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Hedayati N, Safari MH, Milasi YE, Kahkesh S, Farahani N, Khoshnazar SM, Dorostgou Z, Alaei E, Alimohammadi M, Rahimzadeh P, Taheriazam A, Hashemi M. Modulation of the PI3K/Akt signaling pathway by resveratrol in cancer: molecular mechanisms and therapeutic opportunity. Discov Oncol 2025; 16:669. [PMID: 40323335 PMCID: PMC12052642 DOI: 10.1007/s12672-025-02471-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 04/23/2025] [Indexed: 05/08/2025] Open
Abstract
The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is a critical intracellular signaling pathway that is pivotal in various cellular functions. It is in senescence, survival, and growth under normal physiological and pathological conditions, including neoplasms. Additionally, this pathway has been recognized as essential for the regulation of the cell cycle. Several previous studies have indicated that the PI3K/Akt signaling pathway can be influenced by various natural products, with resveratrol (3,4',5-trihydroxy-trans-stilbene) being a particularly important phytoalexin polyphenol in this context. This review explores the impact of the PI3K/Akt signaling pathway on the initiation and advancement of various cancerous conditions and the potential of resveratrol to target this signaling mechanism. The review begins by summarizing the anti-tumor capabilities of resveratrol and then emphasizes the significant role of the PI3K/Akt signaling pathway in the progression of multiple malignancies. Finally, we discuss the therapeutic effects of resveratrol on human neoplasms, from brain cancers to gastrointestinal malignancies, through regulation of this signaling cascade.
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Affiliation(s)
- Neda Hedayati
- School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohamad Hosein Safari
- Department of Internal Medicine, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Yaser Eshaghi Milasi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Samaneh Kahkesh
- Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Najma Farahani
- Farhikhtegan Medical Convergent Sciences Research Center, TeMs. C., Islamic Azad University, Tehran, Iran
| | - Seyedeh Mahdieh Khoshnazar
- Gastroenterology and Hepatology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Zahra Dorostgou
- Department of Biochemistry, Neyshabur Branch, Islamic Azad University, Neyshabur, Iran
| | - Elmira Alaei
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Payman Rahimzadeh
- Surgical Research Society (SRS), Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergent Sciences Research Center, TeMs. C., Islamic Azad University, Tehran, Iran.
- Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergent Sciences Research Center, TeMs. C., Islamic Azad University, Tehran, Iran.
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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Yan Z, Liu Y, Yuan Y. The plasticity of epithelial cells and its potential in the induced differentiation of gastric cancer. Cell Death Discov 2024; 10:512. [PMID: 39719478 DOI: 10.1038/s41420-024-02275-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 12/05/2024] [Accepted: 12/13/2024] [Indexed: 12/26/2024] Open
Abstract
Cell plasticity refers to the deviation of cells from normal terminal differentiation states when faced with environmental and genetic toxic stresses, resulting in the phenomenon of transforming into other cell or tissue phenotypes. Unlocking phenotype plasticity has been defined as a hallmark of malignant tumors. The stomach is one of the organs in the body with the highest degree of self-renewal and exhibits significant cell plasticity. In this paper, based on the review of the characteristics of normal differentiation of gastric epithelial cells and their markers, the four main phenotypes of gastric epithelial cell remodeling and their relationship with gastric cancer (GC) are drawn. Furthermore, we summarize the regulatory factors and mechanisms that affect gastric epithelial cell plasticity and outline the current status of research and future prospection for the treatment targeting gastric epithelial cell plasticity. This study has important theoretical reference value for the in-depth exploration of epithelial cell plasticity and the tumor heterogeneity caused by it, as well as for the precise treatment of GC.
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Affiliation(s)
- Ziwei Yan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Yingnan Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China.
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Zhao Y, Tang H, Xu J, Sun F, Zhao Y, Li Y. HNF4A-Bridging the Gap Between Intestinal Metaplasia and Gastric Cancer. Evol Bioinform Online 2024; 20:11769343241249017. [PMID: 38680615 PMCID: PMC11047246 DOI: 10.1177/11769343241249017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Accepted: 04/04/2024] [Indexed: 05/01/2024] Open
Abstract
Background Intestinal metaplasia (IM) of gastric epithelium has traditionally been regarded as an irreversible stage in the process of the Correa cascade. Exploring the potential molecular mechanism of IM is significant for effective gastric cancer prevention. Methods The GSE78523 dataset, obtained from the Gene Expression Omnibus (GEO) database, was analyzed using RStudio software to identify the differently expressed genes (DEGs) between IM tissues and normal gastric epithelial tissues. Subsequently, gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, Gene Set Enrichment Analysis (GESA), and protein-protein interaction (PPI) analysis were used to find potential genes. Additionally, the screened genes were analyzed for clinical, immunological, and genetic correlation aspects using single gene clinical correlation analysis (UALCAN), Tumor-Immune System Interactions Database (TISIDB), and validated through western blot experiments. Results Enrichment analysis showed that the lipid metabolic pathway was significantly associated with IM tissues and the apolipoprotein B (APOB) gene was identified in the subsequent analysis. Experiment results and correlation analysis showed that the expression of APOB was higher in IM tissues than in normal tissues. This elevated expression of APOB was also found to be associated with the expression levels of hepatocyte nuclear factor 4A (HNF4A) gene. HNF4A was also found to be associated with immune cell infiltration to gastric cancer and was linked to the prognosis of gastric cancer patients. Moreover, HNF4A was also highly expressed in both IM tissues and gastric cancer cells. Conclusion Our findings indicate that HNF4A regulates the microenvironment of lipid metabolism in IM tissues by targeting APOB. Higher expression of HNF4A tends to lead to a worse prognosis in gastric cancer patients implying it may serve as a predictive indicator for the progression from IM to gastric cancer.
