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Shah SAR, Mumtaz M, Sharif S, Mustafa I, Nayila I. Helicobacter pylori and gastric cancer: current insights and nanoparticle-based interventions. RSC Adv 2025; 15:5558-5570. [PMID: 39967885 PMCID: PMC11834156 DOI: 10.1039/d4ra07886a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 02/07/2025] [Indexed: 02/20/2025] Open
Abstract
Background: H. pylori is recognized as one of the main causes of gastric cancer, and this type of cancer is considered as one of the leading diseases causing cancer deaths all over the world. Knowledge on the interactions between H. pylori and gastric carcinogenesis is important for designing preventive measures. Objective: the objective of this review is to summarize the available literature on H. pylori and gastric cancer, specifically regarding the molecular mechanisms, nanoparticle-based therapy and clinical developments. Methods: the databases including PubMed, Google Scholar and web of science were searched as well as papers from 2010 to 2024 were considered for review. Research literature on H. pylori, gastric cancer, nanoparticles, nanomedicine, and therapeutic interventions was summarized for current findings and possible treatments. Results: the presence of H. pylori in gastric mucosa causes chronic inflammation and several molecular alterations such as DNA alteration, epigenetic changes and activation of oncogenic signaling pathways which causes gastric carcinogenesis. Conventional antibiotic treatments have some issues because of the constantly rising levels of antibiotic resistance. Lipid based nanoformulations, polymeric and metallic nanoparticles have been delivered in treatment of H. pylori to improve drug delivery and alter immunological responses. Conclusion: nanoparticle based interventions have been widely explored as drug delivery systems by improving the treatment strategies against H. pylori induced gastric cancer. Further studies and clinical trials are required to bring these findings into a clinical setting in order to possibly alter the management of H. pylori related gastric malignancies.
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Affiliation(s)
- Syed Ali Raza Shah
- Institute of Molecular Biology and Biotechnology (IMBB), The University of Lahore Lahore Pakistan
| | - Maria Mumtaz
- Institute of Molecular Biology and Biotechnology (IMBB), The University of Lahore Lahore Pakistan
| | - Sumaira Sharif
- Institute of Molecular Biology and Biotechnology (IMBB), The University of Lahore Lahore Pakistan
| | - Imtiaz Mustafa
- Institute of Molecular Biology and Biotechnology (IMBB), The University of Lahore Lahore Pakistan
| | - Iffat Nayila
- Department of Pharmacy, The University of Lahore Sargodha Campus Sargodha Pakistan
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2
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Kanwal R, Esposito JE, Jawed B, Zakir SK, Pulcini R, Martinotti R, Botteghi M, Gaudio F, Martinotti S, Toniato E. Exploring the Role of Epithelial-Mesenchymal Transcriptional Factors Involved in Hematological Malignancy and Solid Tumors: A Systematic Review. Cancers (Basel) 2025; 17:529. [PMID: 39941895 PMCID: PMC11817253 DOI: 10.3390/cancers17030529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 01/13/2025] [Accepted: 01/26/2025] [Indexed: 02/16/2025] Open
Abstract
BACKGROUND The epithelial mesenchymal transition (EMT) is a biological process in which epithelial cells lose their polarity and adhesion characteristics, and adopt a mesenchymal phenotype. While the EMT naturally occurs during tissue fibrosis, wound healing, and embryonic development, it can be exploited by cancer cells and is strongly associated with cancer stem cell formation, tissue invasiveness, apoptosis, and therapy resistance. Transcription factors (TFs) such as SNAIL, ZEB, and TWIST play a pivotal role in driving the EMT. This systematic review aims to assess the impact of EMT-TFs on hematological malignancy and solid tumors. METHODS English-language literature published between 2010 and 2024 was systematically reviewed, utilizing databases such as PubMed and Google Scholar. RESULTS A total of 3250 studies were extracted. Of these, 92 publications meeting the inclusion criteria were analyzed to elucidate the role of EMT-TFs in cancer. The results demonstrated that the EMT-TFs play a critical role in both hematological and solid tumor development and progression. They promote invasive, migratory, and metastatic properties in these tumors, and contribute to therapeutic challenges by enhancing chemoresistance. A strong correlation between EMT-TFs and poor overall survival has been identified. CONCLUSIONS Our research concluded that EMT-TFs may serve as important predictive and prognostic factors, as well as potential therapeutic targets to mitigate cancer progression.
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Affiliation(s)
- Rimsha Kanwal
- Centre of Advanced Studies and Technology, Department of Innovative Technology in Medicine and Dentistry, G.d’ Annunzio University, 66100 Chieti, Italy; (R.K.); (J.E.E.); (B.J.); (S.K.Z.); (R.P.); (E.T.)
- Unit of Clinical Pathology and Microbiology, Miulli Generale Hospital, 70021 Acquaviva delle Fonti, Italy
| | - Jessica Elisabetta Esposito
- Centre of Advanced Studies and Technology, Department of Innovative Technology in Medicine and Dentistry, G.d’ Annunzio University, 66100 Chieti, Italy; (R.K.); (J.E.E.); (B.J.); (S.K.Z.); (R.P.); (E.T.)
| | - Bilal Jawed
- Centre of Advanced Studies and Technology, Department of Innovative Technology in Medicine and Dentistry, G.d’ Annunzio University, 66100 Chieti, Italy; (R.K.); (J.E.E.); (B.J.); (S.K.Z.); (R.P.); (E.T.)
- Unit of Clinical Pathology and Microbiology, Miulli Generale Hospital, 70021 Acquaviva delle Fonti, Italy
| | - Syed Khuram Zakir
- Centre of Advanced Studies and Technology, Department of Innovative Technology in Medicine and Dentistry, G.d’ Annunzio University, 66100 Chieti, Italy; (R.K.); (J.E.E.); (B.J.); (S.K.Z.); (R.P.); (E.T.)
- Unit of Clinical Pathology and Microbiology, Miulli Generale Hospital, 70021 Acquaviva delle Fonti, Italy
| | - Riccardo Pulcini
- Centre of Advanced Studies and Technology, Department of Innovative Technology in Medicine and Dentistry, G.d’ Annunzio University, 66100 Chieti, Italy; (R.K.); (J.E.E.); (B.J.); (S.K.Z.); (R.P.); (E.T.)
| | - Riccardo Martinotti
- Residency Program in Clinical Oncology, Faculty of Medicine, Umberto I University Hospital, University of Rome “La Sapienza”, 00185 Rome, Italy;
| | - Matteo Botteghi
- Experimental Pathology Research Group, Department of Clinical and Molecular Sciences, Universita Politecnica delle Marche, 60126 Ancona, Italy;
| | - Francesco Gaudio
- Unit of Haematology, Department of Medicine and Surgeon, F. Miulli University Hospital, LUM University, Casamassima, 70010 Bari, Italy
| | - Stefano Martinotti
- Unit of Clinical Pathology, Department of Medicine and Surgeon, F. Miulli University Hospital, LUM University, Casamassima, 70010 Bari, Italy
| | - Elena Toniato
- Centre of Advanced Studies and Technology, Department of Innovative Technology in Medicine and Dentistry, G.d’ Annunzio University, 66100 Chieti, Italy; (R.K.); (J.E.E.); (B.J.); (S.K.Z.); (R.P.); (E.T.)
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Paroha R, Wang J, Lee S. PDCD4 as a marker of mTOR pathway activation and therapeutic target in mycobacterial infections. Microbiol Spectr 2024; 12:e0006224. [PMID: 38912807 PMCID: PMC11302300 DOI: 10.1128/spectrum.00062-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 05/20/2024] [Indexed: 06/25/2024] Open
Abstract
Programmed cell death protein 4 (PDCD4) is instrumental in regulating a range of cellular processes such as translation, apoptosis, signal transduction, and inflammatory responses. There is a notable inverse correlation between PDCD4 and the mammalian target of rapamycin (mTOR) pathway, which is integral to cellular growth control. Activation of mTOR is associated with the degradation of PDCD4. Although the role of PDCD4 is well established in oncogenesis and immune response regulation, its function in mycobacterial infections and its interplay with the mTOR pathway necessitate further elucidation. This study investigates the modulation of PDCD4 expression in the context of mycobacterial infections, revealing a consistent pattern of downregulation across diverse mycobacterial species. This observation underscores the potential utility of PDCD4 as a biomarker for assessing mTOR pathway activation during such infections. Building on this finding, we employed a novel approach using PDCD4-based mTOR (Tor)-signal-indicator (TOSI) reporter cells for the high-throughput screening of FDA-approved drugs, focusing on mTOR inhibitors. This methodology facilitated the identification of several agents, inclusive of known mTOR inhibitors, which upregulated PDCD4 expression and concurrently exhibited efficacy in impeding mycobacterial proliferation within macrophages. These results not only reinforce the significance of PDCD4 as a pivotal marker in the understanding of infectious diseases, particularly mycobacterial infections, but also illuminate its potential in the identification of mTOR inhibitors, thereby contributing to the advancement of therapeutic strategies. IMPORTANCE This study emphasizes the critical role of the mammalian target of rapamycin (mTOR) pathway in macrophage responses to mycobacterial infections, elucidating how mycobacteria activate mTOR, resulting in PDCD4 degradation. The utilization of the (Tor)-signal-indicator (TOSI) vector for real-time monitoring of mTOR activity represents a significant advancement in understanding mTOR regulation during mycobacterial infection. These findings deepen our comprehension of mycobacteria's innate immune mechanisms and introduce PDCD4 as a novel marker for mTOR activity in infectious diseases. Importantly, this research laid the groundwork for high-throughput screening of mTOR inhibitors using FDA-approved drugs, offering the potential for repurposing treatments against mycobacterial infections. The identification of drugs that inhibit mTOR activation opens new avenues for host-directed therapies, marking a significant step forward in combating tuberculosis and other mycobacterial diseases.
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Affiliation(s)
- Ruchi Paroha
- Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, Texas, USA
| | - Jia Wang
- Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, Texas, USA
| | - Sunhee Lee
- Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, Texas, USA
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Lin Y, Liu K, Lu F, Zhai C, Cheng F. Programmed cell death in Helicobacter pylori infection and related gastric cancer. Front Cell Infect Microbiol 2024; 14:1416819. [PMID: 39145306 PMCID: PMC11322058 DOI: 10.3389/fcimb.2024.1416819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 07/08/2024] [Indexed: 08/16/2024] Open
Abstract
Programmed cell death (PCD) plays a crucial role in maintaining the normal structure and function of the digestive tract in the body. Infection with Helicobacter pylori (H. pylori) is an important factor leading to gastric damage, promoting the Correa cascade and accelerating the transition from gastritis to gastric cancer. Recent research has shown that several PCD signaling pathways are abnormally activated during H. pylori infection, and the dysfunction of PCD is thought to contribute to the development of gastric cancer and interfere with treatment. With the deepening of studies on H. pylori infection in terms of PCD, exploring the interaction mechanisms between H. pylori and the body in different PCD pathways may become an important research direction for the future treatment of H. pylori infection and H. pylori-related gastric cancer. In addition, biologically active compounds that can inhibit or induce PCD may serve as key elements for the treatment of this disease. In this review, we briefly describe the process of PCD, discuss the interaction between different PCD signaling pathways and the mechanisms of H. pylori infection or H. pylori-related gastric cancer, and summarize the active molecules that may play a therapeutic role in each PCD pathway during this process, with the expectation of providing a more comprehensive understanding of the role of PCD in H. pylori infection.
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Affiliation(s)
- Yukun Lin
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Kunjing Liu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Fang Lu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Changming Zhai
- Department of Rheumatism, Beijing University of Chinese Medicine Third Affiliated Hospital, Beijing, China
| | - Fafeng Cheng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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5
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Zhou J, Zhang M, Wang H, Zhong X, Yang X. Role of Helicobacter pylori virulence factors and alteration of the Tumor Immune Microenvironment: challenges and opportunities for Cancer Immunotherapy. Arch Microbiol 2024; 206:167. [PMID: 38485861 DOI: 10.1007/s00203-024-03908-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 02/19/2024] [Accepted: 02/22/2024] [Indexed: 03/19/2024]
Abstract
Various forms of malignancies have been linked to Helicobacter pylori. Despite advancements in chemotherapeutic and surgical approaches, the management of cancer, particularly at advanced stages, increasingly relies on the integration of immunotherapy. As a novel, safe therapeutic modality, immunotherapy harnesses the immune system of the patient to treat cancer, thereby broadening treatment options. However, there is evidence that H. pylori infection may influence the effectiveness of immunotherapy in various types of cancer. This association is related to H. pylori virulence factors and the tumor microenvironment. This review discusses the influence of H. pylori infection on immunotherapy in non-gastrointestinal and gastrointestinal tumors, the mechanisms underlying this relationship, and directions for the development of improved immunotherapy strategies.
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Affiliation(s)
- Junyi Zhou
- Department of Oncology, The Huai'an Clinical College of Xuzhou Medical University, Huai'an, Jiangsu, China
| | - Minna Zhang
- Department of Gastroenterology, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China
| | - HongGang Wang
- Department of Gastroenterology, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China
| | - Xiaomin Zhong
- Department of Oncology, The Huai'an Clinical College of Xuzhou Medical University, Huai'an, Jiangsu, China.
| | - XiaoZhong Yang
- Department of Gastroenterology, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China.
