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Zhou X, Matskova L, Zheng S, Wang X, Wang Y, Xiao X, Mo Y, Wölke M, Li L, Zheng Q, Huang G, Zhang Z, Ernberg I. Mechanisms of Anergic Inflammatory Response in Nasopharyngeal Carcinoma Cells Despite Ubiquitous Constitutive NF-κB Activation. Front Cell Dev Biol 2022; 10:861916. [PMID: 35938161 PMCID: PMC9353648 DOI: 10.3389/fcell.2022.861916] [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: 01/25/2022] [Accepted: 06/15/2022] [Indexed: 11/29/2022] Open
Abstract
Commensal microbes cross talk with their colonized mucosa. We show that microbes and their cell wall components induce an inflammatory response in cultured human mucosal cells derived from the nonmalignant nasopharyngeal epithelium (NNE) cells in vitro. NNE cells show significant induction of NF-κB with nuclear shuttling and inflammatory gene response when exposed to Gram-positive bacteria (streptococci) or peptidoglycan (PGN), a component of the Gram-positive bacterial cell wall. This response is abrogated in nasopharyngeal carcinoma (NPC)–derived cell lines. The inflammatory response induced by NF-κB signaling was blocked at two levels in the tumor-derived cells. We found that NF-κB was largely trapped in lipid droplets (LDs) in the cytoplasm of the NPC-derived cells, while the increased expression of lysine-specific histone demethylase 1 (LSD1, a repressive nuclear factor) reduces the response mediated by remaining NF-κB at the promoters responding to inflammatory stimuli. This refractory response in NPC cells might be a consequence of long-term exposure to microbes in vivo during carcinogenic progression. It may contribute to the decreased antitumor immune responses in NPC, among others despite heavy T-helper cell infiltration, and thus facilitate tumor progression.
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Affiliation(s)
- Xiaoying Zhou
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna, Sweden
- Life Science Institute, Guangxi Medical University, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High-Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China
| | - Liudmila Matskova
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna, Sweden
| | - Shixing Zheng
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna, Sweden
- ENT Institute and Department of Otorhinolaryngology, Eye and ENT Hospital, Fudan University, Shanghai, China
| | - Xiaoxia Wang
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna, Sweden
| | - Yifang Wang
- Life Science Institute, Guangxi Medical University, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High-Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China
| | - Xue Xiao
- Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yingxi Mo
- Department of Research, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Marleen Wölke
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna, Sweden
| | - Limei Li
- Key Laboratory of Early Prevention and Treatment for Regional High-Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China
| | - Qian Zheng
- Life Science Institute, Guangxi Medical University, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High-Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China
| | - Guangwu Huang
- Key Laboratory of Early Prevention and Treatment for Regional High-Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China
- Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhe Zhang
- Key Laboratory of Early Prevention and Treatment for Regional High-Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China
- ENT Institute and Department of Otorhinolaryngology, Eye and ENT Hospital, Fudan University, Shanghai, China
| | - Ingemar Ernberg
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna, Sweden
- *Correspondence: Ingemar Ernberg,
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Wang Y, Chu F, Lin J, Li Y, Johnson N, Zhang J, Gai C, Su Z, Cheng H, Wang L, Ding X. Erianin, the main active ingredient of Dendrobium chrysotoxum Lindl, inhibits precancerous lesions of gastric cancer (PLGC) through suppression of the HRAS-PI3K-AKT signaling pathway as revealed by network pharmacology and in vitro experimental verification. JOURNAL OF ETHNOPHARMACOLOGY 2021; 279:114399. [PMID: 34246740 DOI: 10.1016/j.jep.2021.114399] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 06/20/2021] [Accepted: 07/05/2021] [Indexed: 05/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Dendrobium chrysotoxum Lindl, a well-known traditional Chinese medicinal herb used in the treatment of gastric disease, is distinguished as the first of the "nine immortal grasses". Dendrobium chrysotoxum Lindl and the traditional Chinese medicine prescriptions containing Dendrobium chrysotoxum Lindl are often prescribed clinically to treat chronic gastritis and precancerous lesions of gastric cancer (PLGC), showing favorable clinical effects and medicinal value in the prevention of gastric cancer. However, the effective ingredients and pharmacological mechanisms through which Dendrobium chrysotoxum Lindl prevents and treats PLGC have not been adequately identified or interpreted. AIM OF THE STUDY The present study aimed to evaluate the effective ingredients and pharmacological mechanisms of Dendrobium chrysotoxum Lindl in the prevention and treatment of PLGC using network pharmacology. In addition, in vitro verification was performed to evaluate the mechanism of action of Erianin, the main active ingredient in Dendrobium chrysotoxum Lindl, providing experimental evidence for the clinical use of Dendrobium chrysotoxum Lindl in the treatment of PLGC. MATERIALS AND METHODS Using network pharmacology methods, the main ingredients in Dendrobium chrysotoxum Lindl were screened from the ETCM, BATMAN-TCM, and TCMID databases, and their potential targets were predicted using the Swiss Target Prediction platform. The targets related to PLGC were retrieved through the GeneCard database, and the targets common to the main ingredients of Dendrobium chrysotoxum Lindl and PLGC were analyzed. The protein-protein interaction (PPI) network was obtained via the STRING database and analyzed visually using Cytoscape 3.7.2. The underlying mechanisms of the common targets identified through gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were analyzed using DAVID online. The "component-target-pathway" networks of Dendrobium chrysotoxum Lindl and Erianin were visually constructed by Cytoscape 3.7.2. The biological activity evaluation of Erianin's effect on PLGC was carried out using MC cell lines, the PLGC cell model established using MNNG to induce damage in normal gastric mucosal epithelial cell (GES-1). After the intervention of different concentrations of Erianin, MC cell viability was explored using the MTT assays, cell migration was determined by wound healing assays, the cell cycle and apoptosis were analyzed using flow cytometry, and the expression levels of related proteins and their phosphorylation in the HRAS-PI3K-AKT signaling pathway were detected by Western blot. RESULTS The "component-target-pathway" network constructed in this study showed 37 active ingredients from Dendrobium chrysotoxum Lindl and 142 overlapping targets related to both Dendrobium chrysotoxum Lindl and PLGC. The targets were associated with a variety of cancer-related signaling pathways, including Pathways in cancer, PI3K-Akt signaling pathway, Rap1 signaling pathway, Focal adhesion, Ras signaling pathway, and MAPK signaling pathway. Notably, the network showed that Erianin, the primary active ingredient from Dendrobium chrysotoxum Lindl and the component associated with the most targets, could regulate Pathways in cancer, PI3K-AKT signaling pathway, Focal adhesion, Rap1 signaling pathway, cell cycle, and RAS signaling pathway in the treatment of PLGC. Verification through in vitro experiments found that Erianin can significantly inhibit MC cell viability, inhibit cell migration, block the cell cycle in the G2/M phase, and induce cell apoptosis in a dose-dependent manner. The results of the Western blot experiment further showed that Erianin can significantly decrease the protein expression levels of HRAS, AKT, p-AKT, MDM2, Cyclin D1, and p-Gsk3β, and increase the protein expression level of p21, which suggests that Erianin can treat PLGC by regulating the HRAS-PI3K-AKT signaling pathway. CONCLUSION This study explained the positive characteristics of multi-component, multi-target, and multi-approach intervention with Dendrobium chrysotoxum Lindl in the treatment of PLGC. Our results suggest that Erianin may be a promising candidate in the development of prevention and treatment methods for PLGC. This study provided experimental evidence for the clinical use of Dendrobium chrysotoxum Lindl to treat PLGC and prevent gastric cancer.