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Affiliation(s)
| | | | - Jianhua Xu
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Feifei Sun
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yuanyuan Zhao
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yang Li
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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Solé L, Lobo-Jarne T, Cabré-Romans JJ, González A, Fernández L, Marruecos L, Guix M, Cuatrecasas M, López S, Bellosillo B, Torres F, Iglesias M, Bigas A, Espinosa L. Loss of the epithelial marker CDX1 predicts poor prognosis in early-stage CRC patients. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119658. [PMID: 38216091 DOI: 10.1016/j.bbamcr.2024.119658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 12/18/2023] [Accepted: 01/03/2024] [Indexed: 01/14/2024]
Abstract
BACKGROUND We have previously shown that non-curative chemotherapy imposes fetal conversion and high metastatic capacity to cancer cells. From the set of genes differentially expressed in Chemotherapy Resistant Cells, we obtained a characteristic fetal intestinal cell signature that is present in a group of untreated tumors and is sufficient to predict patient prognosis. A feature of this fetal signature is the loss of CDX1. METHODS We have analyzed transcriptomic data in public datasets and performed immunohistochemistry analysis of paraffin embedded tumor samples from two cohorts of colorectal cancer patients. RESULTS We demonstrated that low levels of CDX1 are sufficient to identify patients with poorest outcome at the early tumor stages II and III. Presence tumor areas that are negative for CDX1 staining in stage I cancers is associated with tumor relapse. CONCLUSIONS Our results reveal the actual possibility of incorporating CDX1 immunostaining as a valuable biomarker for CRC patients.
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Affiliation(s)
- Laura Solé
- Program in Cancer Research, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain
| | - Teresa Lobo-Jarne
- Program in Cancer Research, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain
| | - Júlia-Jié Cabré-Romans
- Program in Cancer Research, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain
| | - Antón González
- Pathology Department, Hospital del Mar, Barcelona, Spain
| | | | - Laura Marruecos
- Program in Cancer Research, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain; The Walter and Eliza Hall Institute, Melbourne, Australia
| | - Marta Guix
- Oncology Department, Hospital del Mar, Barcelona, Spain
| | - Miriam Cuatrecasas
- Pathology Department, Centre of Biomedical Diagnosis (CDB), Hospital Clinic, 08036 Barcelona, Spain; Centro de Investigacion Biomedica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Sandra López
- Pathology Department, Centre of Biomedical Diagnosis (CDB), Hospital Clinic, 08036 Barcelona, Spain; Centro de Investigacion Biomedica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
| | | | - Ferran Torres
- Biostatistics Unit, Medical School, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Mar Iglesias
- Pathology Department, Hospital del Mar, Barcelona, Spain; Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain
| | - Anna Bigas
- Program in Cancer Research, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain; Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain; Josep Carreras Leukemia Research Institute, Barcelona, Spain
| | - Lluís Espinosa
- Program in Cancer Research, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain; Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain.
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Takeuchi C, Sato J, Yamamichi N, Kageyama-Yahara N, Sasaki A, Akahane T, Aoki R, Nakajima S, Ito M, Yamamichi M, Liu YY, Sakuma N, Takahashi Y, Sakaguchi Y, Tsuji Y, Sakurai K, Tomida S, Niimi K, Ushijima T, Fujishiro M. Marked intestinal trans-differentiation by autoimmune gastritis along with ectopic pancreatic and pulmonary trans-differentiation. J Gastroenterol 2024; 59:95-108. [PMID: 37962678 PMCID: PMC10810929 DOI: 10.1007/s00535-023-02055-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023]
Abstract
BACKGROUND Autoimmune gastritis (AIG) is a prevalent chronic inflammatory disease with oncogenic potential that causes destruction of parietal cells and severe mucosal atrophy. We aimed to explore the distinctive gene expression profiles, activated signaling pathways, and their underlying mechanisms. METHODS A comprehensive gene expression analysis was conducted using biopsy specimens from AIG, Helicobacter pylori-associated gastritis (HPG), and non-inflammatory normal stomachs. Gastric cancer cell lines were cultured under acidic (pH 6.5) conditions to evaluate changes in gene expression. RESULTS Gastric mucosa with AIG had a unique gene expression profile compared with that with HPG and normal mucosa, such as extensively low expression of ATP4A and high expression of GAST and PAPPA2, which are involved in neuroendocrine tumorigenesis. Additionally, the mucosa with AIG and HPG showed the downregulation of stomach-specific genes and upregulation of small intestine-specific genes; however, intestinal trans-differentiation was much more prominent in AIG samples, likely in a CDX-dependent manner. Furthermore, AIG induced ectopic expression of pancreatic digestion-related genes, PNLIP, CEL, CTRB1, and CTRC; and a master regulator gene of the lung, NKX2-1/TTF1 with alveolar fluid secretion-related genes, SFTPB and SFTPC. Mechanistically, acidic conditions led to the downregulation of master regulator and stemness control genes of small intestine, suggesting that increased environmental pH may cause abnormal intestinal differentiation in the stomach. CONCLUSIONS AIG induces diverse trans-differentiation in the gastric mucosa, characterized by the transactivation of genes specific to the small intestine, pancreas, and lung. Increased environmental pH owing to AIG may cause abnormal differentiation of the gastric mucosa.
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Affiliation(s)
- Chihiro Takeuchi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
- Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan
| | - Junichi Sato
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Nobutake Yamamichi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
- Center for Epidemiology and Preventive Medicine, The University of Tokyo Hospital, Tokyo, Japan.
