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Wu Z, Zhan W, Wu L, Yu L, Xie X, Yu F, Kong W, Bi S, Liu S, Yin G, Zhou J. The Roles of Forkhead Box O3a (FOXO3a) in Bone and Cartilage Diseases - A Narrative Review. Drug Des Devel Ther 2025; 19:1357-1375. [PMID: 40034405 PMCID: PMC11874768 DOI: 10.2147/dddt.s494841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 02/20/2025] [Indexed: 03/05/2025] Open
Abstract
Bone and cartilage diseases are significantly associated with musculoskeletal disability. However, no effective drugs are available to cure them. FOXO3a, a member of the FOXO family, has been implicated in cell proliferation, ROS detoxification, autophagy, and apoptosis. The biological functions of FOXO3a can be modulated by post-translational modifications (PTMs), such as phosphorylation and acetylation. Several signaling pathways, such as MAPK, NF-κB, PI3K/AKT, and AMPK/Sirt1 pathways, have been implicated in the development of bone and cartilage diseases by mediating the expression of FOXO3a. In particular, FOXO3a acts as a transcriptional factor in mediating the expression of various genes, such as MnSOD, CAT, BIM, BBC3, and CDK6. FOXO3a plays a critical role in the metabolism of bone and cartilage. In this article, we mainly discussed the biological functions of FOXO3a in bone and cartilage diseases, such as osteoporosis (OP), osteoarthritis (OA), rheumatoid arthritis (RA), ankylosing spondylitis (AS), and intervertebral disc degeneration (IDD). FOXO3a can promote osteogenic differentiation, induce osteoblast proliferation, inhibit osteoclast activity, suppress chondrocyte apoptosis, and reduce inflammatory responses. Collectively, up-regulation of FOXO3a expression shows beneficial effects, and FOXO3a has become a potential target for bone and cartilage diseases.
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Affiliation(s)
- Zhenyu Wu
- Department of Medical Imaging, First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, People’s Republic of China
- First Clinical Medical College, Gannan Medical University, Ganzhou, 341000, People’s Republic of China
| | - Wang Zhan
- First Clinical Medical College, Gannan Medical University, Ganzhou, 341000, People’s Republic of China
| | - Longhuo Wu
- College of Pharmacy, Gannan Medical University, Ganzhou, 341000, People’s Republic of China
| | - Luhu Yu
- Department of Clinical Laboratory, Ganzhou People’s Hospital, Ganzhou, 341000, People’s Republic of China
| | - Xunlu Xie
- Department of Pathology, Ganzhou People’s Hospital, Ganzhou, 341000, People’s Republic of China
| | - Fang Yu
- Department of Joint Surgery, Ganzhou People’s Hospital, Ganzhou, 341000, People’s Republic of China
| | - Weihao Kong
- Department of Joint Surgery, Ganzhou People’s Hospital, Ganzhou, 341000, People’s Republic of China
| | - Shengrong Bi
- Department of Joint Surgery, Ganzhou People’s Hospital, Ganzhou, 341000, People’s Republic of China
| | - Shiwei Liu
- Department of Joint Surgery, Ganzhou People’s Hospital, Ganzhou, 341000, People’s Republic of China
| | - Guoqiang Yin
- Department of Joint Surgery, Ganzhou Hospital Affiliated to Nanchang University, Ganzhou, 341000, People’s Republic of China
| | - Jianguo Zhou
- Department of Joint Surgery, Ganzhou People’s Hospital, Ganzhou, 341000, People’s Republic of China
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Yang L, Wang G, Tian H, Jia S, Wang S, Cui R, Zhuang A. RBMS1 reflects a distinct microenvironment and promotes tumor progression in ocular melanoma. Exp Eye Res 2024; 246:109990. [PMID: 38969283 DOI: 10.1016/j.exer.2024.109990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 06/25/2024] [Accepted: 07/02/2024] [Indexed: 07/07/2024]
Abstract