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Affiliation(s)
- Yan Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Fuhao Chu
- School of Chinese Materia Medicine, Beijing University of Chinese Medicine, Beijing, China; Institute of Regulatory Science for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Jie Lin
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Yuan Li
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Nadia Johnson
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Jianglan Zhang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Cong Gai
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Zeqi Su
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Hongjie Cheng
- Fangshan Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Linheng Wang
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China.
| | - Xia Ding
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
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Wang W, Qin JJ, Rajaei M, Li X, Yu X, Hunt C, Zhang R. Targeting MDM2 for novel molecular therapy: Beyond oncology. Med Res Rev 2019; 40:856-880. [PMID: 31587329 DOI: 10.1002/med.21637] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 08/20/2019] [Accepted: 08/21/2019] [Indexed: 12/14/2022]
Abstract
The murine double minute 2 (MDM2) oncogene exerts major oncogenic activities in human cancers; it is not only the best-documented negative regulator of the p53 tumor suppressor, but also exerts p53-independent activities. There is an increasing interest in developing MDM2-based targeted therapies. Several classes of MDM2 inhibitors have been evaluated in preclinical models, with a few entering clinical trials, mainly for cancer therapy. However, noncarcinogenic roles for MDM2 have also been identified, demonstrating that MDM2 is involved in many chronic diseases and conditions such as inflammation and autoimmune diseases, dementia and neurodegenerative diseases, heart failure and cardiovascular diseases, nephropathy, diabetes, obesity, and sterility. MDM2 inhibitors have been shown to have promising therapeutic efficacy for treating inflammation and other nonmalignant diseases in preclinical evaluations. Therefore, targeting MDM2 may represent a promising approach for treating and preventing these nonmalignant diseases. In addition, a better understanding of how MDM2 works in nonmalignant diseases may provide new biomarkers for their diagnosis, prognostic prediction, and monitoring of therapeutic outcome. In this review article, we pay special attention to the recent findings related to the roles of MDM2 in the pathogenesis of several nonmalignant diseases, the therapeutic potential of its downregulation or inhibition, and its use as a biomarker.
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Affiliation(s)
- Wei Wang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas.,Drug Discovery Institute, University of Houston, Houston, Texas
| | - Jiang-Jiang Qin
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas
| | - Mehrdad Rajaei
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas
| | - Xin Li
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas
| | - Xiaoyi Yu
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas
| | - Courtney Hunt
- Drug Discovery Institute, University of Houston, Houston, Texas
| | - Ruiwen Zhang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas.,Drug Discovery Institute, University of Houston, Houston, Texas
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Song J, Ma SJ, Luo JH, Liu H, Li L, Zhang ZG, Chen LS, Zhou RX. Downregulation of AKT and MDM2, Melatonin Induces Apoptosis in AGS and MGC803 Cells. Anat Rec (Hoboken) 2019; 302:1544-1551. [PMID: 30809951 DOI: 10.1002/ar.24101] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 10/19/2018] [Accepted: 10/26/2018] [Indexed: 01/04/2023]
Abstract
Melatonin, a neurohormone secreted by the pineal gland, has a variety of biological functions, such as circadian rhythms regulation, anti-oxidative activity, immunomodulatory effects, and anittumor, etc. At present, its antitumor effect has attracted people's attention due to its extensive tissue distribution, good tissue compatibility, and low toxic and side effects. In the gastrointestinal tract, there is high level of melatonin and many studies showed melatonin has effects of anti-gastric cancer. In this experiment, human gastric cancer cell lines AGS and MGC803 were used to investigate the intracellular molecular mechanism of melatonin against gastric cancer. After AGS and MGC803 have been treated with melatonin, the changes of cell morphology and cellular structure were observed under electron microscope. Flow cytometer and apoptosis detection kits were used to analyze the effect of apoptosis on AGS and MGC803. The alterations of apoptosis-related proteins Caspase 9, Caspase 3, and upstream regulators AKT, MDM2 including expression, phosphorylation, and activation were detected to analyze the intracellular molecular mechanism of melatonin inhibiting gastric cancer. In AGS and MGC803 cells with melatonin exposure, cleaved Caspase 9 was upregulated and Caspase 3 was activated; moreover, MDM2 and AKT expression and phosphorylation were downregulated. Melatonin promoted apoptosis of AGS and MGC803 cells by the downregulation of AKT and MDM2. Anat Rec, 302:1544-1551, 2019. © 2019 American Association for Anatomy.
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Affiliation(s)
- Jun Song
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350122, People's Republic of China
| | - Sai-Jun Ma
- Clinical Laboratory, Second Inpatient Department, Fuzhou General Hospital, Fuzhou, Fujian, 350108, People's Republic of China
| | - Jian-Hua Luo
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350122, People's Republic of China
| | - Hui Liu
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350122, People's Republic of China
| | - Li Li
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350122, People's Republic of China
| | - Zhi-Guang Zhang
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350122, People's Republic of China
| | - Lu-Shan Chen
- Pathology, The Affiliated Union Hospital of Fujian Medical University, Fuzhou, Fujian, 350001, People's Republic of China
| | - Rui-Xiang Zhou
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350122, People's Republic of China
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Liu L, Yang L, Chang H, Chen YN, Zhang F, Feng S, Peng J, Ren CC, Zhang XA. CP‑31398 attenuates endometrial cancer cell invasion, metastasis and resistance to apoptosis by downregulating MDM2 expression. Int J Oncol 2019; 54:942-954. [PMID: 30628640 PMCID: PMC6365028 DOI: 10.3892/ijo.2019.4681] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 10/26/2018] [Indexed: 12/21/2022] Open
Abstract
Endometrial cancer (EC) is one of the most common malignancies of the female reproductive system, and metastasis is a major cause of mortality. In this study, we aimed to explore the role of CP-31398 in the migration, invasion and apoptosis of EC cells by its regulation of the expression of the murine double minute 2 (MDM2) gene. For this purpose, EC tissues and adjacent normal tissues were collected, and the positive expression rate of MDM2 in these tissues was assessed. Subsequently, the cellular 50% inhibitory concentration (IC50) of CP-31398 was measured. The EC RL95-2 and KLE cell lines had a higher MDM2 expression and were thus selected for use in subsequent experiments. The EC cells were then treated with CP-31398 (2 µg/ml), and were transfected with siRNA against MDM2 or an MDM2 overexpression plasmid in order to examine the effects of CP-31398 and MDM2 on EC cell activities. The expression of p53, p21, Bad, Bax, B-cell lymphoma-2 (Bcl-2), cytochrome c (Cyt-c), caspase-3, Cox-2, matrix metalloproteinase (MMP)-2 and MMP-9 was measured to further confirm the effects of CP-31398 on cell migration, invasion and apoptosis. Our results indicated that MDM2 was highly expressed in EC tissues. Notably, EC cell viability decreased with the increasing concentrations of CP-31398. The EC cells treated with CP-31398 or siRNA against MDM2 exhibited an increased apoptosis and a suppressed migration and invasion, corresponding to an increased expression of p53, p21, Bad, Bax, Cyt-c and caspase-3, as well as to a decreased expression of Bcl-2, Cox-2, MMP-2 and MMP-9. Moreover, treatment with CP-31398 and siRNA against MDM2 further enhanced these effects. Taken together, the findings of this study indicate that the CP-31398-mediated downregulation of MDM2 may suppress EC progression via its inhibitory role in EC cell migration, invasion and resistance to apoptosis. Therefore, treatment with CP-31398 may prove to be possible therapeutic strategy for EC.