| | - Natsuko Kageyama-Yahara
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Akiko Sasaki
- Department of Gastroenterology, Medicine Center, Shonan Kamakura General Hospital, Kanagawa, Japan
| | - Takemi Akahane
- Department of Gastroenterology, Nara Medical University, Nara, Japan
| | - Rika Aoki
- Tokushima Health Screening Center, Tokushima, Japan
| | - Shigemi Nakajima
- Department of General Medicine, Japan Community Healthcare Organization Shiga Hospital, Consortium for Community Medicine, Shiga University of Medical Science, Shiga, Japan
| | - Masayoshi Ito
- Department of Gastroenterology, Yotsuya Medical Cube, Tokyo, Japan
| | - Mitsue Yamamichi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Yu-Yu Liu
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
- Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan
| | - Nobuyuki Sakuma
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
- Center for Epidemiology and Preventive Medicine, The University of Tokyo Hospital, Tokyo, Japan
| | - Yu Takahashi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Yoshiki Sakaguchi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Yosuke Tsuji
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Kouhei Sakurai
- Department of Pathology, Fujita Health University School of Medicine, Aichi, Japan
| | - Shuta Tomida
- Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama, Japan
| | - Keiko Niimi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
- Center for Epidemiology and Preventive Medicine, The University of Tokyo Hospital, Tokyo, Japan
| | - Toshikazu Ushijima
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
- Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
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Xie D, Wu C, Wang D, Nisma Lena BA, Liu N, Ye G, Sun M. Wei-fu-chun tablet halted gastric intestinal metaplasia and dysplasia associated with inflammation by regulating the NF-κB pathway. JOURNAL OF ETHNOPHARMACOLOGY 2024; 318:117020. [PMID: 37567428 DOI: 10.1016/j.jep.2023.117020] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 08/06/2023] [Accepted: 08/08/2023] [Indexed: 08/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Chi006Eese herbal medicine Weifuchun Tablets (WFC) approved by the State Food and Drug Administration in 1982 has been widely used in treating a variety of chronic stomach disorders including Chronic atrophic gastritis (CAG) and Gastric precancerous lesions in China clinically. This study aimed to investigate the efficacy and potential mechanism of WFC in treating Gastric intestinal metaplasia (GIM) and Gastric dysplasia (GDys). MATERIALS AND METHODS Rat GIM and GDys established by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) combined with hot paste, ethanol injury, and intermittent fasting were intervened by WFC. Body weight, histopathology, pH of gastric acid, pepsin activity, intestinal metaplasia index and inflammation were detected. Rat bone marrow derived macrophages (BMDMs) pretreated with WFC were stimulated by LPS. Inflammatory factors and the nuclear factor-kappa B (NF-κB) pathway were assessed. GES-1 cells pretreated by WFC were stimulated by MNNG and TNF-α, intestinal metaplasia index, the NF-κB pathway and interaction between P65 and CDX2 were detected. RESULTS WFC improved rat body weight, histopathology, pH value of gastric acid, activity of gastric pepsin, intestinal metaplasia (CDX2), inflammation (IL-1β, IL-6 and TNF-α), macrophage aggregation (CD68) in gastric mucosa in rat GIM and GDys. WFC inhibited inflammation (IL-1β and TNF-α) by inactivating the NF-κB pathway. WFC reduced the expression of CDX2 by inhibiting the binding of CDX2 promoter TSS upstream region with p65. CONCLUSION WFC blocked GIM and GDys associated with inflammation by regulating the NF-κB pathway.
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Affiliation(s)
- Dong Xie
- Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Chao Wu
- Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Dan Wang
- Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Bahaji Azami Nisma Lena
- Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Ningning Liu
- Department of Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Guan Ye
- Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Shanghai, China.
| | - Mingyu Sun
- Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Radak M, Ghamari N, Fallahi H. Identification of common factors among fibrosarcoma, rhabdomyosarcoma, and osteosarcoma by network analysis. Biosystems 2024; 235:105093. [PMID: 38052344 DOI: 10.1016/j.biosystems.2023.105093] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 11/13/2023] [Accepted: 11/23/2023] [Indexed: 12/07/2023]
Abstract
Sarcoma cancers are uncommon malignant tumors, and there are many subgroups, including fibrosarcoma (FS), which mainly affects middle-aged and older adults in deep soft tissues. Rhabdomyosarcoma (RMS), on the other hand, is the most common soft-tissue sarcoma in children and is located in the head and neck area. Osteosarcomas (OS) is the predominant form of primary bone cancer among young adults, primarily resulting from sporadically random mutations. This frequently results in the dissemination of cancer cells to the lungs, commonly known as metastasis. Mesodermal cells are the origin of sarcoma cancers. In this study, a rather radical approach has been applied. Instead of comparing homogenous cancer types, we focus on three main subtypes of sarcoma: fibrosarcoma, rhabdomyosarcoma, and osteosarcoma, and compare their gene expression with normal cell groups to identify the differentially expressed genes (DEGs). Next, by applying protein-protein interaction (PPI) network analysis, we determine the hub genes and crucial factors, such as transcription factors (TFs), affected by these types of cancer. Our findings indicate a modification in a range of pathways associated with cell cycle, extracellular matrix, and DNA repair in these three malignancies. Results showed that fibrosarcoma (FS), rhabdomyosarcoma (RMS), and osteosarcoma (OS) had 653, 1270, and 2823 differentially expressed genes (DEGs), respectively. Interestingly, there were 24 DEGs common to all three types. Network analysis showed that the fibrosarcoma network had two sub-networks identified in FS that contributed to the catabolic process of collagen via the G-protein coupled receptor signaling pathway. The rhabdomyosarcoma network included nine sub-networks associated with cell division, extracellular matrix organization, mRNA splicing via spliceosome, and others. The osteosarcoma network has 13 sub-networks, including mRNA splicing, sister chromatid cohesion, DNA repair, etc. In conclusion, the common DEGs identified in this study have been shown to play significant and multiple roles in various other cancers based on the literature review, indicating their significance.
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Affiliation(s)
- Mehran Radak
- Department of Biology, School of Sciences, Razi University, Baq-e-Abrisham, Kermanshah, 6714967346, Iran.
| | - Nakisa Ghamari
- Department of Biology, School of Sciences, Razi University, Baq-e-Abrisham, Kermanshah, 6714967346, Iran.
| | - Hossein Fallahi
- Department of Biology, School of Sciences, Razi University, Baq-e-Abrisham, Kermanshah, 6714967346, Iran.
