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Gdowicz-Kłosok A, Krześniak M, Łasut-Szyszka B, Butkiewicz D, Rusin M. Antibacterial Activity of the p53 Tumor Suppressor Protein-How Strong Is the Evidence? Int J Mol Sci 2025; 26:4416. [PMID: 40362653 DOI: 10.3390/ijms26094416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 04/28/2025] [Accepted: 05/02/2025] [Indexed: 05/15/2025] Open
Abstract
The p53 tumor suppressor is best known for controlling the cell cycle, apoptosis, DNA repair, and metabolism, but it also regulates immunity and is able to impede the live cycle of viruses. For this reason, these infectious agents encode proteins which inactivate p53. However, what is less known is that p53 can also be inactivated by human pathogenic bacteria. It is probably not due to collateral damage, but specific targeting, because p53 could interfere with their multiplication. The mechanisms of the antibacterial activity of p53 are poorly known. However, they can be inferred from the results of high-throughput studies, which have identified more than a thousand p53-activated genes. As it turns out, many of these genes code proteins which have proven or plausible antibacterial functions like the efficient detection of bacteria by pattern recognition receptors, the induction of pro-inflammatory pyroptosis, the recruitment of immune cells, direct bactericidal activity, and the presentation of bacterial metabolites to lymphocytes. Probably there are more antibacterial, p53-regulated functions which were overlooked because laboratory animals are kept in sterile conditions. In this review, we present the outlines of some intriguing antibacterial mechanisms of p53 which await further exploration. Definitely, this area of research deserves more attention, especially in light of the appearance of antibiotic-resistant bacterial strains.
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Affiliation(s)
- Agnieszka Gdowicz-Kłosok
- Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-101 Gliwice, Poland
| | - Małgorzata Krześniak
- Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-101 Gliwice, Poland
| | - Barbara Łasut-Szyszka
- Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-101 Gliwice, Poland
| | - Dorota Butkiewicz
- Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-101 Gliwice, Poland
| | - Marek Rusin
- Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-101 Gliwice, Poland
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Vimonish R, Capelli-Peixoto J, Johnson W, Kappmeyer L, Saelao P, Taus N, Chung C, Ueti M. Transcriptomic analysis of Rhipicephalus microplus hemocytes from female ticks infected with Babesia bovis or Babesia bigemina. Parasit Vectors 2025; 18:37. [PMID: 39901199 PMCID: PMC11789329 DOI: 10.1186/s13071-025-06662-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Accepted: 01/07/2025] [Indexed: 02/05/2025] Open
Abstract
BACKGROUND Tick hemolymph is a sterile fluid that carries nutrients to maintain tick health. The hemolymph creates a hostile environment for invaders including the destruction of microorganisms by its circulating hemocytes. However, Babesia parasites escape and disseminate to other organs through the hemolymph to continue their transmission life cycle. Still, it is unknown how tick hemocytes respond to B. bovis or B. bigemina infection. In this study, we conducted a transcriptomic analysis of hemocytes from female Rhipicephalus microplus ticks infected with Babesia parasites to understand how gene expression changes during parasite infection. METHODS During Babesia acute infection, female R. microplus ticks were fed on bovines to acquire parasites. Engorged females were collected and incubated to develop Babesia kinetes in tick hemolymph. The hemolymph was examined to identify ticks that were highly infected with Babesia kinetes. Hemocyte cells were collected from replete female ticks infected with Babesia bovis or Babesia bigemina to perform high-throughput RNA-sequencing (RNA-Seq) analysis. RESULTS This study identified major changes in the gene profile of tick hemocytes during Babesia infection. The main groups of hemocyte genes that were altered during Babesia infection were associated with metabolism, immunity, and cytoskeletal rearrangement. Upregulated genes were mainly involved in defense mechanisms, while downregulated genes were related to cell proliferation and apoptosis. However, the expression of hemocyte genes varied among Babesia species' infections, and it reflected the changes that occurred in the tick's physiology, including growth, reproduction, and skeletal muscle development. CONCLUSIONS The differential gene expression of R. microplus hemocytes revealed that genes highly regulated upon Babesia infection were related to metabolism, tick immunity, cell growth, apoptosis, development, metabolism, and reproduction. Additional research is necessary to further define the genes that exhibited varying expression levels in hemocytes during the infection. The findings of this study will enhance our understanding on how Babesia parasites survive in the hostile environment of ticks and perpetuate their transmission cycle, ultimately contributing to the spread of bovine babesiosis.
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Affiliation(s)
- Rubikah Vimonish
- Program in Vector-Borne Diseases, Department of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, WA, USA.
| | - Janaina Capelli-Peixoto
- Program in Vector-Borne Diseases, Department of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, WA, USA
| | - Wendell Johnson
- Program in Vector-Borne Diseases, Department of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, WA, USA
| | | | - Perot Saelao
- Veterinary Pest Genetic Research Unit, USDA-ARS, Kerrville, TX, USA
| | - Naomi Taus
- Animal Disease Research Unit, USDA-ARS, Pullman, WA, USA
| | - Chungwon Chung
- Animal Disease Research Unit, USDA-ARS, Pullman, WA, USA
| | - Massaro Ueti
- Program in Vector-Borne Diseases, Department of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, WA, USA
- Animal Disease Research Unit, USDA-ARS, Pullman, WA, USA
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Jalise SZ, Habibi S, Fath-Bayati L, Habibi MA, Ababzadeh S, Hosseinzadeh F. Role and Interplay of Different Signaling Pathways Involved in Sciatic Nerve Regeneration. J Mol Neurosci 2024; 74:108. [PMID: 39531101 DOI: 10.1007/s12031-024-02286-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 10/27/2024] [Indexed: 11/16/2024]
Abstract
Regeneration of the sciatic nerve is a sophisticated process that involves the interplay of several signaling pathways that orchestrate the cellular responses critical to regeneration. Among the key pathways are the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/AKT, cyclic adenosine monophosphate (cAMP), and Janus kinase/signal transducers and transcription activators (JAK/STAT) pathways. In particular, the cAMP pathway modulates neuronal survival and axonal regrowth. It influences various cellular behaviors and gene expression that are essential for nerve regeneration. MAPK is indispensable for Schwann cell differentiation and myelination, whereas PI3K/AKT is integral to the transcription, translation, and cell survival processes that are vital for nerve regeneration. Furthermore, GTP-binding proteins, including those of the Ras homolog gene family (Rho), regulate neural cell adhesion, migration, and survival. Notch signaling also appears to be effective in the early stages of nerve regeneration and in preventing skeletal muscle fibrosis after injury. Understanding the intricate mechanisms and interactions of these pathways is vital for the development of effective therapeutic strategies for sciatic nerve injuries. This review underscores the need for further research to fill existing knowledge gaps and improve therapeutic outcomes.
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Affiliation(s)
- Saeedeh Zare Jalise
- Department of Tissue Engineering and Applied Cell Sciences, School of Medicine, Qom University of Medical Sciences, Qom, Iran
- Cellular and Molecular Research Centre, Qom University of Medical Sciences, Qom, Iran
| | - Sina Habibi
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Leyla Fath-Bayati
- Department of Tissue Engineering and Applied Cell Sciences, School of Medicine, Qom University of Medical Sciences, Qom, Iran
- Cellular and Molecular Research Centre, Qom University of Medical Sciences, Qom, Iran
| | - Mohammad Amin Habibi
- Clinical Research Development Center, Shahid Beheshti Hospital, Qom University of Medical Sciences, Qom, Iran
| | - Shima Ababzadeh
- Department of Tissue Engineering and Applied Cell Sciences, School of Medicine, Qom University of Medical Sciences, Qom, Iran.
- Cellular and Molecular Research Centre, Qom University of Medical Sciences, Qom, Iran.
| | - Faezeh Hosseinzadeh
- Department of Tissue Engineering and Applied Cell Sciences, School of Medicine, Qom University of Medical Sciences, Qom, Iran.
- Cellular and Molecular Research Centre, Qom University of Medical Sciences, Qom, Iran.
- Clinical Trial Center, Qom University of Medical Sciences, Qom, Iran.
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Riaz F, Zhang J, Pan F. Forces at play: exploring factors affecting the cancer metastasis. Front Immunol 2024; 15:1274474. [PMID: 38361941 PMCID: PMC10867181 DOI: 10.3389/fimmu.2024.1274474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 01/19/2024] [Indexed: 02/17/2024] Open
Abstract
Metastatic disease, a leading and lethal indication of deaths associated with tumors, results from the dissemination of metastatic tumor cells from the site of primary origin to a distant organ. Dispersion of metastatic cells during the development of tumors at distant organs leads to failure to comply with conventional treatments, ultimately instigating abrupt tissue homeostasis and organ failure. Increasing evidence indicates that the tumor microenvironment (TME) is a crucial factor in cancer progression and the process of metastatic tumor development at secondary sites. TME comprises several factors contributing to the initiation and progression of the metastatic cascade. Among these, various cell types in TME, such as mesenchymal stem cells (MSCs), lymphatic endothelial cells (LECs), cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), T cells, and tumor-associated macrophages (TAMs), are significant players participating in cancer metastasis. Besides, various other factors, such as extracellular matrix (ECM), gut microbiota, circadian rhythm, and hypoxia, also shape the TME and impact the metastatic cascade. A thorough understanding of the functions of TME components in tumor progression and metastasis is necessary to discover new therapeutic strategies targeting the metastatic tumor cells and TME. Therefore, we reviewed these pivotal TME components and highlighted the background knowledge on how these cell types and disrupted components of TME influence the metastatic cascade and establish the premetastatic niche. This review will help researchers identify these altered components' molecular patterns and design an optimized, targeted therapy to treat solid tumors and restrict metastatic cascade.