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Affiliation(s)
- Ling Liu
- Department of Gynecologic Oncology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Li Yang
- Department of Gynecologic Oncology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Hui Chang
- Laboratory of Tumor Precision Medicine, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Yan-Nan Chen
- Department of Gynecologic Oncology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Feng Zhang
- Department of Gynecologic Oncology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Shuo Feng
- Department of Gynecologic Oncology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Juan Peng
- Department of Gynecologic Oncology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Chen-Chen Ren
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Xiao-An Zhang
- Department of Imaging, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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Polycystic Ovarian Condition May Be a Risk Factor for Ovarian Tumor Development in the Laying Hen Model of Spontaneous Ovarian Cancer. J Immunol Res 2018; 2018:2590910. [PMID: 30596106 PMCID: PMC6286744 DOI: 10.1155/2018/2590910] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 08/26/2018] [Accepted: 09/17/2018] [Indexed: 12/28/2022] Open
Abstract
Chronic inflammation and long-standing oxidative stress are potential predisposing factors for developing malignancies, including ovarian cancer (OVCA). Information on the association of ovarian chronic abnormal conditions, including polycystic ovarian syndrome (PCOS), with the development of OVCA is unknown. The goal of this study was to examine if polycystic ovarian conditions are associated with OVCA development. In the exploratory study, 3-4-year-old laying hens were randomly selected and examined for the presence of polycystic ovaries with cancer (PCOC). In the prospective study, hens were monitored by ultrasound scanning to detect the incidence of a polycystic ovaries and subsequent development of OVCA. Tissues from normal ovaries and PCOC were examined for macrophage infiltration, expression of interleukin-16, and superoxide dismutase 2. The exploratory study detected spontaneous PCOC at early and late stages in hens. PCOC in hens were accompanied with influx of macrophages (17.33 ± 2.26 in PCOC at the early stage and 24.24 ± 2.5 in PCOC at the late stage in 20 mm2 areas of tissue as compared with 6.77 ± 1.58 in normal hens). Expression of interleukin-16 was more than 2.5-fold higher and superoxide dismutase 2 was approximately 3-fold higher in PCOC hens than normal hens. The prospective study showed the development of OVCA in some hens with polycystic ovarian condition (PCO). PCOC development in hens was associated with chronic inflammation in the ovary. Laying hens may represent a potential model for the study of spontaneous PCOS and its long-term risk of PCOC development.
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Aboushousha T, Helal N, Hammam O, Ibrahim M, Khaled S, Mostafa A, Anas A. Overview of MDM2 and B-RAF Expression in Gastric Lesions. Open Access Maced J Med Sci 2018; 6:1795-1802. [PMID: 30455751 PMCID: PMC6236038 DOI: 10.3889/oamjms.2018.338] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 09/10/2018] [Accepted: 09/11/2018] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Globally, gastric cancer (GC) it is the fourth most common cancer and the third cause of cancer-related deaths. Overexpression of MDM2 and B-RAF appeared to be increased in malignancy and associated with poor prognosis in several human tumours, but their role in gastric cancer remains controversial. AIM We had investigated the immunohistochemical expression of MDM2 and B-RAF in 136 gastric lesions with/without H. pylori association. MATERIAL AND METHODS Studied specimens include chronic gastritis (32), intestinal type GC (70), diffuse GC (22) and gastrointestinal stromal tumours (GIST) (12). RESULTS MDM2 expression increased significantly in intestinal GC compared to other groups (p < 0.001), while B-RAF expression increased significantly in GIST compared to other groups (p < 0.001). H. pylori increased expression of MDM2 in intestinal GC cases but did not affect B-RAF expression. MDM2 expression correlated with high grade of tumor differentiation (p < 0.001), deep invasion (p < 0.05), nodal metastases (p < 0.05) and distant metastases (p < 0.1) in intestinal GC, while B-RAF expression did not correlate with TNM stage (p < 0.1). CONCLUSION MDM2 up-regulation was more frequent in intestinal GC, while B-RAF up-regulation was more frequent in GIST compared to other groups; MDM2 expression in intestinal GC was correlated with H. pylori association, high grade of differentiation, deep invasion, nodal and distant metastases, meanwhile, B-RAF expression was correlated with high-grade intestinal GC but did not correlate with H. pylori or TNM stage. The possible role of both MDM2 and B-RAF in predicting progression of gastric tumours and prognosis deserves further investigations.
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Affiliation(s)
- Tarek Aboushousha
- Department of Pathology, Theodor Bilharz Research Institute, Imbaba, Giza, Egypt
| | - Noha Helal
- Department of Pathology, Theodor Bilharz Research Institute, Imbaba, Giza, Egypt
| | - Olfat Hammam
- Department of Pathology, Theodor Bilharz Research Institute, Imbaba, Giza, Egypt
| | - Manar Ibrahim
- Faculty of Biotechnology, October University of Modern Sciences and Arts, Giza, Egypt
| | - Samar Khaled
- Faculty of Biotechnology, October University of Modern Sciences and Arts, Giza, Egypt
| | - Amr Mostafa
- Department of Surgery, Theodor Bilharz Research Institute, Imbaba, Giza, Egypt
| | - Amgad Anas
- Department of Hepato-Gastroenterology, Theodor Bilharz Research Institute, Giza, Egypt
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Chen XZ, Huang CZ, Hu WX, Liu Y, Yao XQ. Gastric Cancer Screening by Combined Determination of Serum Helicobacter pylori Antibody and Pepsinogen Concentrations: ABC Method for Gastric Cancer Screening. Chin Med J (Engl) 2018; 131:1232-1239. [PMID: 29722342 PMCID: PMC5956776 DOI: 10.4103/0366-6999.231512] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Objective: Gastroscopy combined with gastric mucosa biopsies is currently regarded as a gold standard for diagnosis of gastric cancer. However, its application is restricted in clinical practice due to its invasive property. A new noninvasive population screening process combining the assay of anti-Helicobacter pylori antibody and serum pepsinogen (PG) (ABC method) is adopted to recognize the high-risk patients for further endoscopy examination, avoiding the unnecessary gastroscopy for most population and saving the cost consumption for mass screening annually. Nevertheless, controversies exist for the grouping of ABC method and the intervals of gastroscopy surveillance for each group. In this review, we summarized these popular concerned topics for providing useful references to the healthcare practitioner in clinical practice. Data Sources: The PubMed databases were systematically searched from the inception dates to November 22, 2017, using the keywords “Helicobacter pylori,” “Pepsinogens,” and “Stomach Neoplasms.” Study Selection: Original articles and reviews on the topics were selected. Results: Anti-H. pylori antibody and serum PG concentration showed significant changes under the different status of H. pylori infection and the progression of atrophic gastritis, which can be used for risk stratification of gastric cancer in clinic. In addition, anti-H. pylori antibody titer can be used for further risk stratification of gastric cancer contributing to determine better endoscopy surveillance interval. Conclusions: The early detection and diagnosis of gastric cancer benefit from the risk stratification, but the cutoff values for H. pylori antibody and serum PG concentration require further modification.