Ocular melanoma, including uveal melanoma (UM) and conjunctival melanoma (CM), is the most common ocular cancer among adults with a high rate of recurrence and poor prognosis. Loss of epigenetic homeostasis disturbed gene expression patterns, resulting in oncogenesis. Herein, we comprehensively analyzed the DNA methylation, transcriptome profiles, and corresponding clinical information of UM patients through multiple machine-learning algorithms, finding that a methylation-driven gene RBMS1 was correlated with poor clinical outcomes of UM patients. RNA-seq and single-cell RNA-seq analyses revealed that RBMS1 reflected diverse tumor microenvironments, where high RBMS1 expression marked an immune active TME. Furthermore, we found that tumor cells were identified to have the higher communication probability in RBMS1+ state. The functional enrichment analysis revealed that RBMS1 was associated with pigment granule and melanosome, participating in cell proliferation as well as apoptotic signaling pathway. Biological experiments were performed and demonstrated that the silencing of RBMS1 inhibited ocular melanoma proliferation and promoted apoptosis. Our study highlighted that RBMS1 reflects a distinct microenvironment and promotes tumor progression in ocular melanoma, contributing to the therapeutic customization and clinical decision-making.
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Affiliation(s)
- Ludi Yang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, PR China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, PR China
| | - Gaoming Wang
- Department of Medical Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, PR China
| | - Hao Tian
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, PR China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, PR China
| | - Shichong Jia
- Tianjin Eye Hospital, Tianjin Key Lab of Ophthalmology and Visual Science, Nankai University Affiliated Eye Hospital, Tianjin Eye Institute, Tianjin, 300020, PR China
| | - Shaoyun Wang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, PR China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, PR China.
| | - Ran Cui
- Department of Medical Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, PR China.
| | - Ai Zhuang
- Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, PR China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, PR China.
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Sameti P, Tohidast M, Amini M, Bahojb Mahdavi SZ, Najafi S, Mokhtarzadeh A. The emerging role of MicroRNA-182 in tumorigenesis; a promising therapeutic target. Cancer Cell Int 2023; 23:134. [PMID: 37438760 DOI: 10.1186/s12935-023-02972-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 06/13/2023] [Indexed: 07/14/2023] Open
Abstract
A wide range of studies have indicated that microRNAs (miRNAs), a type of small single-stranded regulatory RNAs, are dysregulated in a different variety of human cancers. Therefore, they are expected to play important roles in tumorigenesis by functioning as oncogenic (oncomiRs) or tumor-suppressive miRNAs. Subsequently, their potential as diagnostic and therapeutic targets for malignancies has attracted attention in recent years. In particular, studies have revealed the aberrant expression of miR-182 through tumorigenesis and its important roles in various aspects of malignancies, including proliferation, metastasis, and chemoresistance. Accumulating reports have illustrated that miR-182, as a dual-role regulator, directly or indirectly regulates the expression of a wide range of genes and modulates the activity of various signaling pathways involved in tumor progression, such as JAK / STAT3, Wnt / β-catenin, TGF-β, and P13K / AKT. Therefore, considering the high therapeutic and diagnostic potential of miR-182, this review aims to point out the effects of miR-182 dysregulation on the signaling pathways involved in tumorigenesis.