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Affiliation(s)
- Farooq Riaz
- Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen, China
| | - Jing Zhang
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Fan Pan
- Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen, China
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Wu L, Xue Q, Xia X. High expression of TRIP13 is associated with tumor progression in H. pylori infection induced gastric cancer. Mutat Res 2024; 828:111854. [PMID: 38492425 DOI: 10.1016/j.mrfmmm.2024.111854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 03/05/2024] [Accepted: 03/06/2024] [Indexed: 03/18/2024]
Abstract
BACKGROUND/OBJECTIVE H. pylori is a recognized bacterial carcinogen in the world to cause gastric cancer (GC). However, the molecular mechanism of H. pylori infection-induced GC is not completely clear. Thus, there is an urgent need to reveal the precise mechanisms regulating cancer development due to H. pylori infection. METHODS GEO microarray databases and TCGA databases were extracted for the analysis of different expression genes (DEGs). Then, Kaplan-Meier Plotter was used for prognostic analysis. Functional enrichment analysis of TRIP13 was performed by metascape database and TIMER database. Specific role of TRIP13 in GC with H. pylori infection was confirmed by CCK8, cell cycle analysis and WB. RESULTS A total 10 DEGs were substantially elevated in GC and H. pylori+ tissues and might be associated with H. pylori infection in GC and only the highly expressed TRIP13 was statistically associated with poor prognosis in GC patients. Meanwhile, TRIP13 were upregulated in both CagA-transfected epithelial cells and GC cells. And TRIP13 deficiency inhibited cell proliferation and arrested the cell cycle at the G1 phase. CONCLUSION Our study suggested that high expression of TRIP13 can promote the proliferation, cell cycle in GC cells, which could be used as a biomarker for H. pylori infection GC.
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Affiliation(s)
- Longxiang Wu
- Department of Gastrointestinal Surgery, Affiliated Tumor Hospital of Nantong University, Nantong Tumor Hospital, Nantong, Jiangsu 226361, China
| | - Qiu Xue
- Department of Gastrointestinal Surgery, Affiliated Tumor Hospital of Nantong University, Nantong Tumor Hospital, Nantong, Jiangsu 226361, China
| | - Xiaochun Xia
- Department of Radiation Oncology, Affiliated Tumor Hospital of Nantong University, Nantong Tumor Hospital, Nantong, Jiangsu 226361, China.
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Zhao JY, Yuan XK, Luo RZ, Wang LX, Gu W, Yamane D, Feng H. Phospholipase A and acyltransferase 4/retinoic acid receptor responder 3 at the intersection of tumor suppression and pathogen restriction. Front Immunol 2023; 14:1107239. [PMID: 37063830 PMCID: PMC10102619 DOI: 10.3389/fimmu.2023.1107239] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 03/22/2023] [Indexed: 04/03/2023] Open
Abstract
Phospholipase A and acyltransferase (PLAAT) 4 is a class II tumor suppressor with phospholipid metabolizing abilities. It was characterized in late 2000s, and has since been referred to as 'tazarotene-induced gene 3' (TIG3) or 'retinoic acid receptor responder 3' (RARRES3) as a key downstream effector of retinoic acid signaling. Two decades of research have revealed the complexity of its function and regulatory roles in suppressing tumorigenesis. However, more recent findings have also identified PLAAT4 as a key anti-microbial effector enzyme acting downstream of interferon regulatory factor 1 (IRF1) and interferons (IFNs), favoring protection from virus and parasite infections. Unveiling the molecular mechanisms underlying its action may thus open new therapeutic avenues for the treatment of both cancer and infectious diseases. Herein, we aim to summarize a brief history of PLAAT4 discovery, its transcriptional regulation, and the potential mechanisms in tumor prevention and anti-pathogen defense, and discuss potential future directions of PLAAT4 research toward the development of therapeutic approaches targeting this enzyme with pleiotropic functions.
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Affiliation(s)
- Jian-Yong Zhao
- Hospital of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Cangzhou, Hebei, China
| | - Xiang-Kun Yuan
- Hospital of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Cangzhou, Hebei, China
| | - Rui-Zhen Luo
- Hospital of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Cangzhou, Hebei, China
| | - Li-Xin Wang
- Hospital of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Cangzhou, Hebei, China
| | - Wei Gu
- School of Medicine, Chongqing University, Chongqing, China
| | - Daisuke Yamane
- Department of Diseases and Infection, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Hui Feng
- School of Medicine, Chongqing University, Chongqing, China
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Lee SD, Jeong H, Hwang BR, Yu BM, Cho Y, Nam KT, Kim H, Lee YC. Helicobacter pylori promotes epithelial-to-mesenchymal transition by downregulating CK2β in gastric cancer cells. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166588. [PMID: 36404440 DOI: 10.1016/j.bbadis.2022.166588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/17/2022] [Accepted: 10/25/2022] [Indexed: 11/16/2022]
Abstract
Strains of Helicobacter pylori that are positive for the oncoprotein CagA (cytotoxin-associated gene A) are associated with gastric cancer and might be related to the epithelial-to-mesenchymal transition (EMT). Casein kinase 2 (CK2) is a serine/threonine protein kinase that plays a major role in tumorigenesis through signaling pathways related to the EMT. However, the role played by the interaction between CagA and CK2 in gastric carcinogenesis is poorly understood. Although CK2α protein expression remained unchanged during H. pylori infection, we found that CK2α kinase activity was increased in gastric epithelial cells. We also found that the CK2β protein level decreased in H. pylori-infected gastric cancer cells in CagA-dependent manner and demonstrated that CagA induced CK2β degradation via HDM2 (human double minute 2; its murine equivalent is MDM2). We observed that CagA induced HDM2 protein phosphorylation and that p53 levels were decreased in H. pylori-infected gastric cancer cells. In addition, downregulation of CK2β induced AKT Ser473 phosphorylation and decreased the AKT Ser129 phosphorylation level in gastric cancer cells. We also found that the downregulation of CK2β triggered the upregulation of Snail levels in gastric cancer cells. Furthermore, our in vivo experiments and functional assays of migration and colony formation suggest that CK2β downregulation is a major factor responsible for the EMT in gastric cancer. Therefore, CK2 could be a key mediator of the EMT in H. pylori-infected gastric cancer and could serve as a molecular target for gastric cancer treatment.
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Affiliation(s)
- So Dam Lee
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Haengdueng Jeong
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Bo Ram Hwang
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Byeong Min Yu
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yejin Cho
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Ki Teak Nam
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyunki Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong Chan Lee
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea; Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
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Proinflammatory and Cancer-Promoting Pathobiont Fusobacterium nucleatum Directly Targets Colorectal Cancer Stem Cells. Biomolecules 2022; 12:biom12091256. [PMID: 36139097 PMCID: PMC9496236 DOI: 10.3390/biom12091256] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/30/2022] [Accepted: 09/05/2022] [Indexed: 11/24/2022] Open
Abstract
Intestinal bacterial communities participate in gut homeostasis and are recognized as crucial in bowel inflammation and colorectal cancer (CRC). Fusobacterium nucleatum (Fn), a pathobiont of the oral microflora, has recently emerged as a CRC-associated microbe linked to disease progression, metastasis, and a poor clinical outcome; however, the primary cellular and/or microenvironmental targets of this agent remain elusive. We report here that Fn directly targets putative colorectal cancer stem cells (CR-CSCs), a tumor cell subset endowed with cancer re-initiating capacity after surgery and chemotherapy. A patient-derived CSC line, highly enriched (70%) for the stem marker CD133, was expanded as tumor spheroids, dissociated, and exposed in vitro to varying amounts (range 100–500 MOI) of Fn. We found that Fn stably adheres to CSCs, likely by multiple interactions involving the tumor-associated Gal-GalNac disaccharide and the Fn-docking protein CEA-family cell adhesion molecule 1 (CEACAM-1), robustly expressed on CSCs. Importantly, Fn elicited innate immune responses in CSCs and triggered a growth factor-like, protein tyrosine phosphorylation cascade largely dependent on CEACAM-1 and culminating in the activation of p42/44 MAP kinase. Thus, the direct stimulation of CSCs by Fn may contribute to microbiota-driven colorectal carcinogenesis and represent a target for innovative therapies.
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Omran M, Fouda M, Abdelwahab AO, Nabeel MM, Abdelaziz AO, Omran D, Shousha HI. P53 is a risk factor of de-novo hepatitis C-related hepatocellular carcinoma treated with direct-acting antivirals: a case-control study. Eur J Gastroenterol Hepatol 2022; 34:220-226. [PMID: 33079785 DOI: 10.1097/meg.0000000000001962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND The mechanisms underlying de-novo hepatocellular carcinoma (HCC) after direct-acting antivirals (DAAs) is still under investigation. This work aims to study P53 and hepatocyte growth factor (HGF) as possible diagnostics of de-novo hepatocellular carcinoma (HCC) following DAAs in comparison to alpha-fetoprotein (AFP). METHOD This case-control study included 166 patients with liver cirrhosis divided into group-1: patients without HCC (n = 50), group-2: patients with de-novo HCC following DAAs, and achieved sustained virological response (n = 50), and group-3: patients with HCC without DAAs (n = 66). P53 antibody and HGF were determined using a quantitative sandwich enzyme immunoassay technique (Cusabio Co, Houston, USA). RESULTS Patients with HCC showed significantly higher HGF. Patients with de-novo HCC following DAAs had significantly higher P53 than HCC without DAAs (P < 0.0001). The multiple logistic regression analysis showed that the P53 levels were significantly associated with susceptibility to de-novo HCC (P value = 0.004). The best overall formula was constructed for HCC diagnosis by entering significant markers into the regression model. A three markers model was developed = (1.22 + AFP X 0.002 + HGF X 0.001 + P53 X 0.001). The medians (percentiles) of combined three markers were 1.8 (1.0-2.1) in liver cirrhosis and 2.2 (2.0-2.9) in all HCC (P < 0.00001). The AUC of combined markers was greater than a single marker. The AUC was 0.87 to differentiate HCC from liver cirrhosis; AUC 0.91 to differentiate de-novo HCC after DAAs from liver cirrhosis. CONCLUSION P53 may serve as a diagnostic marker for de-novo HCC after DAAs therapy. HGF may serve as a diagnostic marker for HCC but not specific for de-novo HCC after DAAs therapy.