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Jamal Eddin TM, Nasr SM, Gupta I, Zayed H, Al Moustafa AE. Helicobacter pylori and epithelial mesenchymal transition in human gastric cancers: An update of the literature. Heliyon 2023; 9:e18945. [PMID: 37609398 PMCID: PMC10440535 DOI: 10.1016/j.heliyon.2023.e18945] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 07/25/2023] [Accepted: 08/03/2023] [Indexed: 08/24/2023] Open
Abstract
Gastric cancer, a multifactorial disease, is considered one of the most common malignancies worldwide. In addition to genetic and environmental risk factors, infectious agents, such as Epstein-Barr virus (EBV) and Helicobacter pylori (H.pylori) contribute to the onset and development of gastric cancer. H. pylori is a type I carcinogen that colonizes the gastric epithelium of approximately 50% of the world's population, thus increasing the risk of gastric cancer development. On the other hand, epithelial mesenchymal transition (EMT) is a fundamental process crucial to embryogenic growth, wound healing, organ fibrosis and cancer progression. Several studies associate gastric pathogen infection of the epithelium with EMT initiation, provoking cancer metastasis in the gastric mucosa through various molecular signaling pathways. Additionally, EMT is implicated in the progression and development of H. pylori-associated gastric cancer. In this review, we recapitulate recent findings elucidating the association between H. pylori infection in EMT promotion leading to gastric cancer progression and metastasis.
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Affiliation(s)
- Tala M. Jamal Eddin
- College of Health Sciences, QU Health, Qatar University, PO Box 2713, Doha, Qatar
| | - Shahd M.O. Nasr
- College of Health Sciences, QU Health, Qatar University, PO Box 2713, Doha, Qatar
| | - Ishita Gupta
- College of Medicine, QU Health, Qatar University, PO Box 2713, Doha, Qatar
| | - Hatem Zayed
- College of Health Sciences, QU Health, Qatar University, PO Box 2713, Doha, Qatar
| | - Ala-Eddin Al Moustafa
- College of Medicine, QU Health, Qatar University, PO Box 2713, Doha, Qatar
- Biomedical Research Center, Qatar University, PO Box 2713, Doha, Qatar
- Oncology Department, Faculty of Medicine, McGill University, Montreal, QC, H3G 2M1, Canada
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Nakazawa N, Yokobori T, Sohda M, Hosoi N, Watanabe T, Shimoda Y, Ide M, Sano A, Sakai M, Erkhem-Ochir B, Ogawa H, Shirabe K, Saeki H. Significance of Lipopolysaccharides in Gastric Cancer and Their Potential as a Biomarker for Nivolumab Sensitivity. Int J Mol Sci 2023; 24:11790. [PMID: 37511547 PMCID: PMC10380503 DOI: 10.3390/ijms241411790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 07/18/2023] [Accepted: 07/20/2023] [Indexed: 07/30/2023] Open
Abstract
Lipopolysaccharides are a type of polysaccharide mainly present in the bacterial outer membrane of Gram-negative bacteria. Recent studies have revealed that lipopolysaccharides contribute to the immune response of the host by functioning as a cancer antigen. We retrospectively recruited 198 patients with gastric cancer who underwent surgery. The presence of lipopolysaccharides was determined using immunohistochemical staining, with the intensity score indicating positivity. The relationship between lipopolysaccharides and CD8, PD-L1, TGFBI (a representative downstream gene of TGF-β signaling), wnt3a, and E-cadherin (epithelial-mesenchymal transition marker) was also investigated. Thereafter, we identified 20 patients with advanced gastric cancer receiving nivolumab and investigated the relationship between lipopolysaccharides and nivolumab sensitivity. After staining for lipopolysaccharides in the nucleus of cancer cells, 150 negative (75.8%) and 48 positive cases (24.2%) were found. The lipopolysaccharide-positive group showed increased cancer stromal TGFBI expression (p < 0.0001) and PD-L1 expression in cancer cells (p = 0.0029). Lipopolysaccharide positivity was significantly correlated with increased wnt3a signaling (p = 0.0028) and decreased E-cadherin expression (p = 0.0055); however, no significant correlation was found between lipopolysaccharide expression and overall survival rate (p = 0.71). In contrast, high TGFBI expression in the presence of LPS was associated with a worse prognosis than that in the absence of LPS (p = 0.049). Among cases receiving nivolumab, the lipopolysaccharide-negative and -positive groups had disease control rates of 66.7% and 11.8%, respectively (p = 0.088). Lipopolysaccharide positivity was associated with wnt3a, TGF-β signaling, and epithelial-mesenchymal transition and was considered to tend to promote therapeutic resistance to nivolumab.
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Affiliation(s)
- Nobuhiro Nakazawa
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan
| | - Takehiko Yokobori
- Division of Integrated Oncology Research, Gunma University, Initiative for Advanced Research (GIAR), Maebashi 371-8511, Japan
| | - Makoto Sohda
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan
| | - Nobuhiro Hosoi
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan
| | - Takayoshi Watanabe
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan
| | - Yuki Shimoda
- Department of Diagnostic Pathology, Gunma University Graduate School of Medicine, Gunma University, 3-39-22 Showa-machi, Maebashi 371-8511, Japan
| | - Munenori Ide
- Department of Diagnostic Pathology, Gunma University Graduate School of Medicine, Gunma University, 3-39-22 Showa-machi, Maebashi 371-8511, Japan
| | - Akihiko Sano
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan
| | - Makoto Sakai
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan
| | - Bilguun Erkhem-Ochir
- Division of Integrated Oncology Research, Gunma University, Initiative for Advanced Research (GIAR), Maebashi 371-8511, Japan
| | - Hiroomi Ogawa
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan
| | - Ken Shirabe
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan
| | - Hiroshi Saeki
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8510, Japan
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Bolori S, Shegefti S, Baghaei K, Yadegar A, Moon KM, Foster LJ, Nasiri MJ, Dabiri H. The Effects of Helicobacter pylori-Derived Outer Membrane Vesicles on Hepatic Stellate Cell Activation and Liver Fibrosis In Vitro. BIOMED RESEARCH INTERNATIONAL 2023; 2023:4848643. [PMID: 37090196 PMCID: PMC10116224 DOI: 10.1155/2023/4848643] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 11/05/2022] [Accepted: 03/05/2023] [Indexed: 04/25/2023]
Abstract
INTRODUCTION Helicobacter pylori is a prevalent pathogenic bacterium that resides in the human stomach. Outer membrane vesicles (OMVs) are known as nanosized cargos released by H. pylori, which have been proposed to have a key role in disease progression, pathogenesis, and modulation of the immune system. There are multiple evidences for the role of H. pylori in extragastroduodenal illnesses especially liver-related disorders. However, the precise mechanism of H. pylori extragastroduodenal pathogenesis still remains unclear. In the current study, we aimed to determine the impact of H. pylori-isolated OMVs on hepatic stellate cell (HSC) activation and expression of liver fibrosis markers. MATERIALS AND METHODS Five H. pylori clinical strains with different genotype profiles were used. Helicobacter pylori OMVs were isolated using ultracentrifugation and were analyzed by scanning electron microscopy (SEM) and dynamic light scattering (DLS). Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis was applied to determine protein components of H. pylori-derived OMVs. Cell viability of LX-2 human hepatic stellate cell line exposed to OMVs was measured by MTT assay. LX-2 cells were treated with OMVs for 24 h. The gene expression of α-SMA, E-cadherin, vimentin, snail, and β-catenin was analyzed using quantitative real-time PCR. The protein expression of α-SMA, as a well-studied profibrotic marker, was evaluated with immunocytochemistry. RESULTS Our results showed that H. pylori strains released round shape nanovesicles ranging from 50 to 500 nm. Totally, 112 various proteins were identified in OMVs by proteomic analysis. The isolated OMVs were negative for both CagA and VacA virulence factors. Treatment of HSCs with H. pylori-derived OMVs significantly increased the expression of fibrosis markers. CONCLUSIONS In conclusion, the present study demonstrated that H. pylori-derived OMVs could promote HSC activation and induce the expression of hepatic fibrosis markers. Further research is required to elucidate the definite role of H. pylori-derived OMVs in liver fibrosis and liver-associated disorders.
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Affiliation(s)
- Shahin Bolori
- Microbiology Department, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saina Shegefti
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorder Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Yadegar
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kyung-Mee Moon
- Department of Biochemistry & Molecular Biology, Michael Smith Laboratories, University of British Columbia, Canada
| | - Leonard J. Foster
- Department of Biochemistry & Molecular Biology, Michael Smith Laboratories, University of British Columbia, Canada
| | - Mohammad Javad Nasiri
- Microbiology Department, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hossein Dabiri
- Microbiology Department, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Galvin S, Moran GP, Healy CM. Influence of site and smoking on malignant transformation in the oral cavity: Is the microbiome the missing link? FRONTIERS IN ORAL HEALTH 2023; 4:1166037. [PMID: 37035251 PMCID: PMC10076759 DOI: 10.3389/froh.2023.1166037] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 03/01/2023] [Indexed: 04/11/2023] Open
Abstract
The tongue and floor of the mouth are high-risk sites for oral squamous cell carcinoma (OSCC), while smoking is its most significant risk factor. Recently, questions have been raised as to the role of the oral microbiome in OSCC because of a wealth of evidence demonstrating that the microbiome of OSCC differs from that of healthy mucosa. However, oral site and smoking also have a significant impact on oral microbial communities, and to date, the role these factors play in influencing the dysbiotic microbial communities of OSCC and precursor lesions has not been considered. This review aims to examine the influence of site and smoking on the oral microbiome and, in turn, whether these microbiome changes could be involved in oral carcinogenesis.
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Affiliation(s)
- Sheila Galvin
- Division of Oral and Maxillofacial Surgery, Oral Medicine and Oral Pathology, School of Dental Science, Trinity College Dublin, Dublin Dental University Hospital, Dublin, Ireland
- Correspondence: Sheila Galvin
| | - Gary P. Moran
- Division of Oral Biosciences, School of Dental Science, Trinity College Dublin, Dublin Dental University Hospital, Dublin, Ireland
| | - Claire M. Healy
- Division of Oral and Maxillofacial Surgery, Oral Medicine and Oral Pathology, School of Dental Science, Trinity College Dublin, Dublin Dental University Hospital, Dublin, Ireland
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Islas JF, Quiroz-Reyes AG, Delgado-Gonzalez P, Franco-Villarreal H, Delgado-Gallegos JL, Garza-Treviño EN, Gonzalez-Villarreal CA. Cancer Stem Cells in Tumor Microenvironment of Adenocarcinoma of the Stomach, Colon, and Rectum. Cancers (Basel) 2022; 14:3948. [PMID: 36010940 PMCID: PMC9405851 DOI: 10.3390/cancers14163948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/29/2022] [Accepted: 08/09/2022] [Indexed: 11/17/2022] Open
Abstract
Gastrointestinal adenocarcinomas are one of the world's deadliest cancers. Cancer stem cells and the tissue microenvironment are highly regulated by cell and molecular mechanisms. Cancer stem cells are essential for maintenance and progression and are associated with resistance to conventional treatments. This article reviews the current knowledge of the role of the microenvironment during the primary establishment of gastrointestinal adenocarcinomas in the stomach, colon, and rectum and its relationship with cancer stem cells. We also describe novel developments in cancer therapeutics, such as targeted therapy, and discuss the advantages and disadvantages of different treatments for improving gastrointestinal cancer prognosis.
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Affiliation(s)
- Jose Francisco Islas
- Biochemistry and Molecular Medicine Department, School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey 64460, Mexico
| | - Adriana G. Quiroz-Reyes
- Biochemistry and Molecular Medicine Department, School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey 64460, Mexico
| | - Paulina Delgado-Gonzalez
- Biochemistry and Molecular Medicine Department, School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey 64460, Mexico
| | | | - Juan Luis Delgado-Gallegos
- Biochemistry and Molecular Medicine Department, School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey 64460, Mexico
| | - Elsa N. Garza-Treviño
- Biochemistry and Molecular Medicine Department, School of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey 64460, Mexico
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Old and New Aspects of H. pylori-Associated Inflammation and Gastric Cancer. CHILDREN 2022; 9:children9071083. [PMID: 35884067 PMCID: PMC9322908 DOI: 10.3390/children9071083] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 07/17/2022] [Accepted: 07/18/2022] [Indexed: 12/16/2022]
Abstract
H. pylori is involved in the development of 80% of gastric cancers and 5.5% of all malignant conditions worldwide. Its persistence within the host’s stomach causes chronic inflammation, which is a well-known hallmark of carcinogenesis. A wide range of cytokines was reported to be involved in the initiation and long-term persistence of this local and systemic inflammation. IL-8 was among the first cytokines described to be increased in patients with H. pylori infection. Although, this cytokine was initially identified to exert a chemoattracting effect that represents a trigger for the activation of inflammatory cells within H.-pylori-infected mucosa, more recent studies failed in encountering any association between IL-8 and H. pylori infection. IL-6 is a multifunctional, pleiotropic and multipotent cytokine involved in mediating the interaction between innate and adaptive immunity with a dichotomous role acting as both a proinflammatory and an anti-inflammatory cytokine depending on the signaling pathway. IL-1α functions as a promoter of angiogenesis and vascular endothelial cell proliferation in gastric carcinoma since it is closely related to H.-pylori-induced inflammation in children. IL-1β is an essential trigger and enhancer of inflammation. The association between a low IL-1β level and an increased TNF-α level might be considered a risk factor for peptic ulcer disease in the setting of H. pylori infection. IL-10 downregulates both cytotoxic inflammatory responses and cell-mediated immune responses. H. pylori uses the immunosuppressive role of IL-10 to favor its escape from the host’s immune system. TGFβ is a continuous inflammatory mediator that promotes the adherence of H. pylori to the host’s cells and their subsequent colonization. The role of H.-pylori-induced inflammatory responses in the onset of gastric carcinogenesis seems to represent the missing puzzle piece for designing effective preventive and therapeutic strategies in patients with H.-pylori-associated gastric cancer.