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Affiliation(s)
- Pouriya Sameti
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Tohidast
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Amini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Souzan Najafi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Dybska E, Nowak JK, Banaszkiewicz A, Szaflarska-Popławska A, Kierkuś J, Kwiecień J, Grzybowska-Chlebowczyk U, Walkowiak J. Methylation of RUNX3 Promoter 2 in the Whole Blood of Children with Ulcerative Colitis. Genes (Basel) 2022; 13:genes13091568. [PMID: 36140736 PMCID: PMC9498668 DOI: 10.3390/genes13091568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/22/2022] [Accepted: 08/30/2022] [Indexed: 12/03/2022] Open
Abstract
Ulcerative colitis (UC) results from a complex interplay between the environment, gut microbiota, host genetics, and immunity. Runt-related transcription factor 3 (RUNX3) regulates Th1/Th2 balance and, thus, the synthesis of cytokines and inflammation. We aimed to analyze the dependence of RUNX3 promoter 2 (P2) methylation level on: age, sex, body mass index (BMI), C-reactive protein (CRP), serum albumin, disease duration, Pediatric Ulcerative Colitis Activity Index (PUCAI), the Paris classification, and exposure to medications. This multicenter, cross-sectional study recruited hospitalized children with UC. Methylation of RUNX3 P2 was measured with methylation-sensitive restriction enzymes in the whole blood DNA. Sixty-four children were enrolled, with a mean age of 14.5 ± 2.8 years. Half of them were female (51.6%), and the average BMI Z-score was −0.44 ± 1.14. The mean methylation of RUNX3 P2 was 54.1 ± 13.3%. The methylation level of RUNX3 P2 did not correlate with age, sex, nutritional status, CRP, albumin, PUCAI, or the extent of colitis (Paris E1–E4). RUNX3 P2 methylation did not differ between patients recruited within two and a half months of diagnosis and children who had UC for at least a year. Current or past exposure to biologics, immunosuppressants, or steroids was not associated with RUNX3 P2 methylation. Methylation of RUNX3 promoter 2 in whole blood DNA does not seem to be associated with the characteristics of UC in children.
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Affiliation(s)
- Emilia Dybska
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, 60-572 Poznan, Poland
| | - Jan Krzysztof Nowak
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, 60-572 Poznan, Poland
| | - Aleksandra Banaszkiewicz
- Department of Pediatric Gastroenterology and Nutrition, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Anna Szaflarska-Popławska
- Department of Pediatric Endoscopy and Gastrointestinal Function Testing, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-094 Bydgoszcz, Poland
| | - Jarosław Kierkuś
- Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, The Children’s Memorial Health Institute, 04-730 Warsaw, Poland
| | - Jarosław Kwiecień
- Department of Pediatrics, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 41-800 Zabrze, Poland
| | - Urszula Grzybowska-Chlebowczyk
- Department of Pediatrics, Faculty of Medical Sciences, Medical University of Silesia in Katowice, 40-752 Katowice, Poland
| | - Jarosław Walkowiak
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, 60-572 Poznan, Poland
- Correspondence:
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Chen YH, Li CL, Chen WJ, Liu J, Wu HT. Diverse roles of FOXO family members in gastric cancer. World J Gastrointest Oncol 2021; 13:1367-1382. [PMID: 34721771 PMCID: PMC8529928 DOI: 10.4251/wjgo.v13.i10.1367] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 07/06/2021] [Accepted: 08/13/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is the fifth most diagnosed cancer and the third leading cause of cancer-related death worldwide. Although progress has been made in diagnosis, surgical resection, systemic chemotherapy, and immunotherapy, patients with GC still have a poor prognosis. The overall 5-year survival rate in patients with advanced GC is less than 5%. The FOXO subfamily, of the forkhead box family of transcription factors, consists of four members, FOXO1, FOXO3, FOXO4, and FOXO6. This subfamily plays an important role in many cellular processes, such as cell cycle, cell growth, apoptosis, autophagy, stress resistance, protection from aggregate toxicity, DNA repair, tumor suppression, and metabolism, in both normal tissue and malignant tumors. Various studies support a role for FOXOs as tumor suppressors based on their ability to inhibit angiogenesis and metastasis, and promote apoptosis, yet several other studies have shown that FOXOs might also promote tumor progression in certain circumstances. To elucidate the diverse roles of FOXOs in GC, this article systematically reviews the cellular functions of FOXOs in GC to determine potential therapeutic targets and treatment strategies for patients with GC.
