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Zeng Q, Zeng S, Dai X, Ding Y, Huang C, Ruan R, Xiong J, Tang X, Deng J. MDM2 inhibitors in cancer immunotherapy: Current status and perspective. Genes Dis 2024; 11:101279. [PMID: 39263534 PMCID: PMC11388719 DOI: 10.1016/j.gendis.2024.101279] [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: 10/30/2023] [Revised: 02/13/2024] [Accepted: 02/21/2024] [Indexed: 09/13/2024] Open
Abstract
Murine double minute 2 (MDM2) plays an essential role in the cell cycle, apoptosis, DNA repair, and oncogene activation through p53-dependent and p53-independent signaling pathways. Several preclinical studies have shown that MDM2 is involved in tumor immune evasion. Therefore, MDM2-based regulation of tumor cell-intrinsic immunoregulation and the immune microenvironment has attracted increasing research attention. In recent years, immune checkpoint inhibitors targeting PD-1/PD-L1 have been widely used in the clinic. However, the effectiveness of a single agent is only approximately 20%-40%, which may be related to primary and secondary drug resistance caused by the dysregulation of oncoproteins. Here, we reviewed the role of MDM2 in regulating the immune microenvironment, tumor immune evasion, and hyperprogression during immunotherapy. In addition, we summarized preclinical and clinical findings on the use of MDM2 inhibitors in combination with immunotherapy in tumors with MDM2 overexpression or amplification. The results reveal that the inhibition of MDM2 could be a promising strategy for enhancing immunotherapy.
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Affiliation(s)
- Qinru Zeng
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
- Jiangxi Key Laboratory for Individual Cancer Therapy, Nanchang, Jiangxi 330006, China
| | - Shaocheng Zeng
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
- Jiangxi Key Laboratory for Individual Cancer Therapy, Nanchang, Jiangxi 330006, China
| | - Xiaofeng Dai
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
- Jiangxi Key Laboratory for Individual Cancer Therapy, Nanchang, Jiangxi 330006, China
| | - Yun Ding
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
- Jiangxi Key Laboratory for Individual Cancer Therapy, Nanchang, Jiangxi 330006, China
| | - Chunye Huang
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
- Jiangxi Key Laboratory for Individual Cancer Therapy, Nanchang, Jiangxi 330006, China
| | - Ruiwen Ruan
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
- Jiangxi Key Laboratory for Individual Cancer Therapy, Nanchang, Jiangxi 330006, China
| | - Jianping Xiong
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
- Jiangxi Key Laboratory for Individual Cancer Therapy, Nanchang, Jiangxi 330006, China
| | - Xiaomei Tang
- Department of Oncology, Jiangxi Chest Hospital, Nanchang, Jiangxi 330006, China
| | - Jun Deng
- Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
- Jiangxi Key Laboratory for Individual Cancer Therapy, Nanchang, Jiangxi 330006, China
- Postdoctoral Innovation Practice Base, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China
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Xu H, Huang K, Shi M, Gong H, Han M, Tian W, Wang X, Zhang D. MicroRNAs in Helicobacter pylori-infected gastric cancer: Function and clinical application. Pharmacol Res 2024; 205:107216. [PMID: 38761883 DOI: 10.1016/j.phrs.2024.107216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 05/10/2024] [Accepted: 05/11/2024] [Indexed: 05/20/2024]
Abstract
Gastric cancer (GC) is the leading cause of cancer-related death worldwide, and it is associated with a combination of genetic, environmental, and microbial risk factors. Helicobacter pylori (H. pylori) is classified as a type I carcinogen, however, the exact regulatory mechanisms underlying H. pylori-induced GC are incompletely defined. MicroRNAs (miRNAs), one of small non-coding RNAs, negatively regulate gene expression through binding to their target genes. Dysregulation of miRNAs is crucial in human cancer. A noteworthy quantity of aberrant miRNAs induced by H. pylori through complex regulatory networks have been identified. These miRNAs substantially affect genetic instability, cell proliferation, apoptosis, invasion, metastasis, autophagy, chemoresistance, and the tumor microenvironment, leading to GC development and progression. Importantly, some H. pylori-associated miRNAs hold promise as therapeutic tools and biomarkers for GC prevention, diagnosis, and prognosis. Nonetheless, clinical application of miRNAs remains in its infancy with multiple issues, including sensitivity and specificity, stability, reliable delivery systems, and off-target effects. Additional research on the specific molecular mechanisms and more clinical data are still required. This review investigated the biogenesis, regulatory mechanisms, and functions of miRNAs in H. pylori-induced GC, offering novel insights into the potential clinical applications of miRNA-based therapeutics and biomarkers.
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Affiliation(s)
- Huimei Xu
- Department of Gastroenterology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China; Key Laboratory of Digestive Diseases, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China
| | - Ke Huang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730030, China; Key Laboratory of Dental Maxillofacial Reconstruction and Biological Intelligence Manufacturing, School of Stomatology, Lanzhou University, Lanzhou 730030, China
| | - Mingxuan Shi
- Key Laboratory of Dental Maxillofacial Reconstruction and Biological Intelligence Manufacturing, School of Stomatology, Lanzhou University, Lanzhou 730030, China
| | - Hang Gong
- Department of Gastroenterology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China; Key Laboratory of Digestive Diseases, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China
| | - Mengyu Han
- Department of Gastroenterology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China; Key Laboratory of Digestive Diseases, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China
| | - Wenji Tian
- Department of Gastroenterology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China; Key Laboratory of Digestive Diseases, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China
| | - Xiaoying Wang
- Department of Emergency, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China.
| | - Dekui Zhang
- Department of Gastroenterology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China; Key Laboratory of Digestive Diseases, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China.
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Ashrafizadeh M, Mohan CD, Rangappa S, Zarrabi A, Hushmandi K, Kumar AP, Sethi G, Rangappa KS. Noncoding RNAs as regulators of STAT3 pathway in gastrointestinal cancers: Roles in cancer progression and therapeutic response. Med Res Rev 2023; 43:1263-1321. [PMID: 36951271 DOI: 10.1002/med.21950] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 10/09/2022] [Accepted: 02/28/2023] [Indexed: 03/24/2023]
Abstract
Gastrointestinal (GI) tumors (cancers of the esophagus, gastric, liver, pancreas, colon, and rectum) contribute to a large number of deaths worldwide. STAT3 is an oncogenic transcription factor that promotes the transcription of genes associated with proliferation, antiapoptosis, survival, and metastasis. STAT3 is overactivated in many human malignancies including GI tumors which accelerates tumor progression, metastasis, and drug resistance. Research in recent years demonstrated that noncoding RNAs (ncRNAs) play a major role in the regulation of many signaling pathways including the STAT3 pathway. The major types of endogenous ncRNAs that are being extensively studied in oncology are microRNAs, long noncoding RNAs, and circular RNAs. These ncRNAs can either be tumor-promoters or tumor-suppressors and each one of them imparts their activity via different mechanisms. The STAT3 pathway is also tightly modulated by ncRNAs. In this article, we have elaborated on the tumor-promoting role of STAT3 signaling in GI tumors. Subsequently, we have comprehensively discussed the oncogenic as well as tumor suppressor functions and mechanism of action of ncRNAs that are known to modulate STAT3 signaling in GI cancers.