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12
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He J, Hu W, Ouyang Q, Zhang S, He L, Chen W, Li X, Hu C. Helicobacter pylori infection induces stem cell-like properties in Correa cascade of gastric cancer. Cancer Lett 2022; 542:215764. [PMID: 35654291 DOI: 10.1016/j.canlet.2022.215764] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 05/16/2022] [Accepted: 05/26/2022] [Indexed: 02/09/2023]
Abstract
Gastric cancer (GC) is the fourth leading cause of cancer-related death. Its poor prognosis is attributed to unclear pathogenesis. Currently, the most widely accepted model for elucidating the mechanism of GC is the Correa cascade, which covers several histological lesions of the gastric mucosa. GC stem cells (CSCs) are crucial for oncogenesis in the Correa cascade and GC progression. As Helicobacter pylori (H. pylori) is the etiological factor in the Correa cascade, growing evidence suggests that enhancement of gastric stem cell-like properties and increase in CSCs correlate with H. pylori infection. In this paper, we review recent studies that present pathogenic mechanisms by which H. pylori induces gastric stem cell-like properties and CSCs, which may supplement the existing Correa model of GC. First, the dysfunction of developmental signaling pathways associated with H. pylori infection leads to the enhancement of gastric stemness. Second, H. pylori infection promotes alteration of the gastric mucosal microenvironment. In addition, epithelial-mesenchymal transition (EMT) may contribute to H. pylori-induced gastric stemness. Taken together, understanding these pathogeneses will provide potential therapeutic targets for the treatment of CSCs and malignant GC in H. pylori induced-Correa cascade of GC.
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Affiliation(s)
- JunJian He
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - WeiChao Hu
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Qin Ouyang
- Department of Medicinal Chemistry, College of Pharmacy, Army Medical University, Chongqing, 400038, China
| | - ShengWei Zhang
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - LiJiao He
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - WeiYan Chen
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - XinZhe Li
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
| | - ChangJiang Hu
- Department of Gastroenterology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
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13
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Jun Y, Suh YS, Park S, Lee J, Kim JI, Lee S, Lee WP, Anczuków O, Yang HK, Lee C. Comprehensive Analysis of Alternative Splicing in Gastric Cancer Identifies Epithelial-Mesenchymal Transition Subtypes Associated with Survival. Cancer Res 2022; 82:543-555. [PMID: 34903603 PMCID: PMC9359730 DOI: 10.1158/0008-5472.can-21-2117] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 10/25/2021] [Accepted: 12/03/2021] [Indexed: 01/07/2023]
Abstract
Alternatively spliced RNA isoforms are a hallmark of tumors, but their nature, prevalence, and clinical implications in gastric cancer have not been comprehensively characterized. We systematically profiled the splicing landscape of 83 gastric tumors and matched normal mucosa, identifying and experimentally validating eight splicing events that can classify all gastric cancers into three subtypes: epithelial-splicing (EpiS), mesenchymal-splicing (MesS), and hybrid-splicing. These subtypes were associated with distinct molecular signatures and epithelial-mesenchymal transition markers. Subtype-specific splicing events were enriched in motifs for splicing factors RBM24 and ESRP1, which were upregulated in MesS and EpiS tumors, respectively. A simple classifier based only on RNA levels of RBM24 and ESRP1, which can be readily implemented in the clinic, was sufficient to distinguish gastric cancer subtypes and predict patient survival in multiple independent patient cohorts. Overall, this study provides insights into alternative splicing in gastric cancer and the potential clinical utility of splicing-based patient classification. SIGNIFICANCE This study presents a comprehensive analysis of alternative splicing in the context of patient classification, molecular mechanisms, and prognosis in gastric cancer.
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Affiliation(s)
- Yukyung Jun
- The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.,Ewha-JAX Cancer Immunotherapy Research Center, Ewha Womans University, Seoul, Korea.,Center for Supercomputing Applications, Division of National Supercomputing, Korea Institute of Science and Technology Information, Daejeon, Korea
| | - Yun-Suhk Suh
- The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.,Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.,Department of Surgery, Seoul National University Hospital, Seoul, Korea.,Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea
| | - SungHee Park
- The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut
| | - Jieun Lee
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jong-Il Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Sanghyuk Lee
- Ewha-JAX Cancer Immunotherapy Research Center, Ewha Womans University, Seoul, Korea.,Department of Life Science, Ewha Womans University, Seoul, Korea
| | - Wan-Ping Lee
- The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.,The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,School of Cyber Science and Engineering, Xi'an Jiaotong University, Xi'an, China.,Corresponding Authors: Charles Lee, The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06032. Phone: 860-837-2458; E-mail: ; Han-Kwang Yang, ; Olga Anczuków, ; and Wan-Ping Lee,
| | - Olga Anczuków
- The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.,Corresponding Authors: Charles Lee, The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06032. Phone: 860-837-2458; E-mail: ; Han-Kwang Yang, ; Olga Anczuków, ; and Wan-Ping Lee,
| | - Han-Kwang Yang
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.,Department of Surgery, Seoul National University Hospital, Seoul, Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.,Corresponding Authors: Charles Lee, The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06032. Phone: 860-837-2458; E-mail: ; Han-Kwang Yang, ; Olga Anczuków, ; and Wan-Ping Lee,
| | - Charles Lee
- The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.,Ewha-JAX Cancer Immunotherapy Research Center, Ewha Womans University, Seoul, Korea.,Department of Life Science, Ewha Womans University, Seoul, Korea.,The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Corresponding Authors: Charles Lee, The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06032. Phone: 860-837-2458; E-mail: ; Han-Kwang Yang, ; Olga Anczuków, ; and Wan-Ping Lee,
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14
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Zhu YD, Ba H, Chen J, Zhang M, Li P. Celastrus orbiculatus Extract Reduces Stemness of Gastric Cancer Stem Cells by Targeting PDCD4 and EIF3H. Integr Cancer Ther 2021; 20:15347354211058168. [PMID: 34802261 PMCID: PMC8606975 DOI: 10.1177/15347354211058168] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Celastrus orbiculatus ethyl acetate extract (COE) has shown a strong anti-gastric cancer effect, but the understanding of its mechanism is still lacking. The results of previous studies indicated that COE may be able to inhibit the stemness of gastric cancer stem cells (GCSCs) by regulating PDCD4 and EIF3H expression. AIMS To explore if COE could inhibit the stemness of GCSCs by regulating PDCD4 and EIF3H expression in vitro and in vivo. PROCEDURE The GCSCs model was established by stem cell-conditioned culture. Spheroid formation and flow cytometry assays were used to detect the effect of COE on the spheroid formation ability of GCSCs and the percentage of CD44+/CD24+ and ALDH+ cell subpopulations. Western blot analysis was applied to measure the expression of GCSCs biomarkers (Nanog, Oct-4, and SOX-2), PDCD4, and EIF3H in GCSCs treated with COE; and RT-PCR was performed to investigate the effect of COE on PDCD4 mRNA expression in GCSCs. An in vivo tumorigenicity experiment was also conducted to evaluate the effect of COE on tumor-initiating ability of GCSCs in vivo; and the expression of PDCD4 and EIF3H in xenograft tissues was examined by immunohistochemistry (IHC) staining. RESULTS After culture in stem cell-conditioned medium, SGC7901 cells manifested significantly enhanced spheroid formation ability, upregulated Nanog, Oct-4, and SOX-2 expression and increased percentages of CD44+/CD24+ and ALDH+ cell subpopulations, indicating successful establishment of the GCSCs model. COE treatment significantly inhibited the spheroid formation ability of GCSCs and reduced the percentage of CD44+/CD24+ and ALDH+ cell subpopulations. The western blot analysis showed a significant decrease of Nanog, Oct-4, SOX-2, and EIF3H expression and an increase of PDCD4 expression in GCSCs after COE treatment in a concentration-dependent manner. COE treatment also significantly upregulated the mRNA expression of PDCD4 in GCSCs. In addition, COE displayed a strong inhibitory effect on the tumor-initiating ability of GCSCs in vivo and upregulated PDCD4 and downregulated EIF3H expression in xenograft tissues. CONCLUSION COE may be able to inhibit GC growth by suppressing the stemness of GCSCs via regulating PDCD4 and EIF3H expression.
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Affiliation(s)
| | - He Ba
- Medical University of Anhui, Anhui, China
| | - Jie Chen
- Medical University of Anhui, Anhui, China
| | - Mei Zhang
- Medical University of Anhui, Anhui, China
| | - Ping Li
- Medical University of Anhui, Anhui, China
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15
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Abdi E, Latifi-Navid S, Abedi Sarvestani F, Esmailnejad MH. Emerging therapeutic targets for gastric cancer from a host- Helicobacter pylori interaction perspective. Expert Opin Ther Targets 2021; 25:685-699. [PMID: 34410200 DOI: 10.1080/14728222.2021.1971195] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Gastric cancer (GC) has the higher genetic, cytologic, and architectural heterogeneity compared to other gastrointestinal cancers. By inducing gastric inflammation, Helicobacter pylori (HP) may lead to GC through combining bacterial factors with host factors. In this regard, identification of the major therapeutic targets against the host-HP interactions plays a critical role in GC prevention, diagnosis, and treatment. AREAS COVERED This study offers new insights into the promising therapeutic targets against the angiogenesis, invasion, or metastasis of GC from a host-HP interaction perspective. To this end, MEDLINE, EMBASE, LILACS, AIM, and IndMed databases were searched for relevant articles since 1992. EXPERT OPINION Wnt signaling and COX pathway have a well-documented history in the genesis of GC by HP and might be considered as the most promising targets for early GC treatment. Destroying HP may decrease the risk of GC, but it cannot fully hinder the GC development induced by HP infection. Therefore, targeting HP-activated pathways, especially COX-2/Wnt/beta-catenin/VEGF, TLR2/TLR9/COX-2, COX2-PGE2, and NF-κB/COX-2, as well as EPHA2, MMPs, and miR-543/SIRT1 axis, can be an effective measure in the early treatment of GC. However, different clinical trials and large, multi-center cohorts are required to validate these potentially effective targets for GC therapy.
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Affiliation(s)
- Esmat Abdi
- Department of Biology, Faculty of Sciences, University of Mohaghegh Ardabili, Ardabil, Iran
| | - Saeid Latifi-Navid
- Department of Biology, Faculty of Sciences, University of Mohaghegh Ardabili, Ardabil, Iran
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16
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Săsăran MO, Meliț LE, Dobru ED. MicroRNA Modulation of Host Immune Response and Inflammation Triggered by Helicobacter pylori. Int J Mol Sci 2021; 22:ijms22031406. [PMID: 33573346 PMCID: PMC7866828 DOI: 10.3390/ijms22031406] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 01/26/2021] [Accepted: 01/26/2021] [Indexed: 12/15/2022] Open
Abstract
Helicobacter pylori (H. pylori) remains the most-researched etiological factor for gastric inflammation and malignancies. Its evolution towards gastric complications is dependent upon host immune response. Toll-like receptors (TLRs) recognize surface and molecular patterns of the bacterium, especially the lipopolysaccharide (LPS), and act upon pathways, which will finally lead to activation of the nuclear factor-kappa B (NF-kB), a transcription factor that stimulates release of inflammatory cytokines. MicroRNAs (MiRNAs) finely modulate TLR signaling, but their expression is also modulated by activation of NF-kB-dependent pathways. This review aims to focus upon several of the most researched miRNAs on this subject, with known implications in host immune responses caused by H. pylori, including let-7 family, miRNA-155, miRNA-146, miRNA-125, miRNA-21, and miRNA-221. TLR-LPS interactions and their afferent pathways are regulated by these miRNAs, which can be considered as a bridge, which connects gastric inflammation to pre-neoplastic and malignant lesions. Therefore, they could serve as potential non-invasive biomarkers, capable of discriminating H. pylori infection, as well as its associated complications. Given that data on this matter is limited in children, as well as for as significant number of miRNAs, future research has yet to clarify the exact involvement of these entities in the progression of H. pylori-associated gastric conditions.