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Affiliation(s)
- Mohamed Omran
- Chemistry Department, Faculty of Science, Helwan University
| | - Manar Fouda
- Chemistry Department, Faculty of Science, Helwan University
| | | | | | | | - Dalia Omran
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Hend Ibrahim Shousha
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
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Borozan I, Zaidi SH, Harrison TA, Phipps AI, Zheng J, Lee S, Trinh QM, Steinfelder RS, Adams J, Banbury BL, Berndt SI, Brezina S, Buchanan DD, Bullman S, Cao Y, Farris AB, Figueiredo JC, Giannakis M, Heisler LE, Hopper JL, Lin Y, Luo X, Nishihara R, Mardis ER, Papadopoulos N, Qu C, Reid EEG, Thibodeau SN, Harlid S, Um CY, Hsu L, Gsur A, Campbell PT, Gallinger S, Newcomb PA, Ogino S, Sun W, Hudson TJ, Ferretti V, Peters U. Molecular and Pathology Features of Colorectal Tumors and Patient Outcomes Are Associated with Fusobacterium nucleatum and Its Subspecies animalis. Cancer Epidemiol Biomarkers Prev 2022; 31:210-220. [PMID: 34737207 PMCID: PMC8755593 DOI: 10.1158/1055-9965.epi-21-0463] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 06/27/2021] [Accepted: 10/21/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Fusobacterium nucleatum (F. nucleatum) activates oncogenic signaling pathways and induces inflammation to promote colorectal carcinogenesis. METHODS We characterized F. nucleatum and its subspecies in colorectal tumors and examined associations with tumor characteristics and colorectal cancer-specific survival. We conducted deep sequencing of nusA, nusG, and bacterial 16s rRNA genes in tumors from 1,994 patients with colorectal cancer and assessed associations between F. nucleatum presence and clinical characteristics, colorectal cancer-specific mortality, and somatic mutations. RESULTS F. nucleatum, which was present in 10.3% of tumors, was detected in a higher proportion of right-sided and advanced-stage tumors, particularly subspecies animalis. Presence of F. nucleatum was associated with higher colorectal cancer-specific mortality (HR, 1.97; P = 0.0004). This association was restricted to nonhypermutated, microsatellite-stable tumors (HR, 2.13; P = 0.0002) and those who received chemotherapy [HR, 1.92; confidence interval (CI), 1.07-3.45; P = 0.029). Only F. nucleatum subspecies animalis, the main subspecies detected (65.8%), was associated with colorectal cancer-specific mortality (HR, 2.16; P = 0.0016), subspecies vincentii and nucleatum were not (HR, 1.07; P = 0.86). Additional adjustment for tumor stage suggests that the effect of F. nucleatum on mortality is partly driven by a stage shift. Presence of F. nucleatum was associated with microsatellite instable tumors, tumors with POLE exonuclease domain mutations, and ERBB3 mutations, and suggestively associated with TP53 mutations. CONCLUSIONS F. nucleatum, and particularly subspecies animalis, was associated with a higher colorectal cancer-specific mortality and specific somatic mutated genes. IMPACT Our findings identify the F. nucleatum subspecies animalis as negatively impacting colorectal cancer mortality, which may occur through a stage shift and its effect on chemoresistance.
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Affiliation(s)
- Ivan Borozan
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Syed H Zaidi
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Tabitha A Harrison
- Public Health Sciences Division, Fred Hutchinson Cancer Research Centre, Seattle, Washington
| | - Amanda I Phipps
- Public Health Sciences Division, Fred Hutchinson Cancer Research Centre, Seattle, Washington
| | - Jiayin Zheng
- Public Health Sciences Division, Fred Hutchinson Cancer Research Centre, Seattle, Washington
| | - Stephen Lee
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Quang M Trinh
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Robert S Steinfelder
- Public Health Sciences Division, Fred Hutchinson Cancer Research Centre, Seattle, Washington
| | - Jeremy Adams
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Barbara L Banbury
- Public Health Sciences Division, Fred Hutchinson Cancer Research Centre, Seattle, Washington
| | - Sonja I Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Stefanie Brezina
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Daniel D Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia
- The University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia
- Familial Cancer Clinic, Genetic Medicine, The Royal Melbourne Hospital, Parkville, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
| | - Susan Bullman
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Yin Cao
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine in St. Louis, St Louis, Missouri
- Siteman Cancer Center, Washington University School of Medicine in St. Louis, St Louis, Missouri
| | - Alton B Farris
- Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Jane C Figueiredo
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Marios Giannakis
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | | | - John L Hopper
- The University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia
| | - Yi Lin
- Public Health Sciences Division, Fred Hutchinson Cancer Research Centre, Seattle, Washington
| | - Xuemei Luo
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Reiko Nishihara
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Elaine R Mardis
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio
| | - Nickolas Papadopoulos
- Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medicine, Baltimore, Maryland
| | - Conghui Qu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Centre, Seattle, Washington
| | - Emma E G Reid
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Stephen N Thibodeau
- Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Sophia Harlid
- Oncology, Department of Radiation Sciences, Faculty of Medicine, Umeå University, Umeå, Sweden
| | - Caroline Y Um
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Centre, Seattle, Washington
- Department of Biostatistics, School of Public Health, University of Washington, Seattle, Washington
| | - Andrea Gsur
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Peter T Campbell
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia
| | - Steven Gallinger
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
- Lunenfeld-Tanenbaum Research Institute, Sinai Health, University of Toronto, Toronto, Ontario, Canada
- General Surgery, Surgery and Critical Care Program, University Health Network Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Polly A Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Centre, Seattle, Washington
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington
| | - Shuji Ogino
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
- Cancer Immunology Program, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts
- Cancer Epidemiology Program, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts
| | - Wei Sun
- Public Health Sciences Division, Fred Hutchinson Cancer Research Centre, Seattle, Washington
| | - Thomas J Hudson
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Vincent Ferretti
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
- CHU Sainte-Justine Research Center, University of Montreal, Montreal, Quebec, Canada
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Centre, Seattle, Washington.
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington
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11
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Dang W, Cao P, Yan Q, Yang L, Wang Y, Yang J, Xin S, Zhang J, Li J, Long S, Zhang W, Zhang S, Lu J. IGFBP7-AS1 is a p53-responsive long noncoding RNA downregulated by Epstein-Barr virus that contributes to viral tumorigenesis. Cancer Lett 2021; 523:135-147. [PMID: 34634383 DOI: 10.1016/j.canlet.2021.10.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 09/16/2021] [Accepted: 10/05/2021] [Indexed: 01/15/2023]
Abstract
Epstein-Barr virus (EBV) is closely related to the development of several malignancies, such as B-cell lymphoma (B-CL), by the mechanism through which these malignancies develop remains largely unknown. We previously observed downregulation of the long noncoding RNA (lncRNA) IGFBP7-AS1 in response to EBV infection. However, the role of IGFBP7-AS1 in EBV-associated cancers has not been clarified. Here, we found that expression of IGFBP7-AS1, as well as its sense gene IGFBP7, is decreased in EBV-positive B-CL cells and clinical tissues. IGFBP7-AS1 stabilizes IGFBP7 mRNA by forming a duplex based on their overlapping regions. The tumour suppressor p53 transcriptionally activates IGFBP7-AS1 expression by binding to the promoter region of the lncRNA gene. The IGFBP7-AS1 expression is able to be rescued in EBV-positive cells in wild-type (wt) p53-dependent manner. IGFBP7-AS1 inhibits the proliferation and promotes the apoptosis of B-CL cells. Moreover, tumorigenic properties due to the depletion of IGFBP7-AS1 were restored by exogenous expression of IGFBP7 or wt-p53. Furthermore, the functional p53/IGFBP7-AS1/IGFBP7 axis facilitates apoptosis by suppressing the production and secretion of the NPPB signal peptide and further regulating the cGMP-PKG signalling pathway. This study demonstrates that EBV promotes tumorigenesis, particularly in B-CL progression, by downregulating the novel p53-responsive lncRNA IGFBP7-AS1.
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Affiliation(s)
- Wei Dang
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China; NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China; Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China
| | - Pengfei Cao
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China
| | - Qijia Yan
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China
| | - Li Yang
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China; NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China; Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China
| | - Yiwei Wang
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China; NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China; Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China
| | - Jing Yang
- NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China
| | - Shuyu Xin
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China; Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China
| | - Jing Zhang
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China; NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China; Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China
| | - Jing Li
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China; NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China; Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China
| | - Sijing Long
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China; NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China; Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China
| | - Wentao Zhang
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China; NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China; Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China
| | - Senmiao Zhang
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China; NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China; Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China
| | - Jianhong Lu
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; Department of Microbiology, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China; NHC Key Laboratory of Carcinogenesis, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, 410078, Hunan, China; Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410080, Hunan, China; China-Africa Research Center of Infectious Diseases, Central South University, Changsha, 410013, Hunan, China.