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Affiliation(s)
- Milad Ashrafizadeh
- Department of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, China
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chakrabhavi D Mohan
- Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, India
| | - Shobith Rangappa
- Adichunchanagiri Institute for Molecular Medicine, Adichunchanagiri University, Nagamangala Taluk, India
| | - Ali Zarrabi
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul, Sariyer, Turkey
| | - Kiavash Hushmandi
- Division of Epidemiology, Faculty of Veterinary Medicine, Department of Food Hygiene and Quality Control, University of Tehran, Tehran, Iran
| | - Alan Prem Kumar
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Gautam Sethi
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Kashyap D, Rele S, Bagde PH, Saini V, Chatterjee D, Jain AK, Pandey RK, Jha HC. Comprehensive insight into altered host cell-signaling cascades upon Helicobacter pylori and Epstein-Barr virus infections in cancer. Arch Microbiol 2023; 205:262. [PMID: 37310490 DOI: 10.1007/s00203-023-03598-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 05/22/2023] [Accepted: 05/23/2023] [Indexed: 06/14/2023]
Abstract
Cancer is characterized by mutagenic events that lead to disrupted cell signaling and cellular functions. It is one of the leading causes of death worldwide. Literature suggests that pathogens, mainly Helicobacter pylori and Epstein-Barr virus (EBV), have been associated with the etiology of human cancer. Notably, their co-infection may lead to gastric cancer. Pathogen-mediated DNA damage could be the first and crucial step in the carcinogenesis process that modulates numerous cellular signaling pathways. Altogether, it dysregulates the metabolic pathways linked with cell growth, apoptosis, and DNA repair. Modulation in these pathways leads to abnormal growth and proliferation. Several signaling pathways such RTK, RAS/MAPK, PI3K/Akt, NFκB, JAK/STAT, HIF1α, and Wnt/β-catenin are known to be altered in cancer. Therefore, this review focuses on the oncogenic roles of H. pylori, EBV, and its associated signaling cascades in various cancers. Scrutinizing these signaling pathways is crucial and may provide new insights and targets for preventing and treating H. pylori and EBV-associated cancers.
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Affiliation(s)
- Dharmendra Kashyap
- Lab No. POD 1B 602, Infection Bio-Engineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, 453552, India
| | - Samiksha Rele
- Lab No. POD 1B 602, Infection Bio-Engineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, 453552, India
| | - Pranit Hemant Bagde
- Lab No. POD 1B 602, Infection Bio-Engineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, 453552, India
| | - Vaishali Saini
- Lab No. POD 1B 602, Infection Bio-Engineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, 453552, India
| | | | | | - Rajan Kumar Pandey
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177, Solna, Sweden
| | - Hem Chandra Jha
- Lab No. POD 1B 602, Infection Bio-Engineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, 453552, India.
- Centre for Rural Development and Technology, Indian Institute of Technology Indore, Madhya Pradesh, 453552, Indore, India.
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Kong X, He Z, Ji Z, Fu T, Yuan X, Zhou H, Shao Z, Zhang W. A Circulating MicroRNA-375 for the Detection of Liver Cancer: A Meta-Analysis. Genet Test Mol Biomarkers 2022; 26:564-572. [PMID: 36577123 DOI: 10.1089/gtmb.2022.0128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Background: Liver cancer is one of the most frequently diagnosed malignant tumors, with an extremely high incidence rate. Diagnosis of liver cancer is difficult with the existing methods and improved biomarkers are urgently needed. A number of studies have established a link between abnormal miR-375 expression and liver cancer. Therefore, we conducted a systematic analysis to appraise whether miR-375 can be used as a screening tool for liver cancer detection. Methods: Through a systematic database search, studies investigating miR-375 expression in serum by the quantitative real-time reverse transcription-PCR (qRT-PCR) method were included in the study. A total of 1,100 participants (576 with liver cancer and 534 without liver cancer) were recruited. The efficacy of microRNA-375 in the detection of liver cancer was assessed by sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under curve (AUC). Results: The pooled sensitivity and specificity of miR-375 in the detection of liver cancer were 0.91 (95% confidence interval [CI]: 0.74-0.98) and 0.83 (95% CI: 0.67-0.92), respectively. Furthermore, the pooled PLR was 5.40 (95% CI: 2.58-11.31), NLR was 0.10 (95% CI: 0.03-0.36), DOR was 52.52 (95% CI: 10.02-275.42), and AUC was 0.93 (95% CI: 0.90-0.95), indicating that miR-375 is effective at detecting liver cancer. Conclusions: According to our meta-analysis, measuring serum miR-375 has high sensitivity and specificity, which will facilitate its clinical application in liver cancer monitoring.
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Affiliation(s)
- Xiangyu Kong
- School of Public Health, Baotou Medical College, Baotou City, Inner Mongolia.,Department of Epidemiology, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, The Air Force Medical University, Xi'an, China
| | - Zhen He
- Department of Epidemiology, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, The Air Force Medical University, Xi'an, China
| | - Zhaohua Ji
- Department of Epidemiology, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, The Air Force Medical University, Xi'an, China
| | - Ting Fu
- Department of Epidemiology, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, The Air Force Medical University, Xi'an, China
| | - Xiaojie Yuan
- Department of Epidemiology, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, The Air Force Medical University, Xi'an, China
| | - Haowei Zhou
- School of Public Health, Baotou Medical College, Baotou City, Inner Mongolia.,Department of Epidemiology, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, The Air Force Medical University, Xi'an, China
| | - Zhongjun Shao
- Department of Epidemiology, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, The Air Force Medical University, Xi'an, China
| | - Weilu Zhang
- Department of Epidemiology, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, The Air Force Medical University, Xi'an, China
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Choi JM, Kim SG. Effect of Helicobacter pylori Eradication on Epigenetic Changes in Gastric Cancer-related Genes. THE KOREAN JOURNAL OF HELICOBACTER AND UPPER GASTROINTESTINAL RESEARCH 2021. [DOI: 10.7704/kjhugr.2021.0042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
It is known that gastric carcinogenesis results from the progressive changes from chronic gastritis to gastric atrophy, intestinal metaplasia, dysplasia, and invasive carcinoma. Several genetic and epigenetic alterations are involved in this process, and Helicobacter pylori (H. pylori) infection is believed to induce the initiation and progression of these steps. From an epigenetic point of view, H. pylori induces hypermethylation of genes involved in the development of gastric cancer and regulates the expression of various microRNAs (miRNAs). These H. pylori-related epigenetic changes are accumulated not only at the site of neoplasm but also in the adjacent non-cancerous gastric mucosa. Thereby, a state vulnerable to gastric cancer known as an epigenetic field defect is formed. H. pylori eradication can have an effective chemopreventive effect in gastric carcinogenesis. However, the molecular biological changes that occur in the stomach environment during H. pylori eradication have not yet been established. Several studies have reported that H. pylori eradication can restore infection-related changes, especially epigenetic alterations in gastric cancer-related genes, but some studies have shown otherwise. Simply put, it appears that the recovery of methylated gastric cancer-related genes and miRNAs during H. pylori eradication may vary among genes and may also differ depending on the histological subtype of the gastric mucosa. In this review, we will discuss the potential mechanism of gastric cancer prevention by H. pylori eradication, mainly from an epigenetic perspective.
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Zhang Z, Chen S, Fan M, Ruan G, Xi T, Zheng L, Guo L, Ye F, Xing Y. Helicobacter pylori induces gastric cancer via down-regulating miR-375 to inhibit dendritic cell maturation. Helicobacter 2021; 26:e12813. [PMID: 33938607 DOI: 10.1111/hel.12813] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 04/12/2021] [Accepted: 04/13/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Recent studies and clinical samples have demonstrated that Helicobacter pylori could induce the downregulation of miR-375 in the stomach and promote gastric carcinogenesis. However, whether the immune cells are affected by Helicobacter pylori due to the downregulation of miR-375 is unclear. MATERIALS AND METHODS In this study, we constructed an overexpression and knockdown of miR-375 and Helicobacter pylori infection cell models in vitro. In addition, the maturity of dendritic cells (DCs) and the expression of IL-6, IL-10, and VEGF at the transcriptional and translational levels were analyzed. Changes in the JAK2-STAT3 signaling pathway were detected. In vivo, the number changes in CD4+ T and CD8+ T cells and the size changes of tumors via models of transplantable subcutaneous tumors were also analyzed. RESULTS A cell model of Helicobacter pylori and gastric cancer was used to identify the expression of miR-375 and the maturity of dendritic cells. This study found that Helicobacter pylori could downregulate miR-375, which regulates the expression of cytokines IL-6, IL-10, and VEGF in the stomach. MiR-375 regulated the expression of cytokines IL-6, IL-10, and VEGF through the JAK2-STAT3 signaling pathway in vitro. In addition, we found that Helicobacter pylori regulates the maturation of dendritic cells through miR-375. These results were further verified in vivo, and miR-375 diminishes tumor size was also demonstrated. This study showed that immature DCs caused a decrease in the number of CD4+ and CD8+ T cells. CONCLUSIONS This study demonstrated that Helicobacter pylori can inhibit miRNA-375 expression in the stomach. Downregulated miR-375 activates the JAK2-STAT3 pathway. Activating the JAK2-STAT3 signaling pathway promotes the secretion of IL-6, IL-10, and VEGF, leading to immature differentiation of DCs and induction of gastric cancer.