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Affiliation(s)
- Maria Oana Săsăran
- Department of Pediatrics III, “George Emil Palade” University of Medicine, Pharmacy, Sciences and Technology of Târgu Mureș, Gheorghe Marinescu Street no 38, 540136 Târgu Mureș, Romania;
| | - Lorena Elena Meliț
- Department of Pediatrics I, “George Emil Palade” University of Medicine, Pharmacy, Sciences and Technol-ogy of Târgu Mureș, Gheorghe Marinescu Street no 38, 540136 Târgu Mureș, Romania
- Correspondence: ; Tel.: +40-742-984744
| | - Ecaterina Daniela Dobru
- Department of Internal Medicine VII, “George Emil Palade” University of Medicine, Pharmacy, Sciences and Technology of Târgu Mureș, Gheorghe Marinescu Street no 38, 540136 Târgu Mureș, Romania;
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17
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Kozak J, Forma A, Czeczelewski M, Kozyra P, Sitarz E, Radzikowska-Büchner E, Sitarz M, Baj J. Inhibition or Reversal of the Epithelial-Mesenchymal Transition in Gastric Cancer: Pharmacological Approaches. Int J Mol Sci 2020; 22:ijms22010277. [PMID: 33383973 PMCID: PMC7795012 DOI: 10.3390/ijms22010277] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/22/2020] [Accepted: 12/24/2020] [Indexed: 12/12/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) constitutes one of the hallmarks of carcinogenesis consisting in the re-differentiation of the epithelial cells into mesenchymal ones changing the cellular phenotype into a malignant one. EMT has been shown to play a role in the malignant transformation and while occurring in the tumor microenvironment, it significantly affects the aggressiveness of gastric cancer, among others. Importantly, after EMT occurs, gastric cancer patients are more susceptible to the induction of resistance to various therapeutic agents, worsening the clinical outcome of patients. Therefore, there is an urgent need to search for the newest pharmacological agents targeting EMT to prevent further progression of gastric carcinogenesis and potential metastases. Therapies targeted at EMT might be combined with other currently available treatment modalities, which seems to be an effective strategy to treat gastric cancer patients. In this review, we have summarized recent advances in gastric cancer treatment in terms of targeting EMT specifically, such as the administration of polyphenols, resveratrol, tangeretin, luteolin, genistein, proton pump inhibitors, terpenes, other plant extracts, or inorganic compounds.
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Affiliation(s)
- Joanna Kozak
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Alicja Forma
- Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (A.F.); (M.C.)
| | - Marcin Czeczelewski
- Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (A.F.); (M.C.)
| | - Paweł Kozyra
- Student Research Group, Independent Radiopharmacy Unit, Faculty of Pharmacy, Medical University of Lublin, PL-20093 Lublin, Poland;
| | - Elżbieta Sitarz
- 1st Department of Psychiatry, Psychotherapy and Early Intervention, Medical University of Lublin, Gluska Street 1, 20-439 Lublin, Poland;
| | - Elżbieta Radzikowska-Büchner
- Department of Plastic Surgery, Central Clinical Hospital of the Ministry of the Interior in Warsaw, 01-211 Warsaw, Poland;
| | - Monika Sitarz
- Department of Conservative Dentistry with Endodontics, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Jacek Baj
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland;
- Correspondence:
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18
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Baj J, Forma A, Sitarz M, Portincasa P, Garruti G, Krasowska D, Maciejewski R. Helicobacter pylori Virulence Factors-Mechanisms of Bacterial Pathogenicity in the Gastric Microenvironment. Cells 2020; 10:27. [PMID: 33375694 PMCID: PMC7824444 DOI: 10.3390/cells10010027] [Citation(s) in RCA: 201] [Impact Index Per Article: 40.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/18/2020] [Accepted: 12/22/2020] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer constitutes one of the most prevalent malignancies in both sexes; it is currently the fourth major cause of cancer-related deaths worldwide. The pathogenesis of gastric cancer is associated with the interaction between genetic and environmental factors, among which infection by Helicobacter pylori (H. pylori) is of major importance. The invasion, survival, colonization, and stimulation of further inflammation within the gastric mucosa are possible due to several evasive mechanisms induced by the virulence factors that are expressed by the bacterium. The knowledge concerning the mechanisms of H. pylori pathogenicity is crucial to ameliorate eradication strategies preventing the possible induction of carcinogenesis. This review highlights the current state of knowledge and the most recent findings regarding H. pylori virulence factors and their relationship with gastric premalignant lesions and further carcinogenesis.
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Affiliation(s)
- Jacek Baj
- Department of Anatomy, Medical University of Lublin, 20-400 Lublin, Poland;
| | - Alicja Forma
- Chair and Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Monika Sitarz
- Department of Conservative Dentistry with Endodontics, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Piero Portincasa
- Clinica Medica “Augusto Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Gabriella Garruti
- Section of Endocrinology, Department of Emergency and Organ Transplantations, University of Bari “Aldo Moro” Medical School, Piazza G. Cesare 11, 70124 Bari, Italy;
| | - Danuta Krasowska
- Department of Dermatology, Venerology and Paediatric Dermatology of Medical University of Lublin, 20-081 Lublin, Poland;
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19
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Programmed cell death 4 modulates lysosomal function by inhibiting TFEB translation. Cell Death Differ 2020; 28:1237-1250. [PMID: 33100324 DOI: 10.1038/s41418-020-00646-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 10/10/2020] [Accepted: 10/13/2020] [Indexed: 12/27/2022] Open
Abstract
Transcription factor EB (TFEB) is a master regulator of autophagy and lysosomal biogenesis. The post-translational phosphorylation modulations of TFEB by mTOR and ERK signaling can determine its nucleocytoplasmic shuttling and activity in response to nutrient availability. However, regulations of TFEB at translational level are rarely known. Here, we found that programmed cell death 4 (PDCD4), a tumor suppressor, decreased levels of nuclear TFEB to inhibit lysosome biogenesis and function. Mechanistically, PDCD4 reduces global pool of TFEB by suppressing TFEB translation in an eIF4A-dependent manner, rather than influencing mTOR- and ERK2-dependnet TFEB nucleocytoplasmic shuttling. Both of MA3 domains within PDCD4 are required for TFEB translation inhibition. Furthermore, TFEB is required for PDCD4-mediated lysosomal function suppression. In the tumor microenvironment, PDCD4 deficiency promotes the anti-tumor effect of macrophage via enhancing TFEB expression. Our research reveals a novel PDCD4-dependent TFEB translational regulation and supports PDCD4 as a potential therapeutic target for lysosome dysfunction related diseases.
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20
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The changing face of gastric cancer: epidemiologic trends and advances in novel therapies. Cancer Gene Ther 2020; 28:390-399. [PMID: 33009508 DOI: 10.1038/s41417-020-00234-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 08/19/2020] [Accepted: 09/21/2020] [Indexed: 02/07/2023]
Abstract
Gastric cancer is an aggressive solid-tumor malignancy with poor prognosis. The epidemiologic face of gastric cancer is changing and further insight into its heterogenous immunohistopathologic nature is needed to develop personalized therapies for specific patient populations. In this review, we highlight changes in gastric cancer epidemiology with a special emphasis on racial and ethnic variations and discuss the implications of current clinical and preclinical treatment advances.
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21
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Shin CM. Alternations of Gastric Microbiota with Mucosal Atrophy and Intestinal Metaplasia. THE KOREAN JOURNAL OF HELICOBACTER AND UPPER GASTROINTESTINAL RESEARCH 2020. [DOI: 10.7704/kjhugr.2020.0037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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22
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Baj J, Korona-Głowniak I, Forma A, Maani A, Sitarz E, Rahnama-Hezavah M, Radzikowska E, Portincasa P. Mechanisms of the Epithelial-Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer. Cells 2020; 9:1055. [PMID: 32340207 PMCID: PMC7225971 DOI: 10.3390/cells9041055] [Citation(s) in RCA: 105] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 04/16/2020] [Accepted: 04/17/2020] [Indexed: 12/11/2022] Open
Abstract
Helicobacter pylori (H. pylori) is one of the most common human pathogens, affecting half of the world's population. Approximately 20% of the infected patients develop gastric ulcers or neoplastic changes in the gastric stroma. An infection also leads to the progression of epithelial-mesenchymal transition within gastric tissue, increasing the probability of gastric cancer development. This paper aims to review the role of H. pylori and its virulence factors in epithelial-mesenchymal transition associated with malignant transformation within the gastric stroma. The reviewed factors included: CagA (cytotoxin-associated gene A) along with induction of cancer stem-cell properties and interaction with YAP (Yes-associated protein pathway), tumor necrosis factor α-inducing protein, Lpp20 lipoprotein, Afadin protein, penicillin-binding protein 1A, microRNA-29a-3p, programmed cell death protein 4, lysosomal-associated protein transmembrane 4β, cancer-associated fibroblasts, heparin-binding epidermal growth factor (HB-EGF), matrix metalloproteinase-7 (MMP-7), and cancer stem cells (CSCs). The review summarizes the most recent findings, providing insight into potential molecular targets and new treatment strategies for gastric cancer.
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Affiliation(s)
- Jacek Baj
- Chair and Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Izabela Korona-Głowniak
- Department of Pharmaceutical Microbiology with Laboratory for Microbiological Diagnostics, Medical University of Lublin, Chodzki 1 Street, 20-093 Lublin, Poland;
| | - Alicja Forma
- Chair and Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Amr Maani
- Chair and Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Elżbieta Sitarz
- Chair and 1st Department of Psychiatry, Psychotherapy and Early Intervention, Medical University of Lublin, Gluska Street 1, 20-439 Lublin, Poland;
| | - Mansur Rahnama-Hezavah
- Chair and Department of Oral Surgery, Medical University of Lublin, 20-081 Lublin, Poland;
| | - Elżbieta Radzikowska
- Department of Plastic Surgery, Central Clinical Hospital of the MSWiA in Warsaw, 01-211 Warsaw, Poland;
| | - Piero Portincasa
- Clinica Medica A. Murri, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro Medical School, 70126 Bari, Italy;
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23
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Baj J, Brzozowska K, Forma A, Maani A, Sitarz E, Portincasa P. Immunological Aspects of the Tumor Microenvironment and Epithelial-Mesenchymal Transition in Gastric Carcinogenesis. Int J Mol Sci 2020; 21:2544. [PMID: 32268527 PMCID: PMC7177728 DOI: 10.3390/ijms21072544] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 03/30/2020] [Accepted: 04/02/2020] [Indexed: 12/11/2022] Open
Abstract
Infection with Helicobacter pylori, a Gram-negative, microaerophilic pathogen often results in gastric cancer in a subset of affected individuals. This explains why H. pylori is the only bacterium classified as a class I carcinogen by the World Health Organization. Several studies have pinpointed mechanisms by which H. pylori alters signaling pathways in the host cell to cause diseases. In this article, the authors have reviewed 234 studies conducted over a span of 18 years (2002-2020). The studies investigated the various mechanisms associated with gastric cancer induction. For the past 1.5 years, researchers have discovered new mechanisms contributing to gastric cancer linked to H. pylori etiology. Alongside alteration of the host signaling pathways using oncogenic CagA pathways, H. pylori induce DNA damage in the host and alter the methylation of DNA as a means of perturbing downstream signaling. Also, with H. pylori, several pathways in the host cell are activated, resulting in epithelial-to-mesenchymal transition (EMT), together with the induction of cell proliferation and survival. Studies have shown that H. pylori enhances gastric carcinogenesis via a multifactorial approach. What is intriguing is that most of the targeted mechanisms and pathways appear common with various forms of cancer.
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Affiliation(s)
- Jacek Baj
- Chair and Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (A.F.); (A.M.)
| | - Karolina Brzozowska
- Chair and Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Alicja Forma
- Chair and Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (A.F.); (A.M.)
| | - Amr Maani
- Chair and Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (A.F.); (A.M.)
| | - Elżbieta Sitarz
- Chair and 1st Department of Psychiatry, Psychotherapy and Early Intervention, Medical University of Lublin, Gluska Street 1, 20-439 Lublin, Poland;
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, 70124 Bari, Italy;
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24
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Zhang S, Li C, Liu J, Geng F, Shi X, Li Q, Lu Z, Pan Y. Fusobacterium nucleatum promotes epithelial-mesenchymal transiton through regulation of the lncRNA MIR4435-2HG/miR-296-5p/Akt2/SNAI1 signaling pathway. FEBS J 2020; 287:4032-4047. [PMID: 31997506 PMCID: PMC7540502 DOI: 10.1111/febs.15233] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 01/03/2020] [Accepted: 01/27/2020] [Indexed: 12/23/2022]
Abstract
Fusobacterium nucleatum, an anaerobic oral opportunistic pathogen associated with periodontitis, has been considered to be associated with the development of oral squamous cell carcinoma (OSCC). However, the initial host molecular alterations induced by F. nucleatum infection which may promote predisposition to malignant transformation through epithelial–mesenchymal transition (EMT) have not yet been clarified. In the present study, we monitored the ability of F. nucleatum to induce EMT‐associated features, and our results showed that F. nucleatum infection promoted cell migration in either noncancerous human immortalized oral epithelial cells (HIOECs) or the two OSCC cell lines SCC‐9 and HSC‐4, but did not accelerate cell proliferation or cell cycle progression. Mesenchymal markers, including N‐cadherin, Vimentin, and SNAI1, were upregulated, while E‐cadherin was decreased and was observed to translocate to the cytoplasm. Furthermore, FadA adhesin and heat‐inactivated F. nucleatum were found to cause a similar effect as the viable bacterial cells. The upregulated lncRNA MIR4435‐2HG identified by the high‐throughput sequencing was demonstrated to negatively regulate the expression of miR‐296‐5p, which was downregulated in F. nucleatum‐infected HIOECs and SCC‐9 cells. The binding of MIR4435‐2HG and miR‐296‐5p was validated via a dual‐luciferase reporter assay. Additionally, knockdown of MIR4435‐2HG with siRNA leads to a decrease in SNAI1 expression, while miR‐296‐5p could further negatively and indirectly regulate SNAI1 expression via Akt2. Therefore, our study demonstrated that F. nucleatum infection could trigger EMT via lncRNA MIR4435‐2HG/miR‐296‐5p/Akt2/SNAI1 signaling pathway, and EMT process may be a probable link between F. nucleatum infection and initiation of oral epithelial carcinomas.