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12
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Lees A, Sessler T, McDade S. Dying to Survive-The p53 Paradox. Cancers (Basel) 2021; 13:3257. [PMID: 34209840 PMCID: PMC8268032 DOI: 10.3390/cancers13133257] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 06/18/2021] [Accepted: 06/24/2021] [Indexed: 12/13/2022] Open
Abstract
The p53 tumour suppressor is best known for its canonical role as "guardian of the genome", activating cell cycle arrest and DNA repair in response to DNA damage which, if irreparable or sustained, triggers activation of cell death. However, despite an enormous amount of work identifying the breadth of the gene regulatory networks activated directly and indirectly in response to p53 activation, how p53 activation results in different cell fates in response to different stress signals in homeostasis and in response to p53 activating anti-cancer treatments remains relatively poorly understood. This is likely due to the complex interaction between cell death mechanisms in which p53 has been activated, their neighbouring stressed or unstressed cells and the local stromal and immune microenvironment in which they reside. In this review, we evaluate our understanding of the burgeoning number of cell death pathways affected by p53 activation and how these may paradoxically suppress cell death to ensure tissue integrity and organismal survival. We also discuss how these functions may be advantageous to tumours that maintain wild-type p53, the understanding of which may provide novel opportunity to enhance treatment efficacy.
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Affiliation(s)
- Andrea Lees
- Patrick G Johnston Centre for Cancer Research, Queen’s University, Belfast BT9 7AE, UK;
| | | | - Simon McDade
- Patrick G Johnston Centre for Cancer Research, Queen’s University, Belfast BT9 7AE, UK;
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13
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Palrasu M, Zaika E, El-Rifai W, Que J, Zaika AI. Role of Bacterial and Viral Pathogens in Gastric Carcinogenesis. Cancers (Basel) 2021; 13:1878. [PMID: 33919876 PMCID: PMC8070847 DOI: 10.3390/cancers13081878] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/02/2021] [Accepted: 04/11/2021] [Indexed: 01/10/2023] Open
Abstract
Gastric cancer (GC) is one of the deadliest malignancies worldwide. In contrast to many other tumor types, gastric carcinogenesis is tightly linked to infectious events. Infections with Helicobacter pylori (H. pylori) bacterium and Epstein-Barr virus (EBV) are the two most investigated risk factors for GC. These pathogens infect more than half of the world's population. Fortunately, only a small fraction of infected individuals develops GC, suggesting high complexity of tumorigenic processes in the human stomach. Recent studies suggest that the multifaceted interplay between microbial, environmental, and host genetic factors underlies gastric tumorigenesis. Many aspects of these interactions still remain unclear. In this review, we update on recent discoveries, focusing on the roles of various gastric pathogens and gastric microbiome in tumorigenesis.
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Affiliation(s)
- Manikandan Palrasu
- Department of Surgery, University of Miami, Miami, FL 33136, USA; (M.P.); (E.Z.); (W.E.-R.)
| | - Elena Zaika
- Department of Surgery, University of Miami, Miami, FL 33136, USA; (M.P.); (E.Z.); (W.E.-R.)
| | - Wael El-Rifai
- Department of Surgery, University of Miami, Miami, FL 33136, USA; (M.P.); (E.Z.); (W.E.-R.)
- Department of Veterans Affairs, Miami VA Healthcare System, Miami, FL 33136, USA
| | - Jianwen Que
- Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA;
| | - Alexander I. Zaika
- Department of Surgery, University of Miami, Miami, FL 33136, USA; (M.P.); (E.Z.); (W.E.-R.)
- Department of Veterans Affairs, Miami VA Healthcare System, Miami, FL 33136, USA
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14
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Saha G, Chiranjivi AK, Khamar BM, Prerna K, Kumar M, Dubey VK. BLIMP-1 Mediated Downregulation of TAK1 and p53 Molecules Is Crucial in the Pathogenesis of Kala-Azar. Front Cell Infect Microbiol 2020; 10:594431. [PMID: 33194842 PMCID: PMC7658262 DOI: 10.3389/fcimb.2020.594431] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 10/06/2020] [Indexed: 11/13/2022] Open
Abstract
Precise regulation of inflammasome is critical during any pathogenic encounter. The whole innate immune system comprising of pattern recognition receptors (PRRs) relies on its ability to sense microbes. The fate of cellular death in infected cells depends mostly on the activation of these inflammasome, the dysregulation of which, due to functional manipulation by various pathogens, leads to be the cause of many human diseases. Here, an interesting finding has been observed which is related to how Leishmania donovani parasites exploit various host mediator molecules to cause immunosuppression. Here we report for the first time that the parasites check pyroptosis in the infected cells in-vitro by BLIMP-1 mediated suppression of TAK1 and p53 proteins. This might be one of the reasons how parasites evade the pro-inflammatory response of the host cells. Further understandings and validations are required to come up with better therapeutic approaches against kala-azar.
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Affiliation(s)
- Gundappa Saha
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, India
| | - Adarsh Kumar Chiranjivi
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, India
| | - Bakulesh M Khamar
- Research & Development, Cadila Pharmaceuticals Limited, Ahmedabad, India
| | - Kumari Prerna
- School of Biochemical Engineering, Indian Institute of Technology Banaras Hindu University (BHU), Varanasi, India
| | - Manish Kumar
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, India
| | - Vikash Kumar Dubey
- School of Biochemical Engineering, Indian Institute of Technology Banaras Hindu University (BHU), Varanasi, India
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15
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Chen SD, Pan HY, Huang JB, Liu XP, Li JH, Ho CJ, Tsai MH, Yang JL, Chen SF, Chen NC, Chuang YC. Circulating MicroRNAs from Serum Exosomes May Serve as a Putative Biomarker in the Diagnosis and Treatment of Patients with Focal Cortical Dysplasia. Cells 2020; 9:cells9081867. [PMID: 32785072 PMCID: PMC7465068 DOI: 10.3390/cells9081867] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/03/2020] [Accepted: 08/08/2020] [Indexed: 12/12/2022] Open
Abstract
Focal cortical dysplasia (FCD) is a congenital malformation of cortical development where the cortical neurons located in the brain area fail to migrate in the proper formation. Epilepsy, particularly medically refractory epilepsy, is the most common clinical presentation for all types of FCD. This study aimed to explore the expression change of circulating miRNAs in patients with FCD from serum exosomes. A total of nine patients with FCD and four healthy volunteers were enrolled in this study. The serum exosomes were isolated from the peripheral blood of the subjects. Transmission electron microscopy (TEM) was used to identify the exosomes. Both exosomal markers and neuronal markers were detected by Western blotting analysis to prove that we could obtain central nervous system-derived exosomes from the circulation. The expression profiles of circulating exosomal miRNAs were assessed using next-generation sequencing analysis (NGS). We obtained a total of 107 miRNAs with dominant fold change (>2-fold) from both the annotated 5p-arm and 3p-arm of 2780 mature miRNAs. Based on the integrated platform of HMDD v3.2, miRway DB and DIANA-miRPath v3.0 online tools, and confirmed by MiRBase analysis, four potentially predicted miRNAs from serum exosomes in patients with FCD were identified, including miR194-2-5p, miR15a-5p, miR-132-3p, and miR-145-5p. All four miRNAs presented upregulated expression in patients with FCD compared with controls. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and pathway category of four target miRNAs, we found eight possible signaling pathways that may be related to FCD. Among them, we suggest that the mTOR signaling pathway, PI3K-Akt signaling pathway, p53 signaling pathway, and cell cycle regulation and TGF-beta signaling pathway are high-risk pathways that play a crucial role in the pathogenesis of FCD and refractory epilepsy. Our results suggest that the circulating miRNAs from exosomes may provide a potential biomarker for diagnostic, prognostic, and therapeutic adjuncts in patients with FCD and refractory epilepsy.
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Affiliation(s)
- Shang-Der Chen
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (S.-D.C.); (C.-J.H.); (M.-H.T.); (S.-F.C.); (N.-C.C.)
- Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (X.-P.L.); (J.-H.L.); (J.-L.Y.)
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Hsiu-Yung Pan
- Department of Emergency Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (H.-Y.P.); (J.-B.H.)
| | - Jyun-Bin Huang
- Department of Emergency Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (H.-Y.P.); (J.-B.H.)
| | - Xuan-Ping Liu
- Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (X.-P.L.); (J.-H.L.); (J.-L.Y.)
| | - Jie-Hau Li
- Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (X.-P.L.); (J.-H.L.); (J.-L.Y.)
| | - Chen-Jui Ho
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (S.-D.C.); (C.-J.H.); (M.-H.T.); (S.-F.C.); (N.-C.C.)
| | - Meng-Han Tsai
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (S.-D.C.); (C.-J.H.); (M.-H.T.); (S.-F.C.); (N.-C.C.)
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Jenq-Lin Yang
- Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (X.-P.L.); (J.-H.L.); (J.-L.Y.)
| | - Shu-Fang Chen
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (S.-D.C.); (C.-J.H.); (M.-H.T.); (S.-F.C.); (N.-C.C.)
| | - Nai-Ching Chen
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (S.-D.C.); (C.-J.H.); (M.-H.T.); (S.-F.C.); (N.-C.C.)
| | - Yao-Chung Chuang
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (S.-D.C.); (C.-J.H.); (M.-H.T.); (S.-F.C.); (N.-C.C.)
- Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; (X.-P.L.); (J.-H.L.); (J.-L.Y.)