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Affiliation(s)
- Zhenxing Zhang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Simiao Chen
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Menghui Fan
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Guojing Ruan
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Tao Xi
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Lufeng Zheng
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Le Guo
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Feng Ye
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yingying Xing
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
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Lin M, Vanneste BGL, Yu Q, Chen Z, Peng J, Cai X. Hyperprogression under immunotherapy: a new form of immunotherapy response?-a narrative literature review. Transl Lung Cancer Res 2021; 10:3276-3291. [PMID: 34430364 PMCID: PMC8350090 DOI: 10.21037/tlcr-21-575] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 07/26/2021] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Update the last known review, and summarize the definitions, diagnostic criteria, reported risk factors, possible mechanisms and potential biomarkers of hyperprogressive disease (HPD) under immunotherapy. BACKGROUND Immunotherapy is a relatively new systemic therapy adding a new method of treatment of especially advanced cancer patients. In a variety of immunotherapies, however, an unexpected acceleration of tumor growth, known as HPD, is observed in approximately 30% of patients after immune checkpoint inhibitor (ICI) treatment. HPD has a deleterious survival effect on patients and represents an urgent issue for both clinicians and patients. Existing literature has reviewed and summarized the definition, diagnostic criteria, reported risk factors and possible mechanisms of hyperprogression. However, with the gradual deepening of the exploration of HPD, researchers have made significant breakthroughs in elucidating the mechanism and mechanism of HPD and exploring biomarkers. METHODS The search was conducted on Google Scholar and PubMed in January and May of 2021. We searched among English papers with no limitation on the publication year. We have included retrospective studies, case reports and basic researches related to HPD in the collection, we also referred to some review articles on HPD in recent years. A qualitative-interpretive approach was used for data extraction. CONCLUSIONS HPD is considered to be an acceleration of tumor growth after ICI treatment that is not only due to immune infiltration but also due to real disease progression, with an incidence of about 4-30% in all retrospective published studies to date. Currently, the most widely used criteria of HPD contain Response Evaluation Criteria in Solid Tumors (RECIST) and tumor growth rate (TGR) or tumor growth kinetics. The common risk factors and underlying mechanisms of HPD have not yet been fully elucidated. However, based on the poor prognosis of HPD, there have been many advances in the exploration of biomarkers in recent years, like the prediction of HPD, such as LDH levels of peripheral blood, liquid biopsy, and radiomics, etc.
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Affiliation(s)
- Miaozhen Lin
- Department of VIP Impatient, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ben G. L. Vanneste
- Department of Radiation Oncology (MAASTRO Clinic), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Qiwen Yu
- Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Zebin Chen
- Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Jiayu Peng
- Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Xiuyu Cai
- Department of VIP Impatient, Sun Yat-sen University Cancer Center, Guangzhou, China
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Wang C, Hu Y, Yang H, Wang S, Zhou B, Bao Y, Huang Y, Luo Q, Yang C, Xie X, Yang S. Function of Non-coding RNA in Helicobacter pylori-Infected Gastric Cancer. Front Mol Biosci 2021; 8:649105. [PMID: 34046430 PMCID: PMC8144459 DOI: 10.3389/fmolb.2021.649105] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 03/10/2021] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer is a common malignant tumor of the digestive system. Its occurrence and development are the result of a combination of genetic, environmental, and microbial factors. Helicobacter pylori infection is a chronic infection that is closely related to the occurrence of gastric tumorigenesis. Non-coding RNA has been demonstrated to play a very important role in the organism, exerting a prominent role in the carcinogenesis, proliferation, apoptosis, invasion, metastasis, and chemoresistance of tumor progression. H. pylori infection affects the expression of non-coding RNA at multiple levels such as genetic polymorphisms and signaling pathways, thereby promoting or inhibiting tumor progression or chemoresistance. This paper mainly introduces the relationship between H. pylori-infected gastric cancer and non-coding RNA, providing a new perspective for gastric cancer treatment.
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Affiliation(s)
- Chao Wang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yiyang Hu
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Huan Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Sumin Wang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Bo Zhou
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yulu Bao
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yu Huang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Qiang Luo
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Chuan Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Xia Xie
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Shiming Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
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Sokolova O, Naumann M. Manifold role of ubiquitin in Helicobacter pylori infection and gastric cancer. Cell Mol Life Sci 2021; 78:4765-4783. [PMID: 33825941 PMCID: PMC8195768 DOI: 10.1007/s00018-021-03816-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 02/22/2021] [Accepted: 03/18/2021] [Indexed: 02/07/2023]
Abstract
Infection with H. pylori induces a strong host cellular response represented by induction of a set of molecular signaling pathways, expression of proinflammatory cytokines and changes in proliferation. Chronic infection and inflammation accompanied by secretory dysfunction can result in the development of gastric metaplasia and gastric cancer. Currently, it has been determined that the regulation of many cellular processes involves ubiquitinylation of molecular effectors. The binding of ubiquitin allows the substrate to undergo a change in function, to interact within multimolecular signaling complexes and/or to be degraded. Dysregulation of the ubiquitinylation machinery contributes to several pathologies, including cancer. It is not understood in detail how H. pylori impacts the ubiquitinylation of host substrate proteins. The aim of this review is to summarize the existing literature in this field, with an emphasis on the role of E3 ubiquitin ligases in host cell homeodynamics, gastric pathophysiology and gastric cancer.
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Affiliation(s)
- Olga Sokolova
- Medical Faculty, Otto Von Guericke University, Institute of Experimental Internal Medicine, 39120 Magdeburg, Germany
| | - Michael Naumann
- Medical Faculty, Otto Von Guericke University, Institute of Experimental Internal Medicine, 39120 Magdeburg, Germany
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Prinz C, Mese K, Weber D. MicroRNA Changes in Gastric Carcinogenesis: Differential Dysregulation during Helicobacter pylori and EBV Infection. Genes (Basel) 2021; 12:genes12040597. [PMID: 33921696 PMCID: PMC8073778 DOI: 10.3390/genes12040597] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/05/2021] [Accepted: 04/14/2021] [Indexed: 12/11/2022] Open
Abstract
Despite medical advances, gastric-cancer (GC) mortality remains high in Europe. Bacterial infection with Helicobacter pylori (H. pylori) and viral infection with the Epstein–Barr virus (EBV) are associated with the development of both distal and proximal gastric cancer. Therefore, the detection of these infections and the prediction of further cancer development could be clinically significant. To this end, microRNAs (miRNAs) could serve as promising new tools. MiRNAs are highly conserved noncoding RNAs that play an important role in gene silencing, mainly acting via translational repression and the degradation of mRNA targets. Recent reports demonstrate the downregulation of numerous miRNAs in GC, especially miR-22, miR-145, miR-206, miR-375, and miR-490, and these changes seem to promote cancer-cell invasion and tumor spreading. The dysregulation of miR-106b, miR-146a, miR-155, and the Let-7b/c complex seems to be of particular importance during H. pylori infection or gastric carcinogenesis. In contrast, many reports describe changes in host miRNA expression and outline the effects of bamHI-A region rightward transcript (BART) miRNA in EBV-infected tissue. The differential regulation of these miRNA, acting alone or in close interaction when both infections coexist, may therefore enable us to detect cancer earlier. In this review, we focus on the two different etiologies of gastric cancer and outline the molecular pathways through which H. pylori- or EBV-induced changes might synergistically act via miR-155 dysregulation to potentiate cancer risk. The three markers, namely, H. pylori presence, EBV infection, and miR-155 expression, may be checked in routine biopsies to evaluate the risk of developing gastric cancer.