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Affiliation(s)
- Shuwei Zhang
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Shenyang, China
| | - Chen Li
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Shenyang, China.,Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University, Shenyang, China
| | - Junchao Liu
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Shenyang, China
| | - Fengxue Geng
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Shenyang, China
| | - Xiaoting Shi
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Shenyang, China
| | - Qian Li
- Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University, Shenyang, China
| | - Ze Lu
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Shenyang, China
| | - Yaping Pan
- Department of Periodontics, School and Hospital of Stomatology, China Medical University, Shenyang, China.,Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University, Shenyang, China
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25
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Hu Y, Wei X, Lv Y, Xie X, Yang L, He J, Tao X, Ma Y, Su Y, Wu L, Fang W, Liu Z. EIF3H interacts with PDCD4 enhancing lung adenocarcinoma cell metastasis. Am J Cancer Res 2020; 10:179-195. [PMID: 32064160 PMCID: PMC7017739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 12/16/2019] [Indexed: 06/10/2023] Open
Abstract
Lung adenocarcinoma (LUAD) is a common type of lung cancer characterized by a high incidence of local invasion and metastasis. Programmed cell death factor 4 (PDCD4) is a well-recognized tumor suppressor gene involved in LUAD, however its precise regulatory mechanism remains elusive. This is the first study to report an inverse regulatory relationship between PDCD4 and eukaryotic translation initiation factor 3 subunit H (EIF3H) in LUAD. Co-immunoprecipitation assays combined with mass spectrometry and immunofluorescent co-localization indicated that PDCD4 interacted with EIF3H. Overexpression of PDCD4 in LUAD cells reduced EIF3H mRNA and protein levels by suppressing c-Jun-induced EIF3H transcription. Further, an elevated level of EIF3H protein was found in LUAD tissues compared with para-cancerous normal lung tissues, and was found to be an unfavorable factor promoting LUAD pathogenesis. Moreover, the negative correlation between PDCD4 and EIF3H protein expression was confirmed in LUAD tissues. Functional analyses showed that EIF3H overexpression promoted LUAD cell migration and invasion in vitro as well as metastasis in nude mice by activating epithelial-mesenchymal transition (EMT) signaling. Conversely, EIF3H knockdown with small interfering RNAs reversed these changes in LUAD cells. Furthermore, we discovered that introduction of PDCD4 to EIF3H-overexpressing LUAD cells abrogated the function of EIF3H, reducing migration and invasion of LUAD cells by downregulating EMT signaling. Taken together, our findings identified a previously unknown negative regulation of PDCD4 on EIF3H and confirmed EIF3H as an oncogenic factor in LUAD by enhancing EMT signaling, which was abrogated by PDCD4.
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Affiliation(s)
- Yingying Hu
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical UniversityGuangzhou 510095, Guangdong, P. R. China
| | - Xiao Wei
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical UniversityGuangzhou 510095, Guangdong, P. R. China
| | - Yumin Lv
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical UniversityGuangzhou 510095, Guangdong, P. R. China
| | - Xin Xie
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical UniversityGuangzhou 510095, Guangdong, P. R. China
| | - Liu Yang
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical UniversityGuangzhou 510095, Guangdong, P. R. China
| | - Jingjing He
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical UniversityGuangzhou 510095, Guangdong, P. R. China
| | - Xingyu Tao
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical UniversityGuangzhou 510095, Guangdong, P. R. China
| | - Yuting Ma
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical UniversityGuangzhou 510095, Guangdong, P. R. China
| | - Yun Su
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical UniversityGuangzhou 510095, Guangdong, P. R. China
| | - Liyang Wu
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical UniversityGuangzhou 510095, Guangdong, P. R. China
| | - Weiyi Fang
- Cancer Institute, Southern Medical UniversityGuangzhou 510515, Guangdong, P. R. China
| | - Zhen Liu
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical UniversityGuangzhou 510095, Guangdong, P. R. China
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26
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Wang W, Xie G, Ren Z, Xie T, Li J. Gene Selection for the Discrimination of Colorectal Cancer. Curr Mol Med 2019; 20:415-428. [PMID: 31746296 DOI: 10.2174/1566524019666191119105209] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 10/29/2019] [Accepted: 10/31/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND Colorectal cancer (CRC) is the third most common cancer worldwide. Cancer discrimination is a typical application of gene expression analysis using a microarray technique. However, microarray data suffer from the curse of dimensionality and usual imbalanced class distribution between the majority (tumor samples) and minority (normal samples) classes. Feature gene selection is necessary and important for cancer discrimination. OBJECTIVES To select feature genes for the discrimination of CRC. METHODS We improve the feature selection algorithm based on differential evolution, DEFSw by using RUSBoost classifier and weight accuracy instead of the common classifier and evaluation measure for selecting feature genes from imbalance data. We firstly extract differently expressed genes (DEGs) from the CRC dataset of the TCGA and then select the feature genes from the DEGs using the improved DEFSw algorithm. Finally, we validate the selected feature gene sets using independent datasets and retrieve the cancer related information for these genes based on text mining through the Coremine Medical online database. RESULTS We select out 16 single-gene feature sets for colorectal cancer discrimination and 19 single-gene feature sets only for colon cancer discrimination. CONCLUSIONS In summary, we find a series of high potential candidate biomarkers or signatures, which can discriminate either or both of colon cancer and rectal cancer with high sensitivity and specificity.
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Affiliation(s)
- Wenhui Wang
- Network Information Center, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.,National Engineering Research Center of Digital Life, Sun Yat-sen University, Guangzhou, China.,Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Guanglei Xie
- Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Zhonglu Ren
- College of Medical Information Engineering, Guangdong Pharmaceutical University, Guangzhou, China
| | - Tingyan Xie
- Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Jinming Li
- Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
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27
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Zhu Y, Liu L, Hu L, Dong W, Zhang M, Liu Y, Li P. Effect of Celastrus orbiculatus in inhibiting Helicobacter pylori induced inflammatory response by regulating epithelial mesenchymal transition and targeting miR-21/PDCD4 signaling pathway in gastric epithelial cells. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 19:91. [PMID: 31035975 PMCID: PMC6489279 DOI: 10.1186/s12906-019-2504-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Accepted: 04/15/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND The extract of Celastrus orbiculatus (COE) have been studied for anti-Helicobacter pylori (H. pylori) activity and anti-cancer effects in vitro and in vivo. However, the molecular mechanism by which COE inhibits H. pylori-induced inflammatory response has not been fully elucidated so far. METHODS The effects of COE on viability, morphological changes, inflammatory cytokine secretion, protein and mRNA expression were analyzed by MTT assay, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, western blot and real-time PCR (RT-PCR), respectively. The methylation level of programmed cell death 4 (PDCD4) promoter was investigated by methylation-specific PCR. (MSP) . RESULTS COE effectively inhibited the H.pylori-induced inflammatory response by regulating epithelial-mesenchymal transition (EMT). The methylation level of PDCD4 promoter was suppressed by COE, which increased the expression ofPDCD4. Moreover, COE could inhibit microRNA-21 (miR-21) expression, as shown by an enhancement of its target gene PDCD4. Furthermore, both miR-21 over-expression and PDCD4 silencing attenuated the anti-inflammatory effect. of COE. CONCLUSIONS COE inhibits H. pylori induced inflammatory response through regulating EMT, correlating with inhibition of miR-21/PDCD4 signal pathways in gastric epithelial cells.
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Affiliation(s)
- Yaodong Zhu
- Chinese Integrative Medicine Oncology Department, First Affiliated Hospital of Medical University of Anhui, Hefei, 230000 Anhui China
| | - Lei Liu
- General Surgery Department, First Affiliated Hospital of Medical University of Anhui, Hefei, 230000 Anhui China
| | - Lei Hu
- Emergency Department, First Affiliated Hospital of Medical University of Anhui, Hefei, 230000 Anhui China
| | - Wenqing Dong
- Chinese Integrative Medicine Oncology Department, First Affiliated Hospital of Medical University of Anhui, Hefei, 230000 Anhui China
| | - Mei Zhang
- Chinese Integrative Medicine Oncology Department, First Affiliated Hospital of Medical University of Anhui, Hefei, 230000 Anhui China
| | - Yanqing Liu
- Institute of Combining Chinese Traditional and Western Medicine, Medical College, Yangzhou University, Yangzhou, 225009 Jiangsu China
| | - Ping Li
- Chinese Integrative Medicine Oncology Department, First Affiliated Hospital of Medical University of Anhui, Hefei, 230000 Anhui China
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28
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O'Rourke F, Kempf VAJ. Interaction of bacteria and stem cells in health and disease. FEMS Microbiol Rev 2019; 43:162-180. [DOI: 10.1093/femsre/fuz003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 01/11/2019] [Indexed: 12/11/2022] Open
Affiliation(s)
- Fiona O'Rourke
- Institut für Medizinische Mikrobiologie und Krankenhaushygiene, University Hospital, Goethe University, Paul-Ehrlich-Str. 40, D-60596 Frankfurt am Main, Germany
| | - Volkhard A J Kempf
- Institut für Medizinische Mikrobiologie und Krankenhaushygiene, University Hospital, Goethe University, Paul-Ehrlich-Str. 40, D-60596 Frankfurt am Main, Germany
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29
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Marques MS, Melo J, Cavadas B, Mendes N, Pereira L, Carneiro F, Figueiredo C, Leite M. Afadin Downregulation by Helicobacter pylori Induces Epithelial to Mesenchymal Transition in Gastric Cells. Front Microbiol 2018; 9:2712. [PMID: 30473688 PMCID: PMC6237830 DOI: 10.3389/fmicb.2018.02712] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2018] [Accepted: 10/23/2018] [Indexed: 12/30/2022] Open
Abstract
Afadin is a cytoplasmic protein of the adherens junctions, which regulates the formation and stabilization of both the adherens and the tight junctions. Aberrant expression of Afadin has been shown in cancer and its loss has been associated with epithelial-to-mesenchymal transition (EMT). EMT is characterized by the change from an epithelial to a mesenchymal phenotype, with modifications on the expression of adhesion molecules and acquisition of a migratory and invasive cell behavior. While it is known that Helicobacter pylori disrupts the tight and the adherens junctions and induces EMT, the effect of the bacteria on Afadin is still unknown. The aim of this study was to disclose the effect of H. pylori on Afadin and its impact in the induction of an EMT phenotype in gastric cells. Using two different cell lines, we observed that H. pylori infection decreased Afadin protein levels, independently of CagA, T4SS, and VacA virulence factors. H. pylori infection of cell lines recapitulated several EMT features, displacing and downregulating multiple proteins from cell–cell junctions, and increasing the expression of ZEB1, Vimentin, Slug, N-cadherin, and Snail. Silencing of Afadin by RNAi promoted delocalization of junctional proteins from the cell–cell contacts, increased paracellular permeability, and decreased transepithelial electrical resistance, all compatible with impaired junctional integrity. Afadin silencing also led to increased expression of the EMT marker Snail, and to the formation of actin stress fibers, together with increased cell motility and invasion. Finally, and in line with our in vitro data, the gastric mucosa of individuals infected with H. pylori showed decrease/loss of Afadin membrane staining at cell–cell contacts significantly more frequently than uninfected individuals. In conclusion, Afadin is downregulated by H. pylori infection in vitro and in vivo, and its downregulation leads to the emergence of EMT and to the acquisition of an aggressive phenotype in gastric cells, which can contribute to gastric carcinogenesis.
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Affiliation(s)
- Miguel Sardinha Marques
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Ipatimup - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.,Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Joana Melo
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Ipatimup - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal
| | - Bruno Cavadas
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Ipatimup - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal
| | - Nuno Mendes
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Ipatimup - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | - Luísa Pereira
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Ipatimup - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.,Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Fátima Carneiro
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Ipatimup - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.,Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal.,Department of Pathology, Centro Hospitalar São João, Porto, Portugal
| | - Ceu Figueiredo
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Ipatimup - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.,Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Marina Leite
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Ipatimup - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.,Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal
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30
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Molaei F, Forghanifard MM, Fahim Y, Abbaszadegan MR. Molecular Signaling in Tumorigenesis of Gastric Cancer. IRANIAN BIOMEDICAL JOURNAL 2018; 22:217-230. [PMID: 29706061 PMCID: PMC5949124 DOI: 10.22034/ibj.22.4.217] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2017] [Revised: 01/28/2018] [Accepted: 02/03/2018] [Indexed: 02/07/2023]
Abstract
Gastric cancer (GC) is regarded as the fifth most common cancer and the third cause of cancer-related deaths worldwide. Mechanism of GC pathogenesis is still unclear and relies on multiple factors, including environmental and genetic characteristics. One of the most important environmental factors of GC occurrence is infection with Helicobacter pylori that is classified as class one carcinogens. Dysregulation of several genes and pathways play an essential role during gastric carcinogenesis. Dysregulation of developmental pathways such as Wnt/β-catenin signaling, Hedgehog signaling, Hippo pathway, Notch signaling, nuclear factor-kB, and epidermal growth factor receptor have been found in GC. Epithelial-mesenchymal transition, as an important process during embryogenesis and tumorigenesis, is supposed to play a role in initiation, invasion, metastasis, and progression of GC. Although surgery is the main therapeutic modality of the disease, the understanding of biological processes of cell signaling pathways may help to develop new therapeutic targets for GC.