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Neurology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Biological Science, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
- Correspondence:
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16
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Palrasu M, Zaika E, El-Rifai W, Garcia-Buitrago M, Piazuelo MB, Wilson KT, Peek RM, Zaika AI. Bacterial CagA protein compromises tumor suppressor mechanisms in gastric epithelial cells. J Clin Invest 2020; 130:2422-2434. [PMID: 32250340 PMCID: PMC7190987 DOI: 10.1172/jci130015] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 01/22/2020] [Indexed: 01/01/2023] Open
Abstract
Approximately half of the world's population is infected with the stomach pathogen Helicobacter pylori. Infection with H. pylori is the main risk factor for distal gastric cancer. Bacterial virulence factors, such as the oncoprotein CagA, augment cancer risk. Yet despite high infection rates, only a fraction of H. pylori-infected individuals develop gastric cancer. This raises the question of defining the specific host and bacterial factors responsible for gastric tumorigenesis. To investigate the tumorigenic determinants, we analyzed gastric tissues from human subjects and animals infected with H. pylori bacteria harboring different CagA status. For laboratory studies, well-defined H. pylori strain B128 and its cancerogenic derivative strain 7.13, as well as various bacterial isogenic mutants were employed. We found that H. pylori compromises key tumor suppressor mechanisms: the host stress and apoptotic responses. Our studies showed that CagA induces phosphorylation of XIAP E3 ubiquitin ligase, which enhances ubiquitination and proteasomal degradation of the host proapoptotic factor Siva1. This process is mediated by the PI3K/Akt pathway. Inhibition of Siva1 by H. pylori increases survival of human cells with damaged DNA. It occurs in a strain-specific manner and is associated with the ability to induce gastric tumor.
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Affiliation(s)
- Manikandan Palrasu
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Elena Zaika
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Wael El-Rifai
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
- Department of Veterans Affairs, Miami VA Healthcare System, Miami, Florida, USA
| | - Monica Garcia-Buitrago
- Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Maria Blanca Piazuelo
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Keith T. Wilson
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Veterans Affairs, VA Tennessee Valley Health Care System, Nashville, Tennessee, USA
| | - Richard M. Peek
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Alexander I. Zaika
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
- Department of Veterans Affairs, Miami VA Healthcare System, Miami, Florida, USA
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17
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A MicroRNA Network Controls Legionella pneumophila Replication in Human Macrophages via LGALS8 and MX1. mBio 2020; 11:mBio.03155-19. [PMID: 32209695 PMCID: PMC7157531 DOI: 10.1128/mbio.03155-19] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Cases of Legionella pneumophila pneumonia occur worldwide, with potentially fatal outcome. When causing human disease, Legionella injects a plethora of virulence factors to reprogram macrophages to circumvent immune defense and create a replication niche. By analyzing Legionella-induced changes in miRNA expression and genomewide chromatin modifications in primary human macrophages, we identified a cell-autonomous immune network restricting Legionella growth. This network comprises three miRNAs governing expression of the cytosolic RNA receptor DDX58/RIG-I, the tumor suppressor TP53, the antibacterial effector LGALS8, and MX1, which has been described as an antiviral factor. Our findings for the first time link TP53, LGALS8, DDX58, and MX1 in one miRNA-regulated network and integrate them into a functional node in the defense against L. pneumophila. Legionella pneumophila is an important cause of pneumonia. It invades alveolar macrophages and manipulates the immune response by interfering with signaling pathways and gene transcription to support its own replication. MicroRNAs (miRNAs) are critical posttranscriptional regulators of gene expression and are involved in defense against bacterial infections. Several pathogens have been shown to exploit the host miRNA machinery to their advantage. We therefore hypothesize that macrophage miRNAs exert positive or negative control over Legionella intracellular replication. We found significant regulation of 85 miRNAs in human macrophages upon L. pneumophila infection. Chromatin immunoprecipitation and sequencing revealed concordant changes of histone acetylation at the putative promoters. Interestingly, a trio of miRNAs (miR-125b, miR-221, and miR-579) was found to significantly affect intracellular L. pneumophila replication in a cooperative manner. Using proteome-analysis, we pinpointed this effect to a concerted downregulation of galectin-8 (LGALS8), DExD/H-box helicase 58 (DDX58), tumor protein P53 (TP53), and then MX dynamin-like GTPase 1 (MX1) by the three miRNAs. In summary, our results demonstrate a new miRNA-controlled immune network restricting Legionella replication in human macrophages.
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Hayward RJ, Marsh JW, Humphrys MS, Huston WM, Myers GSA. Early Transcriptional Landscapes of Chlamydia trachomatis-Infected Epithelial Cells at Single Cell Resolution. Front Cell Infect Microbiol 2019; 9:392. [PMID: 31803632 PMCID: PMC6877545 DOI: 10.3389/fcimb.2019.00392] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 11/01/2019] [Indexed: 12/22/2022] Open
Abstract
Chlamydia are Gram-negative obligate intracellular bacterial pathogens responsible for a variety of disease in humans and animals worldwide. Chlamydia trachomatis causes trachoma in disadvantaged populations, and is the most common bacterial sexually transmitted infection in humans, causing reproductive tract disease. Antibiotic therapy successfully treats diagnosed chlamydial infections, however asymptomatic infections are common. High-throughput transcriptomic approaches have explored chlamydial gene expression and infected host cell gene expression. However, these were performed on large cell populations, averaging gene expression profiles across all cells sampled and potentially obscuring biologically relevant subsets of cells. We generated a pilot dataset, applying single cell RNA-Seq (scRNA-Seq) to C. trachomatis infected and mock-infected epithelial cells to assess the utility, pitfalls and challenges of single cell approaches applied to chlamydial biology, and to potentially identify early host cell biomarkers of chlamydial infection. Two hundred sixty-four time-matched C. trachomatis-infected and mock-infected HEp-2 cells were collected and subjected to scRNA-Seq. After quality control, 200 cells were retained for analysis. Two distinct clusters distinguished 3-h cells from 6- and 12-h. Pseudotime analysis identified a possible infection-specific cellular trajectory for Chlamydia-infected cells, while differential expression analyses found temporal expression of metallothioneins and genes involved with cell cycle regulation, innate immune responses, cytoskeletal components, lipid biosynthesis and cellular stress. We find that changes to the host cell transcriptome at early times of C. trachomatis infection are readily discernible by scRNA-Seq, supporting the utility of single cell approaches to identify host cell biomarkers of chlamydial infection, and to further deconvolute the complex host response to infection.
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Affiliation(s)
- Regan J. Hayward
- Faculty of Science, School of Life Sciences, The ithree Institute, University of Technology Sydney, Ultimo, NSW, Australia
| | - James W. Marsh
- Department of Microbiome Science, Max Planck Institute for Developmental Biology, Tübingen, Germany
| | - Michael S. Humphrys
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Wilhelmina M. Huston
- Faculty of Science, School of Life Sciences, University of Technology Sydney, Ultimo, NSW, Australia
| | - Garry S. A. Myers
- Faculty of Science, School of Life Sciences, The ithree Institute, University of Technology Sydney, Ultimo, NSW, Australia
- Faculty of Science, School of Life Sciences, University of Technology Sydney, Ultimo, NSW, Australia
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Dash S, Aydin Y, Moroz K. Chaperone-Mediated Autophagy in the Liver: Good or Bad? Cells 2019; 8:E1308. [PMID: 31652893 PMCID: PMC6912708 DOI: 10.3390/cells8111308] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 10/17/2019] [Accepted: 10/22/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection triggers autophagy processes, which help clear out the dysfunctional viral and cellular components that would otherwise inhibit the virus replication. Increased cellular autophagy may kill the infected cell and terminate the infection without proper regulation. The mechanism of autophagy regulation during liver disease progression in HCV infection is unclear. The autophagy research has gained a lot of attention recently since autophagy impairment is associated with the development of hepatocellular carcinoma (HCC). Macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA) are three autophagy processes involved in the lysosomal degradation and extracellular release of cytosolic cargoes under excessive stress. Autophagy processes compensate for each other during extreme endoplasmic reticulum (ER) stress to promote host and microbe survival as well as HCC development in the highly stressed microenvironment of the cirrhotic liver. This review describes the molecular details of how excessive cellular stress generated during HCV infection activates CMA to improve cell survival. The pathological implications of stress-related CMA activation resulting in the loss of hepatic innate immunity and tumor suppressors, which are most often observed among cirrhotic patients with HCC, are discussed. The oncogenic cell programming through autophagy regulation initiated by a cytoplasmic virus may facilitate our understanding of HCC mechanisms related to non-viral etiologies and metabolic conditions such as uncontrolled type II diabetes. We propose that a better understanding of how excessive cellular stress leads to cancer through autophagy modulation may allow therapeutic development and early detection of HCC.
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Affiliation(s)
- Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
- Southeast Louisiana Veterans Health Care System, 2400 Canal Street, New Orleans, LA 70119, USA.
| | - Yucel Aydin
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
| | - Krzysztof Moroz
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
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20
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Afrasiabi S, Pourhajibagher M, Bahador A. The Photomodulation Activity of Metformin Against Oral Microbiome. J Lasers Med Sci 2019; 10:241-250. [PMID: 31749953 PMCID: PMC6817791 DOI: 10.15171/jlms.2019.39] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Periodontitis is one of the most common inflammatory diseases of the periodontium, which results in the inflammatory destruction of supporting structures around teeth and is closely associated with the development of systemic disease. Due to a wide variety of antibiotic resistance periodontopathic bacteria, photodynamic therapy (PDT) is a non-invasive adjunctive therapeutic modality that is capable of destroying the whole range of microbes. Metformin (Metf) is an antidiabetic drug, and recent studies suggest that cancer patients who receive Metf and are exposed to radiotherapy and chemotherapy show better outcomes. Our surveys in this review introduce Metf as a potent stimulus in increasing the efficacy of PDT in the induction of destruction in microbial cells.
