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Ding T, Xu H, Zhang X, Yang F, Zhang J, Shi Y, Bai Y, Yang J, Chen C, Zhu C, Zhang H. Prohibitin 2 orchestrates long noncoding RNA and gene transcription to accelerate tumorigenesis. Nat Commun 2024; 15:8385. [PMID: 39333493 PMCID: PMC11436821 DOI: 10.1038/s41467-024-52425-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 09/05/2024] [Indexed: 09/29/2024] Open
Abstract
The spatial co-presence of aberrant long non-coding RNAs (lncRNAs) and abnormal coding genes contributes to malignancy development in various tumors. However, precise coordinated mechanisms underlying this phenomenon in tumorigenesis remains incompletely understood. Here, we show that Prohibitin 2 (PHB2) orchestrates the transcription of an oncogenic CASC15-New-Isoform 2 (CANT2) lncRNA and the coding tumor-suppressor gene CCBE1, thereby accelerating melanoma tumorigenesis. In melanoma cells, PHB2 initially accesses the open chromatin sites at the CANT2 promoter, recruiting MLL2 to augment H3K4 trimethylation and activate CANT2 transcription. Intriguingly, PHB2 further binds the activated CANT2 transcript, targeting the promoter of the tumor-suppressor gene CCBE1. This interaction recruits histone deacetylase HDAC1 to decrease H3K27 acetylation at the CCBE1 promoter and inhibit its transcription, significantly promoting tumor cell growth and metastasis both in vitro and in vivo. Our study elucidates a PHB2-mediated mechanism that orchestrates the aberrant transcription of lncRNAs and coding genes, providing an intriguing epigenetic regulatory model in tumorigenesis.
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Affiliation(s)
- Tianyi Ding
- State Key Laboratory of Cardiology and Medical Innovation Center, Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Research Center for Stem Cells, School of Life Science and Technology, Tongji University, Shanghai, 200092, China
- Jiangxi Province Key Laboratory of Organ Development and Epigenetics, Clinical Medical Research Center, Affiliated Hospital of Jinggangshan University, Medical Department of Jinggangshan University, Ji'an, 343009, China
- School of Life Science, Jinggangshan University, Ji'an, 343009, China
| | - Haowen Xu
- State Key Laboratory of Cardiology and Medical Innovation Center, Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Research Center for Stem Cells, School of Life Science and Technology, Tongji University, Shanghai, 200092, China
- Jiangxi Province Key Laboratory of Organ Development and Epigenetics, Clinical Medical Research Center, Affiliated Hospital of Jinggangshan University, Medical Department of Jinggangshan University, Ji'an, 343009, China
- School of Life Science, Jinggangshan University, Ji'an, 343009, China
| | - Xiaoyu Zhang
- State Key Laboratory of Cardiology and Medical Innovation Center, Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Research Center for Stem Cells, School of Life Science and Technology, Tongji University, Shanghai, 200092, China
- Jiangxi Province Key Laboratory of Organ Development and Epigenetics, Clinical Medical Research Center, Affiliated Hospital of Jinggangshan University, Medical Department of Jinggangshan University, Ji'an, 343009, China
- School of Life Science, Jinggangshan University, Ji'an, 343009, China
| | - Fan Yang
- State Key Laboratory of Cardiology and Medical Innovation Center, Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Research Center for Stem Cells, School of Life Science and Technology, Tongji University, Shanghai, 200092, China
- Jiangxi Province Key Laboratory of Organ Development and Epigenetics, Clinical Medical Research Center, Affiliated Hospital of Jinggangshan University, Medical Department of Jinggangshan University, Ji'an, 343009, China
- School of Life Science, Jinggangshan University, Ji'an, 343009, China
| | - Jixing Zhang
- State Key Laboratory of Cardiology and Medical Innovation Center, Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Research Center for Stem Cells, School of Life Science and Technology, Tongji University, Shanghai, 200092, China
- Jiangxi Province Key Laboratory of Organ Development and Epigenetics, Clinical Medical Research Center, Affiliated Hospital of Jinggangshan University, Medical Department of Jinggangshan University, Ji'an, 343009, China
- School of Life Science, Jinggangshan University, Ji'an, 343009, China
| | - Yibing Shi
- State Key Laboratory of Cardiology and Medical Innovation Center, Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Research Center for Stem Cells, School of Life Science and Technology, Tongji University, Shanghai, 200092, China
- Jiangxi Province Key Laboratory of Organ Development and Epigenetics, Clinical Medical Research Center, Affiliated Hospital of Jinggangshan University, Medical Department of Jinggangshan University, Ji'an, 343009, China
- School of Life Science, Jinggangshan University, Ji'an, 343009, China
| | - Yiran Bai
- State Key Laboratory of Cardiology and Medical Innovation Center, Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Research Center for Stem Cells, School of Life Science and Technology, Tongji University, Shanghai, 200092, China
- Jiangxi Province Key Laboratory of Organ Development and Epigenetics, Clinical Medical Research Center, Affiliated Hospital of Jinggangshan University, Medical Department of Jinggangshan University, Ji'an, 343009, China
- School of Life Science, Jinggangshan University, Ji'an, 343009, China
| | - Jiaqi Yang
- State Key Laboratory of Cardiology and Medical Innovation Center, Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Research Center for Stem Cells, School of Life Science and Technology, Tongji University, Shanghai, 200092, China
- Jiangxi Province Key Laboratory of Organ Development and Epigenetics, Clinical Medical Research Center, Affiliated Hospital of Jinggangshan University, Medical Department of Jinggangshan University, Ji'an, 343009, China
- School of Life Science, Jinggangshan University, Ji'an, 343009, China
| | - Chaoqun Chen
- State Key Laboratory of Cardiology and Medical Innovation Center, Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Research Center for Stem Cells, School of Life Science and Technology, Tongji University, Shanghai, 200092, China
- Jiangxi Province Key Laboratory of Organ Development and Epigenetics, Clinical Medical Research Center, Affiliated Hospital of Jinggangshan University, Medical Department of Jinggangshan University, Ji'an, 343009, China
- School of Life Science, Jinggangshan University, Ji'an, 343009, China
| | - Chengbo Zhu
- State Key Laboratory of Cardiology and Medical Innovation Center, Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Research Center for Stem Cells, School of Life Science and Technology, Tongji University, Shanghai, 200092, China
- Jiangxi Province Key Laboratory of Organ Development and Epigenetics, Clinical Medical Research Center, Affiliated Hospital of Jinggangshan University, Medical Department of Jinggangshan University, Ji'an, 343009, China
- School of Life Science, Jinggangshan University, Ji'an, 343009, China
| | - He Zhang
- State Key Laboratory of Cardiology and Medical Innovation Center, Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Research Center for Stem Cells, School of Life Science and Technology, Tongji University, Shanghai, 200092, China.