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Affiliation(s)
- Fatemeh Molaei
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Yasaman Fahim
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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31
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Zhang X, Shi D, Liu YP, Chen WJ, Wu D. Effects of the Helicobacter pylori Virulence Factor CagA and Ammonium Ion on Mucins in AGS Cells. Yonsei Med J 2018; 59:633-642. [PMID: 29869461 PMCID: PMC5990679 DOI: 10.3349/ymj.2018.59.5.633] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 04/17/2018] [Accepted: 04/25/2018] [Indexed: 12/22/2022] Open
Abstract
PURPOSE To investigate the effects of Helicobacter pylori (H. pylori)-CagA and the urease metabolite NH₄⁺ on mucin expression in AGS cells. MATERIALS AND METHODS AGS cells were transfected with CagA and/or treated with different concentrations of NH₄CL. Mucin gene and protein expression was assessed by qPCR and immunofluorescence assays, respectively. RESULTS CagA significantly upregulated MUC5AC, MUC2, and MUC5B expression in AGS cells, but did not affect E-cadherin and MUC6 expression. MUC5AC, MUC6, and MUC2 expression in AGS cells increased with increasing NH₄⁺ concentrations until reaching a peak level at 15 mM. MUC5B mRNA expression in AGS cells (NH₄⁺ concentration of 15 mM) was significantly higher than that at 0, 5, and 10 mM NH₄⁺. No changes in E-cadherin expression in AGS cells treated with NH₄⁺ were noted, except at 20 mM. The expression of MUC5AC, MUC2, and MUC6 mRNA in CagA-transfected AGS cells at an NH₄⁺ concentration of 15 mM was significantly higher than that at 0 mM, and decreased at higher concentrations. The expression of MUC5B mRNA increased with increases in NH₄⁺ concentration, and was significantly higher compared to that in untreated cells. No significant change in the expression of E-cadherin mRNA in CagA-transfected AGS cells was observed. Immunofluorescence assays confirmed the observed changes. CONCLUSION H. pylori may affect the expression of MUC5AC, MUC2, MUC5B, and MUC6 in AGS cells via CagA and/or NH₄⁺, but not E-cadherin.
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Affiliation(s)
- Xiaoyu Zhang
- Department of Gastroenterology, Henan University of Chinese Medicine, Zhengzhou, China
| | - Ding Shi
- Department of Gastroenterology, Ningbo No. 2 Hospital, Ningbo, China.
| | - Yong Pan Liu
- Department of Gastroenterology, the First People's Hospital of Yuhang District, Hangzhou, China
| | - Wu Jie Chen
- Department of Gastroenterology, Ningbo No. 2 Hospital, Ningbo, China
| | - Dong Wu
- Department of Gastroenterology, Ningbo No. 2 Hospital, Ningbo, China
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32
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Wang Q, Yang HS. The role of Pdcd4 in tumour suppression and protein translation. Biol Cell 2018; 110:10.1111/boc.201800014. [PMID: 29806708 PMCID: PMC6261700 DOI: 10.1111/boc.201800014] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 05/03/2018] [Accepted: 05/13/2018] [Indexed: 01/07/2023]
Abstract
Programmed cell death 4 (Pdcd4), a tumour suppressor, is frequently down-regulated in various types of cancer. Pdcd4 has been demonstrated to efficiently suppress tumour promotion, progression and proliferation. The biochemical function of Pdcd4 is a protein translation inhibitor. Although the fact that Pdcd4 inhibits protein translation has been known for more than a decade, the mechanism by which Pdcd4 controls tumorigenesis through translational regulation of its target genes is still not fully understood. Recent studies show that Pdcd4 inhibits translation of stress-activated-protein kinase interacting protein 1 to suppress tumour invasion, depicting a picture of how Pdcd4 inhibits tumorigenesis through translational inhibition. Thus, understanding the mechanism of how Pdcd4 attenuates tumorigenesis by translational control should provide a new strategy for combating cancer.
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Affiliation(s)
- Qing Wang
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky
| | - Hsin-Sheng Yang
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky
- Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, Kentucky
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33
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Shi J, Cheng C, Ma J, Liew CC, Geng X. Gene expression signature for detection of gastric cancer in peripheral blood. Oncol Lett 2018; 15:9802-9810. [PMID: 29928354 PMCID: PMC6004726 DOI: 10.3892/ol.2018.8577] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 11/07/2017] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer (stomach cancer) is the fifth most common malignancy and the third leading cause of cancer-associated mortality worldwide. Identifying gastric cancer patients at an early and curable stage of the disease is essential if mortality rates for this disease are to decrease. A non-invasive blood-based test that is an indicator of gastric cancer risk would likely be of benefit in identifying gastric cancer patients at an early stage, and such a test may enhance clinical decision making. This study identified a four-gene expression signature in peripheral blood samples associated with gastric cancer. A total of 216 blood samples were collected, including those from 36 gastric cancer patients, 55 healthy controls and 125 patients with other carcinomas, and gene expression profiles were examined using an Affymetrix Gene Profiling microarray. Blood gene expression profiles were compared between patients with stomach cancer, healthy controls and patients affected with other malignancies. A four-gene panel was identified comprising purine-rich element binding protein B, structural maintenance of chromosomes 1A, DENN/MADD domain containing 1B and programmed cell death 4. The four-gene panel discriminated gastric cancer with an area under the receiver-operating-characteristic curve of 0.99, an accuracy of 95%, sensitivity of 92% and specificity of 96%. The non-invasive nature of the blood test, together with the relatively high accuracy of the four-gene panel may assist physicians in gastric cancer screening decision making.
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Affiliation(s)
- Jianing Shi
- Department of General Surgery, The Second Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
| | - Changming Cheng
- Sentinel Center, Shanghai Biomedical Laboratory, Shanghai 200436, P.R. China.,National Engineering Center for Biochip at Shanghai, Shanghai Biochip Co., Ltd., Shanghai 201203, P.R. China
| | - Jun Ma
- Department of Research, Golden Health Diagnostics Inc., Yancheng, Jiangsu 224000, P.R. China
| | - Choong-Chin Liew
- Sentinel Center, Shanghai Biomedical Laboratory, Shanghai 200436, P.R. China.,Department of Research, Golden Health Diagnostics Inc., Yancheng, Jiangsu 224000, P.R. China.,Department of Clinical Pathology and Laboratory Medicine, University of Toronto, Toronto, Ontario, ON M5S 1A8, Canada.,Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Xiaoping Geng
- Department of General Surgery, The Second Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
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Nicolè L, Cappellesso R, Sanavia T, Guzzardo V, Fassina A. MiR-21 over-expression and Programmed Cell Death 4 down-regulation features malignant pleural mesothelioma. Oncotarget 2018; 9:17300-17308. [PMID: 29707109 PMCID: PMC5915117 DOI: 10.18632/oncotarget.24644] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2018] [Accepted: 02/27/2018] [Indexed: 12/26/2022] Open
Abstract
Background Differential diagnosis between malignant pleural mesothelioma (MPM) and benign mesothelial conditions is still challenging and there is a lack of useful markers. Programmed cell death 4 (PDCD4) is a well-known tumor suppressor gene in several cancers, its post-transcriptional activity is directly controlled by miR-21, whose over-expression has been recently reported in MPM compared to normal mesothelium. Aim of this study was to test this suppressor gene as a possible new marker of malignant transformation in mesothelial cells, as well as a new prognostic marker. Methods PDCD4 nuclear expression was assessed by immunohistochemistry (IHC) in 40 non-neoplastic pleural (NNP) and 40 MPM formalin-fixed and paraffin-embedded specimens. PDCD4 and miR-21 expressions were analyzed by qRT-PCR in all cases. In situ hybridization (ISH) of miR-21 was performed in 5 representative cases of both groups. The prognostic relevance of PDCD4 was assessed in a public available gene expression dataset. Results IHC showed that PDCD4 nuclear expression was significantly lower in MPM than in NNP. PDCD4 was down-regulated, whereas miR-21 was over-expressed in MPM cases compared to NNP ones. ISH detected miR-21 only in MPM specimens. Down-expression of PDCD4 was found significantly associated with short overall survival in publicly available data. Conclusions These findings highlighted a switch between PDCD4 and miR-21 expression in MPM. Further studies should assess the diagnostic reliability of these two markers for MPM in biopsy and effusion specimens.
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Affiliation(s)
- Lorenzo Nicolè
- Department of Medicine, Surgical Pathology & Cytopathology Unit, University of Padova, Padova, Italy
| | - Rocco Cappellesso
- Department of Medicine, Surgical Pathology & Cytopathology Unit, University of Padova, Padova, Italy
| | - Tiziana Sanavia
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Vincenza Guzzardo
- Department of Medicine, Surgical Pathology & Cytopathology Unit, University of Padova, Padova, Italy
| | - Ambrogio Fassina
- Department of Medicine, Surgical Pathology & Cytopathology Unit, University of Padova, Padova, Italy
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Liu J, Zhai R, Zhao J, Kong F, Wang J, Jiang W, Xin Q, Xue X, Luan Y. Programmed cell death 4 overexpression enhances sensitivity to cisplatin via the JNK/c-Jun signaling pathway in bladder cancer. Int J Oncol 2018; 52:1633-1642. [PMID: 29512740 DOI: 10.3892/ijo.2018.4303] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Accepted: 02/28/2018] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to evaluate the effects of programmed cell death 4 (PDCD4) on cell proliferation and apoptosis, and to elucidate the potential role of the Jun N-terminal kinase (JNK)/c-Jun pathway in human bladder cancer (BCa) cells. Mixed BCa cells were transfected with plasmids containing PDCD4 (PDCD4-pcDNA3). The sensitivity to cisplatin was analyzed using cell viability, invasion/migration, apoptosis, flow cytometry, wound healing and Transwell assays at different transfection times. Furthermore, epithelial-to-mesenchymal transition (EMT) markers were detected by immunofluorescence staining, and the protein expression of c-Jun, and phosphorylated Jun N-terminal kinase (p-JNK) and c-Jun (p-c-Jun, Ser-73) were also tested using western blotting. It was observed that BCa cell proliferation and invasion and tumor growth were significantly inhibited, whereas apoptosis was enhanced in PDCD4-transfected cells treated with cisplatin compared with controls. Moreover, the western blotting and immunofluorescence results demonstrated that PDCD4 upregulated the expression of epithelial cell markers, but downregulated the expression of mesenchymal cell markers. Furthermore, overexpression of PDCD4 reduced the protein levels of p-JNK and p-c-Jun. Taken together, the findings of the present study indicate that PDCD4 enhances the sensitivity of BCa cells to cisplatin, partially via regulation of the JNK/c-Jun pathway, and reverses EMT. In conclusion, the results of the present study suggested that PDCD4, a nuclear/cytoplasmic shuttling protein with multiple functions, plays an important role in the development and progression of human BCa.
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Affiliation(s)
- Junli Liu
- Laboratory of Clinical Molecular Biology, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Ruirui Zhai
- Department of Pediatrics, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Jingjie Zhao
- Laboratory of Clinical Molecular Biology, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Feng Kong
- Central Research Laboratory, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Jue Wang
- Central Research Laboratory, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Wen Jiang
- Central Research Laboratory, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Qian Xin
- Central Research Laboratory, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Xia Xue
- Department of Pharmacy, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Yun Luan
- Central Research Laboratory, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
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36
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Han YM, Kim KJ, Jeong M, Park JM, Go EJ, Kang JX, Hong SP, Hahm KB. Suppressed Helicobacter pylori-associated gastric tumorigenesis in Fat-1 transgenic mice producing endogenous ω-3 polyunsaturated fatty acids. Oncotarget 2018; 7:66606-66622. [PMID: 27528223 PMCID: PMC5341824 DOI: 10.18632/oncotarget.11261] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Accepted: 07/28/2016] [Indexed: 12/12/2022] Open
Abstract
Dietary approaches to preventing Helicobacter pylori (H. pylori)-associated gastric carcinogenesis are widely accepted because surrounding break-up mechanisms are mandatory for cancer prevention, however, eradication alone has been proven to be insufficient. Among these dietary interventions, omega-3-polyunsaturated-fatty acids (ω-3 PUFAs) are often the first candidate selected. However, there was no trial of fatty acids in preventing H. pylori-associated carcinogenesis and inconclusive results have been reported, likely based on inconsistent dietary administration. In this study, we developed an H. pylori initiated-, high salt diet promoted-gastric tumorigenesis model and conducted a comparison between wild-type (WT) and Fat-1-transgenic (TG)-mice. Gross and pathological lesions in mouse stomachs were evaluated at 16, 24, 32, and 45 weeks after H. pylori infection, and the underlying molecular changes to explain the cancer preventive effects were investigated. Significant changes in: i) ameliorated gastric inflammations at 16 weeks of H. pylori infection, ii) decreased angiogenic growth factors at 24 weeks, iii) attenuated atrophic gastritis and tumorigenesis at 32 weeks, and iv) decreased gastric cancer at 45 weeks were all noted in Fat-1-TG-mice compared to WT-mice. While an increase in the expression of Cyclooxygenase (COX)-2, and reduced expression of the tumor suppressive 15-PGDH were observed in WT-mice throughout the experimental periods, the expression of Hydroxyprostaglandin dehydrogenase (15-PGDH) was preserved in Fat-1-TG-mice. Using a comparative protein array, attenuated expressions of proteins implicated in proliferation and inflammation were observed in Fat-1-TG-mice compared to WT-mice. Conclusively, long-term administration of ω-3 PUFAs can suppress H. pylori-induced gastric tumorigenesis through a dampening of inflammation and reduced proliferation in accordance with afforded rejuvenation.