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Affiliation(s)
- Shima Afrasiabi
- Department of Microbiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Pourhajibagher
- Dental Research Center, Dentistry Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Bahador
- Oral Microbiology Laboratory, Department of Microbiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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21
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Eisenreich W, Rudel T, Heesemann J, Goebel W. How Viral and Intracellular Bacterial Pathogens Reprogram the Metabolism of Host Cells to Allow Their Intracellular Replication. Front Cell Infect Microbiol 2019; 9:42. [PMID: 30886834 PMCID: PMC6409310 DOI: 10.3389/fcimb.2019.00042] [Citation(s) in RCA: 132] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 02/08/2019] [Indexed: 12/12/2022] Open
Abstract
Viruses and intracellular bacterial pathogens (IBPs) have in common the need of suitable host cells for efficient replication and proliferation during infection. In human infections, the cell types which both groups of pathogens are using as hosts are indeed quite similar and include phagocytic immune cells, especially monocytes/macrophages (MOs/MPs) and dendritic cells (DCs), as well as nonprofessional phagocytes, like epithelial cells, fibroblasts and endothelial cells. These terminally differentiated cells are normally in a metabolically quiescent state when they are encountered by these pathogens during infection. This metabolic state of the host cells does not meet the extensive need for nutrients required for efficient intracellular replication of viruses and especially IBPs which, in contrast to the viral pathogens, have to perform their own specific intracellular metabolism to survive and efficiently replicate in their host cell niches. For this goal, viruses and IBPs have to reprogram the host cell metabolism in a pathogen-specific manner to increase the supply of nutrients, energy, and metabolites which have to be provided to the pathogen to allow its replication. In viral infections, this appears to be often achieved by the interaction of specific viral factors with central metabolic regulators, including oncogenes and tumor suppressors, or by the introduction of virus-specific oncogenes. Less is so far known on the mechanisms leading to metabolic reprogramming of the host cell by IBPs. However, the still scant data suggest that similar mechanisms may also determine the reprogramming of the host cell metabolism in IBP infections. In this review, we summarize and compare the present knowledge on this important, yet still poorly understood aspect of pathogenesis of human viral and especially IBP infections.
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Affiliation(s)
- Wolfgang Eisenreich
- Chair of Biochemistry, Department of Chemistry, Technische Universität München, Garching, Germany
| | - Thomas Rudel
- Chair of Microbiology, Biocenter, University of Würzburg, Würzburg, Germany
| | - Jürgen Heesemann
- Max von Pettenkofer-Institute, Ludwig Maximilian University of Munich, Munich, Germany
| | - Werner Goebel
- Max von Pettenkofer-Institute, Ludwig Maximilian University of Munich, Munich, Germany
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22
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Guo Q, Jing FJ, Qu HJ, Xu W, Han B, Xing XM, Ji HY, Jing FB. Ubenimex Reverses MDR in Gastric Cancer Cells by Activating Caspase-3-Mediated Apoptosis and Suppressing the Expression of Membrane Transport Proteins. BIOMED RESEARCH INTERNATIONAL 2019; 2019:4390839. [PMID: 30915355 PMCID: PMC6402206 DOI: 10.1155/2019/4390839] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 12/09/2018] [Accepted: 12/27/2018] [Indexed: 02/06/2023]
Abstract
Gastric cancer (GC) is one of the most malignant tumors, accounting for 10% of deaths caused by all cancers. Chemotherapy is often necessary for treatment of GC; the FOLFOX regimen is extensively applied. However, multidrug resistance (MDR) of GC cells prevents wider application of this treatment. Ubenimex, an inhibitor of CD13, is used as an immune adjuvant to treat hematological malignancies. Here, we demonstrate that CD13 expression positively correlates with MDR development in GC cells. Moreover, Ubenimex reverses the MDR of SGC7901/X and MKN45/X cells and enhances their sensitivity to FOLFOX, in part by decreasing CD13 expression, which is accompanied by downregulation of Bcl-xl, Bcl-2, and survivin expression; increased expression of Bax; and activation of the caspase-3-mediated apoptotic cascade. In addition, Ubenimex downregulates expression of membrane transport proteins, such as P-gp and MRP1, by inhibiting phosphorylation in the PI3K/AKT/mTOR pathway to increase intracellular accumulations of 5-fluorouracil and oxaliplatin, a process for which downregulation of CD13 expression is essential. Therefore, the present results reveal a previously uncharacterized function of CD13 in promoting MDR development in GC cells and suggest that Ubenimex is a candidate for reversing the MDR of GC cells.
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Affiliation(s)
- Qie Guo
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, China
| | - Fan-jing Jing
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, China
| | - Hai-jun Qu
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, China
| | - Wen Xu
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, China
| | - Bing Han
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, China
| | - Xiao-min Xing
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, China
| | - Hong-yan Ji
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, China
| | - Fan-Bo Jing
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, China
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23
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Borchsenius SN, Daks A, Fedorova O, Chernova O, Barlev NA. Effects of mycoplasma infection on the host organism response via p53/NF‐κB signaling. J Cell Physiol 2018; 234:171-180. [DOI: 10.1002/jcp.26781] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 04/23/2018] [Indexed: 12/31/2022]
Affiliation(s)
| | - Alexandra Daks
- Institute of Cytology RAS, Laboratory of Gene Expression Regulation Saint‐Petersburg Russia
| | - Olga Fedorova
- Institute of Cytology RAS, Laboratory of Gene Expression Regulation Saint‐Petersburg Russia
| | - Olga Chernova
- Kazan Scientific Center Kazan Institute of Biochemistry and Biophysics, Laboratory “Omics Technology”, Russian Academy of Sciences Kazan Russia
| | - Nickolai A. Barlev
- Institute of Cytology RAS, Laboratory of Gene Expression Regulation Saint‐Petersburg Russia
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24
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Canonico B, Di Sario G, Cesarini E, Campana R, Luchetti F, Zamai L, Ortolani C, Nasoni MG, Baffone W, Papa S. Monocyte Response to Different Campylobacter jejuni Lysates Involves Endoplasmic Reticulum Stress and the Lysosomal⁻Mitochondrial Axis: When Cell Death Is Better Than Cell Survival. Toxins (Basel) 2018; 10:E239. [PMID: 29899248 PMCID: PMC6024708 DOI: 10.3390/toxins10060239] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 06/06/2018] [Accepted: 06/11/2018] [Indexed: 12/18/2022] Open
Abstract
Campylobacter jejuni is a Gram-negative spiral-shaped bacterium, commonly associated with gastroenteritis in humans. It explicates its virulence also by the cytolethal distending toxin (CDT), able to cause irreversible cell cycle arrest. Infection by C. jejuni may result in the development of the Guillain⁻Barré Syndrome, an acute peripheral neuropathy. Symptoms of this disease could be caused by CDT-induced cell death and a subsequent inflammatory response. We tested C. jejuni lysates from different strains on donor monocytes: in fact, monocytes are potent producers of both pro- and anti-inflammatory cytokines, playing a major role in innate immunity and in non-specific host responses. We found, by cytometric and confocal analyses, that mitochondria and lysosomes were differently targeted: The C. jejuni strain that induced the most relevant mitochondrial alterations was the ATCC 33291, confirming an intrinsic apoptotic pathway, whereas the C. jejuni ISS 1 wild-type strain mostly induced lysosomal alterations. Lysates from all strains induced endoplasmic reticulum (ER) stress in monocytes, suggesting that ER stress was not associated with CDT but to other C. jejuni virulence factors. The ER data were consistent with an increase in cytosolic Ca2+ content induced by the lysates. On the contrary, the changes in lysosomal acidic compartments and p53 expression (occurring together from time 0, T0, to 24 h) were mainly due to CDT. The loss of p53 may prevent or impede cell death and it was not observable with the mutant strain. CDT not only was responsible for specific death effects but also seemed to promote an apoptotic stimuli-resisting pathway.
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Affiliation(s)
- Barbara Canonico
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy.
| | - Gianna Di Sario
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy.
| | - Erica Cesarini
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy.
| | - Raffaella Campana
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy.
| | - Francesca Luchetti
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy.
| | - Loris Zamai
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy.
| | - Claudio Ortolani
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy.
| | - Maria Gemma Nasoni
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy.
| | - Wally Baffone
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy.
| | - Stefano Papa
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy.
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25
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Rikkerink EHA. Pathogens and Disease Play Havoc on the Host Epiproteome-The "First Line of Response" Role for Proteomic Changes Influenced by Disorder. Int J Mol Sci 2018. [PMID: 29518008 PMCID: PMC5877633 DOI: 10.3390/ijms19030772] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Organisms face stress from multiple sources simultaneously and require mechanisms to respond to these scenarios if they are to survive in the long term. This overview focuses on a series of key points that illustrate how disorder and post-translational changes can combine to play a critical role in orchestrating the response of organisms to the stress of a changing environment. Increasingly, protein complexes are thought of as dynamic multi-component molecular machines able to adapt through compositional, conformational and/or post-translational modifications to control their largely metabolic outputs. These metabolites then feed into cellular physiological homeostasis or the production of secondary metabolites with novel anti-microbial properties. The control of adaptations to stress operates at multiple levels including the proteome and the dynamic nature of proteomic changes suggests a parallel with the equally dynamic epigenetic changes at the level of nucleic acids. Given their properties, I propose that some disordered protein platforms specifically enable organisms to sense and react rapidly as the first line of response to change. Using examples from the highly dynamic host-pathogen and host-stress response, I illustrate by example how disordered proteins are key to fulfilling the need for multiple levels of integration of response at different time scales to create robust control points.