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Affiliation(s)
- Yu-Han Chen
- Department of Clinical Medicine, Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Changjiang Scholar's Laboratory, Department of Physiology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Chun-Lan Li
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Changjiang Scholar's Laboratory, Department of Physiology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Wen-Jia Chen
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Changjiang Scholar's Laboratory, Department of Physiology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Changjiang Scholar's Laboratory, Department of Physiology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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Xu S, Ma Y, Chen Y, Pan F. Role of Forkhead box O3a transcription factor in autoimmune diseases. Int Immunopharmacol 2021; 92:107338. [PMID: 33412391 DOI: 10.1016/j.intimp.2020.107338] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 12/05/2020] [Accepted: 12/22/2020] [Indexed: 02/07/2023]
Abstract
Forkhead box O3a (FOXO3a) transcription factor, the most important member of Forkhead box O family, is closely related to cell proliferation, apoptosis, autophagy, oxidative stress and aging. The downregulation of FOXO3a has been verified to be associated with the poor prognosis, severer malignancy and chemoresistance in several human cancers. The activity of FOXO3a mainly regulated by phosphorylation of protein kinase B. FOXO3a plays a vital role in promoting the apoptosis of immune cells. FOXO3a could also modulate the activation, differentiation and function of T cells, regulate the proliferation and function of B cells, and mediate dendritic cells tolerance and immunity. FOXO3a accommodates the immune response through targeting nuclear factor kappa-B and FOXP3, as well as regulating the expression of cytokines. Besides, FOXO3a participates in intercellular interactions. FOXO3a inhibits dendritic cells from producing interleukin-6, which inhibits B-cell lymphoma-2 (BCL-2) and BCL-XL expression, thereby sparing resting T cells from apoptosis and increasing the survival of antigen-stimulated T cells. Recently, plentiful evidences further illustrated the significance of FOXO3a in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, myositis, multiple sclerosis, and systemic sclerosis. In this review, we focused on the biological function of FOXO3a and related signaling pathways regarding immune system, and summarized the potential role of FOXO3a in the pathogenesis, progress and therapeutic potential of autoimmune diseases.
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Affiliation(s)
- Shanshan Xu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Yubo Ma
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Yuting Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
| | - Faming Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China.
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Han R, Hao S, Lu C, Zhang C, Lin C, Li L, Wang Y, Hu C, He Y. Aspirin sensitizes osimertinib-resistant NSCLC cells in vitro and in vivo via Bim-dependent apoptosis induction. Mol Oncol 2020; 14:1152-1169. [PMID: 32239624 PMCID: PMC7266273 DOI: 10.1002/1878-0261.12682] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 03/17/2020] [Accepted: 03/28/2020] [Indexed: 12/17/2022] Open
Abstract
Osimertinib, a third-generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), provides marked clinical benefit for patients with EGFR-activating mutations. Unfortunately, limited treatments exist for patients who acquire osimertinib resistance. We observed two 'special' patients who regained an antitumor response with osimertinib plus aspirin treatment. As previous data indicate that aspirin induces antiproliferative effects in tumor cells, we designed a preclinical study to explore whether aspirin combined with osimertinib could synergistically sensitize osimertinib-resistant non-small-cell lung cancer (NSCLC) cells. The effects of combined treatment with osimertinib and aspirin on osimertinib-resistant NSCLC cell lines were examined in vitro and in vivo. The combination of osimertinib and aspirin induced strong antiproliferative and proapoptotic effects in osimertinib-resistant NSCLC cells through inhibition of Akt/FoxO3a signaling component phosphorylation and increased Bim expression. Furthermore, Bim knockdown by siRNA significantly attenuated osimertinib resensitization by aspirin. In vivo, combination of aspirin and osimertinib significantly decreased tumor growth of PC-9GROR cell xenografts. Data of patients with NSCLC who received osimertinib treatment at Daping Hospital between January 2015 and January 2019 were reviewed retrospectively. According to clinical data for 45 patients with NSCLC, retrospective analysis showed that the median progression-free survival was significantly longer in the osimertinib plus aspirin group than in the osimertinib group. In summary, aspirin synergistically enhances the antitumor activity of osimertinib in osimertinib-resistant lung cancer cells through promoting Bim-dependent apoptosis. This combination therapy may be effective in overcoming acquired resistance to osimertinib and prolonging survival in patients with NSCLC.