- Jiangxi Province Key Laboratory of Organ Development and Epigenetics, Clinical Medical Research Center, Affiliated Hospital of Jinggangshan University, Medical Department of Jinggangshan University, Ji'an, 343009, China.
- School of Life Science, Jinggangshan University, Ji'an, 343009, China.
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Zhang J, Dong C, Lin Y, Shang L, Ma J, Hu R, Wang H. Causal relationship between gut microbiota and gastric cancer: A two‑sample Mendelian randomization analysis. Mol Clin Oncol 2024; 20:38. [PMID: 38628559 PMCID: PMC11019462 DOI: 10.3892/mco.2024.2736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 03/06/2024] [Indexed: 04/19/2024] Open
Abstract
The gut microbiota is associated with GC; however, the causal association between the gut microbiota and GC remains to be determined. The aim of the present study was to investigate the causal association between gut microbiota and gastric cancer (GC) from the perspective of Mendelian randomization (MR). The present study performed MR analysis using summary statistics from a genome-wide association study of the gut microbiome and GC. Inverse-variance weighted, MR-Egger and weighted median methods were used to investigate the causal relationship between gut microbiota and GC. Heterogeneity tests were performed using Cochrane's Q statistic. Horizontal polytropy was detected using Mendelian Randomization Pleiotropy RESidual Sum and Outlier were eliminated. Estimates from MR indicated that nine gut microorganism remained stable with regard to acceptance of heterogeneity and sensitivity methods. Among them, the genera Prevotella 7, Roseburia and Ruminococcaceae UCG014 were associated with an increased risk of GC; by contrast, the family Enterobacteriaceae, the genera Allisonella, Lachnospiraceae FCS020, Ruminococcaceae UCG004 and Ruminococcaceae UCG009, and the order Enterobacteriales decreased the risk of GC development. The present study demonstrated the potential importance of modulating the abundance of gut microbiota for the prevention and treatment of GC.
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Affiliation(s)
- Jianling Zhang
- General Surgery Ward 5, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Chunlu Dong
- General Surgery Ward 3, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Yanyan Lin
- General Surgery Ward 3, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Lifeng Shang
- Department of General Surgery, Qingdao Eighth People's Hospital, Qingdao, Shandong 266000, P.R. China
| | - Junming Ma
- Department of General Surgery, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia 750000, P.R. China
| | - Ruiping Hu
- Department of Endocrinology, The Third People's Hospital of Gansu Province, Lanzhou, Gansu 730000, P.R. China
| | - Hejing Wang
- Department of Healthcare-Associated Infection Control, The Third People's Hospital of Gansu Province, Lanzhou, Gansu 730000, P.R. China
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Wang J, Du L, Chen X. Oncolytic virus: A catalyst for the treatment of gastric cancer. Front Oncol 2022; 12:1017692. [PMID: 36505792 PMCID: PMC9731121 DOI: 10.3389/fonc.2022.1017692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 11/02/2022] [Indexed: 11/25/2022] Open
Abstract
Gastric cancer (GC) is a leading contributor to global cancer incidence and mortality. According to the GLOBOCAN 2020 estimates of incidence and mortality for 36 cancers in 185 countries produced by the International Agency for Research on Cancer (IARC), GC ranks fifth and fourth, respectively, and seriously threatens the survival and health of people all over the world. Therefore, how to effectively treat GC has become an urgent problem for medical personnel and scientific workers at this stage. Due to the unobvious early symptoms and the influence of some adverse factors such as tumor heterogeneity and low immunogenicity, patients with advanced gastric cancer (AGC) cannot benefit significantly from treatments such as radical surgical resection, radiotherapy, chemotherapy, and targeted therapy. As an emerging cancer immunotherapy, oncolytic virotherapies (OVTs) can not only selectively lyse cancer cells, but also induce a systemic antitumor immune response. This unique ability to turn unresponsive 'cold' tumors into responsive 'hot' tumors gives them great potential in GC therapy. This review integrates most experimental studies and clinical trials of various oncolytic viruses (OVs) in the diagnosis and treatment of GC. It also exhaustively introduces the concrete mechanism of invading GC cells and the viral genome composition of adenovirus and herpes simplex virus type 1 (HSV-1). At the end of the article, some prospects are put forward to determine the developmental directions of OVTs for GC in the future.
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Affiliation(s)
- Junqing Wang
- School of the 1st Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Linyong Du
- Key Laboratory of Laboratory Medicine, Ministry of Education of China, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang, China,*Correspondence: Xiangjian Chen, ; Linyong Du,
| | - Xiangjian Chen
- School of the 1st Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China,*Correspondence: Xiangjian Chen, ; Linyong Du,
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Cui H, Li H, Wu H, Du F, Xie X, Zeng S, Zhang Z, Dong K, Shang L, Jing C, Li L. A novel 3'tRNA-derived fragment tRF-Val promotes proliferation and inhibits apoptosis by targeting EEF1A1 in gastric cancer. Cell Death Dis 2022; 13:471. [PMID: 35585048 PMCID: PMC9117658 DOI: 10.1038/s41419-022-04930-6] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 05/03/2022] [Accepted: 05/09/2022] [Indexed: 12/14/2022]
Abstract
At present, it is commonly believed that tRFs and tiRNAs are formed by the specific and selective shear of tRNAs under certain pressure stimulation, rather than by random degradation of tRNA. tRFs and tiRNAs have been reported to contribute to the biological process of a variety of human cancers. However, the evidence for the mechanisms of tRFs and tiRNAs in the occurrence and development of gastric cancer (GC) is still insufficient. Here, we aimed to explore the carcinogenic roles of tRFs and tiRNAs in GC with RNA-sequencing technique, and found a novel 3'tRNA-derived fragment tRF-Val was significantly upregulated in GC tissues and cell lines. tRF-Val expression was positively correlated with tumor size and the depth of tumor invasion in GC tissues. Functionally, tRF-Val promoted proliferation and invasion, and inhibited apoptosis in GC cells. Mechanistically, tRF-Val directly bound to the chaperone molecule EEF1A1, mediated its transport into the nucleus and promoted its interaction with MDM2 (a specific p53 E3 ubiquitin ligase), thus inhibiting the downstream molecular pathway of p53 and promoting GC progression. These findings provided a new potential therapeutic target for GC and a new explanation for the occurrence of GC.