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Affiliation(s)
- Erik H A Rikkerink
- The New Zealand Institute for Plant & Food Research Ltd., 120 Mt. Albert Rd., Private Bag 92169, Auckland 1025, New Zealand.
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26
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Li N, Xie C, Lu NH. p53, a potential predictor of Helicobacter pylori infection-associated gastric carcinogenesis? Oncotarget 2018; 7:66276-66286. [PMID: 27556187 PMCID: PMC5323233 DOI: 10.18632/oncotarget.11414] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2016] [Accepted: 08/13/2016] [Indexed: 12/14/2022] Open
Abstract
Helicobacter pylori (H. pylori) is an ancient and persistent inhabitant of the human stomach that is closely linked to the development of gastric cancer (GC). . Emerging evidence suggests that H. pylori strain interactions with gastric epithelial cells subvert the best- characterized p53 tumour suppressor pathway. A high prevalence of p53 mutations is related to H. pylori infection. H. pylori also accelerates p53 protein degradation by disturbing the MDM2-P53 feedback loop. Additionally, H. pylori triggers the alteration of other p53 isoforms. Dysregulation of p53 by H. pylori infection contributes to gastric carcinogenesis by mediating cell proliferation and apoptosis. This review focuses on the regulation of p53 in H. pylori infection-associated GC.
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Affiliation(s)
- Nianshuang Li
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Chuan Xie
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Nong-Hua Lu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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27
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Barabutis N, Dimitropoulou C, Gregory B, Catravas JD. Wild-type p53 enhances endothelial barrier function by mediating RAC1 signalling and RhoA inhibition. J Cell Mol Med 2018; 22:1792-1804. [PMID: 29363851 PMCID: PMC5824363 DOI: 10.1111/jcmm.13460] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 10/02/2017] [Indexed: 12/13/2022] Open
Abstract
Inflammation is the major cause of endothelial barrier hyper‐permeability, associated with acute lung injury and acute respiratory distress syndrome. This study reports that p53 “orchestrates” the defence of vascular endothelium against LPS, by mediating the opposing actions of Rac1 and RhoA in pulmonary tissues. Human lung microvascular endothelial cells treated with HSP90 inhibitors activated both Rac1‐ and P21‐activated kinase, which is an essential element of vascular barrier function. 17AAG increased the phosphorylation of both LIMK and cofilin, in contrast to LPS which counteracted those effects. Mouse lung microvascular endothelial cells exposed to LPS exhibited decreased expression of phospho‐cofilin. 17AAG treatment resulted in reduced levels of active cofilin. Silencing of cofilin pyridoxal phosphate phosphatase (PDXP) blocked the LPS‐induced hyper‐permeability, and P53 inhibition reversed the 17AAG‐induced PDXP down‐regulation. P190RHOGAP suppression enhanced the LPS‐triggered barrier dysfunction in endothelial monolayers. 17AAG treatment resulted in P190RHOGAP induction and blocked the LPS‐induced pMLC2 up‐regulation in wild‐type mice. Pulmonary endothelial cells from “super p53” mice, which carry additional p53‐tg alleles, exhibited a lower response to LPS than the controls. Collectively, our findings help elucidate the mechanisms by which p53 operates to enhance barrier function.
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Affiliation(s)
- Nektarios Barabutis
- Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, USA
| | | | - Betsy Gregory
- Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, USA
| | - John D Catravas
- Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, USA.,School of Medical Diagnostic & Translational Sciences, College of Health Sciences, Old Dominion University, Norfolk, VA, USA
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28
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Aydin Y, Chatterjee A, Chandra PK, Chava S, Chen W, Tandon A, Dash A, Chedid M, Moehlen MW, Regenstein F, Balart LA, Cohen A, Lu H, Wu T, Dash S. Interferon-alpha-induced hepatitis C virus clearance restores p53 tumor suppressor more than direct-acting antivirals. Hepatol Commun 2017; 1:256-269. [PMID: 29404458 PMCID: PMC5721446 DOI: 10.1002/hep4.1025] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 02/07/2017] [Accepted: 02/11/2017] [Indexed: 12/15/2022] Open
Abstract
The mechanism why hepatitis C virus (HCV) clearance by direct-acting antivirals (DAAs) does not eliminate the risk of hepatocellular carcinoma (HCC) among patients with advanced cirrhosis is unclear. Many viral and bacterial infections degrade p53 in favor of cell survival to adapt an endoplasmic reticulum (ER)-stress response. In this study, we examined whether HCV clearance by interferon-alpha or DAAs normalizes the ER stress and restores the expression of p53 tumor suppressor in cell culture. We found that HCV infection induces chronic ER stress and unfolded protein response in untransformed primary human hepatocytes. The unfolded protein response induces chaperone-mediated autophagy (CMA) in infected primary human hepatocytes and Huh-7.5 cells that results in degradation of p53 and induced expression of mouse double minute 2 (Mdm2). Inhibition of p53/Mdm2 interactions by small molecule (nutlin-3) or silencing Mdm2 did not rescue the p53 degradation, indicating that HCV infection induces degradation of p53 independent of the Mdm2 pathway. Interestingly, we found that HCV infection degrades p53 in a lysosome-dependent mechanism because lysosome-associated membrane protein 2A silencing restored p53 degradation. Our results show that HCV clearance induced by interferon-alpha-based antiviral therapies normalizes the ER-stress response and restores p53, whereas HCV clearance by DAAs does neither. We show that decreased expression of p53 in HCV-infected cirrhotic liver is associated with expression of chaperones associated with ER stress and the CMA response. Conclusion: HCV-induced ER stress and CMA promote p53 degradation in advanced liver cirrhosis. HCV clearance by DAAs does not restore p53, which provides a potential explanation for why a viral cure by DAAs does not eliminate the HCC risk among patients with advanced liver disease. We propose that resolving the ER-stress response is an alternative approach to reducing HCC risk among patients with cirrhosis after viral cure. (Hepatology Communications 2017;1:256-269).
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Affiliation(s)
- Yucel Aydin
- Department of Medicine, Division of Gastroenterology and Hepatology Tulane University Health Sciences Center New Orleans LA
| | - Animesh Chatterjee
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center New Orleans LA
| | - Partha K Chandra
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center New Orleans LA
| | - Srinivas Chava
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center New Orleans LA
| | - Weina Chen
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center New Orleans LA
| | - Anamika Tandon
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center New Orleans LA
| | - Asha Dash
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center New Orleans LA
| | - Milad Chedid
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center New Orleans LA
| | - Martin W Moehlen
- Department of Medicine, Division of Gastroenterology and Hepatology Tulane University Health Sciences Center New Orleans LA
| | - Frederic Regenstein
- Department of Medicine, Division of Gastroenterology and Hepatology Tulane University Health Sciences Center New Orleans LA
| | - Luis A Balart
- Department of Medicine, Division of Gastroenterology and Hepatology Tulane University Health Sciences Center New Orleans LA
| | - Ari Cohen
- Liver Transplant Surgery Section Ochsner Medical Center New Orleans LA
| | - Hua Lu
- Department of Biochemistry Tulane University Health Sciences Center New Orleans LA
| | - Tong Wu
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center New Orleans LA
| | - Srikanta Dash
- Department of Medicine, Division of Gastroenterology and Hepatology Tulane University Health Sciences Center New Orleans LA.,Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center New Orleans LA
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29
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Abstract
The excitement around the entry into the clinic of the first generation of p53-specific drugs has become muted as the hoped-for dramatic clinical responses have not yet been seen. However, these pioneer molecules have become exceptionally powerful tools in the analysis of the p53 pathway and, as a result, a whole spectrum of new interventions are being explored. These include entirely novel and innovative approaches to drug discovery, such as the use of exon-skipping antisense oligonucleotides and T-cell-receptor-based molecules. The extraordinary resources available to the p53 community in terms of reagents, models, and collaborative networks are generating breakthrough approaches to medicines for oncology and also for other diseases in which aberrant p53 signaling plays a role.
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30
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Microbial carcinogenic toxins and dietary anti-cancer protectants. Cell Mol Life Sci 2017; 74:2627-2643. [PMID: 28238104 PMCID: PMC5487888 DOI: 10.1007/s00018-017-2487-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 02/03/2017] [Accepted: 02/06/2017] [Indexed: 12/16/2022]
Abstract
Several toxins are known which account for the ability of some bacteria to initiate or promote carcinogenesis. These ideas are summarised and evidence is discussed for more specific mechanisms involving chymotrypsin and the bacterial chymotryptic enzyme subtilisin. Subtilisin and Bacillus subtilis are present in the gut and environment and both are used commercially in agriculture, livestock rearing and meat processing. The enzymes deplete cells of tumour suppressors such as deleted in colorectal cancer (DCC) and neogenin, so their potential presence in the food chain might represent an important link between diet and cancer. Over-eating increases secretion of chymotrypsin which is absorbed from the gut and could contribute to several forms of cancer linked to obesity. Inhibition of these serine proteases by Bowman–Birk inhibitors in fruit and vegetables could account for some of the protective effects of a plant-rich diet. These interactions represent previously unknown non-genetic mechanisms for the modification of tumour suppressor proteins and provide a plausible explanation contributing to both the pro-oncogenic effects of meat products and the protective activity of a plant-rich diet. The data suggest that changes to farming husbandry and food processing methods to remove these sources of extrinsic proteases might significantly reduce the incidence of several cancers.