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Affiliation(s)
- Xian-Zhe Chen
- Second Clinical Medical College, Southern Medical University, Guangzhou, Guangdong 510515; Department of General Surgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China
| | - Cheng-Zhi Huang
- Department of General Surgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080; Medical College, Shantou University, Shantou, Guangdong 515063, China
| | - Wei-Xian Hu
- Second Clinical Medical College, Southern Medical University, Guangzhou, Guangdong 510515; Department of General Surgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China
| | - Ying Liu
- Reproductive Department, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China
| | - Xue-Qing Yao
- Second Clinical Medical College, Southern Medical University, Guangzhou, Guangdong 510515; Department of General Surgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China
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Machlowska J, Maciejewski R, Sitarz R. The Pattern of Signatures in Gastric Cancer Prognosis. Int J Mol Sci 2018; 19:1658. [PMID: 29867026 PMCID: PMC6032410 DOI: 10.3390/ijms19061658] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Revised: 05/26/2018] [Accepted: 05/30/2018] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer is one of the most common malignancies worldwide and it is a fourth leading cause of cancer-related death. Carcinogenesis is a multistage disease process specified by the gradual procurement of mutations and epigenetic alterations in the expression of different genes, which finally lead to the occurrence of a malignancy. These genes have diversified roles regarding cancer development. Intracellular pathways are assigned to the expression of different genes, signal transduction, cell-cycle supervision, genomic stability, DNA repair, and cell-fate destination, like apoptosis, senescence. Extracellular pathways embrace tumour invasion, metastasis, angiogenesis. Altered expression patterns, leading the different clinical responses. This review highlights the list of molecular biomarkers that can be used for prognostic purposes and provide information on the likely outcome of the cancer disease in an untreated individual.
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Affiliation(s)
- Julita Machlowska
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland.
| | - Ryszard Maciejewski
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland.
| | - Robert Sitarz
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland.
- Department of Surgery, St. John's Cancer Center, 20-090 Lublin, Poland.
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Li N, Xie C, Lu NH. p53, a potential predictor of Helicobacter pylori infection-associated gastric carcinogenesis? Oncotarget 2018; 7:66276-66286. [PMID: 27556187 PMCID: PMC5323233 DOI: 10.18632/oncotarget.11414] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2016] [Accepted: 08/13/2016] [Indexed: 12/14/2022] Open
Abstract
Helicobacter pylori (H. pylori) is an ancient and persistent inhabitant of the human stomach that is closely linked to the development of gastric cancer (GC). . Emerging evidence suggests that H. pylori strain interactions with gastric epithelial cells subvert the best- characterized p53 tumour suppressor pathway. A high prevalence of p53 mutations is related to H. pylori infection. H. pylori also accelerates p53 protein degradation by disturbing the MDM2-P53 feedback loop. Additionally, H. pylori triggers the alteration of other p53 isoforms. Dysregulation of p53 by H. pylori infection contributes to gastric carcinogenesis by mediating cell proliferation and apoptosis. This review focuses on the regulation of p53 in H. pylori infection-associated GC.
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Affiliation(s)
- Nianshuang Li
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Chuan Xie
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Nong-Hua Lu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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11
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The Strong Cell-based Hydrogen Peroxide Generation Triggered by Cold Atmospheric Plasma. Sci Rep 2017; 7:10831. [PMID: 28883477 PMCID: PMC5589829 DOI: 10.1038/s41598-017-11480-x] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 08/24/2017] [Indexed: 12/21/2022] Open
Abstract
Hydrogen peroxide (H2O2) is an important signaling molecule in cancer cells. However, the significant secretion of H2O2 by cancer cells have been rarely observed. Cold atmospheric plasma (CAP) is a near room temperature ionized gas composed of neutral particles, charged particles, reactive species, and electrons. Here, we first demonstrated that breast cancer cells and pancreatic adenocarcinoma cells generated micromolar level H2O2 during just 1 min of direct CAP treatment on these cells. The cell-based H2O2 generation is affected by the medium volume, the cell confluence, as well as the discharge voltage. The application of cold atmospheric plasma (CAP) in cancer treatment has been intensively investigated over the past decade. Several cellular responses to CAP treatment have been observed including the consumption of the CAP-originated reactive species, the rise of intracellular reactive oxygen species, the damage on DNA and mitochondria, as well as the activation of apoptotic events. This is a new previously unknown cellular response to CAP, which provides a new prospective to understand the interaction between CAP and cells in vitro and in vivo. The short-lived reactive species in CAP may activate cells in vivo to generate long-lived reactive species such as H2O2, which may trigger immune attack on tumorous tissues via the H2O2-mediated lymphocyte activation.
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12
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Nakajima N, Kozu K, Kobayashi S, Nishiyama R, Okubo R, Akai Y, Moriyama M, Kinukawa N. The expression of IGF-1R in Helicobacter pylori-infected intestinal metaplasia and gastric cancer. J Clin Biochem Nutr 2016; 59:53-7. [PMID: 27499580 PMCID: PMC4933692 DOI: 10.3164/jcbn.16-11] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 02/07/2016] [Indexed: 02/06/2023] Open
Abstract
Overexpression of IGF-1R has been demonstrated in gastrointestinal cancers, and its expression is reported as the result of the loss of tumor suppressors. IL-16 is involved in the pathophysiological process of chronic inflammatory diseases. The aim of this study is to determine the changes in the expression of IGF-1R in intestinal metaplasia (IM) and gastric cancer (GC) as well as the effect of Helicobacter pylori (H. pylori) and IL-16 on cell proliferation and IGF-1R expression in gastric cells. AGS cells were incubated with combinations of IL-16 and H. pylori. Gastric cell proliferation was studied by BrdU uptake. In H. pylori infected mucosa, IGF-1R was significantly higher in IM than chronic gastritis (CG), and also higher in GC than CG and IM. H. pylori significantly decreased BrdU uptake. IL-16 increased BrdU uptake and IGF-1R on AGS cells which had been decreased by H. pylori. Co-incubation with IL-16 increased the expression of IGF-1R mRNA in H. pylori infected cells. We conclude that the expression of IGF-1R in H. pylori infected gastric mucosa may indicate an early stage of carcinogenesis. The IL-16 secretion by H. pylori can be a trigger for the expression of IGF-1R, and it may also be a factor for gastric carcinogenesis.