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Affiliation(s)
- Huaiping Cui
- grid.27255.370000 0004 1761 1174Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 250021 Jinan, Shandong China ,grid.460018.b0000 0004 1769 9639Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021 Jinan, Shandong China ,grid.460018.b0000 0004 1769 9639Shandong Provincial Laboratory of Translational Medicine Engineering for Digestive Tumors, Shandong Provincial Hospital, 250021 Jinan, Shandong China
| | - Han Li
- grid.452422.70000 0004 0604 7301Department of Gastrointestinal Surgery, the First Affiliated Hospital of Shandong First Medical University, Shandong Provincial Qianfoshan Hospital, 250013 Jinan, Shandong China
| | - Hao Wu
- grid.27255.370000 0004 1761 1174Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 250021 Jinan, Shandong China
| | - Fengying Du
- grid.27255.370000 0004 1761 1174Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 250021 Jinan, Shandong China
| | - Xiaozhou Xie
- grid.460018.b0000 0004 1769 9639Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021 Jinan, Shandong China
| | - Shujie Zeng
- grid.27255.370000 0004 1761 1174Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 250021 Jinan, Shandong China
| | - Zihao Zhang
- grid.27255.370000 0004 1761 1174Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 250021 Jinan, Shandong China
| | - Kangdi Dong
- grid.460018.b0000 0004 1769 9639Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021 Jinan, Shandong China
| | - Liang Shang
- grid.27255.370000 0004 1761 1174Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 250021 Jinan, Shandong China ,grid.460018.b0000 0004 1769 9639Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021 Jinan, Shandong China ,grid.460018.b0000 0004 1769 9639Shandong Provincial Laboratory of Translational Medicine Engineering for Digestive Tumors, Shandong Provincial Hospital, 250021 Jinan, Shandong China
| | - Changqing Jing
- grid.27255.370000 0004 1761 1174Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 250021 Jinan, Shandong China ,grid.460018.b0000 0004 1769 9639Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021 Jinan, Shandong China ,grid.460018.b0000 0004 1769 9639Shandong Provincial Laboratory of Translational Medicine Engineering for Digestive Tumors, Shandong Provincial Hospital, 250021 Jinan, Shandong China
| | - Leping Li
- grid.27255.370000 0004 1761 1174Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 250021 Jinan, Shandong China ,grid.460018.b0000 0004 1769 9639Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021 Jinan, Shandong China ,grid.460018.b0000 0004 1769 9639Shandong Provincial Laboratory of Translational Medicine Engineering for Digestive Tumors, Shandong Provincial Hospital, 250021 Jinan, Shandong China
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Kolb AL, Reynoso M, Matheny RW. Comparison of CRISPR and adenovirus-mediated Myd88 knockdown in RAW 264.7 cells and responses to lipopolysaccharide stimulation. J Biol Methods 2021; 8:e151. [PMID: 34514012 PMCID: PMC8411032 DOI: 10.14440/jbm.2021.359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 05/08/2021] [Accepted: 05/09/2021] [Indexed: 11/23/2022] Open
Abstract
Genomic manipulation offers the possibility for novel therapies in lieu of medical interventions in use today. The ability to genetically restore missing inflammatory genes will have a monumental impact on our current immunotherapy treatments. This study compared the efficacy of two different genetic manipulation techniques: clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) transfection to adenoviral transduction to determine which method would provide the most transient and stable knockdown of myeloid differentiation primary response 88 (MyD88). MyD88 is a major regulator of nuclear factor kappa light chain enhancer of activated B cells (NFκB) pathway in Raw 264.7 macrophages. Following genetic manipulation, cells were treated for 24 h with Lipopolysaccharide (LPS) to stimulate the inflammatory pathway. Confirmation of knockdown was determined by western immunoblotting and quantification of band density. Both CRISPR/Cas9 and adenoviral transduction produced similar knockdown efficiency (~64% and 60%, respectively) in MyD88 protein 48 h post adenoviral transduction. NFκB phosphorylation was increased in CRISPR/Cas9-mediated MyD88 knockdown and control cells, but not in adenovirus-mediated MyD88 knockdown cells, following LPS administration. CRISPR/Cas9-mediated MyD88 knockdown macrophages treated with LPS for 24 h showed a 65% reduction in tumor necrosis factor alpha (TNFα) secretion, and a 67% reduction in interleukin-10 (IL-10) secretion when compared to LPS-stimulated control cells (P ≤ 0.01 for both). LPS did not stimulate TNFα or IL-10 secretion in adenovirus-mediated control or MyD88 knockdown cells. These data demonstrate that Raw 264.7 macrophages maintain responsiveness to inflammatory stimuli following CRISPR/Cas9-mediated reductions in MyD88, but not following adenovirus-mediated MyD88 knockdown.
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Affiliation(s)
- Alexander L Kolb
- Military Performance Division, US Army Research Institute of Environmental Medicine, 10 General Greene Ave., Building 42, Natick, MA 01760, USA
| | - Marinaliz Reynoso
- Military Performance Division, US Army Research Institute of Environmental Medicine, 10 General Greene Ave., Building 42, Natick, MA 01760, USA
| | - Ronald W Matheny
- Military Operational Medicine Research Program, 810 Schreider St./MRDC-RTO/B201, Ft. Detrick, MD 21702, USA
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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: 42] [Impact Index Per Article: 10.5] [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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The changing face of gastric cancer: epidemiologic trends and advances in novel therapies. Cancer Gene Ther 2020; 28:390-399. [PMID: 33009508 DOI: 10.1038/s41417-020-00234-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 08/19/2020] [Accepted: 09/21/2020] [Indexed: 02/07/2023]
Abstract
Gastric cancer is an aggressive solid-tumor malignancy with poor prognosis. The epidemiologic face of gastric cancer is changing and further insight into its heterogenous immunohistopathologic nature is needed to develop personalized therapies for specific patient populations. In this review, we highlight changes in gastric cancer epidemiology with a special emphasis on racial and ethnic variations and discuss the implications of current clinical and preclinical treatment advances.
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Abstract
Gastric cancer is an active topic of clinical and basic research due to high morbidity and mortality. To date, gastrectomy and chemotherapy are the only therapeutic options for gastric cancer patients, but drug resistance, either acquired or primary, is the main cause for treatment failure. Differences in development and response to cancer treatments have been observed among ethnically diverse GC patient populations. In spite of major incidence, GC Asian patients have a significantly better prognosis and response to treatments than Caucasian ones due to genetic discordances between the two populations. Gene therapy could be an alternative strategy to overcome such issues and especially CRISPR/Cas9 represents one of the most intriguing gene-editing system. Thus, in this review article, we want to provide an update on the currently used therapies for the treatment of advanced GC. Graphical abstract.