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Affiliation(s)
- Rui Han
- Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing, China
| | - Shuai Hao
- Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing, China
| | - Conghua Lu
- Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing, China
| | - Chong Zhang
- Department of Ultrasound, The First Affiliated Hospital of Chongqing Medical University, China
| | - Caiyu Lin
- Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing, China
| | - Li Li
- Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing, China
| | - Yubo Wang
- Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing, China
| | - Chen Hu
- Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing, China
| | - Yong He
- Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing, China
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Li Z, Fan P, Deng M, Zeng C. The roles of RUNX3 in cervical cancer cells in vitro. Oncol Lett 2018; 15:8729-8734. [PMID: 29805611 DOI: 10.3892/ol.2018.8419] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Accepted: 03/21/2018] [Indexed: 01/28/2023] Open
Abstract
RUNX3 serves an important role in development of various types of human cancer. The purpose of the present study was to investigate the potential biological function of RUNX3 in cervical cancer cells. In the present study, a RUNX3 overexpressed model was constructed in Hce1 cells by PCDNA3.1-RUNX3 transfection. Western blot analysis was used to measure RUNX3 expression in cervical cancer cells. Immunofluorescence analysis was performed to examine subcellular localization of RUNX3 in cervical cancer cells. Effects of RUNX3 expression on proliferation, migration and invasion of cervical cancer cells were detected by colony formation assay, wound healing assay and Transwell assay, respectively. Immunofluorescence confirmed the nuclear location of RUNX3 in cervical cancer cell. Result sindicated that upregulation of RUNX3 expression inhibited proliferation, migration and invasion of cervical cancer cells. However, knockdown of RUNX3 expression promoted the proliferation, migration and invasion of cervical cancer cells. Hence, RUNX3 may serve as a tumor suppressor gene in cervical cancer.
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Affiliation(s)
- Zhen Li
- Department of Pathology, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Pan Fan
- Department of Pathology, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Min Deng
- Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, Guangdong 510095, P.R. China
| | - Chao Zeng
- Department of Pathology, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
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Wu N, Huang Y, Zou Z, Gimenez-Capitan A, Yu L, Hu W, Zhu L, Sun X, Sanchez JJ, Guan W, Liu B, Rosell R, Wei J. High BIM mRNA levels are associated with longer survival in advanced gastric cancer. Oncol Lett 2017; 13:1826-1834. [PMID: 28454330 DOI: 10.3892/ol.2017.5660] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 04/22/2016] [Indexed: 02/06/2023] Open
Abstract
Chemotherapy drugs, including 5-fluorouracil (5-FU), oxaliplatin and docetaxel, are commonly used in the treatment of gastric cancer (GC). Apoptosis-relevant genes may be associated with drug resistance. In the present study, the messenger RNA (mRNA) expression levels of B-cell lymphoma 2 interacting mediator of cell death (BIM), astrocyte elevated gene-1 (AEG-1) and AXL receptor tyrosine kinase (AXL) were investigated in 131 advanced GC samples, and the expression levels of these genes were correlated with patients' overall survival (OS). All 131 patients received first-line FOLFOX combination chemotherapy with folinic acid and 5-FU, in which 56 patients were further treated with second-line docetaxel-based chemotherapy. A correlation between the mRNA expression levels of BIM and AEG-1 was observed (rs=0.30; P=0.002). There was no association between the mRNA expression levels of any of the individual genes analyzed and OS in patients only receiving first-line FOLFOX chemotherapy. In a subgroup of patients receiving docetaxel-based second-line chemotherapy, those with high or intermediate levels of BIM exhibited a median OS of 18.2 months [95% confidence interval (CI), 12.8-23.6], compared with 9.6 months (95% CI, 8.9-10.3) in patients with low BIM levels (P=0.008). However, there was no correlation between the mRNA expression levels of AEG-1 or AXL and OS. The risk of mortality was higher in patients with low BIM mRNA levels than in those with high or intermediate BIM mRNA levels (hazard ratio, 2.61; 95% CI, 1.21-5.62; P=0.010). Therefore, BIM may be considered as a biomarker to identify whether patients could benefit from docetaxel-based second-line chemotherapy in GC.