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Khayyat A, Esmaeil Pour MA, Poursina O, Zohouri SA, Jian PV, Patel N, Amin A. Evaluations of Biomarkers CDX1 and CDX2 in Gastric Cancer Prognosis: A Meta-analysis. INTERNATIONAL JOURNAL OF MOLECULAR AND CELLULAR MEDICINE 2024; 13:1-19. [PMID: 39156870 PMCID: PMC11329936 DOI: 10.22088/ijmcm.bums.13.1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 05/14/2024] [Accepted: 05/29/2024] [Indexed: 08/20/2024]
Abstract
CDX1 and CDX2 are homeobox-type transcription factors that are potential biomarkers and are associated with prognostic significance in intestinal-type gastric cancer early disease before lymph node metastasis is associated with better prognosis. In addition, the genes IDH 1 and IDH 2 previously known to be involved in brain cancer are implicated in cancer-related molecular signatures as a result new targeted personalized therapies may be possible. Our retrospective study determined the correlation between CDX markers and clinicopathologic data including survival in patients with gastric cancer. This study included studies from 1997 to December 2022 a meta-analysis to provide odds ratios (ORs) and relative risks (RRs). We discussed in detail the impact of IDH 1/2 on the prognosis of gastric cancer outcomes and potential therapeutic strategies. Our meta-analysis included 20 studies identifying 11,163 patients with gastric cancer. We found that CDX 1 overexpression was associated with better overall survival (pooled HR: 1.28) and CDX 2 expression and better 3-year survival (pooled HR: 1.64) and 5-year survival was the pooled HR was correlated 1 94 with both showing statistical correlation. Evidence suggests that IDH 1/2 mutations and CDX 1/2 overexpression are closely associated with metabolic abnormalities epigenetic changes and mutations evidence suggests the potential for novel targeted therapies in gastric cancer. CDX 1/2 overexpression is associated with a favorable prognosis in gastric cancer cases. Further studies are needed to explore the clinical significance of IDH 1/2 mutations and CDX 1/2 expression.
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Affiliation(s)
- Azadeh Khayyat
- Department of Pathology, Medical College of Wisconsin, WI, USA.
| | | | | | - Seyed Amir Zohouri
- College student, Simon Fraser University, Department of Science, BC, Canada.
| | | | - Neel Patel
- Department of Public Health, Icahn School of Medicine at Mount Sinai, NY, USA.
| | - Ami Amin
- Department of Pathology, Brown University, RI, USA.
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9
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Gao X, Han W, Chen L, Li H, Zhou F, Bai B, Yan J, Guo Y, Liu K, Li W, Li R, Yuan Q, Zhang J, Lu Y, Zhao X, Ji G, Li M, Zhao Q, Wu K, Li Z, Nie Y. Association of CDX2 and mucin expression with chemotherapeutic benefits in patients with stage II/III gastric cancer. Cancer Med 2023; 12:17613-17631. [PMID: 37602699 PMCID: PMC10523976 DOI: 10.1002/cam4.6379] [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: 07/07/2022] [Revised: 07/05/2023] [Accepted: 07/17/2023] [Indexed: 08/22/2023] Open
Abstract
BACKGROUND Better predictors of patients with stage II/III gastric cancer (GC) most likely to benefit from adjuvant chemotherapy are urgently needed. This study aimed to assess the ability of CDX2 and mucin markers to predict prognosis and fluorouracil-based adjuvant chemotherapy benefits. METHODS CDX2 and mucin protein expressions were examined by immunohistochemistry and compared with survival and adjuvant chemotherapy benefits in a prospective evaluation cohort of 782 stage II/III GC patients. Then, the main findings were validated in an independent validation cohort (n = 386) and an external mRNA sequencing dataset (ACRG cohort, n = 193). RESULTS In the evaluation cohort, CDX2, CD10, MUC2, MUC5AC, and MUC6 expressions were observed in 59.7%, 26.7%, 27.6%, 55.1%, and 57.7% of patients, respectively. However, only the expression of CDX2 was found to be associated with adjuvant chemotherapy benefits. Most importantly, CDX2-negative patients had a poorer prognosis when treated with surgery only, while the prognosis of CDX2-negative and CDX2-positive patients was similar when receiving postoperative adjuvant chemotherapy. Further analysis revealed that patients with CDX2 negative tumors benefited from chemotherapy (5-year overall survival rates: 60.0% with chemotherapy vs. 23.2% with surgery-only, p < 0.001), whereas patients with CDX2 positive tumors did not (pinteraction = 0.004). Consistent results were obtained in the validation and ACRG cohorts. CONCLUSIONS Negative expression of CDX2 is an independent risk factor for survival in stage II/III GC, but subsequent adjuvant chemotherapy is able to compensate for this unfavorable effect. Therefore, active chemotherapy is more urgent for patients with negative CDX2 expression than for patients with positive CDX2 expression.
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Affiliation(s)
- Xianchun Gao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
- Department of Health Statistics, Shaanxi Key Laboratory of Free Radical Biology and Medicine and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Preventive MedicineFourth Military Medical UniversityXi'anChina
| | - Weili Han
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Ling Chen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Pathology, Xijing Hospital and School of Basic MedicineFourth Military Medical UniversityXi'anChina
| | - Hongwei Li
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Fenli Zhou
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Bin Bai
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Junya Yan
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Yong Guo
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Pathology, Xijing Hospital and School of Basic MedicineFourth Military Medical UniversityXi'anChina
| | - Kun Liu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Wenjiao Li
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Renlong Li
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Qiangqiang Yuan
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Jiehao Zhang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Yuanyuan Lu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Xiaodi Zhao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Gang Ji
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Mengbin Li
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Qingchuan Zhao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Kaichun Wu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
| | - Zengshan Li
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Pathology, Xijing Hospital and School of Basic MedicineFourth Military Medical UniversityXi'anChina
| | - Yongzhan Nie
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anChina
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Gharakhyli EA, Tabar Molla Hassan A, Alipour M, Vahidi S, Samadani AA. The effect of miR-372-5p regulation on CDX1 and CDX2 in the gastric cancer cell line. Horm Mol Biol Clin Investig 2023; 44:271-276. [PMID: 36848481 DOI: 10.1515/hmbci-2022-0045] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 02/08/2023] [Indexed: 03/01/2023]
Abstract
OBJECTIVES MicroRNA expression disruptions play an important function in the expansion of gastric cancer. Previous investigation has indicated that miR-372-5p doing as an oncogene in several malignancies. CDX1 and CDX2, as target genes of miR-372-5p, play the role of tumor suppressors and oncogenes in gastric cancer cells, respectively. The current investigation explored the effects of miR-372-5p regulation on CDX2 and CDX1 in AGS cell lines and studied their molecular mechanism. METHODS hsa-miR-372-5p miRCURY LNA miRNA Inhibitors and Mimic were transfected into AGS cell line. The cell viability and cell cycle calculation were defined by MTT assay and flow cytometry, respectively. The Expression levels of miR-372-5p, CDX1, CDX2 and transfection efficiency were measured using Real-time PCR. Statistical investigation p values <0.05 were considered to be meaningful. RESULTS miR-372-5p particularly was upregulated in control cells and also after transfection by mimic. While its expression was reduced by the inhibitor. Upregulation of miR-372-5p remarkably increased cell growth and led to accumulation in the G2/M phase, although the inhibitor decreased cell growth and accumulation in the S phase. Accordingly, upregulation of miR-372-5p increased CDX2 and decreased CDX1 expression. By inhibition of miR-372-5p, expression of CDX2 was decreased and expression of CDX1 was increased. CONCLUSIONS Up and down-regulation of miR-372-5P has a potential effect on the expression levels of its target genes, CDX1 and CDX22. Accordingly, the downregulation of miR-372-5p may be assumed as a possible therapeutic target in treating gastric cancer.