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Affiliation(s)
- Noriko Nakajima
- Department of Gastroenterology and Hepatology, Nihon University School of Medicine, 1-6 Kandasurugadai, Chiyoda-ku, Tokyo 101-8309, Japan
| | - Karina Kozu
- Department of Gastroenterology and Hepatology, Nihon University School of Medicine, 1-6 Kandasurugadai, Chiyoda-ku, Tokyo 101-8309, Japan
| | - Shun Kobayashi
- Department of Gastroenterology and Hepatology, Nihon University School of Medicine, 1-6 Kandasurugadai, Chiyoda-ku, Tokyo 101-8309, Japan
| | - Ryu Nishiyama
- Department of Gastroenterology and Hepatology, Nihon University School of Medicine, 1-6 Kandasurugadai, Chiyoda-ku, Tokyo 101-8309, Japan
| | - Rie Okubo
- Department of Gastroenterology and Hepatology, Nihon University School of Medicine, 1-6 Kandasurugadai, Chiyoda-ku, Tokyo 101-8309, Japan
| | - Yuichi Akai
- Department of Gastroenterology and Hepatology, Nihon University School of Medicine, 1-6 Kandasurugadai, Chiyoda-ku, Tokyo 101-8309, Japan
| | - Mitsuhiko Moriyama
- Department of Gastroenterology and Hepatology, Nihon University School of Medicine, 1-6 Kandasurugadai, Chiyoda-ku, Tokyo 101-8309, Japan
| | - Noriko Kinukawa
- Department of Pathology, Nihon University School of Medicine, 1-6 Kandasurugadai, Chiyoda-ku, Tokyo 101-8309, Japan
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De Falco M, Lucariello A, Iaquinto S, Esposito V, Guerra G, De Luca A. Molecular Mechanisms of Helicobacter pylori Pathogenesis. J Cell Physiol 2015; 230:1702-7. [PMID: 25639461 DOI: 10.1002/jcp.24933] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Accepted: 01/16/2015] [Indexed: 12/12/2022]
Abstract
Helicobacter pylori infects 50% of mankind. The vast majority of H. pylori infection occurs in the developing countries where up to 80% of the middle-aged adults may be infected. Bacterial infection causes an inflammatory response that proceeds through a series of intermediated stages of precancerous lesions (gastritis, atrophy, intestinal metaplasia, and dysplasia). Among infected individuals, approximately 10% develops severe gastric lesions such as peptic ulcer disease, 1-3% progresses to gastric cancer (GC) with a low 5-year survival rate, and 0.1% develops mucosa-associated lymphoid tissue (MALT). GC is one of the most common cancer and the third leading cause of cancer-related deaths worldwide. In this review, we have summarized the most recent papers about molecular mechanisms of H. pylori pathogenesis. The main important steps of H. pylori infection such as adhesion, entry in epithelial gastric cells, activation of intracellular pathways until epigenetic modifications have been described.
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Affiliation(s)
- Maria De Falco
- Department of Biology, University Federico II of Naples, Naples, Italy; National Institute of Biostructures and Biosystems (INBB), Rome, Italy
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14
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Shu X, Yang Z, Li ZH, Chen L, Zhou XD, Xie Y, Lu NH. Helicobacter pylori Infection Activates the Akt-Mdm2-p53 Signaling Pathway in Gastric Epithelial Cells. Dig Dis Sci 2015; 60:876-886. [PMID: 25480405 DOI: 10.1007/s10620-014-3470-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2014] [Accepted: 11/27/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUNDS AND AIMS Although Helicobacter pylori is widely accepted as a causative factor of many gastric diseases, the signaling pathways affected by H. pylori and subsequent effects on cell apoptosis and proliferation remain unclear. Here, we investigated the molecular mechanisms mediating H. pylori infection in gastric epithelial cells. METHODS Tissues from 160 patients with various gastric diseases with or without H. pylori infection were obtained and analyzed by immunohistochemistry for Akt, pAkt, Mdm2, p53, and Bax expression. In vitro, human gastric epithelial cells, GES-1, were incubated with H. pylori culture filtrates. Cell viability was measured by MTT assay. Apoptosis was evaluated by Annexin V/PI double staining followed by flow cytometry, DNA electrophoresis, and comet assay. mRNA and protein expression was assessed by RT-PCR and Western blot analysis. RESULTS In patient tissues, H. pylori infection was associated with significantly elevated levels of pAkt in chronic nonatrophic gastritis (CNAG), Mdm2 in dysplasia, p53 in metaplastic atrophy (MA), and Bax in CNAG and MA. In vitro, H. pylori culture filtrates reduced GES-1 cell viability in a time- and dose-dependent manner, induced G0/G1 arrest, triggered apoptosis, and increased DNA fragmentation. Mdm2 and Bax mRNA expression and pAkt, Mdm2, p53, and Bax protein expression were significantly upregulated when treated with H. pylori culture filtrates. Akt inhibition by LY294002 decreased Mdm2 expression, upregulated p53, and enhanced H. pylori-induced growth inhibition of GES-1 cells. CONCLUSIONS These findings suggest that Akt-Mdm2-p53 signaling is involved in the molecular response of GES-1 cells to H. pylori infection.
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Affiliation(s)
- Xu Shu
- Department of Gastroenterology, The First Affiliated Hospital, Nanchang University, Nanchang, 330006, Jiangxi, China,
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Wang BY, Cao J, Chen JW, Liu QY. Triptolide induces apoptosis of gastric cancer cells via inhibiting the overexpression of MDM2. Med Oncol 2014; 31:270. [PMID: 25280518 DOI: 10.1007/s12032-014-0270-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Accepted: 09/23/2014] [Indexed: 12/17/2022]
Abstract
Triptolide has been reported to exhibit antitumor effects in several cancers. This study investigates the mechanism by which triptolide induces apoptosis of gastric cancer cells. Gastric biopsies were collected for histological evaluation and detection of murine double minute 2 (MDM2) expression. Gastric cancer cells were cultured and treated with different concentrations of triptolide at indicated time points. The expression of MDM2, p53 protein, and target proteins including p21, PUMA, and X-linked inhibitor of apoptosis protein (XIAP) was detected. Apoptosis of cells treated with or without triptolide was evaluated. Our results showed that MDM2 protein was overexpressed in gastric cancer (p < 0.01, resp.). Triptolide induced significant apoptosis of gastric cancer cells in a dose- and time-dependent manner (p < 0.05). In addition, treatment with triptolide strongly inhibited the overexpression of MDM2 in gastric cancer cells, and this MDM2 inhibition led to increased levels of p53 protein and inhibition of XIAP (p < 0.05). However, triptolide failed to increase the expression of p53 target protein p21 and PUMA (p > 0.05). In conclusion, triptolide may induce apoptosis of gastric cancer cells via the inhibition of MDM2 overexpression in a p53-independent manner.