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Affiliation(s)
- Nandie Wu
- The Comprehensive Cancer Centre of Drum Tower Hospital, Department of Oncology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu 210008, P.R. China
| | - Ying Huang
- The Comprehensive Cancer Centre of Drum Tower Hospital, Department of Oncology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu 210008, P.R. China
| | - Zhengyun Zou
- The Comprehensive Cancer Centre of Drum Tower Hospital, Department of Oncology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu 210008, P.R. China
| | - Ana Gimenez-Capitan
- Pangaea Biotech, Department of Oncology, USP Dexeus University Institute, Barcelona 08001, Spain
| | - Lixia Yu
- The Comprehensive Cancer Centre of Drum Tower Hospital, Department of Oncology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu 210008, P.R. China
| | - Wenjing Hu
- The Comprehensive Cancer Centre of Drum Tower Hospital, Department of Oncology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu 210008, P.R. China
| | - Lijing Zhu
- The Comprehensive Cancer Centre of Drum Tower Hospital, Department of Oncology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu 210008, P.R. China
| | - Xia Sun
- The Comprehensive Cancer Centre of Drum Tower Hospital, Department of Oncology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu 210008, P.R. China
| | - Jose Javier Sanchez
- Department of Preventive Medicine and Public Health, Autonomous University of Madrid, Madrid 28001, Spain
| | - Wenxian Guan
- Department of General Surgery, The Affiliated Drum Tower Hospital of Nanjing University, Medical School of Nanjing University, Nanjing, Jiangsu 210008, P.R. China
| | - Baorui Liu
- The Comprehensive Cancer Centre of Drum Tower Hospital, Department of Oncology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu 210008, P.R. China
| | - Rafael Rosell
- Pangaea Biotech, Department of Oncology, USP Dexeus University Institute, Barcelona 08001, Spain.,Department of Medical Oncology, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Barcelona 08916, Spain
| | - Jia Wei
- The Comprehensive Cancer Centre of Drum Tower Hospital, Department of Oncology, The Affiliated Drum Tower Hospital of Nanjing University, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu 210008, P.R. China
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Go H, Jang JY, Kim PJ, Kim YG, Nam SJ, Paik JH, Kim TM, Heo DS, Kim CW, Jeon YK. MicroRNA-21 plays an oncogenic role by targeting FOXO1 and activating the PI3K/AKT pathway in diffuse large B-cell lymphoma. Oncotarget 2016; 6:15035-49. [PMID: 25909227 PMCID: PMC4558134 DOI: 10.18632/oncotarget.3729] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2015] [Accepted: 03/11/2015] [Indexed: 12/13/2022] Open
Abstract
The prognostic implications of miR-21, miR-17-92 and miR-155 were evaluated in diffuse large B-cell lymphoma (DLBCL) patients, and novel mechanism by which miR-21 contributes to the oncogenesis of DLBCL by regulating FOXO1 and PI3K/AKT/mTOR pathway was investigated. The expressions of miR-21, miR-17-92 and miR-155 measured by quantitative reverse-transcription-PCR were significantly up-regulated in DLBCL tissues (n=200) compared to control tonsils (P=0.012, P=0.001 and P<0.0001). Overexpression of miR-21 and miR-17-92 was significantly associated with shorter progression-free survival (P=0.003 and P=0.014) and overall survival (P=0.004 and P=0.012). High miR-21 was an independent prognostic factor in DLBCL patients treated with rituximab-combined chemotherapy. MiR-21 level was inversely correlated with the levels of FOXO1 and PTEN in DLBCL cell lines. Reporter-gene assay showed that miR-21 directly targeted and suppressed the FOXO1 expression, and subsequently inhibited Bim transcription in DLBCL cells. MiR-21 also down-regulated PTEN expression and consequently activated the PI3K/AKT/mTOR pathway, which further decreased FOXO1 expression. Moreover, miR-21 inhibitor suppressed the expression and activity of MDR1, thereby sensitizing DLBCL cells to doxorubicin. These data demonstrated that miR-21 plays an important oncogenic role in DLBCL by modulating the PI3K/AKT/mTOR/FOXO1 pathway at multiple levels resulting in strong prognostic implication. Therefore, targeting miR-21 may have therapeutic relevance in DLBCL.