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Affiliation(s)
- Christian Prinz
- Medizinische Klinik 2, Helios Universitätsklinikum Wuppertal, 42283 Wuppertal, Germany;
- Lehrstuhl Innere Medizin 1, University of Witten/Herdecke gGmbH, 42283 Wuppertal, Germany;
- Correspondence: ; Tel.: +49-202-896-2243; Fax: +49-202-896-2740
| | - Kemal Mese
- Lehrstuhl Innere Medizin 1, University of Witten/Herdecke gGmbH, 42283 Wuppertal, Germany;
- Institute of Virology, University of Göttingen, 37075 Göttingen, Germany
| | - David Weber
- Medizinische Klinik 2, Helios Universitätsklinikum Wuppertal, 42283 Wuppertal, Germany;
- Lehrstuhl Innere Medizin 1, University of Witten/Herdecke gGmbH, 42283 Wuppertal, Germany;
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12
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Isoforms of the p53 Family and Gastric Cancer: A Ménage à Trois for an Unfinished Affair. Cancers (Basel) 2021; 13:cancers13040916. [PMID: 33671606 PMCID: PMC7926742 DOI: 10.3390/cancers13040916] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/06/2021] [Accepted: 02/17/2021] [Indexed: 12/17/2022] Open
Abstract
Simple Summary The p53 family is a complex family of transcription factors with different cellular functions that are involved in several physiological processes. A massive amount of data has been accumulated on their critical role in the tumorigenesis and the aggressiveness of cancers of different origins. If common features are observed, there are numerous specificities that may reflect particularities of the tissues from which the cancers originated. In this regard, gastric cancer tumorigenesis is rather remarkable, as it is induced by bacterial and viral infections, various chemical carcinogens, and familial genetic alterations, which provide an example of the variety of molecular mechanisms responsible for cell transformation and how they impact the p53 family. This review summarizes the knowledge gathered from over 40 years of research on the role of the p53 family in gastric cancer, which still displays one of the most elevated mortality rates amongst all types of cancers. Abstract Gastric cancer is one of the most aggressive cancers, with a median survival of 12 months. This illustrates its complexity and the lack of therapeutic options, such as personalized therapy, because predictive markers do not exist. Thus, gastric cancer remains mostly treated with cytotoxic chemotherapies. In addition, less than 20% of patients respond to immunotherapy. TP53 mutations are particularly frequent in gastric cancer (±50% and up to 70% in metastatic) and are considered an early event in the tumorigenic process. Alterations in the expression of other members of the p53 family, i.e., p63 and p73, have also been described. In this context, the role of the members of the p53 family and their isoforms have been investigated over the years, resulting in conflicting data. For instance, whether mutations of TP53 or the dysregulation of its homologs may represent biomarkers for aggressivity or response to therapy still remains a matter of debate. This uncertainty illustrates the lack of information on the molecular pathways involving the p53 family in gastric cancer. In this review, we summarize and discuss the most relevant molecular and clinical data on the role of the p53 family in gastric cancer and enumerate potential therapeutic innovative strategies.
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Exosome-mediated delivery of functionally active miRNA-375-3p mimic regulate epithelial mesenchymal transition (EMT) of colon cancer cells. Life Sci 2021; 269:119035. [PMID: 33450254 DOI: 10.1016/j.lfs.2021.119035] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/20/2020] [Accepted: 01/03/2021] [Indexed: 12/12/2022]
Abstract
AIMS EMT is the process by which a polarized epithelial cell undergoes several changes leading to highly invasive and fibroblast-like morphology. It has been described that miR-375 is inversely associated with EMT in cancerous patients and can effectively inhibit invasion and migration of tumor cells. Here, we investigate whether miR-375 mimic delivered by tumor-derived exosomes could reverse EMT process. MAIN METHODS The exosomes were isolated from HT-29 and SW480. Subsequently, exosomes were loaded with miR-375-3p mimic applying modified calcium chloride method. Quantitative real-time PCR was used for evaluation of the loading efficiency of miR-375 mimic in the exosomes. The effects of miR-375 loaded tumor exosomes (TEXomiR) on EMT process investigated using flow cytometry, cell morphology, and invasion and migration assay. KEY FINDINGS The in vitro results showed that the tumor derived exosomes can efficiently deliver miR-375 mimic to reduce the expression of β-catenin, vimentin, ZEB1, and snail. In contrast, TEXomiR significantly increased the expression of E- cadherin in EMT process. Furthermore, the migration and invasion abilities of HT-29 and SW480 cells were inhibited by TEXomiR. The expression of CD44 and CD133 are increased in EMT process. Flow cytometry evaluation demonstrated that treatment with TEXomiR significantly decreased the expression of CD44 and CD133 in SW480 cell line. SIGNIFICANCE Our results imply that colon cancer cells-derived exosomes could be used as an effective nonvehicle to deliver miR-375-3p mimic. Moreover, TEXomiR may be a potent therapeutic agent for the treatment of metastatic colorectal cancer.
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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: 198] [Impact Index Per Article: 39.6] [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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Danbaran GR, Aslani S, Sharafkandi N, Hemmatzadeh M, Hosseinzadeh R, Azizi G, Jadidi-Niaragh F, Babaie F, Mohammadi H. How microRNAs affect the PD-L1 and its synthetic pathway in cancer. Int Immunopharmacol 2020; 84:106594. [PMID: 32416456 DOI: 10.1016/j.intimp.2020.106594] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 04/27/2020] [Accepted: 05/08/2020] [Indexed: 12/17/2022]
Abstract
Programmed cell death-ligand 1 (PD-L1) is a glycoprotein that is expressed on the cell surface of both hematopoietic and nonhematopoietic cells. PD-L1 play a role in the immune tolerance and protect self-tissues from immune system attack. Dysfunction of this molecule has been highlighted in the pathogenesis of tumors, autoimmunity, and infectious disorders. MicroRNAs (miRNAs) are endogenous molecules that are classified as small non-coding RNA with approximately 20-22 nucleotides (nt) length. The function of miRNAs is based on complementary interactions with target mRNA via matching completely or incompletely. The result of this function is decay of the target mRNA or preventing mRNA translation. In the past decades, several miRNAs have been discovered which play an important role in the regulation of PD-L1 in various malignancies. In this review, we discuss the effect of miRNAs on PD-L1 expression and consider the effect of miRNAs on the synthetic pathway of PD-L1, especially during cancers.
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Affiliation(s)
| | - Saeed Aslani
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nadia Sharafkandi
- Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Maryam Hemmatzadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ramin Hosseinzadeh
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Gholamreza Azizi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhad Babaie
- Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Hamed Mohammadi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran; Department of Immunology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.
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Pereira J, Santos M, Delabio R, Barbosa M, Smith M, Payão S, Rasmussen L. Analysis of Gene Expression of miRNA-106b-5p and TRAIL in the Apoptosis Pathway in Gastric Cancer. Genes (Basel) 2020; 11:genes11040393. [PMID: 32260540 PMCID: PMC7230378 DOI: 10.3390/genes11040393] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 03/30/2020] [Accepted: 04/01/2020] [Indexed: 12/19/2022] Open
Abstract
Helicobacter pylori (H. pylori) is one of the main causes of gastric gancer. TNF-related apoptosis-inducing ligand (TRAIL) is a protein able to promote apoptosis in cancer cells, however not in gastric cancer, which presents resistance to apoptosis via TRAIL. It is believed that MicroRNA-106b-5p might be involved in this resistance, although its role in Gastric Cancer is unclear. We aimed to determine the expression of microRNA-106b-5p and TRAIL in patients with gastric diseases, infected by H. pylori, and understand the relationship between these genes and their role in apoptosis and the gastric cancer pathways. H. pylori was detected by PCR, gene expression analysis was performed by real-time-qPCR, and bioinformatics analysis was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Cytoscape software. A total of 244 patients were divided into groups (Control, Gastritis, and Cancer); H. pylori was detected in 42.2% of the samples. The cancer group had a poor expression of TRAIL (p < 0.0001) and overexpression of microRNA-106b-5p (p = 0.0005), however, our results confirmed that these genes are not directly related to each other although both are apoptosis-related regulators. Our results also indicated that H. pylori decreases microRNA-106b-5p expression and that this is a carcinogenic bacterium responsible for gastric diseases.