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Hepatitis C Virus Infection Induces Autophagy as a Prosurvival Mechanism to Alleviate Hepatic ER-Stress Response. Viruses 2016; 8:v8050150. [PMID: 27223299 PMCID: PMC4885105 DOI: 10.3390/v8050150] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Revised: 05/04/2016] [Accepted: 05/18/2016] [Indexed: 12/17/2022] Open
Abstract
Hepatitis C virus (HCV) infection frequently leads to chronic liver disease, liver cirrhosis and hepatocellular carcinoma (HCC). The molecular mechanisms by which HCV infection leads to chronic liver disease and HCC are not well understood. The infection cycle of HCV is initiated by the attachment and entry of virus particles into a hepatocyte. Replication of the HCV genome inside hepatocytes leads to accumulation of large amounts of viral proteins and RNA replication intermediates in the endoplasmic reticulum (ER), resulting in production of thousands of new virus particles. HCV-infected hepatocytes mount a substantial stress response. How the infected hepatocyte integrates the viral-induced stress response with chronic infection is unknown. The unfolded protein response (UPR), an ER-associated cellular transcriptional response, is activated in HCV infected hepatocytes. Over the past several years, research performed by a number of laboratories, including ours, has shown that HCV induced UPR robustly activates autophagy to sustain viral replication in the infected hepatocyte. Induction of the cellular autophagy response is required to improve survival of infected cells by inhibition of cellular apoptosis. The autophagy response also inhibits the cellular innate antiviral program that usually inhibits HCV replication. In this review, we discuss the physiological implications of the HCV-induced chronic ER-stress response in the liver disease progression.
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Yan J, Liu T, Zhou X, Dang Y, Yin C, Zhang G. FZD6, targeted by miR-21, represses gastric cancer cell proliferation and migration via activating non-canonical wnt pathway. Am J Transl Res 2016; 8:2354-2364. [PMID: 27347343 PMCID: PMC4891448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Accepted: 01/22/2016] [Indexed: 06/06/2023]
Abstract
FZD6 plays crucial roles in human tumorigenesis. However, its mechanism in regulating cancers has not been fully elucidated. In the study, we found that FZD6 repressed gastric cancer cell proliferation and migration via activating non-canonical wnt pathway. In addition, non-canonical wnt pathway ameliorated expression of canonical wnt pathway. We also demonstrated that the FZD6 was involved in miR-21-dependent effects in the canonical and non-canonical wnt pathways in gastric cancer. These findings provide a better understanding of the development and progression of gastric cancer and may be an important implication for future therapy.
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Affiliation(s)
- Jin Yan
- Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical UniversityNanjing, Jiangsu 210000, China
- The First Clinical Medical College, Nanjing Medical UniversityNanjing, Jiangsu 210000, China
| | - Tingyu Liu
- Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical UniversityNanjing, Jiangsu 210000, China
- The First Clinical Medical College, Nanjing Medical UniversityNanjing, Jiangsu 210000, China
| | - Xiaoying Zhou
- Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical UniversityNanjing, Jiangsu 210000, China
- The First Clinical Medical College, Nanjing Medical UniversityNanjing, Jiangsu 210000, China
| | - Yini Dang
- Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical UniversityNanjing, Jiangsu 210000, China
- The First Clinical Medical College, Nanjing Medical UniversityNanjing, Jiangsu 210000, China
| | - Chengqiang Yin
- Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical UniversityNanjing, Jiangsu 210000, China
- The First Clinical Medical College, Nanjing Medical UniversityNanjing, Jiangsu 210000, China
| | - Guoxin Zhang
- Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical UniversityNanjing, Jiangsu 210000, China
- The First Clinical Medical College, Nanjing Medical UniversityNanjing, Jiangsu 210000, China
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Heinrich A, Haarmann H, Zahradnik S, Frenzel K, Schreiber F, Klassert TE, Heyl KA, Endres AS, Schmidtke M, Hofmann J, Slevogt H. Moraxella catarrhalis decreases antiviral innate immune responses by down-regulation of TLR3 via inhibition of p53 in human bronchial epithelial cells. FASEB J 2016; 30:2426-34. [PMID: 26979086 DOI: 10.1096/fj.201500172r] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Accepted: 03/01/2016] [Indexed: 12/11/2022]
Abstract
Chronic obstructive pulmonary disease (COPD) is complicated by infectious exacerbations with acute worsening of respiratory symptoms. Coinfections of bacterial and viral pathogens are associated with more severe exacerbations. Moraxella catarrhalis is one of the most frequent lower respiratory tract pathogens detected in COPD. We therefore studied the impact of M. catarrhalis on the antiviral innate immune response that is mediated via TLR3 and p53. Molecular interactions between M. catarrhalis and normal human bronchial epithelial (NHBE) cells as well as Beas-2B cells were studied using flow cytometry, quantitative PCR analysis, chromatin immunoprecipitation, RNA interference, and ELISA. M. catarrhalis induces a significant down-regulation of TLR3 in human bronchial epithelial cells. In M. catarrhalis-infected cells, expression of p53 was decreased. We detected a reduced binding of p53 to the tlr3 promoter, resulting in reduced TLR3 gene transcription. M. catarrhalis diminished the TLR3-dependent secretion of IFN-β, IFN-λ, and chemokine (C-X-C motif) ligand 8. In addition in M. catarrhalis infected cells, expression of rhinovirus type 1A RNA was increased compared with uninfected cells. M. catarrhalis reduces antiviral defense functions of bronchial epithelial cells, which may increase susceptibility to viral infections.-Heinrich, A., Haarmann, H., Zahradnik, S., Frenzel, K., Schreiber, F., Klassert, T. E., Heyl, K. A., Endres, A.-S., Schmidtke, M., Hofmann, J., Slevogt, H. Moraxella catarrhalis decreases antiviral innate immune responses by down-regulation of TLR3 via inhibition of p53 in human bronchial epithelial cells.
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Affiliation(s)
- Annina Heinrich
- Septomics Research Center, Jena University Hospital, Jena, Germany
| | - Helge Haarmann
- Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany
| | - Sabrina Zahradnik
- Institute of Microbiology and Hygiene, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Katrin Frenzel
- Institute of Medical Virology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Frauke Schreiber
- Septomics Research Center, Jena University Hospital, Jena, Germany
| | | | - Kerstin A Heyl
- Septomics Research Center, Jena University Hospital, Jena, Germany
| | | | - Michaela Schmidtke
- Department of Virology and Antiviral Therapy, School of Medicine, Jena University Hospital, Jena, Germany
| | - Jörg Hofmann
- Institute of Medical Virology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Hortense Slevogt
- Septomics Research Center, Jena University Hospital, Jena, Germany;
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Wang Y, Chen CL, Pan QZ, Wu YY, Zhao JJ, Jiang SS, Chao J, Zhang XF, Zhang HX, Zhou ZQ, Tang Y, Huang XQ, Zhang JH, Xia JC. Decreased TPD52 expression is associated with poor prognosis in primary hepatocellular carcinoma. Oncotarget 2016; 7:6323-34. [PMID: 26575170 PMCID: PMC4868759 DOI: 10.18632/oncotarget.6319] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Accepted: 10/22/2015] [Indexed: 02/07/2023] Open
Abstract
Tumor protein D52 (TPD52) has been indicated to be involved in tumorigenesis of various malignancies. But its role in hepatocellular carcinoma (HCC) is unknown. This study aimed to explore the expression of TPD52 in HCC samples and cell lines using real-time quantitative PCR, western blotting, and immunohistochemistry. The prognostic value of TPD52 in HCC was also analysed. Meanwhile, the mechanism of TPD52 in hepatocarcinogenesis was further investigated by western blotting, immunohistochemistry, over-express and knockdown studies. We found that TPD52 expression was significantly decreased in the HCC tissues and HCC cell lines. TPD52 expression was significantly correlated with tumor-nodes-metastasis (TNM) stage. Kaplan-Meier survival curves showed that high TPD52 expression was associated with improved overall survival (OS) and disease-free survival (DFS) in HCC patients. Multivariate analysis indicated that TPD52 expression was an independent prognostic marker for the OS and DFS of patients. In addition, TPD52 expression was positively correlated with p21 and p53 expression, and was negatively correlated with MDM2, BCL2 and P-GSK-3β expression in HCC. In conclusions, our findings suggested that TPD52 is a potential tumor suppressor in HCC. It may be a novel prognostic biomarker and molecular therapy target for HCC.
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Affiliation(s)
- Ying Wang
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Epidemiology and Health Statistics, Guangdong Key Laboratory of Molecular Epidemiology, Guangdong Pharmaceutical University, Guangzhou, China
| | - Chang-Long Chen
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Qiu-Zhong Pan
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Ying-Yuan Wu
- Department of Gynaecology and Obstetrics, Panyu Branch of Armed Police Corps Hospital of Guangdong, Guangzhou, China
| | - Jing-Jing Zhao
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Shan-Shan Jiang
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Jie Chao
- Department of Epidemiology and Health Statistics, Guangdong Key Laboratory of Molecular Epidemiology, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xiao-Fei Zhang
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Hong-Xia Zhang
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Zi-Qi Zhou
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yan Tang
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Xu-Qiong Huang
- Department of Epidemiology and Health Statistics, Guangdong Key Laboratory of Molecular Epidemiology, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jian-Hua Zhang
- Department of Health Service Management, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jian-Chuan Xia
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
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