciences, Rubião Júnior, s/n, P.O Box: 18618-970, Botucatu, SP, 510, Brazil
| | | | - Wagner José Fávaro
- Farmabrasilis R&D Division, Campinas, SP, Brazil.,Department of Structural and Functional Biology, Laboratory of Urogenital Carcinogenesis and Immunotherapy, UNICAMP - University of Campinas, Campinas, SP, Brazil
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Mirra P, Nigro C, Prevenzano I, Leone A, Raciti GA, Formisano P, Beguinot F, Miele C. The Destiny of Glucose from a MicroRNA Perspective. Front Endocrinol (Lausanne) 2018; 9:46. [PMID: 29535681 PMCID: PMC5834423 DOI: 10.3389/fendo.2018.00046] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Glucose serves as a primary, and for some tissues the unique, fuel source in order to generate and maintain the biological functions. Hyperglycemia is a hallmark of type 2 diabetes and is the direct consequence of perturbations in the glucose homeostasis. Insulin resistance, referred to as a reduced response of target tissues to the hormone, contributes to the development of hyperglycemia. The molecular mechanisms responsible for the altered glucose homeostasis are numerous and not completely understood. MicroRNAs (miRNAs) are now recognized as regulators of the lipid and glucose metabolism and are involved in the onset of metabolic diseases. Indeed, these small non-coding RNA molecules operate in the RNA silencing and posttranscriptional regulation of gene expression and may modulate the levels of kinases and enzymes in the glucose metabolism. Therefore, a better characterization of the function of miRNAs and a deeper understanding of their role in disease may represent a fundamental step toward innovative treatments addressing the causes, not only the symptoms, of hyperglycemia, using approaches aimed at restoring either miRNAs or their specific targets. In this review, we outline the current understanding regarding the impact of miRNAs in the glucose metabolism and highlight the need for further research focused on altered key kinases and enzymes in metabolic diseases.
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Affiliation(s)
- Paola Mirra
- Istituto per l’Endocrinologia e l’Oncologia Sperimentale “Gaetano Salvatore” - CNR, Naples, Italy
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Cecilia Nigro
- Istituto per l’Endocrinologia e l’Oncologia Sperimentale “Gaetano Salvatore” - CNR, Naples, Italy
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Immacolata Prevenzano
- Istituto per l’Endocrinologia e l’Oncologia Sperimentale “Gaetano Salvatore” - CNR, Naples, Italy
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Alessia Leone
- Istituto per l’Endocrinologia e l’Oncologia Sperimentale “Gaetano Salvatore” - CNR, Naples, Italy
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Gregory Alexander Raciti
- Istituto per l’Endocrinologia e l’Oncologia Sperimentale “Gaetano Salvatore” - CNR, Naples, Italy
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Pietro Formisano
- Istituto per l’Endocrinologia e l’Oncologia Sperimentale “Gaetano Salvatore” - CNR, Naples, Italy
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Francesco Beguinot
- Istituto per l’Endocrinologia e l’Oncologia Sperimentale “Gaetano Salvatore” - CNR, Naples, Italy
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Claudia Miele
- Istituto per l’Endocrinologia e l’Oncologia Sperimentale “Gaetano Salvatore” - CNR, Naples, Italy
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
- *Correspondence: Claudia Miele,
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Jin Y, Hong Y, Park CY, Hong Y. Molecular Interactions of Autophagy with the Immune System and Cancer. Int J Mol Sci 2017; 18:ijms18081694. [PMID: 28771183 PMCID: PMC5578084 DOI: 10.3390/ijms18081694] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Revised: 07/28/2017] [Accepted: 07/29/2017] [Indexed: 12/19/2022] Open
Abstract
Autophagy is a highly conserved catabolic mechanism that mediates the degradation of damaged cellular components by inducing their fusion with lysosomes. This process provides cells with an alternative source of energy for the synthesis of new proteins and the maintenance of metabolic homeostasis in stressful environments. Autophagy protects against cancer by mediating both innate and adaptive immune responses. Innate immune receptors and lymphocytes (T and B) are modulated by autophagy, which represent innate and adaptive immune responses, respectively. Numerous studies have demonstrated beneficial roles for autophagy induction as well as its suppression of cancer cells. Autophagy may induce either survival or death depending on the cell/tissue type. Radiation therapy is commonly used to treat cancer by inducing autophagy in human cancer cell lines. Additionally, melatonin appears to affect cancer cell death by regulating programmed cell death. In this review, we summarize the current understanding of autophagy and its regulation in cancer.
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Affiliation(s)
- Yunho Jin
- Department of Rehabilitation Science, Graduate School of Inje University, Gimhae 50834, Korea.
- Ubiquitous Healthcare & Anti-Aging Research Center (u-HARC), Inje University, Gimhae 50834, Korea.
- Biohealth Products Research Center (BPRC), Inje University, Gimhae 50834, Korea.
| | - Yunkyung Hong
- Ubiquitous Healthcare & Anti-Aging Research Center (u-HARC), Inje University, Gimhae 50834, Korea.