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Affiliation(s)
- Young-Min Han
- CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seoul, Korea
| | - Kyung-Jo Kim
- Department of Gastroenterology, University of Ulsan, Seoul Asan Medical Center, Seoul, Korea
| | - Migyeung Jeong
- CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seoul, Korea
| | - Jong-Min Park
- CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seoul, Korea
| | - Eun-Jin Go
- CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seoul, Korea
| | - Jing X Kang
- Laboratory for Lipid Medicine and Technology, Massachusetts General Hospital, Harvard Medical School, Boston, USA
| | - Sung Pyo Hong
- Department of Gastroenterology, CHA Bundang Medical Center, Seongnam, Korea
| | - Ki Baik Hahm
- CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seoul, Korea.,Department of Gastroenterology, CHA Bundang Medical Center, Seongnam, Korea
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37
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Fawzy MS, Toraih EA, Ibrahiem A, Abdeldayem H, Mohamed AO, Abdel-Daim MM. Evaluation of miRNA-196a2 and apoptosis-related target genes: ANXA1, DFFA and PDCD4 expression in gastrointestinal cancer patients: A pilot study. PLoS One 2017; 12:e0187310. [PMID: 29091952 PMCID: PMC5665540 DOI: 10.1371/journal.pone.0187310] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 10/17/2017] [Indexed: 12/26/2022] Open
Abstract
Previous reports have suggested the significant association of miRNAs aberrant expression with tumor initiation, progression and metastasis in cancer, including gastrointestinal (GI) cancers. The current preliminary study aimed to evaluate the relative expression levels of miR-196a2 and three of its selected apoptosis-related targets; ANXA1, DFFA and PDCD4 in a sample of GI cancer patients. Quantitative real-time PCR for miR-196a2 and its selected mRNA targets, as well as immunohistochemical assay for annexin A1 protein expression were detected in 58 tissues with different GI cancer samples. In addition, correlation with the clinicopathological features and in silico network analysis of the selected molecular markers were analyzed. Stratified analyses by cancer site revealed elevated levels of miR-196a2 and low expression of the selected target genes. Annexin protein expression was positively correlated with its gene expression profile. In colorectal cancer, miR-196a over-expression was negatively correlated with annexin A1 protein expression (r = -0.738, p < 0.001), and both were indicators of unfavorable prognosis in terms of poor differentiation, larger tumor size, and advanced clinical stage. Taken together, aberrant expression of miR-196a2 and the selected apoptosis-related biomarkers might be involved in GI cancer development and progression and could have potential diagnostic and prognostic roles in these types of cancer; particularly colorectal cancer, provided the results experimentally validated and confirmed in larger multi-center studies.
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Affiliation(s)
- Manal S. Fawzy
- Department of Medical Biochemistry, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
- Department of Biochemistry, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia
| | - Eman A. Toraih
- Genetics Unit, Department of Histology and Cell Biology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Afaf Ibrahiem
- Department of Pathology, Faculty of Medicine, Mansoura University, Mansours, Egypt
| | - Hala Abdeldayem
- Department of Pathology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Amany O. Mohamed
- Department of Medical Biochemistry, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed M. Abdel-Daim
- Department of Pharmacology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt
- Department of Ophthalmology and Micro-Technology, Yokohama City University, Yokohama, Japan
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38
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Bridge DR, Blum FC, Jang S, Kim J, Cha JH, Merrell DS. Creation and Initial Characterization of Isogenic Helicobacter pylori CagA EPIYA Variants Reveals Differential Activation of Host Cell Signaling Pathways. Sci Rep 2017; 7:11057. [PMID: 28887533 PMCID: PMC5591203 DOI: 10.1038/s41598-017-11382-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 08/23/2017] [Indexed: 12/18/2022] Open
Abstract
The polymorphic CagA toxin is associated with Helicobacter pylori-induced disease. Previous data generated using non-isogenic strains and transfection models suggest that variation surrounding the C-terminal Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs as well as the number of EPIYA motifs influence disease outcome. To investigate potential CagA-mediated effects on host cell signaling, we constructed and characterized a large panel of isogenic H. pylori strains that differ primarily in the CagA EPIYA region. The number of EPIYA-C motifs or the presence of an EPIYA-D motif impacted early changes in host cell elongation; however, the degree of elongation was comparable across all strains at later time points. In contrast, the strain carrying the EPIYA-D motif induced more IL-8 secretion than any other EPIYA type, and a single EPIYA-C motif induced comparable IL-8 secretion as isolates carrying multiple EPIYA-C alleles. Similar levels of ERK1/2 activation were induced by all strains carrying a functional CagA allele. Together, our data suggest that polymorphism in the CagA C-terminus is responsible for differential alterations in some, but not all, host cell signaling pathways. Notably, our results differ from non-isogenic strain studies, thus highlighting the importance of using isogenic strains to study the role of CagA toxin polymorphism in gastric cancer development.
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Affiliation(s)
- Dacie R Bridge
- Uniformed Services University of the Health Sciences, F. Edward Hébert School of Medicine, Department of Microbiology and Immunology, Bethesda, Maryland, 20814, USA
- University of Maryland School of Medicine, Center for Vaccine Development, Division of Geographic Medicine, Department of Medicine, Baltimore Maryland, 21201, USA
| | - Faith C Blum
- Uniformed Services University of the Health Sciences, F. Edward Hébert School of Medicine, Department of Microbiology and Immunology, Bethesda, Maryland, 20814, USA
| | - Sungil Jang
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, South Korea
| | - Jinmoon Kim
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, South Korea
- Department of Applied Life Science, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, South Korea
| | - Jeong-Heon Cha
- Department of Oral Biology, Oral Science Research Center, Yonsei University College of Dentistry, Seoul, South Korea
- Department of Applied Life Science, BK21 Plus Project, Yonsei University College of Dentistry, Seoul, South Korea
- Microbiology & Molecular Biology, Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - D Scott Merrell
- Uniformed Services University of the Health Sciences, F. Edward Hébert School of Medicine, Department of Microbiology and Immunology, Bethesda, Maryland, 20814, USA.
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39
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Ali MU, Ur Rahman MS, Jia Z, Jiang C. Eukaryotic translation initiation factors and cancer. Tumour Biol 2017; 39:1010428317709805. [PMID: 28653885 DOI: 10.1177/1010428317709805] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Recent technological advancements have shown tremendous mechanistic accomplishments in our understanding of the mechanism of messenger RNA translation in eukaryotic cells. Eukaryotic messenger RNA translation is very complex process that includes four phases (initiation, elongation, termination, and ribosome recycling) and diverse mechanisms involving protein and non-protein molecules. Translation regulation is principally achieved during initiation step of translation, which is organized by multiple eukaryotic translation initiation factors. Eukaryotic translation initiation factor proteins help in stabilizing the formation of the functional ribosome around the start codon and provide regulatory mechanisms in translation initiation. Dysregulated messenger RNA translation is a common feature of tumorigenesis. Various oncogenic and tumor suppressive genes affect/are affected by the translation machinery, making the components of the translation apparatus promising therapeutic targets for the novel anticancer drug. This review provides details on the role of eukaryotic translation initiation factors in messenger RNA translation initiation, their contribution to onset and progression of tumor, and how dysregulated eukaryotic translation initiation factors can be used as a target to treat carcinogenesis.
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Affiliation(s)
- Muhammad Umar Ali
- 1 Clinical Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Muhammad Saif Ur Rahman
- 1 Clinical Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhenyu Jia
- 2 Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, China
| | - Cao Jiang
- 1 Clinical Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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40
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Sohn SH, Kim N, Jo HJ, Kim J, Park JH, Nam RH, Seok YJ, Kim YR, Lee DH. Analysis of Gastric Body Microbiota by Pyrosequencing: Possible Role of Bacteria Other Than Helicobacter pylori in the Gastric Carcinogenesis. J Cancer Prev 2017; 22:115-125. [PMID: 28698866 PMCID: PMC5503224 DOI: 10.15430/jcp.2017.22.2.115] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2017] [Accepted: 06/12/2017] [Indexed: 12/15/2022] Open
Abstract
Background Gastric microbiota along with Helicobacter pylori (HP) plays a key role in gastric disease. The aim of our study is to investigate the difference of human gastric microbiota between antrum and body according to disease (control vs. gastric cancer) and HP status. Methods Each antrum and body biopsy was collected from 12 subjects at Seoul National University Bundang Hospital. Gastric microbiota was analyzed by bar-coded 454 pyrosequencing of the 16S rRNA gene. Twelve subjects consisted of HP-negative control (n = 2), HP-negative cancer (n = 2), HP-positive control (n = 3), and HP-positive cancer (n = 5). The analysis was focused on non-HP urease-producing bacteria (UB) and non-HP nitrosating or nitroreducing bacteria (NB) between antrum and body. Results Gastric body samples showed higher diversity compared to gastric antrum mucosa samples but there was no significant difference. The mean of operational taxonomic units was higher in HP(−) cancer than HP(+) cancer (antrum, 273.5 vs. 228.2, P = 0.439; body, 585.5 vs. 183.2, P = 0.053). The number of non-HP UB and non-HP NB was higher in HP(−) cancer groups than the others. These differences were more pronounced in the body (P = 0.051 and P = 0.081, respectively). Analysis of overlap of non-HP UB and non-HP NB revealed the higher composition of Streptococcus pseudopneumoniae, S. parasanguinis, and S. oralis in HP(−) cancer groups than the others, only in the body (P = 0.030) but not in the antrum (P = 0.123). Conclusions Higher diversity and higher composition of S. pseudopneumoniae, S. parasanguinis, and S. oralis in HP(−) cancer group than the other groups in the body suggest that analysis of microbiota from body mucosa could be beneficial to identify a role of non-HP bacteria in the gastric carcinogenesis.
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Affiliation(s)
- Sung-Hwa Sohn
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyun Jin Jo
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jaeyeon Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Ji Hyun Park
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Ryoung Hee Nam
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Yeong-Jae Seok
- Department of Biological Sciences and Institute of Microbiology, Seoul National University, Seoul, Korea
| | - Yeon-Ran Kim
- Department of Biological Sciences and Institute of Microbiology, Seoul National University, Seoul, Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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41
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Xia P, Xu XY. Epithelial–mesenchymal transition and gastric cancer stem cell. Tumour Biol 2017; 39:1010428317698373. [DOI: 10.1177/1010428317698373] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Gastric cancer remains a big health problem in China. Gastric cancer cells contain a small subpopulation of cells that exhibit capabilities of differentiation and tumorigenicity. A putative explanation for ineffective therapy is the presence of cancer stem-like cells. Side population cells, which have cancer stem-like cells’ property, are characterized by the high efflux ability of Hoechst 33342 dye. Side population cells have been isolated from gastric cancer cell lines in previous studies. The epithelial–mesenchymal transition is very important in the invasion and metastasis of epithelial-derived cancers. More and more studies showed that gastric cancer stem-like cells possess high invasive ability and epithelial–mesenchymal transition property. A brief overview of the recent advancements in gastric cancer stem-like cells and epithelial–mesenchymal transition will be helpful for providing novel insight into gastric cancer treatment.
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Affiliation(s)
- Pu Xia
- Department of Cell Biology, College of Basic Medical Science, Liaoning Medical University, Jinzhou, P.R. China
| | - Xiao-Yan Xu
- Department of Pathophysiology, College of Basic Medical Sciences, China Medical University, Shenyang, P.R. China
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42
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Román-Román A, Martínez-Carrillo DN, Atrisco-Morales J, Azúcar-Heziquio JC, Cuevas-Caballero AS, Castañón-Sánchez CA, Reyes-Ríos R, Betancourt-Linares R, Reyes-Navarrete S, Cruz-Del Carmen I, Camorlinga-Ponce M, Cortés-Malagón EM, Fernández-Tilapa G. Helicobacter pylori vacA s1m1 genotype but not cagA or babA2 increase the risk of ulcer and gastric cancer in patients from Southern Mexico. Gut Pathog 2017; 9:18. [PMID: 28413454 PMCID: PMC5390388 DOI: 10.1186/s13099-017-0167-z] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Accepted: 04/05/2017] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The vacA, cagA and babA2 genotypes of Helicobacter pylori are associated with gastric pathology. The objectives were to determine the frequency of infection and distribution of the vacA, cagA and babA2 genotypes of H. pylori in patients with gastric ulcer, chronic gastritis and gastric cancer, and to evaluate the association of virulent genotypes with diagnosis. METHODS We studied 921 patients with symptoms of dyspepsia or with presumptive diagnosis of gastric cancer. The DNA of H. pylori and the vacA, cagA and babA2 genes was detected by PCR in total DNA from gastric biopsies. The association of H. pylori and of its cagA, vacA and babA2 genotypes with diagnosis was determined by calculating the odds ratio (OR). RESULTS Chronic gastritis was confirmed in 767 patients, gastric ulcer in 115 and cancer in 39. The prevalence of H. pylori was 47.8, 49.6 and 61.5% in those groups, respectively. H. pylori was more frequent in the surrounding tissue (69.2%) than in the tumor (53.8%). The vacA s1m1 genotype predominated in the three groups (45.2, 61.4 and 83.3%, respectively). H. pylori was associated with cancer (ORadjusted = 2.08; 95% CI 1.05-4.13; p = 0.035) but not with ulcer (ORadjusted = 1.07; 95% CI 0.71-1.61; p = 0.728). The s1m1 genotype was associated with ulcer and cancer (ORadjusted = 2.02; 95% CI 1.12-3.62; p = 0.019 and ORadjusted = 6.58; 95% CI 2.15-20.08; p = 0.001, respectively). babA2 was associated with gastric cancer, and cagA was not associated with the diagnosis. CONCLUSIONS In population from Southern Mexico, H. pylori and the s1m1 genotype were associated with gastric cancer and the s1m1/cagA+/babA2+ strains predominated in tumor and adjacent tissue.