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Affiliation(s)
- Bo-Yong Wang
- Department of General Surgery, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430071, Hubei, China
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16
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Wang F, Meng W, Wang B, Qiao L. Helicobacter pylori-induced gastric inflammation and gastric cancer. Cancer Lett 2014; 345:196-202. [PMID: 23981572 DOI: 10.1016/j.canlet.2013.08.016] [Citation(s) in RCA: 564] [Impact Index Per Article: 51.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2013] [Revised: 08/07/2013] [Accepted: 08/13/2013] [Indexed: 02/06/2023]
Abstract
Helicobacter pylori (H. pylori) infect over half of the world's population. The prevalence of H. pylori infection and the predominant genotype of H. pylori virulence factors vary considerably across different geographical regions. H. pylori could uniquely persist for decades in the harsh stomach environment, where it damages the gastric mucosa and changes the pattern of gastric hormone release, thereby affects gastric physiology. By utilizing various virulence factors, H. pylori targets different cellular proteins to modulate the host inflammatory response and initiate multiple "hits" on the gastric mucosa, resulting in chronic gastritis and peptic ulceration. Among the long-term consequences of H. pylori infection is gastric malignancies, particularly gastric cancer (GC) and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. As such, H. pylori has been recognized as a class I carcinogen by the International Agency for Research on Cancer. Despite a close causal link between H. pylori infection and the development of gastric malignancies, the precise mechanisms involved in this process are still obscure. Studies over the past two decades have revealed that H. pylori exert oncogenic effects on gastric mucosa through a complex interaction between bacterial factors, host factors, and environmental factors. Numerous signaling pathways can be activated by H. pylori. In this review, we aim to elaborate on the recent developments in the pathophysiological mechanisms of H. pylori-induced gastric inflammation and gastric cancer.
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Affiliation(s)
- Fei Wang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Province, China
| | - Wenbo Meng
- The Second Department of General Surgery, The First Hospital of Lanzhou University, Hepatopancreatobiliary Surgery Institute of Gansu Province, Clinical Medical College Cancer, Center of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Bingyuan Wang
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China.
| | - Liang Qiao
- Storr Liver Unit at Westmead Millennium Institute, The University of Sydney at Westmead Hospital, Westmead, NSW 2145, Australia.
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17
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Wang HP, Zhu YL, Shao W. Role of Helicobacter pylori virulence factor cytotoxin-associated gene A in gastric mucosa-associated lymphoid tissue lymphoma. World J Gastroenterol 2013; 19:8219-8226. [PMID: 24363512 PMCID: PMC3857444 DOI: 10.3748/wjg.v19.i45.8219] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 11/01/2013] [Accepted: 11/13/2013] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) infection might initiate and contribute to the progression of lymphoma from gastric mucosa-associated lymphoid tissue (MALT). Increasing evidence shows that eradication of H. pylori with antibiotic therapy can lead to regression of gastric MALT lymphoma and can result in a 10-year sustained remission. The eradication of H. pylori is the standard care for patients with gastric MALT lymphoma. Cytotoxin-associated gene A (CagA) protein, one of the most extensively studied H. pylori virulence factors, is strongly associated with the gastric MALT lymphoma. CagA possesses polymorphisms according to its C-terminal structure and displays different functions among areas and races. After being translocated into B lymphocytes via type IV secretion system, CagA deregulates intracellular signaling pathways in both tyrosine phosphorylation-dependent and -independent manners and/or some other pathways, and thereby promotes lymphomagenesis. A variety of proteins including p53 and protein tyrosine phosphatases-2 are involved in the malignant transformation induced by CagA. Mucosal inflammation is the foundational mechanism underlying the occurrence and development of gastric MALT lymphoma.
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18
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Pan X, Li Y, Feng J, Wang X, Hao B, Shi R, Zhang G. A functional polymorphism T309G in MDM2 gene promoter, intensified by Helicobacter pylori lipopolysaccharide, is associated with both an increased susceptibility and poor prognosis of gastric carcinoma in Chinese patients. BMC Cancer 2013; 13:126. [PMID: 23506213 PMCID: PMC3621260 DOI: 10.1186/1471-2407-13-126] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2012] [Accepted: 03/04/2013] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Studies on the association between MDM2 SNP309 (T > G) and gastric cancer have reported conflicting results. Thus, the aim of this study was to investigate whether MDM2 SNP309 is associated with susceptibility and prognosis of gastric carcinoma in Chinese patients. METHODS Total of 574 gastric carcinoma cases and 574 age- and sex-matched healthy controls were included. MDM2 polymorphism was detected by PCR- RFLP and infection of Helicobacter pylori (H. pylori) by a validated serology test. The functionality of MDM2 SNP309, with or without H. pylori lipopolysaccharide (LPS), was examined by dual-luciferase assay. Kaplan-Meier survival curves were used to evaluate survival. Additional, a meta-analysis was conducted to verity the findings. RESULTS MDM2 SNP309G/G genotype was associated with an increased risk of gastric carcinoma when compared with T/T genotype or T carriers (both P < 0.01), and a joint effect between MDM2 SNP309G/G and H. pylori infection was observed to intensify gastric carcinoma risk. SNP309G/G was identified as an independent marker of poor overall survival of carcinoma. In vitro, the luciferase assay further showed an increased transcriptional activity of SNP309G allele compared with SNP309T allele, and the function of polymorphism T309G in MDM2 gene promoter was intensified by H. pylori LPS. Pooled results from the meta-analysis confirmed that SNP309G/G genotype had a significantly increased risk of gastric carcinoma compared with T/T genotype or T carriers, consistent with the case-control findings. CONCLUSIONS MDM2 SNP309G allele is associated with an increased risk and poor prognosis of gastric carcinoma in Chinese patients. Additional, there is a joint effect of MDM2 SNP309G/G allele and H. pylori infection on gastric carcinoma development, which may attribute to H. pylori LPS.
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Affiliation(s)
- Xiaolin Pan
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Yuqin Li
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Jin Feng
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaoyong Wang
- Department of Gastroenterology, Changzhou No.2 People’s Hospital, Affiliated with Nanjing Medical University, Changzhou 213000, China
| | - Bo Hao
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Ruihua Shi
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Guoxin Zhang
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
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Cheung DY, Kim TH. [Helicobacter pylori in human stomach: can it be called mutualism or a disease?]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2012; 59:329-37. [PMID: 22617526 DOI: 10.4166/kjg.2012.59.5.329] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Helicobacter pylori (H. pylori) has been a major concern as a gastric pathogen with unique features since discovered in the end of the 20th century. Recent data on comparative genome study have revealed that H. pylori has successfully survived with its host though over 58,000 years of evolution and migration from continent to continent. To maintain the symbiotic relationship with human, H. pylori has come up with ways to induce host tolerance as well as exert harmful injuries. Studies about H. pylori have accumulated the knowledge about how the cellular and molecular interactions are controlled and regulated to decide whether the symbiotic relationship is directed to diseases or peaceful mutualism. We reviewed recent literatures and research outcomes about the H. pylori and host interaction in molecular and cellular basis.