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Affiliation(s)
- Jéssica Pereira
- Marilia Medical School (FAMEMA), Marília, São Paulo 17519-030, Brazil; (J.P.); (M.S.); (R.D.); (S.P.)
| | - Mônica Santos
- Marilia Medical School (FAMEMA), Marília, São Paulo 17519-030, Brazil; (J.P.); (M.S.); (R.D.); (S.P.)
| | - Roger Delabio
- Marilia Medical School (FAMEMA), Marília, São Paulo 17519-030, Brazil; (J.P.); (M.S.); (R.D.); (S.P.)
| | - Mônica Barbosa
- Department of Biosciences and Technology of Institute of Tropical Pathology and Public Health, Federal University of Goias (UFG), Goiânia, Goiás 74605-050, Brazil;
| | - Marília Smith
- Department of Morphology and Genetics, Escola Paulista de Medicina, Federal University of Sao Paulo (UNIFESP), São Paulo 04023-062, Brazil;
| | - Spencer Payão
- Marilia Medical School (FAMEMA), Marília, São Paulo 17519-030, Brazil; (J.P.); (M.S.); (R.D.); (S.P.)
| | - Lucas Rasmussen
- Marilia Medical School (FAMEMA), Marília, São Paulo 17519-030, Brazil; (J.P.); (M.S.); (R.D.); (S.P.)
- Correspondence: ; Tel.: +55-14-34021856
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17
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Prinz C, Weber D. MicroRNA (miR) dysregulation during Helicobacter pylori-induced gastric inflammation and cancer development: critical importance of miR-155. Oncotarget 2020; 11:894-904. [PMID: 32206186 PMCID: PMC7075464 DOI: 10.18632/oncotarget.27520] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 02/06/2020] [Indexed: 02/03/2023] Open
Abstract
Dysregulation of noncoding microRNA molecules has been associated with immune cell activation in the context of Helicobacter pylori induced gastric inflammation as well as carcinogenesis, but also with downregulation of mismatch repair genes, and may interfere with immune checkpoint proteins that lead to the overexpression of antigens on gastric tumor cells. Numerous miR-molecules have been described as important tools and markers in gastric inflammation and cancer development -including miR-21, miR-143, miR-145, miR-201, and miR-335- all of which are downregulated in gastric tumors, and involved in cell cycle growth or tumor invasion. Among the many microRNAs involved in gastric inflammation, adenocarcinoma development and immune checkpoint regulation, miR-155 is notable in that its upregulation is considered a key marker of chronic gastric inflammation that predisposes a patient to gastric carcinogenesis. Among various other miRs, miR-155 is highly expressed in activated B and T cells and in monocytes/macrophages present in chronic gastric inflammation. Notably, miR-155 was shown to downregulate the expression of certain MMR genes, such as MLH1, MSH2, and MSH6. In tumor-infiltrating miR-155-deficient CD8+ T cells, antibodies against immune checkpoint proteins restored the expression of several derepressed miR-155 targets, suggesting that miR-155 may regulate overlapping pathways to promote antitumor immunity. It may thus be of high clinical impact that gastric pathologies mediated by miR-155 result from its overexpression. This suggests that it may be possible to therapeutically attenuate miR-155 levels for gastric cancer treatment and/or to prevent the progression of chronic gastric inflammation into cancer.
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Affiliation(s)
- Christian Prinz
- Lehrstuhl für Innere Medizin1, University of Witten gGmbH, Helios Universitätsklinikum, D-42283 Wuppertal, Germany
| | - David Weber
- Lehrstuhl für Innere Medizin1, University of Witten gGmbH, Helios Universitätsklinikum, D-42283 Wuppertal, Germany
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18
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Dang Y, Liu T, Yan J, Reinhardt JD, Yin C, Ye F, Zhang G. Gastric cancer proliferation and invasion is reduced by macrocalyxin C via activation of the miR-212-3p/Sox6 Pathway. Cell Signal 2020; 66:109430. [PMID: 31726103 DOI: 10.1016/j.cellsig.2019.109430] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 09/03/2019] [Accepted: 09/26/2019] [Indexed: 01/09/2023]
Abstract
Gastric cancer is a malignancy of very poor prognosis and survival rates. Macrocalyxin C is a Chinese herb-derived diterpenoid compound that has been postulated to possess anti-cancer characteristics. Gastic cell viability and stage of cell cycle were assessed using CCK8 assay and flow cytometry, respectively. Cell migration and invation were assessed using the wound healing and Transwell assays. Rate of apoptosis was determined via AV/PI-staining. Athymic nude mice xenograft models were used to evaluate the in vivo efficacy of macrocalyxin C. Western blot, luciferase experiments, cell transfection and real-time PCR allowed further study into the activation of the miR-212-3p/Sox6 pathway during macrocalyxin C treatment. We conclude that macrocalyxin C may halt the proliferation of gastric malignancies through alteration of cell invasion, apoptosis, progression through the cell cycle and cell growth. The macrocalyxin C→miR-212-3p┤Sox6 signal pathway was identified to be involved in Sox6 attenuation through augmentation of miR-212-3p values.
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Affiliation(s)
- Yini Dang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; First Clinical Medical College of Nanjing Medical University, Nanjin, Jiangsu Province, China
| | - TingYu Liu
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; First Clinical Medical College of Nanjing Medical University, Nanjin, Jiangsu Province, China; Department of Gastroenterology, Affiliated Zhongshan Hospital of fudan university, Shanghai, China
| | - Jin Yan
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; First Clinical Medical College of Nanjing Medical University, Nanjin, Jiangsu Province, China
| | - Jan D Reinhardt
- Institute for Disaster Management and Reconstruction, Sichuan University-The Hong Kong Polytechnic University, Chengdu, Sichuan Province, China; Epidemiology of Functioning, Swiss Paraplegic Research, Nottwil, Switzerland
| | - Chengqiang Yin
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; First Clinical Medical College of Nanjing Medical University, Nanjin, Jiangsu Province, China; Department of Gastroenterology, Sir Run Run Hospital Affiliated with Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Feng Ye
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; First Clinical Medical College of Nanjing Medical University, Nanjin, Jiangsu Province, China
| | - Guoxin Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; First Clinical Medical College of Nanjing Medical University, Nanjin, Jiangsu Province, China.
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19
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Chichirau BE, Diechler S, Posselt G, Wessler S. Tyrosine Kinases in Helicobacter pylori Infections and Gastric Cancer. Toxins (Basel) 2019; 11:toxins11100591. [PMID: 31614680 PMCID: PMC6832112 DOI: 10.3390/toxins11100591] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 10/02/2019] [Accepted: 10/09/2019] [Indexed: 12/11/2022] Open
Abstract
Helicobacter pylori (H. pylori) has been identified as a leading cause of gastric cancer, which is one of the most frequent and malignant types of tumor. It is characterized by its rapid progression, distant metastases, and resistance to conventional chemotherapy. A number of receptor tyrosine kinases and non-receptor tyrosine kinases have been implicated in H. pylori-mediated pathogenesis and tumorigenesis. In this review, recent findings of deregulated EGFR, c-Met, JAK, FAK, Src, and c-Abl and their functions in H. pylori pathogenesis are summarized.
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Affiliation(s)
- Bianca E Chichirau
- Department of Biosciences, Paris-Lodron University of Salzburg, 5020 Salzburg, Austria.
| | - Sebastian Diechler
- Department of Biosciences, Paris-Lodron University of Salzburg, 5020 Salzburg, Austria.
| | - Gernot Posselt
- Department of Biosciences, Paris-Lodron University of Salzburg, 5020 Salzburg, Austria.
| | - Silja Wessler
- Cancer Cluster Salzburg, Department of Biosciences, Paris-Lodron University of Salzburg, 5020 Salzburg, Austria.