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Affiliation(s)
| | | | - Majid Alipour
- Department of Cell and Molecular Biology, Babol Branch, Islamic Azad University, Babol, Iran
| | - Sogand Vahidi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ali Akbar Samadani
- Guilan Road Trauma Research Center, Guilan University of Medical Sciences, Rasht, Iran
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11
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Liu H, Zhang X, Fang C, Li S. Resveratrol induces the growth inhibition of CDX-deficient gastric cancer cells using CDX2 and RUNX3 via the β-catenin/TCF4 signaling pathway. Transl Oncol 2023; 35:101727. [PMID: 37354639 DOI: 10.1016/j.tranon.2023.101727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 06/04/2023] [Accepted: 06/17/2023] [Indexed: 06/26/2023] Open
Abstract
This study aimed to determine the expression levels of runt-related transcription factor 3 (RUNX3) and caudal-related homeobox 2 (CDX2) in patients with chronic gastritis, intestinal metaplasia, atypical hyperplasia, and gastric cancer (GC). To analyze the overexpression of CDX2 and the effects of resveratrol (Res) on MKN7 and TMK1 cells, immunohistochemical staining was performed to determine the protein expression levels in tissue samples. The biological activity of MKN7 and TMK1 cells was determined. Relative mRNA and protein expression levels were also determined. RUNX3 expression was positively correlated with CDX2 expression and negatively correlated with β-catenin and transcription factor 4 (TCF-4) levels in GC tissues. Interestingly, RUNX3 expression was negatively correlated with CDX2 expression in other tissues. CDX2 overexpression or Res treatment inhibited cell proliferation, migration, and invasion, while inducing cell apoptosis. Furthermore, RUNX3 and B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax) expression levels were increased, while those of of β-catenin, TCF-4, and Bcl-2 were decreased in the CDX2 group. Upon treatment with lithium chloride (LiCl), the proliferation, migration, and invasion of CDX2-overexpressing MKN7 and TMK1 cells were enhanced. Our results indicate that Res inhibits the growth of MKN7 and TMK1 cells by increasing RUNX3 and CDX2 expression levels, with the potential involvement of the β-catenin/TCF-4 signaling pathway.
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Affiliation(s)
- Hui Liu
- Department of Gastroenterology, Yantai Affiliated Hospital of Binzhou Medical College, Yantai, Shandong, China
| | - Xinxin Zhang
- Department of Gastroenterology, Yantai Affiliated Hospital of Binzhou Medical College, Yantai, Shandong, China
| | - Can Fang
- Department of Gastroenterology, Yantai Affiliated Hospital of Binzhou Medical College, Yantai, Shandong, China
| | - Shuguang Li
- Department of Gastroenterology, Yantai Affiliated Hospital of Binzhou Medical College, Yantai, Shandong, China.
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12
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Zhang JX, Bao SC, Chen J, Chen T, Wei HL, Zhou XY, Li JT, Yan SG. Xiaojianzhong decoction prevents gastric precancerous lesions in rats by inhibiting autophagy and glycolysis in gastric mucosal cells. World J Gastrointest Oncol 2023; 15:464-489. [PMID: 37009319 PMCID: PMC10052669 DOI: 10.4251/wjgo.v15.i3.464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 12/01/2022] [Accepted: 01/16/2023] [Indexed: 03/14/2023] Open
Abstract
BACKGROUND Gastric precancerous lesions (GPL) precede the development of gastric cancer (GC). They are characterized by gastric mucosal intestinal metaplasia and dysplasia caused by various factors such as inflammation, bacterial infection, and injury. Abnormalities in autophagy and glycolysis affect GPL progression, and their effective regulation can aid in GPL treatment and GC prevention. Xiaojianzhong decoction (XJZ) is a classic compound for the treatment of digestive system diseases in ancient China which can inhibit the progression of GPL. However, its specific mechanism of action is still unclear.
AIM To investigate the therapeutic effects of XJZ decoction on a rat GPL model and the mechanisms underlying its effects on autophagy and glycolysis regulation in GPLs.
METHODS Wistar rats were randomly divided into six groups of five rats each and all groups except the control group were subjected to GPL model construction for 18 wk. The rats’ body weight was monitored every 2 wk starting from the beginning of modeling. Gastric histopathology was examined using hematoxylin-eosin staining and Alcian blue-periodic acid-Schiff staining. Autophagy was observed using transmission electron microscopy. The expressions of autophagy, hypoxia, and glycolysis related proteins in gastric mucosa were detected using immunohistochemistry and immunofluorescence. The expressions of the following proteins in gastric tissues: B cell lymphoma/Leukemia-2 and adenovirus E1B19000 interacting protein 3 (Bnip-3), microtubule associated protein 1 light chain 3 (LC-3), moesin-like BCL2-interacting protein 1 (Beclin-1), phosphatidylinositol 3-kimase (PI3K), protein kinase B (AKT), mammalian target of rapamycin (mTOR), p53, AMP-activated protein kinase (AMPK), and Unc-51 like kinase 1 (ULK1) were detected using western blot. The relative expressions of autophagy, hypoxia, and glycolysis related mRNA in gastric tissues was detected using reverse transcription-polymerase chain reaction.