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Zhang YF, Zhang BC, Zhang AR, Wu TT, Liu J, Yu LF, Wang WX, Gao JF, Fang DC, Rao ZG. Co-transduction of ribosomal protein L23 enhances the therapeutic efficacy of adenoviral-mediated p53 gene transfer in human gastric cancer. Oncol Rep 2013; 30:1989-95. [PMID: 23933826 DOI: 10.3892/or.2013.2663] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Accepted: 07/17/2013] [Indexed: 11/05/2022] Open
Abstract
Induction of murine double minute 2 (MDM2) expression is thought to be a determinant of resistance to p53 gene therapy for cancer. Previous studies have revealed that ribosomal protein L23 (RPL23) inhibits MDM2-mediated p53 degradation through direct binding to MDM2. In addition, ectopically expressed RPL23 was reported to interact with MDM2 in both the nucleus and cytoplasm, by which RPL23 indirectly inhibited MDM2-p53 binding. Based on the known molecular properties of the RPL23 protein, it was speculated that co-transduction of RPL23 may protect wild‑type p53 protein from MDM2-mediated inactivation and, thus, improve the effect of delivering therapeutic exogenous p53. To test this hypothesis, we constructed a bicistronic adenoviral vector expressing both the RPL23 and p53 genes (Ad-RPL23/p53) and compared its tumor-suppressor activity in human gastric cancer with that of a single gene vector for p53 (Ad-p53). In the in vivo and in vitro experiments, we observed that treatment with Ad-RPL23/p53 resulted in a stronger antitumor response compared to that obtained using Ad-p53. Moreover, the antitumor response of the bicistronic adenovirus was obtained not only in MGC803 cells (endogenous mutant p53) but also in MKN45 cells (endogenous wild‑type p53) which were initially resistant to p53 gene transfer, indicating that co-transduction of RPL23 also expanded the utility of p53 gene therapy. Furthermore, in an orthotopic nude mouse model of human gastric cancer, we found that the survival benefit was greater after Ad-RPL23/p53 treatment than after Ad-p53. Taken together, the data presented here demonstrate that co-transduction of RPL23 enhances the therapeutic efficacy of adenoviral-mediated p53 gene transfer in models of human gastric cancer and support the use of this strategy for cancer treatment.
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Affiliation(s)
- Ya-Fei Zhang
- Department of Oncology, Wuhan General Hospital of Guangzhou Command, People's Liberation Army, Wuhan, Hubei 430070, P.R. China
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Nagini S. Carcinoma of the stomach: A review of epidemiology, pathogenesis, molecular genetics and chemoprevention. World J Gastrointest Oncol 2012; 4:156-69. [PMID: 22844547 PMCID: PMC3406280 DOI: 10.4251/wjgo.v4.i7.156] [Citation(s) in RCA: 327] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2011] [Revised: 06/04/2012] [Accepted: 06/12/2012] [Indexed: 02/05/2023] Open
Abstract
Carcinoma of the stomach is still the second most common cause of cancer death worldwide, although the incidence and mortality have fallen dramatically over the last 50 years in many regions. The incidence of gastric cancer varies in different parts of the world and among various ethnic groups. Despite advances in diagnosis and treatment, the 5-year survival rate of stomach cancer is only 20 per cent. Stomach cancer can be classified into intestinal and diffuse types based on epidemiological and clinicopathological features. The etiology of gastric cancer is multifactorial and includes both dietary and nondietary factors. The major diet-related risk factors implicated in stomach cancer development include high content of nitrates and high salt intake. Accumulating evidence has implicated the role of Helicobacter pylori (H. pylori) infection in the pathogenesis of gastric cancer. The development of gastric cancer is a complex, multistep process involving multiple genetic and epigenetic alterations of oncogenes, tumor suppressor genes, DNA repair genes, cell cycle regulators, and signaling molecules. A plausible program for gastric cancer prevention involves intake of a balanced diet containing fruits and vegetables, improved sanitation and hygiene, screening and treatment of H. pylori infection, and follow-up of precancerous lesions. The fact that diet plays an important role in the etiology of gastric cancer offers scope for nutritional chemoprevention. Animal models have been extensively used to analyze the stepwise evolution of gastric carcinogenesis and to test dietary chemopreventive agents. Development of multitargeted preventive and therapeutic strategies for gastric cancer is a major challenge for the future.
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Affiliation(s)
- Siddavaram Nagini
- Siddavaram Nagini, Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar-608 002, Tamil Nadu, India
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Tazawa H, Kagawa S, Fujiwara T. MicroRNAs as potential target gene in cancer gene therapy of gastrointestinal tumors. Expert Opin Biol Ther 2011; 11:145-55. [PMID: 21219233 DOI: 10.1517/14712598.2011.542749] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
INTRODUCTION MicroRNA (miRNA) is a small non-coding RNA, which negatively regulates the expression of many target genes, thereby contributing to the modulation of diverse cell fates. Recent advances in molecular biology have revealed the potential role of miRNAs in tumor initiation, progression and metastasis. Aberrant regulation of miRNAs has been frequently reported in a variety of cancers, including gastrointestinal tumors, suggesting that cancer-related miRNAs are promising as novel biomarkers for tumor diagnosis and are potential target genes for cancer gene therapy against gastrointestinal tumors. AREAS COVERED The review focuses on the role of specific miRNAs (miR-192/194/215 and miR-7) in the differentiation of gastrointestinal epithelium and on the role of tumor-suppressive (miR-34, miR-143, miR-145) and oncogenic miRNAs (miR-21, miR-17-92 cluster) in gastrointestinal tumors. Furthermore, the potential role of miRNAs as novel biomarkers and target genes for cancer gene therapy against gastrointestinal tumors are discussed. We will also outline the potential clinical application of miRNAs for tumor diagnosis and cancer gene therapy against gastrointestinal tumors. EXPERT OPINION Exploration of tumor-related miRNAs would provide important opportunities for the development of novel cancer gene therapies aimed at normalizing the critical miRNAs that are deregulated in gastrointestinal tumors.
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Affiliation(s)
- Hiroshi Tazawa
- Okayama University Hospital, Center for Gene and Cell Therapy, Okayama, Japan
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12
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Wong J, Kelly K, Mittra A, Gonzalez SJ, Song KY, Simpson G, Coffin R, Fong Y. A third-generation herpesvirus is effective against gastroesophageal cancer. J Surg Res 2010; 163:214-20. [PMID: 20538290 PMCID: PMC3266820 DOI: 10.1016/j.jss.2010.03.021] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2010] [Revised: 02/18/2010] [Accepted: 03/05/2010] [Indexed: 01/10/2023]
Abstract
BACKGROUND Gastroesophageal cancer remains a leading cause of cancer deaths and is uniformly fatal in patients presenting with metastases and recurrence. This study sets out to determine the effect of a third-generation, replication-competent, oncolytic herpes simplex type 1 virus containing transgenes encoding for a fusogenic membrane glycoprotein and Fcy::Fur, against gastroesophageal cancer. METHODS The cytotoxic effect of the virus was tested on human gastroesophageal cancer cell lines OCUM-2MD3, MKN-45, AGS, MKN-1, MKN-74, and BE-3 at sequential multiplicities of infection (MOI). Cytotoxicity was measured using a lactate dehydrogenase assay. Viral replication was tested by serially diluting supernatants from viral infections and titering on VERO cells via standard plaque assay. Correlations of cytotoxicity and viral replication were also investigated. RESULTS All cell lines were susceptible to viral infection and demonstrated a dose-dependent effect, with greater and faster cytotoxicity at higher MOIs. Viral replication was supported in the cell lines tested, with peak titers by d 5, some supporting as high as >40,000× amplification. Cell lines with longer doubling times (>30 h) also achieved higher viral titers at a MOI of 0.1. Cell lines with shorter doubling times achieved 50% cell kill in fewer days, with an average of 2.3 d for cell lines with doubling times under 30 h compared with 4.4 d for cell lines with doubling times over 30 h. CONCLUSION These results suggest that this third-generation oncolytic herpesvirus can effectively infect and lyse gastroesophageal cancer cells and may provide a novel therapy against gastroesophageal cancer.