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20
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Lian Y, Hu Y, Gan L, Huo YN, Luo HY, Wang XZ. Ssc-novel-miR-106-5p reduces lipopolysaccharide-induced inflammatory response in porcine endometrial epithelial cells by inhibiting the expression of the target gene mitogen-activated protein kinase kinase kinase 14 (MAP3K14). Reprod Fertil Dev 2019; 31:1616-1627. [PMID: 31242957 DOI: 10.1071/rd19097] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 05/12/2019] [Indexed: 12/26/2022] Open
Abstract
As an important gram-negative bacterial outer membrane component, lipopolysaccharide (LPS) plays an important role in bacterial-induced endometritis in sows. However, how LPS induces endometritis is unclear. We stimulated sow endometrial epithelial cells (EECs) with LPS and detected cell viability and tumour necrosis factor-α (TNF-α) and interleukin-1 (IL-1) secretion. LPS affected EEC viability and TNF-α and IL-1 secretion in a dose-dependent manner. LPS induced differential expression in 10 of 393 miRNAs in the EECs (downregulated, nine; upregulated, one). MicroRNA (miRNA) high-throughput sequencing of the LPS-induced EECs plus bioinformatics analysis and the dual-luciferase reporter system revealed a novel miRNA target gene: mitogen-activated protein kinase kinase kinase 14 (MAP3K14). Ssc-novel-miR-106-5p mimic, inhibitor and the nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) phosphorylation inhibitor Bay11-7085 were used to detect EEC nuclear factor-κB phosphorylation levels (p-NF-κB) and TNF-α and IL-1 secretion. MiR-106-5p mimic downregulated MAP3K14 mRNA and protein expression levels, inhibited p-NF-κB levels and decreased IL-1 and TNF-α secretion, whereas miR-106-5p inhibitor had the opposite effect. Bay11-7085 inhibited p-NF-κB expression and TNF-α and IL-1 secretion. These results suggest that LPS downregulates ssc-novel-miR-106-5p expression in sow EECs to increase MAP3K14 expression, which increases p-NF-κB to promote IL-1 and TNF-α secretion.
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Affiliation(s)
- Yu Lian
- Chongqing Key Laboratory of Forage and Herbivore, College of Animal Science and Technology, Southwest University, Beibei, Chongqing 400716, P. R. China
| | - Yu Hu
- Chongqing Key Laboratory of Forage and Herbivore, College of Animal Science and Technology, Southwest University, Beibei, Chongqing 400716, P. R. China
| | - Lu Gan
- Chongqing Key Laboratory of Forage and Herbivore, College of Animal Science and Technology, Southwest University, Beibei, Chongqing 400716, P. R. China
| | - Yuan-Nan Huo
- Chongqing Key Laboratory of Forage and Herbivore, College of Animal Science and Technology, Southwest University, Beibei, Chongqing 400716, P. R. China
| | - Hong-Yan Luo
- College of Resource and Environment, Southwest University, Beibei, Chongqing 400716, P. R. China
| | - Xian-Zhong Wang
- Chongqing Key Laboratory of Forage and Herbivore, College of Animal Science and Technology, Southwest University, Beibei, Chongqing 400716, P. R. China; and Corresponding author.
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21
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Yang YZ, Zhao XJ, Xu HJ, Wang SC, Pan Y, Wang SJ, Xu Q, Jiao RQ, Gu HM, Kong LD. Magnesium isoglycyrrhizinate ameliorates high fructose-induced liver fibrosis in rat by increasing miR-375-3p to suppress JAK2/STAT3 pathway and TGF-β1/Smad signaling. Acta Pharmacol Sin 2019; 40:879-894. [PMID: 30568253 DOI: 10.1038/s41401-018-0194-4] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 11/08/2018] [Indexed: 12/26/2022]
Abstract
Increasing evidence has demonstrated that excessive fructose intake induces liver fibrosis. Epithelial-mesenchymal transition (EMT) driven by transforming growth factor-β1 (TGF-β1)/mothers against decapentaplegic homolog (Smad) signaling activation promotes the occurrence and development of liver fibrosis. Magnesium isoglycyrrhizinate is clinically used as a hepatoprotective agent to treat liver fibrosis, but its underlying molecular mechanism has not been identified. Using a rat model, we found that high fructose intake reduced microRNA (miR)-375-3p expression and activated the janus-activating kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) cascade and TGF-β1/Smad signaling, which is consistent with the EMT and liver fibrosis. To further verify these observations, BRL-3A cells and/or primary rat hepatocytes were exposed to high fructose and/or transfected with a miR-375-3p mimic or inhibitor or treated with a JAK2 inhibitor, and we found that the low expression of miR-375-3p could induce the JAK2/STAT3 pathway to activate TGF-β1/Smad signaling and promote the EMT. Magnesium isoglycyrrhizinate was found to ameliorate high fructose-induced EMT and liver fibrosis in rats. More importantly, magnesium isoglycyrrhizinate increased miR-375-3p expression to suppress the JAK2/STAT3 pathway and TGF-β1/Smad signaling in these animal and cell models. This study provides evidence showing that magnesium isoglycyrrhizinate attenuates liver fibrosis associated with a high fructose diet.
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Zhang Z, Dong Y, Hua J, Xue H, Hu J, Jiang T, Shi L, Du J. A five-miRNA signature predicts survival in gastric cancer using bioinformatics analysis. Gene 2019; 699:125-134. [DOI: 10.1016/j.gene.2019.02.058] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 01/14/2019] [Accepted: 02/21/2019] [Indexed: 12/11/2022]
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Zou D, Xu L, Li H, Ma Y, Gong Y, Guo T, Jing Z, Xu X, Zhang Y. Role of abnormal microRNA expression in Helicobacter pylori associated gastric cancer. Crit Rev Microbiol 2019; 45:239-251. [PMID: 30776938 DOI: 10.1080/1040841x.2019.1575793] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Epidemiological studies have shown that Helicobacter pylori (HP) infection is a risk factor for gastric cancer (GC). HP infection may induce the release of pro-inflammatory mediators, and abnormally increase the level of reactive oxygen species (ROS), nitric oxide (NO), and cytokines in mucosal epithelial cells of the stomach. However, the specific mechanism underlying the pathogenesis of HP-associated GC is still poorly understood. Recent studies have revealed that abnormal microRNA expression may affect the proliferation, differentiation, and apoptosis of mucosal epithelial cells of the stomach to further influence GC occurrence, development, and metastasis. Herein, we summarize the role of abnormal microRNAs in the regulation of HP-associated GC progression. Abnormal microRNA expression in HP-positive GC may be a biomarker for GC diagnosis, occurrence, and development as well as its targeted treatment and prognosis.