RESULTS Treatment with XJZ increased the rats’ body weight and improved GPL-related histopathological manifestations. It also decreased autophagosome and autolysosome formation in gastric tissues and reduced Bnip-3, Beclin-1, and LC-3II expressions, resulting in inhibition of autophagy. Moreover, XJZ down-regulated glycolysis-related monocarboxylate transporter (MCT1), MCT4, and CD147 expressions. XJZ prevented the increase of autophagy level by decreasing gastric mucosal hypoxia, activating the PI3K/AKT/mTOR pathway, inhibiting the p53/AMPK pathway activation and ULK1 Ser-317 and Ser-555 phosphorylation. In addition, XJZ improved abnormal gastric mucosal glucose metabolism by ameliorating gastric mucosal hypoxia and inhibiting ULK1 expression.
CONCLUSION This study demonstrates that XJZ may inhibit autophagy and glycolysis in GPL gastric mucosal cells by improving gastric mucosal hypoxia and regulating PI3K/AKT/mTOR and p53/ AMPK/ULK1 signaling pathways, providing a feasible strategy for the GPL treatment.
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Affiliation(s)
- Jia-Xiang Zhang
- College of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China
- Key Laboratory of Gastrointestinal Diseases and Prescriptions in Shaanxi Province, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China
| | - Sheng-Chuan Bao
- College of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China
- Key Laboratory of Gastrointestinal Diseases and Prescriptions in Shaanxi Province, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China
| | - Juan Chen
- College of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China
- Key Laboratory of Gastrointestinal Diseases and Prescriptions in Shaanxi Province, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China
| | - Ting Chen
- College of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China
- Key Laboratory of Gastrointestinal Diseases and Prescriptions in Shaanxi Province, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China
| | - Hai-Liang Wei
- Key Laboratory of Gastrointestinal Diseases and Prescriptions in Shaanxi Province, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China
- Department of General Surgery, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang 712000, Shaanxi Province, China
| | - Xiao-Yan Zhou
- Key Laboratory of Gastrointestinal Diseases and Prescriptions in Shaanxi Province, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China
- Department of Gastroenterology, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang 712000, Shaanxi Province, China
| | - Jing-Tao Li
- Departments of Infectious Disease, The Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang 712000, Shaanxi Province, China
| | - Shu-Guang Yan
- College of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China
- Key Laboratory of Gastrointestinal Diseases and Prescriptions in Shaanxi Province, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China
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The Transition from Gastric Intestinal Metaplasia to Gastric Cancer Involves POPDC1 and POPDC3 Downregulation. Int J Mol Sci 2021; 22:ijms22105359. [PMID: 34069715 PMCID: PMC8160799 DOI: 10.3390/ijms22105359] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 05/09/2021] [Accepted: 05/12/2021] [Indexed: 12/24/2022] Open
Abstract
Intestinal metaplasia (IM) is an intermediate step in the progression from premalignant to malignant stages of gastric cancer (GC). The Popeye domain containing (POPDC) gene family encodes three transmembrane proteins, POPDC1, POPDC2, and POPDC3, initially described in muscles and later in epithelial and other cells, where they function in cell–cell interaction, and cell migration. POPDC1 and POPDC3 downregulation was described in several tumors, including colon and gastric cancers. We questioned whether IM-to-GC transition involves POPDC gene dysregulation. Gastric endoscopic biopsies of normal, IM, and GC patients were examined for expression levels of POPDC1-3 and several suggested IM biomarkers, using immunohistochemistry and qPCR. Immunostaining indicated lower POPDC1 and POPDC3 labeling in IM compared with normal tissues. Significantly lower POPDC1 and POPDC3 mRNA levels were measured in IM and GC biopsies and in GC-derived cell lines. The reduction in focal IM was smaller than in extensive IM that resembled GC tissues. POPDC1 and POPDC3 transcript levels were highly correlated with each other and inversely correlated with LGR5, OLFM4, CDX2, and several mucin transcripts. The association of POPDC1 and POPDC3 downregulation with IM-to-GC transition implicates a role in tumor suppression and highlights them as potential biomarkers for GC progression and prospective treatment targets.
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14
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Correction. Cancer Sci 2021; 112:1331. [PMID: 33675174 DOI: 10.1111/cas.14830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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Lu W, Ni Z, Jiang S, Tong M, Zhang J, Zhao J, Feng C, Jia Q, Wang J, Yao T, Ning H, Shi Y. Resveratrol inhibits bile acid-induced gastric intestinal metaplasia via the PI3K/AKT/p-FoxO4 signalling pathway. Phytother Res 2021; 35:1495-1507. [PMID: 33103284 PMCID: PMC8048559 DOI: 10.1002/ptr.6915] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 10/05/2020] [Accepted: 10/05/2020] [Indexed: 02/06/2023]
Abstract
Gastric intestinal metaplasia (GIM) is the essential pre-malignancy of gastric cancer. Chronic inflammation and bile acid reflux are major contributing factors. As an intestinal development transcription factor, caudal-related homeobox 2 (CDX2) is key in GIM. Resveratrol has potential chemopreventive and anti-tumour effects. The aim of the study is to probe the effect of resveratrol in bile acid-induced GIM. We demonstrated that resveratrol could reduce CDX2 expression in a time- and dose-dependent manner in gastric cell lines. A Cignal Finder 45-Pathway Reporter Array and TranSignal Protein/DNA Array Kit verified that resveratrol could increase Forkhead box O4 (FoxO4) activity and that Chenodeoxycholic acid (CDCA) could reduce FoxO4 activity. Furthermore, bioinformatics analysis showed that FoxO4 could bind to the CDX2 promoter, and these conjectures were supported by chromatin-immunoprecipitation (ChIP) assays. Resveratrol can activate FoxO4 and decrease CDX2 expression by increasing phospho-FoxO4 nucleus trans-location. Resveratrol could increase FoxO4 phosphorylation through the PI3K/AKT pathway. Ectopic FoxO4 expression can up-regulate FoxO4 phosphorylation and suppress CDCA-induced GIM marker expression. Finally, we found a reverse correlation between p-FoxO4 and CDX2 in tissue arrays. This study validates that resveratrol could reduce bile acid-induced GIM through the PI3K/AKT/p-FoxO4 signalling pathway and has a potential reversing effect on GIM, especially that caused by bile acid reflux.