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Affiliation(s)
- Dae Young Cheung
- Department of Internal Medicine, Bucheon St. Mary's Hospital, The Catholic University of Korea, College of Medicine, 327 Sosa-ro, Wonmi-gu, Bucheon 420-717, Korea
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Yang Z, Shu X, Chen L, Chen J, Xie Y, Lu NH. Expression of p53-MDM2 feedback loop related proteins in different gastric pathologies in relation to Helicobacter pylori infection: implications in gastric carcinogenesis. Clin Res Hepatol Gastroenterol 2012; 36:235-43. [PMID: 22306053 DOI: 10.1016/j.clinre.2011.11.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2011] [Revised: 11/08/2011] [Accepted: 11/25/2011] [Indexed: 02/04/2023]
Abstract
AIM To explore the association of p53-MDM2 feedback loop related proteins with gastric pathologies in relation to Helicobacter pylori infection. METHODS Gastric biopsies were obtained from 157 H. pylori-negative and positive patients, including normal gastric mucosa (NGM), chronic gastritis (CG), intestinal metaplasia (IM), dysplasia (Dys), and gastric cancer (GC). The expression of mutant p53, MDM2, Bax and PUMA in gastric tissues was detected by immunohistochemistry. RESULTS Overall expression of MDM2 and Bax is progressively increased from NGM to GC. PUMA expression is increased in CG but subsequently decreased after the development of IM. H. pylori infection is associated with increased mutant p53 and Bax expression but decreased PUMA expression in IM, and increased MDM2 expression in Dys. CONCLUSIONS These results suggest that different p53-MDM2 feedback loop related proteins are distinctly expressed in the various stages of gastric carcinogenesis; their roles in gastric carcinogenesis in the presence of H. pylori infection need to be further investigated.
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Affiliation(s)
- Zhen Yang
- Department of gastroenterology, The First Affiliated Hospital, Nanchang university, Nanchang, 330006, Jiangxi, China
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Liu LM, Yan MG, Yang DH, Sun WW, Zhang JX. The expression of protein inhibitor of activated signal transducers and activators of transcription 3 in the evolutionary process of gastric cancer. Eur J Intern Med 2011; 22:e31-e35. [PMID: 21925039 DOI: 10.1016/j.ejim.2011.04.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2010] [Revised: 04/03/2011] [Accepted: 04/04/2011] [Indexed: 12/17/2022]
Abstract
OBJECTIVE To study the expression of PIAS3 (protein inhibitor of activated signal transducers and activators of transcription 3) in the evolutionary process of gastric cancer. METHODS Samples were taken from the endoscopic biopsy specimens of 125 patients. Gastric mucosal lesions were diagnosed in HE staining, and chronic atrophic gastritis (CAG) with intestinal metaplasia (IM) were distinguished in AB-PAS and HID-AB staining. The expressions of PIAS3 gene in different types of gastric mucosal lesions were detected by immunocytochemistry and in situ hybridization. The results were analyzed using IPP 6.0 image analysis system, from which the average optical density was obtained of positive cells. RESULTS There were 25 patients with chronic superficial gastritis (CSG), 87 CAG (30 with complete intestinal IM, 27 with incomplete intestinal IM, 21 with complete colonic IM, 9 with incomplete colonic IM), 8 dysplasia (DYS) and 5 gastric cancer (GC). In the expressions of PIAS3 mRNA and protein, a difference was not found between the patients with CSG and those with CAG with complete or incomplete intestinal IM; however, a significant difference was statistically found among patients with CSG (or intestinal IM), complete colonic IM, incomplete colonic IM, DYS and GC, expression levels of which stepped down one by one. CONCLUSIONS There are differences in the PIAS3 expression from different stages of gastric precancerous conditions/lesions to GC, which may reveal a close relationship between expression reduction or loss of PIAS3 and gastric tumorigenesis.
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Affiliation(s)
- Liang-Ming Liu
- Songjiang Hospital Affiliated to the First People's Hospital Shanghai Jiaotong University, Shanghai 201600, China.
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22
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Wang L, Zhang XY, Xu L, Liu WJ, Zhang J, Zhang JP. Expression and significance of p53 and mdm2 in atypical intestinal metaplasia and gastric carcinoma. Oncol Lett 2011; 2:707-712. [PMID: 22848253 DOI: 10.3892/ol.2011.292] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2011] [Accepted: 04/05/2011] [Indexed: 01/10/2023] Open
Abstract
Subtypes of intestinal metaplasia may have different manifestations in the carcinogenesis of gastric mucosa. The present study aimed to investigate expression of murine double minute gene 2 (mdm2) in atypical intestinal metaplasia (AIM) and its relationship to gastric carcinoma. Intestinal metaplasia (IM) specimens were obtained from 58 cases. Using a novel classification of IM, the specimens were classified according to morphological changes exhibited in the gastric mucosa; specifically, atypical intestinal metaplasia (AIM) and simple intestinal metaplasia (SIM). The gatric carcinoma specimens were then compared with types I, II and III IM based on different substances present in the mucous. Envision immunohistochemical technique was applied to the detection of the expression of p53 and mdm2 in 58 IM and 30 gastric carcinoma cases. Expression of both p53 and mdm2 proteins was found to be higher in gastric carcinomas (p53, 56.67%, 17/30 and mdm2, 53.33%, 16/30) and AIM (p53, 51.85%, 14/27 and mdm2, 51.85%, 14/27) as compared to SIM (p53, 25.81%, 8/31 and mdm2, 19.35%, 6/31) (P<0.05). A similar pattern of expression of mdm2 protein was found in type I (36.84%, 7/19), type II (38.46%, 10/26) and type III (23.08%, 3/13) IM and gastric carcinoma (53.33%, 16/30). p53 expression was higher in gastric carcinoma (56.67%) compared to type I IM (26.32%) (P<0.05). However, no differences were evident among type II (42.31%, 11/26), type III (46.15%, 6/13) IM and gastric carcinoma. AIM may reveal the precancerous nature of gastric carcinoma more clearly than SIM or the conventional IM subtypes. Additionally, AIM may be involved as a preneoplastic lesion and therefore be an effective indicator in the clinical follow-up of gastric carcinoma patients.
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Affiliation(s)
- Lin Wang
- Department of Pathology, Shandong University School of Medicine, Jinan, Shandong 250012, P.R. China
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Handa O, Naito Y, Yoshikawa T. Redox biology and gastric carcinogenesis: the role of Helicobacter pylori. Redox Rep 2011; 16:1-7. [PMID: 21605492 PMCID: PMC6837368 DOI: 10.1179/174329211x12968219310756] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2010] [Revised: 01/07/2011] [Accepted: 01/08/2011] [Indexed: 12/16/2022] Open
Abstract
Almost half the world's population is infected by Helicobacter pylori (H. pylori). This bacterium increases the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in human stomach, and this has been reported to impact upon gastric inflammation and carcinogenesis. However, the precise mechanism by which H. pylori induces gastric carcinogenesis is presently unclear. Although the main source of ROS/RNS production is possibly the host neutrophil, H. pylori itself produces O₂•⁻. Furthermore, its cytotoxin induces ROS production by gastric epithelial cells, which might affect intracellular signal transduction, resulting in gastric carcinogenesis. Excessive ROS production in gastric epithelial cells can cause DNA damage and thus might be involved in gastric carcinogenesis. Understanding the molecular mechanism of H. pylori-induced carcinogenesis is important for developing new strategies against gastric cancer.