- Biohealth Products Research Center (BPRC), Inje University, Gimhae 50834, Korea.
- Department of Physical Therapy, College of Biomedical Science & Engineering, Inje University, Gimhae 50834, Korea.
| | - Chan Young Park
- Department of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Korea.
| | - Yonggeun Hong
- Department of Rehabilitation Science, Graduate School of Inje University, Gimhae 50834, Korea.
- Ubiquitous Healthcare & Anti-Aging Research Center (u-HARC), Inje University, Gimhae 50834, Korea.
- Biohealth Products Research Center (BPRC), Inje University, Gimhae 50834, Korea.
- Department of Physical Therapy, College of Biomedical Science & Engineering, Inje University, Gimhae 50834, Korea.
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Langevin S, Kuhnell D, Parry T, Biesiada J, Huang S, Wise-Draper T, Casper K, Zhang X, Medvedovic M, Kasper S. Comprehensive microRNA-sequencing of exosomes derived from head and neck carcinoma cells in vitro reveals common secretion profiles and potential utility as salivary biomarkers. Oncotarget 2017; 8:82459-82474. [PMID: 29137278 PMCID: PMC5669904 DOI: 10.18632/oncotarget.19614] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Accepted: 06/29/2017] [Indexed: 12/21/2022] Open
Abstract
Exosomes are nano-scale, membrane encapsulated vesicles that are released by cells into the extracellular space and function as intercellular signaling vectors through horizontal transfer of biologic molecules, including microRNA (miRNA). There is evidence that cancer-derived exosomes enable the tumor to manipulate its microenvironment, thus contributing to the capacity of the tumor for immune evasion, growth, invasion, and metastatic spread. The objective of this study was to characterize differential secretion of exosomal miRNA by head and neck squamous cell carcinoma (HNSCC) and identify a set of candidate biomarkers that could be detected in non-invasive saliva samples. We isolated exosomes from conditioned media from 4 HNSCC cell lines and oral epithelial control cells and applied miRNA-sequencing to comprehensively characterize their miRNA cargo and compare transcript levels of each HNSCC cell line to that of oral epithelial control cells. A candidate set of miRNA differentially secreted by all 4 HNSCC cell lines was further evaluated in saliva collected from HNSCC patients and healthy controls. We observed extensive differences in exosomal miRNA content between HNSCC cells when compared to normal oral epithelial control cells, with a high degree of overlap in exosomal miRNA profiles between the 4 distinct HNSCC cell lines. Importantly, several of the exosomal miRNA secreted solely by cancer cells in culture were detected at substantially elevated levels in saliva from HNSCC patients relative to saliva from healthy controls. These findings provide important insight into tumor biology and yields a promising set of candidate HNSCC biomarkers for use with non-invasive saliva samples.
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Affiliation(s)
- Scott Langevin
- Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Damaris Kuhnell
- Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Tess Parry
- Physical and Computational Sciences Department, Bethany College, Bethany, WV, USA
| | - Jacek Biesiada
- Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Shouxiong Huang
- Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Trisha Wise-Draper
- Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Keith Casper
- Department of Otolaryngology, University of Michigan, Ann Arbor, MI, USA
| | - Xiang Zhang
- Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Mario Medvedovic
- Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Susan Kasper
- Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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Di Franco S, Turdo A, Todaro M, Stassi G. Role of Type I and II Interferons in Colorectal Cancer and Melanoma. Front Immunol 2017; 8:878. [PMID: 28798748 PMCID: PMC5526853 DOI: 10.3389/fimmu.2017.00878] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 07/10/2017] [Indexed: 12/12/2022] Open
Abstract
Cancer can be considered an aberrant organ with a hierarchical composition of different cell populations. The tumor microenvironment, including the immune cells and related cytokines, is crucial during all the steps of tumor development. In particular, type I and II interferons (IFNs) are involved in a plethora of mechanisms that regulate immune responses in cancer, thus balancing immune escape versus immune surveillance. IFNs are involved in both the direct and indirect regulation of cancer cell proliferation and metastatic potential. The mutational background of genes involved in IFNs signaling could serve as a prognostic biomarker and a powerful tool to screen cancer patients eligible for checkpoint blocking therapies. We herewith describe the latest findings regarding the contribution of IFNs in colorectal cancer and melanoma by researching their dual role as either tumor promoter or suppressor, in diverse tumor types, and microenvironmental context. We are reporting the most innovative and promising approaches of IFN-based therapies that have achieved considerable outcomes in clinical oncology practice and explain the possible mechanisms responsible for their failure.
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Affiliation(s)
- Simone Di Franco
- Cellular and Molecular Pathophysiology Laboratory, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy
| | - Alice Turdo
- Cellular and Molecular Pathophysiology Laboratory, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy
| | - Matilde Todaro
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, Palermo, Italy.,DiBiMIS, University of Palermo, Palermo, Italy
| | - Giorgio Stassi
- Cellular and Molecular Pathophysiology Laboratory, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy
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