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Affiliation(s)
- Wenquan Lu
- Department of GastroenterologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive DiseasesAir force Military Medical UniversityXi'anChina
| | - Zhen Ni
- Department of GastroenterologyThe General Hospital of Western Theater CommandChengduChina
| | - Shuqin Jiang
- Pediatric Development and Behavior DepartmentThe third Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Mingfu Tong
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive DiseasesAir force Military Medical UniversityXi'anChina
- Department of GastroenterologyBeijing Chao‐Yang Hospital, Capital Medical UniversityBeijingChina
| | - Jian Zhang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive DiseasesAir force Military Medical UniversityXi'anChina
| | - Jing Zhao
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive DiseasesAir force Military Medical UniversityXi'anChina
- Department of GastroenterologySecond Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Chenchen Feng
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive DiseasesAir force Military Medical UniversityXi'anChina
- Postgraduate DepartmentXi'an Medical UniversityXi'anChina
| | - Qiaoyu Jia
- Department of GastroenterologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Jingyun Wang
- Department of GastroenterologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Tingting Yao
- Department of GastroenterologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Hanbing Ning
- Department of GastroenterologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Yongquan Shi
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive DiseasesAir force Military Medical UniversityXi'anChina
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Chen HY, Hu Y, Lu NH, Zhu Y. Caudal type homeoboxes as a driving force in Helicobacter pylori infection-induced gastric intestinal metaplasia. Gut Microbes 2020; 12:1-12. [PMID: 33031021 PMCID: PMC7553748 DOI: 10.1080/19490976.2020.1809331] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
(H. pylori), a common pathogenic bacterium in the stomach, has been demonstrated to be a major cause of gastric cancer (GC). The typical pathological evolution of H. pylori infection-induced GC involves development from gastric atrophy, via intestinal metaplasia (IM) and dysplasia, to intestinal-type GC. During this process, IM is considered to be an "irreversible point" that significantly increases the risk for GC. Therefore, the elucidation of the mechanism underlying IM is of great significance for the prevention and treatment of gastric mucosal carcinogenesis associated with H. pylori infection. Caudal type homeoboxes (CDXs) are transcription factors involved in intestinal differentiation establishment and the maintenance of normal intestinal mucosa and IM. H. pylori infection increases the expression of CDXs through epigenetic regulation, the nuclear factor-kappaB signaling pathway and its downstream proinflammatory factors, and the transforming growth factor-beta signaling pathway, leading to the progression from normal gastric mucosa to IM. However, the precise mechanisms of gastric intestinal metaplasia have not yet been fully elucidated. In this review, we focus on research progress revealing the functions of CDXs in H. pylori infection-induced IM, as well as the regulators modulating this process.
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Affiliation(s)
- Hong-Yan Chen
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Yi Hu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Nong-Hua Lu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Yin Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China,CONTACT Yin Zhu Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang330006, Jiangxi Province, China
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Casein kinase 2 interacting protein 1 positively regulates caudal-related homeobox 1 in intestinal-type gastric cancer. Chin Med J (Engl) 2020; 133:154-164. [PMID: 31868807 PMCID: PMC7028172 DOI: 10.1097/cm9.0000000000000604] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the most common malignancies, and intestinal-type GC is the main histopathologic type of GC in China. We previously reported that casein kinase 2 interacting protein 1 (CKIP-1) acts as a candidate tumor suppressor in intestinal-type GC. CKIP-1 participates in the regulation of multiple signaling pathways, including the Wnt/β-catenin pathway, of which caudal-related homeobox 1 (CDX1) may be a downstream target gene. The purpose of this study was to investigate the relationship between CKIP-1 and CDX1 in intestinal-type GC. METHODS Sixty-seven gastroscopy biopsy specimens and surgically resected gastric specimens were divided into four groups: gastric mucosa group, intestinal metaplasia (IM) group, dysplasia group, and intestinal-type GC group. The expression levels of CKIP-1 and CDX1 were detected in these groups and GC cell lines, and the correlations between these expression levels were analyzed. SGC7901 and BGC823 cells were divided into CKIP-1 shRNA groups and CKIP-1 over-expression groups, and CDX1 expression was detected. β-Catenin expression was detected in intestinal-type GC tissue samples and CKIP-1 shRNA and CKIP-1 over-expression SGC7901 cells, and its correlation with CKIP-1 expression in intestinal-type GC tissue was analyzed. The Wnt/β-catenin pathway inhibitor DKK-1 and activator LiCl were incubated with SGC7901 cells, BGC823 cells, and CKIP-1 shRNA and CKIP-1 over-expression SGC7901 and BGC823 cells, following which CDX1 and Ki-67 expression were detected. RESULTS The expression levels of CKIP-1 and CDX1 were lower in patients with intestinal-type GC than in patients with IM and dysplasia (both P < 0.05). CKIP-1 and CDX1 expression levels were positively correlated in IM, dysplasia, and intestinal-type GC tissue and cell lines (r = 0.771, P < 0.01; r = 0.597, P < 0.01; r = 0.654, P < 0.01; r = 0.811, P < 0.01, respectively). CDX1 expression was decreased in the CKIP-1 shRNA groups and increased in the CKIP-1 over-expression groups of SGC7901 and BGC823 cells compared to that in the corresponding control groups (both P < 0.05). CKIP-1 expression was negatively correlated with β-catenin expression in intestinal-type GC patients (r = -0.458, P < 0.01). Compared to the control group, β-catenin expression was increased in the CKIP-1 shRNA SGC7901 cell group and decreased in the CKIP-1 over-expression SGC7901 cell group (P < 0.05). CDX1 expression was increased in SGC7901 and BGC823 cells treated with DKK-1, DKK-1 increased CDX1 expression and decreased Ki-67 expression in the CKIP-1 shRNA group; the opposite result was observed in SGC7901 and BGC823 cells treated with LiCl, and LiCl decreased CDX1 expression and increased Ki-67 expression in the CKIP-1 over-expression group (both P < 0.05). CONCLUSIONS Through the Wnt/β-catenin signaling pathway, CKIP-1 may positively regulate CDX1 in intestinal-type GC.