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Affiliation(s)
- Joyce Wong
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA
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13
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Zhang Y, Shi Y, Li X, Du W, Luo G, Gou Y, Wang X, Guo X, Liu J, Ding J, Wu K, Fan D. Inhibition of the p53-MDM2 interaction by adenovirus delivery of ribosomal protein L23 stabilizes p53 and induces cell cycle arrest and apoptosis in gastric cancer. J Gene Med 2010; 12:147-56. [PMID: 20020415 DOI: 10.1002/jgm.1424] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Inhibiting MDM2 activity in tumors that express wild-type (wt) p53 but have high levels of MDM2 protein has been considered an attractive anticancer strategy for many years. Previous studies revealed that human ribosomal protein L23 (RPL23) inhibited MDM2-mediated p53 degradation and thus induced p53 levels as well as its activity, suggesting that it might be a candidate for use as a gene therapy for cancer. In the present study, we evaluated whether targeting this pathway could be of therapeutic value against human gastric carcinoma. METHODS Gastric cancer cell lines carrying wt or mutant p53 gene were infected with adenovirus expressing RPL23 (Ad-RPL23). Cell growth assay, flow cytometry assay and morphology were used to observe the effects of Ad-RPL23 infection on tumor cells, and further, the effect of Ad-RPL23 treatment on tumor growth in vivo was investigated. RESULTS In vitro, adenovirus-mediated RPL23 gene transfer stabilized wt p53 by inhibiting its degradation, and thus resulted in G(1)-S cell cycle arrest and/or apoptosis of human gastric cancer MKN45 and AGS cells carrying wt p53 gene. Adenovirus-mediated RPL23 gene transfer also inhibited the growth of MKN45 tumors in subcutaneous mouse models. CONCLUSIONS The data obtained in the present study suggest that, through the inhibition of the p53-MDM2 interaction, adenovirus delivery of RPL23 can inhibit the proliferation of gastric cancer cells harboring wt p53 in vitro and in vivo. Exogenous RPL23-induced wt p53 stabilization and activation may be a novel therapeutic approach for patients with gastric cancer.
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Affiliation(s)
- Yafei Zhang
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
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14
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Chang JH, Kato N, Muroyama R, Taniguchi H, Guleng B, Dharel N, Shao RX, Tateishi K, Jazag A, Kawabe T, Omata M. Double-stranded RNA-activated protein kinase inhibits hepatitis C virus replication but may be not essential in interferon treatment. Liver Int 2010; 30:311-8. [PMID: 19840259 DOI: 10.1111/j.1478-3231.2009.02144.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND Double-stranded RNA-activated protein kinase (PKR), an interferon (IFN)-stimulated gene, is activated by binding with double-stranded RNA, a putative replicative intermediate of the hepatitis C virus (HCV). Activated PKR phosphorylates the alpha subunit of eukaryotic initiation factor-2 to inhibit the translation of viral protein. AIMS/METHODS We established stable PKR knockdown Huh7 cells using RNA interference and investigated the effect of PKR against HCV replication using a subgenomic replicon that expressed luciferase reporter protein and the JFH1 full-length HCV genome. RESULTS In stable PKR knockdown cells that harboured a subgenomic replicon, luciferase activity was approximately three times higher than that of control cells, indicating that the subgenomic replicon replicated with a higher efficiency in stable PKR knockdown cells than that in control cells. Furthermore, stable PKR knockdown cells secreted significantly more HCV particles than did control cells after transfection with the full-length HCV genome. The replication of the subgenomic replicon was suppressed by the addition of IFN-alpha in both cells. Although the extent of suppression was significantly lower in stable PKR knockdown than control cells using a low concentration (2.5-5 U/ml) of IFN-alpha, even 10 U/ml IFN-alpha suppressed the replication of subgenomic replicon by >98% in both cells. CONCLUSIONS Double-stranded RNA-activated protein kinase plays an important role in suppressing HCV replication in an innate state, but may not be essential in IFN therapy.
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Affiliation(s)
- Jin-Hai Chang
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
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15
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Zhang S, Li Y, Li L, Zhang Y, Gao N, Zhang Z, Zhao H. Phase I Study of Repeated Intraepithelial Delivery of Adenoviral p53 in Patients With Dysplastic Oral Leukoplakia. J Oral Maxillofac Surg 2009; 67:1074-82. [DOI: 10.1016/j.joms.2008.06.079] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2008] [Revised: 03/28/2008] [Accepted: 06/18/2008] [Indexed: 11/16/2022]
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Nishi J, Fumoto S, Ishii H, Kodama Y, Nakashima M, Sasaki H, Nakamura J, Nishida K. Improved stomach selectivity of gene expression following microinstillation of plasmid DNA onto the gastric serosal surface in mice. Eur J Pharm Biopharm 2008; 69:633-9. [DOI: 10.1016/j.ejpb.2007.12.018] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2007] [Revised: 09/01/2007] [Accepted: 12/19/2007] [Indexed: 12/11/2022]
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Trapasso F, Pichiorri F, Gaspari M, Palumbo T, Aqeilan RI, Gaudio E, Okumura H, Iuliano R, Di Leva G, Fabbri M, Birk DE, Raso C, Green-Church K, Spagnoli LG, Venuta S, Huebner K, Croce CM. Fhit interaction with ferredoxin reductase triggers generation of reactive oxygen species and apoptosis of cancer cells. J Biol Chem 2008; 283:13736-44. [PMID: 18319262 PMCID: PMC2376222 DOI: 10.1074/jbc.m709062200] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2007] [Revised: 02/28/2008] [Indexed: 11/06/2022] Open
Abstract
Fhit protein is lost in most cancers, its restoration suppresses tumorigenicity, and virus-mediated FHIT gene therapy induces apoptosis and suppresses tumors in preclinical models. We have used protein cross-linking and proteomics methods to characterize a Fhit protein complex involved in triggering Fhit-mediated apoptosis. The complex includes Hsp60 and Hsp10 that mediate Fhit stability and may affect import into mitochondria, where it interacts with ferredoxin reductase, responsible for transferring electrons from NADPH to cytochrome P450 via ferredoxin. Viral-mediated Fhit restoration increases production of intracellular reactive oxygen species, followed by increased apoptosis of lung cancer cells under oxidative stress conditions; conversely, Fhit-negative cells escape apoptosis, carrying serious oxidative DNA damage that may contribute to an increased mutation rate. Characterization of Fhit interacting proteins has identified direct effectors of the Fhit-mediated apoptotic pathway that is lost in most cancers through loss of Fhit.