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Affiliation(s)
- Adolfo Román-Román
- Laboratorio de Investigación en Bacteriología, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Guerrero México
| | - Dinorah Nashely Martínez-Carrillo
- Laboratorio de Investigación Clínica, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Avenida Lázaro Cárdenas S/N Ciudad Universitaria Sur, Col. La Haciendita, 39087 Chilpancingo, Guerrero México
| | - Josefina Atrisco-Morales
- Laboratorio de Investigación Clínica, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Avenida Lázaro Cárdenas S/N Ciudad Universitaria Sur, Col. La Haciendita, 39087 Chilpancingo, Guerrero México
| | - Julio César Azúcar-Heziquio
- Laboratorio de Investigación Clínica, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Avenida Lázaro Cárdenas S/N Ciudad Universitaria Sur, Col. La Haciendita, 39087 Chilpancingo, Guerrero México
| | - Abner Saúl Cuevas-Caballero
- Laboratorio de Investigación Clínica, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Avenida Lázaro Cárdenas S/N Ciudad Universitaria Sur, Col. La Haciendita, 39087 Chilpancingo, Guerrero México
| | | | - Roxana Reyes-Ríos
- Laboratorio de Investigación Clínica, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Avenida Lázaro Cárdenas S/N Ciudad Universitaria Sur, Col. La Haciendita, 39087 Chilpancingo, Guerrero México
| | | | - Salomón Reyes-Navarrete
- Servicio de Endoscopia, Instituto Estatal de Cancerología "Dr. Arturo Beltrán Ortega", Acapulco, Guerrero México
| | - Iván Cruz-Del Carmen
- Servicio de Endoscopia, Hospital General "Dr. Raymundo Abarca Alarcón", Chilpancingo, Guerrero México
| | - Margarita Camorlinga-Ponce
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, IMSS, Ciudad de México, México
| | - Enoc Mariano Cortés-Malagón
- Laboratorio de Biología Molecular del Cáncer, Unidad de Investigación, Hospital Juárez de México, Ciudad de México, México
| | - Gloria Fernández-Tilapa
- Laboratorio de Investigación Clínica, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Avenida Lázaro Cárdenas S/N Ciudad Universitaria Sur, Col. La Haciendita, 39087 Chilpancingo, Guerrero México
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Singh S, Jha HC. Status of Epstein-Barr Virus Coinfection with Helicobacter pylori in Gastric Cancer. JOURNAL OF ONCOLOGY 2017; 2017:3456264. [PMID: 28421114 PMCID: PMC5379099 DOI: 10.1155/2017/3456264] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 02/14/2017] [Indexed: 12/14/2022]
Abstract
Epstein-Barr virus is a ubiquitous human herpesvirus whose primary infection causes mononucleosis, Burkett's lymphoma, nasopharyngeal carcinoma, autoimmune diseases, and gastric cancer (GC). The persistent infection causes malignancies in lymph and epithelial cells. Helicobacter pylori causes gastritis in human with chronic inflammation. This chronic inflammation is thought to be the cause of genomic instability. About 45%-word population have a probability of having both pathogens, namely, H. pylori and EBV. Approximately 180 per hundred thousand population is developing GC along with many gastric abnormalities. This makes GC the third leading cause of cancer-related death worldwide. Although lots of research are carried out individually for EBV and H. pylori, still there are very few reports available on coinfection of both pathogens. Recent studies suggested that EBV and H. pylori coinfection increases the occurrence of GC as well as the early age of GC detection comparing to individual infection. The aim of this review is to present status on coinfection of both pathogens and their association with GC.
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Affiliation(s)
- Shyam Singh
- Centre for Biosciences and Biomedical Engineering, Indian Institute of Technology, Indore, India
| | - Hem Chandra Jha
- Centre for Biosciences and Biomedical Engineering, Indian Institute of Technology, Indore, India
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Li JZH, Gao W, Ho WK, Lei WB, Wei WI, Chan JYW, Wong TS. The clinical association of programmed cell death protein 4 (PDCD4) with solid tumors and its prognostic significance: a meta-analysis. CHINESE JOURNAL OF CANCER 2016; 35:95. [PMID: 27852288 PMCID: PMC5112731 DOI: 10.1186/s40880-016-0158-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 04/15/2016] [Indexed: 12/26/2022]
Abstract
Background Programmed cell death protein 4 (PDCD4) is a novel tumor suppressor protein involved in programmed cell death. Its association with cancer progression has been observed in multiple tumor models, but evidence supporting its association with solid tumors in humans remains controversial. This study aimed to determine the clinical significance and prognostic value of PDCD4 in solid tumors. Methods A systematic literature review was performed to retrieve publications with available clinical information and survival data. The eligibility of the selected articles was based on the criteria of the Dutch Cochrane Centre proposed by the Meta-analysis Of Observational Studies in Epidemiology group. Pooled odds ratios (ORs), hazard ratios (HRs), and 95% confidence intervals (CIs) for survival analysis were calculated. Publication bias was examined by Begg’s and Egger’s tests. Results Clinical data of 2227 cancer patients with solid tumors from 23 studies were evaluated. PDCD4 expression was significantly associated with the differentiation status of head and neck cancer (OR 4.25, 95% CI 1.87–9.66) and digestive system cancer (OR 2.87, 95% CI 1.84–4.48). Down-regulation of PDCD4 was significantly associated with short overall survival of patients with head and neck (HR: 3.44, 95% CI 2.38–4.98), breast (HR: 1.86, 95% CI 1.36–2.54), digestive system (HR: 2.12, 95% CI 1.75–2.56), and urinary system cancers (HR: 3.16, 95% CI 1.06–9.41). Conclusions The current evidence suggests that PDCD4 down-regulation is involved in the progression of several types of solid tumor and is a potential marker for solid tumor prognoses. Its clinical usefulness should be confirmed by large-scale prospective studies.
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Affiliation(s)
- John Zeng Hong Li
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong, SAR, P. R. China
| | - Wei Gao
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong, SAR, P. R. China
| | - Wai-Kuen Ho
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong, SAR, P. R. China
| | - Wen Bin Lei
- Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, P. R. China
| | - William Ignace Wei
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong, SAR, P. R. China
| | - Jimmy Yu-Wai Chan
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong, SAR, P. R. China
| | - Thian-Sze Wong
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong, SAR, P. R. China.
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Bredenkamp A, Wegener M, Hummel S, Häring AP, Kirsch SF. Versatile process for the stereodiverse construction of 1,3-polyols: iterative chain elongation with chiral building blocks. Chem Commun (Camb) 2016; 52:1875-8. [PMID: 26673147 DOI: 10.1039/c5cc09328g] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
A versatile process for the construction of 1,3-polyols, a key structural element of polyketide-type natural products, is presented. The modular synthesis strategy involves the iterative chain elongation with novel four-carbon building blocks to access all possible stereoisomers of a growing 1,3-polyol chain. These chiral building blocks are designed to install four carbon atoms with two stereogenic centres by performing only four experimentally simple steps per elongation cycle, thus making these building blocks attractive for the realization of a universal platform from which to access a diverse range of polyketidic molecules.
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Affiliation(s)
- Angela Bredenkamp
- Organic Chemistry, Bergische Universität Wuppertal, Gaußstr. 20, 42119 Wuppertal, Germany.
| | - Michael Wegener
- Organic Chemistry, Bergische Universität Wuppertal, Gaußstr. 20, 42119 Wuppertal, Germany.
| | - Sara Hummel
- Organic Chemistry, Bergische Universität Wuppertal, Gaußstr. 20, 42119 Wuppertal, Germany.
| | - Andreas P Häring
- Organic Chemistry, Bergische Universität Wuppertal, Gaußstr. 20, 42119 Wuppertal, Germany.
| | - Stefan F Kirsch
- Organic Chemistry, Bergische Universität Wuppertal, Gaußstr. 20, 42119 Wuppertal, Germany.
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Helicobacter pylori CagA and IL-1β Promote the Epithelial-to-Mesenchymal Transition in a Nontransformed Epithelial Cell Model. Gastroenterol Res Pract 2016; 2016:4969163. [PMID: 27525003 PMCID: PMC4971297 DOI: 10.1155/2016/4969163] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Revised: 05/13/2016] [Accepted: 06/26/2016] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer is the third cause of cancer death worldwide and infection by Helicobacter pylori (H. pylori) is considered the most important risk factor, mainly by the activity of its virulence factor CagA. H. pylori/CagA-induced chronic inflammation triggers a series of gastric lesions of increased severity, starting with gastritis and ending with cancer. IL-1β has been associated with tumor development and invasiveness in different types of cancer, including gastric cancer. Currently, it is not clear if there is an association between CagA and IL-1β at a cellular level. In this study, we analyzed the effects of IL-1β and CagA on MCF-10A nontransformed cells. We found evidence that both CagA and IL-1β trigger the initiation of the epithelial-to-mesenchymal transition characterized by β-catenin nuclear translocation, increased expression of Snail1 and ZEB1, downregulation of CDH1, and morphological changes during MCF-10A acini formation. However, only CagA induced MMP9 activity and cell invasion. Our data support that IL-1β and CagA target the β-catenin pathway, with CagA leading to acquisition of a stage related to aggressive tumors.
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47
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Ma HY, Liu XZ, Liang CM. Inflammatory microenvironment contributes to epithelial-mesenchymal transition in gastric cancer. World J Gastroenterol 2016; 22:6619-6628. [PMID: 27547005 PMCID: PMC4970470 DOI: 10.3748/wjg.v22.i29.6619] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 06/12/2016] [Accepted: 07/06/2016] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is the fifth most common malignancy in the world. The major cause of GC is chronic infection with Helicobacter pylori (H. pylori). Infection with H. pylori leads to an active inflammatory microenvironment that is maintained by immune cells such as T cells, macrophages, natural killer cells, among other cells. Immune cell dysfunction allows the initiation and accumulation of mutations in GC cells, inducing aberrant proliferation and protection from apoptosis. Meanwhile, immune cells can secrete certain signals, including cytokines, and chemokines, to alter intracellular signaling pathways in GC cells. Thus, GC cells obtain the ability to metastasize to lymph nodes by undergoing the epithelial-mesenchymal transition (EMT), whereby epithelial cells lose their epithelial attributes and acquire a mesenchymal cell phenotype. Metastasis is a leading cause of death for GC patients, and the involved mechanisms are still under investigation. In this review, we summarize the current research on how the inflammatory environment affects GC initiation and metastasis via EMT.
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48
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Servetas SL, Bridge DR, Merrell DS. Molecular mechanisms of gastric cancer initiation and progression by Helicobacter pylori. Curr Opin Infect Dis 2016; 29:304-10. [PMID: 26779778 PMCID: PMC5144489 DOI: 10.1097/qco.0000000000000248] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW Infection with the Gram-negative, microaerophilic pathogen Helicobacter pylori results in gastric cancer in a subset of infected individuals. As such, H. pylori is the only WHO classified bacterial class I carcinogen. Numerous studies have identified mechanisms by which H. pylori alters host cell signaling pathways to cause disease. The purpose of this review is to highlight recent studies that explore mechanisms associated with induction of gastric cancer. RECENT FINDINGS Over the last year and a half, new mechanisms contributing to the etiology of H. pylori-associated gastric cancer development have been discovered. In addition to utilizing the oncogenic CagA toxin to alter host cell signaling pathways, H. pylori also induces host DNA damage and alters DNA methylation to perturb downstream signaling. Furthermore, H. pylori activates numerous host cell pathways and proteins that result in epithelial-to-mesenchymal transition and induction of cell survival and proliferation. SUMMARY Mounting evidence suggests that H. pylori promotes gastric carcinogenesis using a multifactorial approach. Intriguingly, many of the targeted pathways and mechanisms show commonality with diverse forms of cancer.
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Affiliation(s)
| | | | - D. Scott Merrell
- Department of Microbiology and Immunology, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland, 20814, United States of America
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Helicobacter pylori upregulates Nanog and Oct4 via Wnt/β-catenin signaling pathway to promote cancer stem cell-like properties in human gastric cancer. Cancer Lett 2016; 374:292-303. [DOI: 10.1016/j.canlet.2016.02.032] [Citation(s) in RCA: 113] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Revised: 02/17/2016] [Accepted: 02/17/2016] [Indexed: 02/06/2023]
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Perez F, Waldeck AR, Krische MJ. Total Synthesis of Cryptocaryol A by Enantioselective Iridium-Catalyzed Alcohol C-H Allylation. Angew Chem Int Ed Engl 2016; 55:5049-52. [PMID: 27079820 PMCID: PMC4834877 DOI: 10.1002/anie.201600591] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Indexed: 11/06/2022]
Abstract
The polyketide natural product cryptocaryol A is prepared in 8 steps via iridium catalyzed enantioselective diol double C-H allylation, which directly generates an acetate-based triketide stereodiad. In 4 previously reported total syntheses, 17-28 steps were required.
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Affiliation(s)
- Felix Perez
- University of Texas at Austin, Department of Chemistry, 105 E 24th St. (A5300), Austin, TX, 78712-1167, USA
| | - Andrew R Waldeck
- University of Texas at Austin, Department of Chemistry, 105 E 24th St. (A5300), Austin, TX, 78712-1167, USA
| | - Michael J Krische
- University of Texas at Austin, Department of Chemistry, 105 E 24th St. (A5300), Austin, TX, 78712-1167, USA.
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