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Affiliation(s)
- Dan Zou
- a The First laboratory of cancer institute , First Hospital of China Medical University , Shenyang , China
| | - Ling Xu
- b Department of Medical Oncology , First Hospital of China Medical University , Shenyang , China
| | - Heming Li
- b Department of Medical Oncology , First Hospital of China Medical University , Shenyang , China.,c Department of Oncology , Affiliated Zhongshan Hospital of Dalian University , Dalian , China
| | - Yanju Ma
- b Department of Medical Oncology , First Hospital of China Medical University , Shenyang , China.,d Department of Medical Oncology , Cancer Hospital of China Medical University , Shenyang , China
| | - Yuehua Gong
- e Department of Tumor Etiology and Screening Department of Cancer Institute and General Surgery, First Hospital of China Medical University , Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department , Shenyang , China
| | - Tianshu Guo
- b Department of Medical Oncology , First Hospital of China Medical University , Shenyang , China
| | - Zhitao Jing
- f Department of Neurosurgery , First Hospital of China Medical University , Shenyang , China
| | - Xiuying Xu
- g Department of Gastroenterology , First Hospital of China Medical University , Shenyang , China
| | - Ye Zhang
- a The First laboratory of cancer institute , First Hospital of China Medical University , Shenyang , China
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Mechanisms of Inflammasome Signaling, microRNA Induction and Resolution of Inflammation by Helicobacter pylori. Curr Top Microbiol Immunol 2019; 421:267-302. [PMID: 31123893 DOI: 10.1007/978-3-030-15138-6_11] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Inflammasome-controlled transcription and subsequent cleavage-mediated activation of mature IL-1β and IL-18 cytokines exemplify a crucial innate immune mechanism to combat intruding pathogens. Helicobacter pylori represents a predominant persistent infection in humans, affecting approximately half of the population worldwide, and is associated with the development of chronic gastritis, peptic ulcer disease, and gastric cancer. Studies in knockout mice have demonstrated that the pro-inflammatory cytokine IL-1β plays a central role in gastric tumorigenesis. Infection by H. pylori was recently reported to stimulate the inflammasome both in cells of the mouse and human immune systems. Using mouse models and in vitro cultured cell systems, the bacterial pathogenicity factors and molecular mechanisms of inflammasome activation have been analyzed. On the one hand, it appears that H. pylori-stimulated IL-1β production is triggered by engagement of the immune receptors TLR2 and NLRP3, and caspase-1. On the other hand, microRNA hsa-miR-223-3p is induced by the bacteria, which controls the expression of NLRP3. This regulating effect by H. pylori on microRNA expression was also described for more than 60 additionally identified microRNAs, indicating a prominent role for inflammatory and other responses. Besides TLR2, TLR9 becomes activated by H. pylori DNA and further TLR10 stimulated by the bacteria induce the secretion of IL-8 and TNF, respectively. Interestingly, TLR-dependent pathways can accelerate both pro- and anti-inflammatory responses during H. pylori infection. Balancing from a pro-inflammation to anti-inflammation phenotype results in a reduction in immune attack, allowing H. pylori to persistently colonize and to survive in the gastric niche. In this chapter, we will pinpoint the role of H. pylori in TLR- and NLRP3 inflammasome-dependent signaling together with the differential functions of pro- and anti-inflammatory cytokines. Moreover, the impact of microRNAs on H. pylori-host interaction will be discussed, and its role in resolution of infection versus chronic infection, as well as in gastric disease development.
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Keck J, Gupta R, Christenson LK, Arulanandam BP. MicroRNA mediated regulation of immunity against gram-negative bacteria. Int Rev Immunol 2017; 36:287-299. [PMID: 28800263 PMCID: PMC6904929 DOI: 10.1080/08830185.2017.1347649] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Evidence over the last couple decades has comprehensively established that short, highly conserved, non-coding RNA species called microRNA (miRNA) exhibit the ability to regulate expression and function of host genes at the messenger RNA (mRNA) level. MicroRNAs play key regulatory roles in immune cell development, differentiation, and protective function. Intrinsic host immune response to invading pathogens rely on intricate orchestrated events in the development of innate and adaptive arms of immunity. We discuss the involvement of miRNAs in regulating these processes against gram negative pathogens in this review.
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Affiliation(s)
- Jonathon Keck
- South Texas Center for Emerging Infectious Diseases and Center of Excellence in Infection Genomics, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249
| | - Rishein Gupta
- South Texas Center for Emerging Infectious Diseases and Center of Excellence in Infection Genomics, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249
| | - Lane K. Christenson
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Bernard P. Arulanandam
- South Texas Center for Emerging Infectious Diseases and Center of Excellence in Infection Genomics, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249
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Lorenzon L, Cippitelli C, Avantifiori R, Uccini S, French D, Torrisi MR, Ranieri D, Mercantini P, Canu V, Blandino G, Cavallini M. Down-regulated miRs specifically correlate with non-cardial gastric cancers and Lauren's classification system. J Surg Oncol 2017; 116:184-194. [PMID: 28475823 DOI: 10.1002/jso.24648] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 03/22/2017] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND OBJECTIVES Gastric cancers are usually characterized using Lauren's classification into intestinal and diffuse types. We previously documented the down-modulation of miR31, miR148a, miR204, and miR375 in gastric cancers. We aimed this manuscript to investigate these miRs with the end-points of diagnosis, Lauren's classification and prognosis. METHODS A total of 117 resected non-cardial adenocarcinomas were evaluated for miRs' expressions. The performance of miRs' expressions for cancer diagnosis was tested using ROC curves. Logistic regression was conducted with the end-point of Lauren's classification. Kaplan-Meier and Cox analyses were performed for OS, DFS, and DSS. miRs' targets were reviewed using PRISMA method and BCL-2 was further investigated in cell lines. RESULTS ROC curves documented that miRs' down-modulation was significant in differentiating cancer versus normal tissues. Diffuse type cancers were associated with female sex, young age, and miR375 higher expression. We confirmed BCL-2 as a miR204 target. However, survival analyses confirmed the pathologic criteria (advanced stages, LNR, and low LNH) as the significant variables correlated to worse prognosis. CONCLUSIONS The down-modulation of miR31, miR148a, miR204, and miR375 is significantly associated with non-cardial gastric cancers and miR375 is specifically linked to Lauren's classification. Nevertheless, standard pathological features display as the independent variables associated with worse prognosis.
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Affiliation(s)
- Laura Lorenzon
- Faculty of Medicine and Psychology, Surgical and Medical Department of Traslational Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Claudia Cippitelli
- Faculty of Medicine and Psychology, Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Riccardo Avantifiori
- Faculty of Medicine and Psychology, Surgical and Medical Department of Traslational Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Stefania Uccini
- Faculty of Medicine and Psychology, Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Deborah French
- Faculty of Medicine and Psychology, Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Maria Rosaria Torrisi
- Faculty of Medicine and Psychology, Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Danilo Ranieri
- Faculty of Medicine and Psychology, Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Paolo Mercantini
- Faculty of Medicine and Psychology, Surgical and Medical Department of Traslational Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Valeria Canu
- Italian National Cancer Institute Regina Elena, Translational Oncogenomic Unit, Rome, Italy
| | - Giovanni Blandino
- Faculty of Medicine and Psychology, Surgical and Medical Department of Traslational Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
| | - Marco Cavallini
- Faculty of Medicine and Psychology, Surgical and Medical Department of Traslational Medicine, University of Rome "La Sapienza", Sant'Andrea Hospital of Rome, Rome, Italy
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Helicobacter pylori: A Paradigm Pathogen for Subverting Host Cell Signal Transmission. Trends Microbiol 2017; 25:316-328. [PMID: 28057411 DOI: 10.1016/j.tim.2016.12.004] [Citation(s) in RCA: 83] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 11/27/2016] [Accepted: 12/07/2016] [Indexed: 02/07/2023]
Abstract
Helicobacter pylori colonizes the gastric mucosa in the human stomach and represents a major risk factor for peptic ulcer disease and gastric cancer. Here, we summarize our current knowledge of the complex impact of H. pylori on manipulating host signalling networks, that is, by the cag pathogenicity island (cagPAI)-encoded type IV secretion system (T4SS). We show that H. pylori infections reflect a paradigm for interspecies contact-dependent molecular communication, which includes the disruption of cell-cell junctions and cytoskeletal rearrangements, as well as proinflammatory, cell cycle-related, proliferative, antiapoptotic, and DNA damage responses. The contribution of these altered signalling cascades to disease outcome is discussed.