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Affiliation(s)
- Francesco Trapasso
- Ohio State University, Comprehensive Cancer Center, Columbus, Ohio 43210, USA
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Khalighinejad N, Hariri H, Behnamfar O, Yousefi A, Momeni A. Adenoviral gene therapy in gastric cancer: A review. World J Gastroenterol 2008; 14:180-4. [PMID: 18186552 PMCID: PMC2675111 DOI: 10.3748/wjg.14.180] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is one of the most common malignancies worldwide. With current therapeutic approaches the prognosis of gastric cancer is very poor, as gastric cancer accounts for the second most common cause of death in cancer related deaths. Gastric cancer like almost all other cancers has a molecular genetic basis which relies on disruption in normal cellular regulatory mechanisms regarding cell growth, apoptosis and cell division. Thus novel therapeutic approaches such as gene therapy promise to become the alternative choice of treatment in gastric cancer. In gene therapy, suicide genes, tumor suppressor genes and anti-angiogenesis genes among many others are introduced to cancer cells via vectors. Some of the vectors widely used in gene therapy are Adenoviral vectors. This review provides an update of the new developments in adenoviral cancer gene therapy including strategies for inducing apoptosis, inhibiting metastasis and targeting the cancer cells.
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Vogiatzi P, Vindigni C, Roviello F, Renieri A, Giordano A. Deciphering the underlying genetic and epigenetic events leading to gastric carcinogenesis. J Cell Physiol 2007; 211:287-95. [PMID: 17238139 DOI: 10.1002/jcp.20982] [Citation(s) in RCA: 86] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Gastric cancer is a common aggressive malignancy. Although its incidence shows considerable variation among different countries, gastric cancer is still a major health problem worldwide. The causes of stomach cancer are not completely understood. What is clear is that gastric cancer is a multi-stage process involving genetic and epigenetic factors. This review is an in-depth study of the known genetic and epigenetic processes in the development of this tumor, and delineates possible approaches in gene and epigenetic therapy.
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Affiliation(s)
- Paraskevi Vogiatzi
- Department of Molecular Biology, Medical Genetics, University of Siena, Siena, Italy
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Abstract
Gastric cancer is one of the most common tumors worldwide. The therapeutic outcome of conventional therapies is inefficient. Thus, new therapeutic strategies are urgently needed. Gene therapy is a promising molecular alternative in the treatment of gastric cancer, including the replacement of defective tumor suppressor genes, the inactivation of oncogenes, the introduction of suicide genes, genetic immunotherapy, anti-angiogenetic gene therapy, and virotherapy. Improved molecular biological techniques and a better understanding of gastric carcinogenesis have allowed us to validate a variety of genes as molecular targets for gene therapy. This review provides an update of the new developments in cancer gene therapy, new principles, techniques, strategies and vector systems, and shows how they may be applied in the treatment of gastric cancer.
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Affiliation(s)
- Andreas P Sutter
- Department of Gastroenterology/Infectious Diseases/Rheumatology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
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Nakamura J, Fumoto S, Shoji K, Kodama Y, Nishi J, Nakashima M, Sasaki H, Nishida K. Stomach-Selective Gene Transfer Following the Administration of Naked Plasmid DNA onto the Gastric Serosal Surface in Mice. Biol Pharm Bull 2006; 29:2082-6. [PMID: 17015955 DOI: 10.1248/bpb.29.2082] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The purpose of the present study was to achieve a stomach-selective gene transfer following the administration of naked plasmid DNA (pDNA) onto the gastric serosal surface in mice. Gene expression in the stomach and other tissues was evaluated by firefly luciferase activity. Six hours after gastric serosal surface instillation of naked pDNA, high gene expression in the stomach was observed. On the contrary, intravenous and intraperitoneal injection of naked pDNA exhibited no detectable gene expression. Following instillation of naked pDNA onto the gastric serosal surface, gene expression in the stomach was significantly higher than in other tissues. Gene expression in the stomach was highest 12 h after the instillation and thereafter decreased gradually. Utilizing a glass-made diffusion cell that is able to limit the contact dimension between the gastric serosal surface and the naked pDNA solution administered, site-specific gene expression in the stomach was achieved. This novel gene transfer method is expected to be a safe and effective treatment against serious stomach diseases.
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Affiliation(s)
- Junzo Nakamura
- Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
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22
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Ohta M, Tateishi K, Kanai F, Watabe H, Kondo S, Guleng B, Tanaka Y, Asaoka Y, Jazag A, Imamura J, Ijichi H, Ikenoue T, Sata M, Miyagishi M, Taira K, Tada M, Kawabe T, Omata M. p53-Independent negative regulation of p21/cyclin-dependent kinase-interacting protein 1 by the sonic hedgehog-glioma-associated oncogene 1 pathway in gastric carcinoma cells. Cancer Res 2005; 65:10822-10829. [PMID: 16322228 DOI: 10.1158/0008-5472.can-05-0777] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
The activation of Hedgehog (Hh) signaling has been implicated in the growth of various tumor types, including gastric carcinoma. However, the precise mechanisms of Hh activation and suppression of tumor growth by the blockade of Hh signaling in gastric carcinoma cells remain unknown. The aim of this study was to elucidate the mechanism of abnormal Hh signaling and the key molecules contributing to dysregulated growth of gastric carcinoma. The Sonic hedgehog (Shh) ligand and its receptor Patched were expressed in all five gastric carcinoma cell lines examined (MKN1, MKN7, MKN45, MKN74, and AGS cells). The blockade of Hh signaling with anti-Shh antibody inhibited the growth of all five gastric carcinoma cell lines. Shh was overexpressed (mean, 12.8-fold) in 8 of 14 (57.0%) cancerous tissue samples from patients with gastric carcinoma as compared with expression in the surrounding noncancerous tissues. The disruption of glioma-associated oncogene 1 (Gli1) by small interfering RNA induced an increase in p21/cyclin-dependent kinase-interacting protein 1 (CIP1), interfered with the G1-S transition, and suppressed cell proliferation. The stimulation or inhibition of Hh signaling did not affect p53 activity and the induction of p21/CIP1 expression and the G1 arrest by inhibition of Hh signaling were not affected by the p53 status. These findings suggest that the overexpression of Shh contributes to constitutive Hh activation and that this signaling pathway negatively regulates p21/CIP1 through a Gli1-dependent and p53-independent mechanism in gastric carcinoma cells.