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Lei D, Sun H, Zhang B. MiR-24 Promotes Cell Growth in Human Glioma by CDX1/PI3K/Akt Signaling Pathway. Cancer Biother Radiopharm 2020; 36:588-599. [PMID: 32876500 DOI: 10.1089/cbr.2020.3711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
MicroRNA-24 (miR-24) has been identified to be related to the development of glioma. However, the exact molecular mechanism of miR-24 in glioma progression remains vague. The aim of the present study was to investigate the role of miR-24 in sepsis and to reveal the associated mechanisms. Quantitative real-time polymerase chain reaction was used to compare the levels of miR-24 in glioma and normal tissue. The miR-24 inhibitor or miR-24 mimic was transfected into glioma cells, and then the effects of miR-24 on cell proliferation and apoptosis were detected using CCK-8 (Cell Counting Kit-8) assay and flow cytometry, respectively. Western blot was used to examine the levels of CDX1 (caudal-type homeobox 1), PI3K, p-PI3K, Akt, p-Akt, Cyclin D1, p27, proliferating cell nuclear antigen, Bcl-2, Bax, and Cleaved-casp3. Luciferase assay was used to identify the target gene of miR-24. An animal model was established in mice to detect the role of miR-24 in vivo. These results suggested that miR-24 was elevated in glioma, and miR-24 could promote glioma progression by facilitating cell proliferation and inducing cell apoptosis through CDX1/PI3K/Akt signaling pathway, indicating a novel pathway underlying progression in glioma cells and providing a potential target for glioma treatment.
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Affiliation(s)
- Dan Lei
- Department of Neurosurgery, Hanyang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China
| | - Huanhuan Sun
- Department of Head, Neck and Thoracic Tumor Surgery, Pu'ai Campus, Central Hospital of Huangshi, Huangshi, China
| | - Bo Zhang
- Second Department of Breast Tumor, Pu'ai Campus, Central Hospital of Huangshi, Huangshi, China
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Nakayama C, Yamamichi N, Tomida S, Takahashi Y, Kageyama‐Yahara N, Sakurai K, Takeuchi C, Inada K, Shiogama K, Nagae G, Ono S, Tsuji Y, Niimi K, Fujishiro M, Aburatani H, Tsutsumi Y, Koike K. Transduced caudal-type homeobox (CDX) 2/CDX1 can induce growth inhibition on CDX-deficient gastric cancer by rapid intestinal differentiation. Cancer Sci 2018; 109:3853-3864. [PMID: 30289576 PMCID: PMC6272106 DOI: 10.1111/cas.13821] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 09/04/2018] [Accepted: 09/20/2018] [Indexed: 12/18/2022] Open
Abstract
Intestinal metaplasia induced by ectopic expression of caudal-type homeobox (CDX)2 and/or CDX1 (CDX) is frequently observed around gastric cancer (GC). Abnormal expression of CDX is also observed in GC and suggests that inappropriate gastrointestinal differentiation plays essential roles in gastric tumorigenesis, but their roles on tumorigenesis remain unelucidated. Publicly available databases show that GC patients with higher CDX expression have significantly better clinical outcomes. We introduced CDX2 and CDX1 genes separately into GC-originated MKN7 and TMK1 cells deficient in CDX. Marked suppression of cell growth and dramatic morphological change into spindle-shaped flat form were observed along with induction of intestinal marker genes. G0-G1 growth arrest was accompanied by changed expression of cell cycle-related genes but not with apoptosis or senescence. Microarray analyses additionally showed decreased expression of gastric marker genes and increased expression of stemness-associated genes. Hierarchical clustering of 111 GC tissues and 21 non-cancerous gastric tissues by selected 18 signature genes based on our transcriptome analyses clearly categorized the 132 tissues into non-cancer, "CDX signature"-positive GC, and "CDX signature"-negative GC. Gene set enrichment analysis indicated that "CDX signature"-positive GC has lower malignant features. Immunohistochemistry of 89 GC specimens showed that 50.6% were CDX2-deficient, 66.3% were CDX1-deficient, and 44.9% were concomitant CDX2/CDX1-deficient, suggesting that potentially targetable GC cases by induced intestinal differentiation are quite common. In conclusion, exogenous expression of CDX2/CDX1 can lead to efficient growth inhibition of CDX-deficient GC cells. It is based on rapidly induced intestinal differentiation, which may be a future therapeutic strategy.
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Affiliation(s)
- Chiemi Nakayama
- Department of GastroenterologyGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Nobutake Yamamichi
- Department of GastroenterologyGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Shuta Tomida
- Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayama UniversityOkayamaJapan
| | - Yu Takahashi
- Department of GastroenterologyGraduate School of MedicineThe University of TokyoTokyoJapan
| | | | - Kouhei Sakurai
- Department of Diagnostic Pathology IIFujita Health University School of MedicineAichiJapan
| | - Chihiro Takeuchi
- Department of GastroenterologyGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Ken‐ichi Inada
- Department of Diagnostic Pathology IIFujita Health University School of MedicineAichiJapan
| | - Kazuya Shiogama
- 1st Department of PathologyFujita Health University School of MedicineAichiJapan
| | - Genta Nagae
- Research Center for Advanced Science and TechnologyThe University of TokyoTokyoJapan
| | - Satoshi Ono
- Department of GastroenterologyGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Yosuke Tsuji
- Department of GastroenterologyGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Keiko Niimi
- Department of GastroenterologyGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Mitsuhiro Fujishiro
- Department of GastroenterologyGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Hiroyuki Aburatani
- Research Center for Advanced Science and TechnologyThe University of TokyoTokyoJapan
| | - Yutaka Tsutsumi
- 1st Department of PathologyFujita Health University School of MedicineAichiJapan
| | - Kazuhiko Koike
- Department of GastroenterologyGraduate School of MedicineThe University of TokyoTokyoJapan
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