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Affiliation(s)
- Osamu Handa
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
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Zhao Y, Zhou Y, Sun Y, Yu A, Yu H, Li W, Liu Z, Zeng J, Li X, Chen C, Jia J. Virulence factor cytotoxin-associated gene A in Helicobacter pylori is downregulated by interferon-γin vitro. ACTA ACUST UNITED AC 2010; 61:76-83. [DOI: 10.1111/j.1574-695x.2010.00750.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Handa O, Naito Y, Yoshikawa T. Helicobacter pylori: a ROS-inducing bacterial species in the stomach. Inflamm Res 2010; 59:997-1003. [PMID: 20820854 DOI: 10.1007/s00011-010-0245-x] [Citation(s) in RCA: 157] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2010] [Revised: 06/09/2010] [Accepted: 08/22/2010] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Reactive oxygen species (ROS) and reactive nitrogen species (RNS) have been reported to impact gastric inflammation and carcinogenesis. However, the precise mechanism by which Helicobacter pylori induces gastric carcinogenesis is presently unclear. AIM This review focuses on H. pylori-induced ROS/RNS production in the host stomach, and its relationship with gastric carcinogenesis. RESULTS Activated neutrophils are the main source of ROS/RNS production in the H. pylori-infected stomach, but H. pylori itself also produces ROS. In addition, extensive recent studies have revealed that H. pylori-induced ROS production in gastric epithelial cells might affect gastric epithelial cell signal transduction, resulting in gastric carcinogenesis. Excessive ROS/RNS production in the stomach can damage DNA in gastric epithelial cells, implying its involvement in gastric carcinogenesis. CONCLUSION Understanding the molecular mechanism behind H. pylori-induced ROS, and its involvement in gastric carcinogenesis, is important for developing new strategies for gastric cancer chemoprevention.
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Affiliation(s)
- Osamu Handa
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kajiicho, Kawaramachidori Hirokouji Agaru, Kamigyou-ku, Kyoto, 602-8566, Japan.
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Chung JW, Kim YJ, Lee SJ, Hahm KB. Korean Red Ginseng: Qualitative and Quantitative Benefits on Helicobacter pylori Infection. J Ginseng Res 2010; 34:77-88. [DOI: 10.5142/jgr.2010.34.2.077] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
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Kim YJ, Chung JW, Lee SJ, Choi KS, Kim JH, Hahm KB. Progression from chronic atrophic gastritis to gastric cancer; tangle, toggle, tackle with Korea red ginseng. J Clin Biochem Nutr 2010; 46:195-204. [PMID: 20490314 PMCID: PMC2872224 DOI: 10.3164/jcbn.10-03] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2010] [Accepted: 01/15/2010] [Indexed: 01/05/2023] Open
Abstract
Key molecular players that link inflammation to carcinogenesis are prostaglandins, cytokines, nuclear factor-κB (NF-κB), chemokines, angiogenic growth factors, and free radicals, all of which lead to increased mutations and altered functions of important enzymes and proteins, for example, activation of oncogenic products and/or inhibition of tumor suppressor proteins, in inflamed tissues, thus contributing to multi-stage carcinogenesis process. Interpreted reversely, the identification of the molecular mechanisms by which chronic inflammation increases cancer risk or optimal intervention of targeted drugs or agents during the inflammation-associated carcinogenic process could be a necessary basis for developing new strategy of cancer prevention at many sites. In this review, we discuss the possibilities for cancer prevention by controlling inflammation process in Helicobacter pylori (H. pylori)-associated inflamed stomach with Korea red ginseng. Korea red ginseng is a good example of a natural herb that has ubiquitous properties that are conductive to stop inflammatory carcinogenesis that is un wanted outcome of H. pylori infection, rendering rejuvenation of chronic atrophic gastritis.
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Affiliation(s)
- Yoon Jae Kim
- Department of Gastroenterology Gachon Graduate School of Medicine, 7-45 Songdo-dong, Yeonsu-gu, Incheon 406-840, Korea
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Zhao D, Liu Z, Ding J, Li W, Sun Y, Yu H, Zhou Y, Zeng J, Chen C, Jia J. Helicobacter pylori CagA upregulation of CIP2A is dependent on the Src and MEK/ERK pathways. J Med Microbiol 2009; 59:259-265. [PMID: 19959630 DOI: 10.1099/jmm.0.014704-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Helicobacter pylori is classified as a class I carcinogenic factor and its persistent colonization in the stomach induces gastric cancer. Cancerous Inhibitor of PP2A (CIP2A) is a newly identified oncoprotein overexpressed in gastric cancer. Serving as a key oncoprotein, CIP2A also participates in regulation of senescence and proliferation of gastric cells. The combination of aberrant CIP2A expression inducing unlimited cell proliferation, and H. pylori infection eliciting aberrant expression of some key proteins, results in the onset of gastric tumorigenesis. However, the relationship between H. pylori infection and CIP2A expression still remains undefined. The aim of our study was to verify the effect of H. pylori infection on CIP2A expression levels and identify H. pylori signalling molecules and corresponding pathways influencing CIP2A expression. Following plasmid-mediated expression of CagA in human gastric cell lines, the cells were infected with H. pylori and CIP2A expression levels were examined by immunoblotting. Signal inhibitors were used to verify which signal pathways were involved. We also performed CIP2A depletion and H. pylori infection after depletion in AGS cells. H. pylori infection-induced CIP2A expression was dependent on cagA gene expression and CagA phosphorylation. Bacterial oncoprotein CagA upregulated CIP2A expression and this upregulation effect was dependent on Src and Ras/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways. H. pylori infection-induced Myc stabilization was partially attenuated by CIP2A depletion. The results of our study provide further information for understanding the mechanism of H. pylori carcinogenesis.
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Affiliation(s)
- Dapeng Zhao
- Department of Microbiology and Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China
| | - Zhifang Liu
- Department of Biochemistry, School of Medicine, Shandong University, Jinan, PR China
| | - Jian Ding
- Department of Microbiology and Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China
| | - Wenjuan Li
- Department of Microbiology and Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China
| | - Yundong Sun
- Department of Microbiology and Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China
| | - Han Yu
- Department of Microbiology and Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China
| | - Yabin Zhou
- Department of Microbiology and Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China
| | - Jiping Zeng
- Department of Biochemistry, School of Medicine, Shandong University, Jinan, PR China
| | - Chunyan Chen
- Department of Microbiology and Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China
| | - Jihui Jia
- Department of Microbiology and Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, PR China
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