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Affiliation(s)
- Miki Ohta
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Hongo, Japan
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Shao RX, Otsuka M, Kato N, Taniguchi H, Hoshida Y, Moriyama M, Kawabe T, Omata M. Acyclic retinoid inhibits human hepatoma cell growth by suppressing fibroblast growth factor-mediated signaling pathways. Gastroenterology 2005; 128:86-95. [PMID: 15633126 DOI: 10.1053/j.gastro.2004.09.077] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is one of the most common human malignancies. Its high mortality rate is mainly a result of high intrahepatic recurrence. The novel synthetic retinoid acyclic retinoid (ACR) has been reported to prevent the recurrence of human HCC after surgical resection of primary tumors, but the molecular mechanisms underlying its effects remain to be elucidated. In this study, we clarified the molecular targets of ACR. METHODS The inhibitory effects by ACR on growth were examined. Intracellular signaling induced by ACR was comprehensively studied by a reporter assay. Gene expression changes by ACR were examined using a microarray. From these results, a candidate signaling pathway modulated by ACR was determined and whether antagonizing this pathway reverses the effect was examined. RESULTS We show that ACR inhibits the growth of HCC cells through the down-regulation of fibroblast growth factor (FGF) receptor 3 expression and FGF-mediated signaling, which in turn suppresses the activity of Rho and serum response factor-mediated transcription. Conversely, overexpression of the active form of FGF receptor 3 or the addition of FGF reverses the ACR-mediated inhibition of growth. In addition, silencing the FGF receptor 3 gene by RNA interference inhibits cell growth. CONCLUSIONS These studies show that ACR is a potent inhibitor of FGF signaling and that selective blocking of the FGF-mediated pathway could be a promising therapeutic approach for the management of patients with HCC.
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Affiliation(s)
- Run-Xuan Shao
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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Tsunemitsu Y, Kagawa S, Tokunaga N, Otani S, Umeoka T, Roth JA, Fang B, Tanaka N, Fujiwara T. Molecular therapy for peritoneal dissemination of xenotransplanted human MKN-45 gastric cancer cells with adenovirus mediated Bax gene transfer. Gut 2004; 53:554-60. [PMID: 15016751 PMCID: PMC1774013 DOI: 10.1136/gut.2003.021683] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Gene therapy is an innovative therapeutic approach for cancer. An adenoviral vector expressing the tumour suppressor p53 gene (Ad/p53) is currently under clinical evaluation for various cancers. We recently developed a binary adenoviral vector system that can express the strong proapoptotic gene Bax (Ad/PGK-GV16+Ad/GT-Bax: Ad/Bax). AIMS To evaluate the potential of Bax gene therapy for gastric cancer, we assessed its antitumour effect in comparison with that of p53. METHODS The human gastric cancer cell lines MKN-1, MKN-7, MKN-28, and MKN-45 were treated with Ad/Bax or Ad/p53, and cell viability, transgene expression, and caspase activation were assessed in vitro. To compare the antitumour effects of Ad/Bax and Ad/p53 treatment in vivo, subcutaneous tumours and peritoneal dissemination of MKN-45 cells were generated in nude mice. Each mouse underwent intratumoral or intraperitoneal administration of viruses and the growth of implanted tumours was observed after treatment. RESULTS Treatment with Ad/Bax and Ad/p53 resulted in marked Bax and p53 protein expression and effective apoptosis induction in MKN-1, MKN-7, and MKN-28 cells in vitro. In contrast, MKN-45 cells showed resistance to Ad/p53 and only treatment with Ad/Bax resulted in activation of caspase 3 expression and massive apoptosis. Ad/Bax treatment was more effective in suppressing both subcutaneous and peritoneally disseminated MKN-45 tumours compared with Ad/p53 treatment. CONCLUSION Ad/Bax treatment significantly inhibited the growth of even p53 resistant gastric cancer in vitro and in vivo. Therefore, adenovirus mediated Bax gene transfer may be useful in gene therapy for gastric cancers.
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Affiliation(s)
- Y Tsunemitsu
- Division of Surgical Oncology, Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan
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Zhang Y, Adachi M, Zhao X, Kawamura R, Imai K. Histone deacetylase inhibitors FK228,N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)amino- methyl]benzamide andm-carboxycinnamic acid bis-hydroxamide augment radiation-induced cell death in gastrointestinal adenocarcinoma cells. Int J Cancer 2004; 110:301-8. [PMID: 15069698 DOI: 10.1002/ijc.20117] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
HDAC inhibitors induce histone hyperacetylation by a relative increase of histone acetyltransferase activity. Histone hyperacetylation may affect chromatin structure and susceptibility to DNA-damaging stress, such as IR. We here investigate whether these inhibitors can radiosensitize human gastric MKN45 and colorectal DLD1 adenocarcinoma cells. In both cells, FK228 pretreatment at minimally toxic concentrations clearly augmented IR-induced cell death, DNA fragmentation and caspase-3/-8 activation. In contrast, 5-FU did not clearly augment IR-induced cell death and caspase-3 activation. FK228 increased expression of proapoptotic BH3-only Bim proteins, and gene transfer-mediated overexpression of Bimalpha radiosensitized DLD1 cells. These data suggest that the FK228-mediated increase of Bim expression may at least partially contribute to its augmentation of radiation-induced apoptosis. However, FK228 did not distinctly affect IR-induced phosphorylation of H2AX, which is an initial event followed by DNA damage. FK228 strongly augmented IR-induced growth suppression of MKN45 tumor xenografts. In addition, other HDAC inhibitors, MS275 and CBHA, similarly augmented IR-induced cell death in both cell types. Our results suggest that these HDAC inhibitors may enhance the efficacy of radiation therapy in gastrointestinal cancer cells.
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Affiliation(s)
- Yubin Zhang
- First Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
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Chen J, Röcken C, Malfertheiner P, Ebert MPA. Recent advances in molecular diagnosis and therapy of gastric cancer. Dig Dis 2004; 22:380-5. [PMID: 15812163 DOI: 10.1159/000083602] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Gastric cancer is the fourth most common malignancy and the second most frequent cause of cancer-related death in the world. It is often diagnosed in advanced stages when treatment options are limited, leading to a poor prognosis. During the past 15 years, much has been learnt about the molecular mechanisms of gastric carcinogenesis and the development of metastases. This coincided with the development of new techniques for functional genomics, including both transcriptomics and proteomics, which significantly improve the ability to explore new molecular alterations involved in carcinogenesis and tumor progression. An improved understanding of the molecular pathology and pathogenesis of gastric cancer may lead to a more rapid development of molecular diagnostic and patient tailored therapeutic targets.