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Lu H, Qi Z, Lin L, Ma L, Li L, Zhang H, Feng L, Su Y. The E6-TAp63β-Dicer feedback loop involves in miR-375 downregulation and epithelial-to-mesenchymal transition in HR-HPV+ cervical cancer cells. Tumour Biol 2016; 37:15805–15811. [PMID: 27812930 DOI: 10.1007/s13277-016-5378-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 09/09/2016] [Indexed: 12/22/2022] Open
Abstract
MiR-375 has been recognized as an important tumor suppressor and is usually downregulated in cervical cancer. However, how it is downregulated in cervical cancer is not clear. By using cancerous and normal cervical tissues, we observed that miR-375 and Dicer are both downregulated and were positively correlated. Overexpression of miR-375 resulted in decreased viral E6 and increased Dicer expression in both Hela and SiHa cells. Previous studies suggest that E6 can induce an accelerated degradation of TAp63β, while TAp63 can bind to and transactivate the Dicer promoter, exerting a direct regulation on transcription of Dicer. In this study, we found that miR-375 overexpression restored TAp63β expression. TAp63β overexpression significantly enhanced transcription and translation of Dicer, which further led to increased mature miR-375 levels. Therefore, we infer that there is an E6-TAp63β-Dicer feedback loop involved in miR-375 dysregulation in cervical cancer. Besides, we observed that enforced TAp63β expression significantly reduced the mesenchymal markers including N-cadherin, Vimentin, Snail, and Slug but increased the epithelial marker E-cadherin in both Hela and SiHa cells. The wound healing assay also confirmed that TAp63β overexpression significantly suppressed cervical cancer cell migration potential. These results suggest that TAp63β can inhibit epithelial-to-mesenchymal transition (EMT) of cervical cancer cells.
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Affiliation(s)
- Hongzhi Lu
- Department of Infectious Disease, the First Hospital of Qinhuangdao, Hebei, 066000, China
| | - Zhengqin Qi
- B-ultrasound Room, the First Hospital of Qinhuangdao, Hebei, 066000, China
| | - Lin Lin
- Department of Gynecology, the First Hospital of Qinhuangdao, Hebei, 066000, China
| | - Li Ma
- Department of Infectious Disease, the First Hospital of Qinhuangdao, Hebei, 066000, China
| | - Li Li
- Department of Infectious Disease, the First Hospital of Qinhuangdao, Hebei, 066000, China
| | - Hong Zhang
- Department of Infectious Disease, the First Hospital of Qinhuangdao, Hebei, 066000, China
| | - Li Feng
- Department of Infectious Disease, the First Hospital of Qinhuangdao, Hebei, 066000, China
| | - Ying Su
- Pediatric Intensive Care Unit, the First Hospital of Qinhuangdao, Hebei, 066000, China.
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Arias Sosa LA, Bernal Gómez BM, Cuspoca Orduz AF. Supresión tumoral por microARN en el cáncer gástrico. GACETA MEXICANA DE ONCOLOGÍA 2016. [DOI: 10.1016/j.gamo.2016.07.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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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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Cytoplasmic Drosha Is Aberrant in Precancerous Lesions of Gastric Carcinoma and Its Loss Predicts Worse Outcome for Gastric Cancer Patients. Dig Dis Sci 2016; 61:1080-90. [PMID: 26694172 DOI: 10.1007/s10620-015-3986-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Accepted: 11/30/2015] [Indexed: 01/13/2023]
Abstract
BACKGROUND The nuclear localization of Drosha is critical for its function as a microRNA maturation regulator. Dephosphorylation of Drosha at serine 300 and serine 302 disrupts its nuclear localization, and aberrant distribution of Drosha has been detected in some tumors. AIMS The purpose of the present study was to assess cytoplasmic/nuclear Drosha expression in gastric cancer carcinogenesis and progression. METHODS Drosha expression and its subcellular location was investigated by immunohistochemical staining of a set of tissue microarrays composed of normal adjacent tissues (374), chronic gastritis (137), precancerous lesions (94), and gastric adenocarcinoma (829) samples, and in gastric cancer cell lines with varying differentiation by immunofluorescence and western blot assay. RESULTS Gradual loss of cytoplasmic Drosha was accompanied by tumor progression in both gastric cancer tissues and cell lines, and was inversely associated with tumor volume (P = 0.002), tumor grade (P < 0.001), tumor stage (P = 0.018), and distant metastasis (P = 0.026). Aberrant high levels of cytoplasmic Drosha were apparent in intestinal metaplasia and dysplasia tissues. The levels of nuclear Drosha were sharply decreased in chronic gastritis and maintained through precancerous lesions to gastric cancer. High levels of cytoplasmic Drosha predicted longer survival (LR = 7.088, P = 0.008) in gastric cancer patients. CONCLUSIONS Our data provide novel insights into gastric cancer that cytoplasmic Drosha potentially plays a role in preventing carcinogenesis and tumor progression, and may be an independent predictor of patient outcome.
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Yang Q, Zhang RW, Sui PC, He HT, Ding L. Dysregulation of non-coding RNAs in gastric cancer. World J Gastroenterol 2015; 21:10956-10981. [PMID: 26494954 PMCID: PMC4607897 DOI: 10.3748/wjg.v21.i39.10956] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 08/28/2015] [Accepted: 09/15/2015] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is one of the most common cancers in the world and a significant threat to the health of patients, especially those from China and Japan. The prognosis for patients with late stage GC receiving the standard of care treatment, including surgery, chemotherapy and radiotherapy, remains poor. Developing novel treatment strategies, identifying new molecules for targeted therapy, and devising screening techniques to detect this cancer in its early stages are needed for GC patients. The discovery of non-coding RNAs (ncRNAs), primarily microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), helped to elucidate the mechanisms of tumorigenesis, diagnosis and treatment of GC. Recently, significant research has been conducted on non-coding RNAs and how the regulatory dysfunction of these RNAs impacts the tumorigenesis of GC. In this study, we review papers published in the last five years concerning the dysregulation of non-coding RNAs, especially miRNAs and lncRNAs, in GC. We summarize instances of aberrant expression of the ncRNAs in GC and their effect on survival-related events, including cell cycle regulation, AKT signaling, apoptosis and drug resistance. Additionally, we evaluate how ncRNA dysregulation affects the metastatic process, including the epithelial-mesenchymal transition, stem cells, transcription factor activity, and oncogene and tumor suppressor expression. Lastly, we determine how ncRNAs affect angiogenesis in the microenvironment of GC. We further discuss the use of ncRNAs as potential biomarkers for use in clinical screening, early diagnosis and prognosis of GC. At present, no ideal ncRNAs have been identified as targets for the treatment of GC.
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Libânio D, Dinis-Ribeiro M, Pimentel-Nunes P. Helicobacter pylori and microRNAs: Relation with innate immunity and progression of preneoplastic conditions. World J Clin Oncol 2015; 6:111-132. [PMID: 26468448 PMCID: PMC4600186 DOI: 10.5306/wjco.v6.i5.111] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Revised: 06/22/2015] [Accepted: 08/04/2015] [Indexed: 02/06/2023] Open
Abstract
The accepted paradigm for intestinal-type gastric cancer pathogenesis is a multistep progression from chronic gastritis induced by Helicobacter pylori (H. pylori) to gastric atrophy, intestinal metaplasia, dysplasia and ultimately gastric cancer. The genetic and molecular mechanisms underlying disease progression are still not completely understood as only a fraction of colonized individuals ever develop neoplasia suggesting that bacterial, host and environmental factors are involved. MicroRNAs are noncoding RNAs that may influence H. pylori-related pathology through the regulation of the transcription and expression of various genes, playing an important role in inflammation, cell proliferation, apoptosis and differentiation. Indeed, H. pylori have been shown to modify microRNA expression in the gastric mucosa and microRNAs are involved in the immune host response to the bacteria and in the regulation of the inflammatory response. MicroRNAs have a key role in the regulation of inflammatory pathways and H. pylori may influence inflammation-mediated gastric carcinogenesis possibly through DNA methylation and epigenetic silencing of tumor suppressor microRNAs. Furthermore, microRNAs influenced by H. pylori also have been found to be involved in cell cycle regulation, apoptosis and epithelial-mesenchymal transition. Altogether, microRNAs seem to have an important role in the progression from gastritis to preneoplastic conditions and neoplastic lesions and since each microRNA can control the expression of hundreds to thousands of genes, knowledge of microRNAs target genes and their functions are of paramount importance. In this article we present a comprehensive review about the role of microRNAs in H. pylori gastric carcinogenesis, identifying the microRNAs downregulated and upregulated in the infection and clarifying their biological role in the link between immune host response, inflammation, DNA methylation and gastric carcinogenesis.
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