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Affiliation(s)
- Jie Chen
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto von Guericke University, Magdeburg, Germany
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Abstract
Gastric cancer is common in China, and its early diagnosis and treatment are difficult. In recent years great progress has been achieved in gene therapy, and a wide array of gene therapy systems for gastric cancer has been investigated. The present article deals with the general principles of gene therapy and then focuses on how these principles may be applied to gastric cancer.
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Affiliation(s)
- Chao Zhang
- Department of General Surgery, Southwest Hospital, Third Military Medical University, Gaotan Yan, Chongqing 400038, China.
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Lee B, Choi J, Kim J, Kim JH, Joo CH, Cho YK, Kim YK, Lee H. Oncolysis of human gastric cancers by an E1B 55 kDa-deleted YKL-1 adenovirus. Cancer Lett 2002; 185:225-33. [PMID: 12169397 DOI: 10.1016/s0304-3835(02)00279-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Advanced gastric cancer cannot be treated with surgery or conventional cancer therapy, which has prompted a search for new therapeutic modalities. Previously, we and other groups showed that E1B 55 kDa-deleted recombinant adenoviruses, such as YKL-1, effectively replicate and induce cytotoxicity in p53-deficient cancer cells while sparing normal cells. Here, we investigated selective YKL-1 replication and resultant cytolysis in human gastric cancer cells. The cytopathic effects were obvious in all five gastric cancer cell lines we examined. Evaluation of p53 expression indicated that only the AGS cell line retained functionally normal p53. Nevertheless, AGS was 10-fold more sensitive to YKL-1 than the other cell lines. Transmission electron microscopy showed typical morphological alterations along with efficient replication of YKL-1 in AGS cells. Therefore, YKL-1 induces preferential cytotoxic effects in human gastric cancer cells in a p53-independent manner, making YKL-1 a promising therapeutic agent for human gastric cancers.
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Affiliation(s)
- Boyoung Lee
- Department of Microbiology, University of Ulsan College of Medicine, P.O. Box 145, 138-736, Seoul, South Korea
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Lan KH, Sheu ML, Hwang SJ, Yen SH, Chen SY, Wu JC, Wang YJ, Kato N, Omata M, Chang FY, Lee SD. HCV NS5A interacts with p53 and inhibits p53-mediated apoptosis. Oncogene 2002; 21:4801-11. [PMID: 12101418 DOI: 10.1038/sj.onc.1205589] [Citation(s) in RCA: 177] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2001] [Revised: 04/09/2002] [Accepted: 04/15/2002] [Indexed: 12/17/2022]
Abstract
Hepatitis C virus (HCV) causes a persistent infection, chronic hepatitis and hepatocellular carcinoma. HCV NS5A, one of non-structural proteins of HCV, was suggested to play a role in oncogenic transformation. Since the tumor suppressor p53 is important for preventing neoplastic transformation, we investigated the functional effects of HCV NS5A on p53. In vitro and in vivo coimmunoprecipitation and confocal microscopy were used to determine the interaction of NS5A and p53. HCV NS5A binds directly to p53 and colocalizes p53 in the perinuclear region. NS5A inhibits transcriptional transactivation by p53 in a dose-dependent manner by use of a reporter assay. Down regulation of endogenous p21/waf1 expression, which is activated by p53 in Hep3B cells, by NS5A was demonstrated by using FLAG- and FLAG-NS5A Hep3B stable cell lines. The effect of NS5A on p53-mediated apoptosis was determined by flow cytometry in both NS5A permanently and transiently transfected Hep3B cells with exogenous p53. The p53-induced apoptosis was abrogated by NS5A and the inhibition effect correlates well with the binding ability of NS5A to p53. In addition, HCV NS5A protein interacts with and colocalizes hTAF(II)32, a component of TFIID and an essential coactivator of p53, in vivo. These results suggest that HCV NS5A interacts with and partially sequestrates p53 and hTAF(II)32 in the cytoplasm and suppresses p53-mediated transcriptional transactivation and apoptosis during HCV infection, which may contribute to the hepatocarcinogenesis of HCV infection.
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Affiliation(s)
- Keng-Hsin Lan
- Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei 11217, Taiwan, Republic of China
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Affiliation(s)
- Danuta Balicki
- Division of Hematology, Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA 92037, USA
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Hecht JR. Adjuvant therapy for gastric cancer: a reality at last. Curr Gastroenterol Rep 2000; 2:478-81. [PMID: 11079050 DOI: 10.1007/s11894-000-0012-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Gastric cancer remains a significant healthcare problem throughout the world and is usually diagnosed at a fairly advanced stage in the West. Despite complete resection of the primary tumor, most patients eventually experience a relapse and die of recurrent disease. Extended surgery has not been shown to improve survival in Western studies. There have been a large number of adjuvant chemotherapy trials over the past several decades, most with negative results. More recently, there is hope for improving these dismal results with a meta-analysis showing a benefit for adjuvant chemotherapy and a large randomized trial, INT-0116, which has just reported a significant survival advantage with combined chemoradiation. These results make adjuvant therapy for completely resected gastric carcinoma the new standard of care, except in the uncommon setting of early intramucosal cancers.
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Affiliation(s)
- J R Hecht
- Division of Hematology/Oncology, UCLA School of Medicine, 2345H PVUB, 10945 LeConte Avenue, Los Angeles, CA 90095, USA.
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Otsuka M, Kato N, Lan K, Yoshida H, Kato J, Goto T, Shiratori Y, Omata M. Hepatitis C virus core protein enhances p53 function through augmentation of DNA binding affinity and transcriptional ability. J Biol Chem 2000; 275:34122-34130. [PMID: 10924497 DOI: 10.1074/jbc.m000578200] [Citation(s) in RCA: 129] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Hepatitis C virus (HCV) causes a persistent infection, chronic hepatitis, and hepatocellular carcinoma. Since there are several reports indicating that some viruses influence the tumor suppressor p53 function, we determined the effects of HCV proteins on p53 function and its mechanism determined by use of a reporter assay. Among seven HCV proteins investigated (core, NS2, NS3, NS4A, NS4B, NS5A, and NS5B), only core protein augmented the transcriptional activity of p53 and increased the expression of p21(waf1) protein, which is a major target of p53. Core protein increased both DNA-binding affinity of p53 in electrophoretic morbidity shift assay and transcriptional ability of p53 itself in a reporter assay. The direct interaction between core protein and C terminus of p53 was also shown by glutathione S-transferase fusion protein binding assay. In addition, core protein interacted with hTAF(II)28, a component of the transcriptional factor complex in vivo and in vitro. These results suggest that HCV core protein interacts with p53 and modulates p53-dependent promoter activities during HCV infection.
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Affiliation(s)
- M Otsuka
- Department of Gastroenterology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan
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Affiliation(s)
- R J Steele
- Department of Surgery and Molecular Oncology, University of Dundee, Scotland, UK
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