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Affiliation(s)
- Heounjeong Go
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.,The Tumor Immunity Medical Research Center, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.,Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Ji-Young Jang
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.,The Tumor Immunity Medical Research Center, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.,The Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, South Korea
| | - Pil-Jong Kim
- Biomedical Knowledge Engineering Laboratory, Seoul National University School of Denistry, Seoul, South Korea
| | - Young-Goo Kim
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.,The Tumor Immunity Medical Research Center, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.,The Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, South Korea
| | - Soo Jeong Nam
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.,The Tumor Immunity Medical Research Center, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Jin Ho Paik
- Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Gyeonggi, South Korea
| | - Tae Min Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea
| | - Dae Seog Heo
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea
| | - Chul-Woo Kim
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.,The Tumor Immunity Medical Research Center, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.,The Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, South Korea
| | - Yoon Kyung Jeon
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.,The Tumor Immunity Medical Research Center, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.,The Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, South Korea
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11
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He SY, Jiang RF, Jiang J, Xiang YS, Wang L. Investigation of methylation and protein expression of the Runx3 gene in colon carcinogenesis. Biomed Rep 2015; 3:687-690. [PMID: 26405546 DOI: 10.3892/br.2015.479] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Accepted: 05/28/2015] [Indexed: 01/15/2023] Open
Abstract
In the present study, the methylation and protein expression of the runt-related transcription factor 3 (Runx3) gene was detected in sporadic colorectal cancer, colonic adenoma and normal colon tissue to evaluate their clinical significance in colorectal carcinogenesis. A total of 34 colonic cancer specimens, 34 colonic adenoma specimens and 34 normal colonic tissue specimens were used in the study. The CpG island methylation status of the Runx3 gene was detected by methylation-specific polymerase chain reaction and the protein expression of Runx3 was detected by immunohistochemistry. The results showed that the rates of methylation of the Runx3 gene in colonic cancer and colonic adenomas were significantly higher than that in the normal colonic tissue (23.5, 20.6 vs. 0.0%; P<0.05). There was no significant difference in the percentage of methylation of the Runx3 gene between colonic adenoma and colonic cancer (P>0.05). The positive percentage of Runx3 protein expression was significantly lower in colonic cancer compared with colonic adenoma and normal tissue (17.7 vs. 61.8, 76.5%; P<0.05). Methylation of the promoter CpG islands of the Runx3 gene is an important genetic event of colon carcinogenesis and may be associated with an altered protein level of Runx3.
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Affiliation(s)
- Shao-Ya He
- Department of Gastroenterology, Anyue People's Hospital, Ziyang, Sichuan 642350, P.R. China
| | - Ren-Fa Jiang
- Department of Gastroenterology, Anyue People's Hospital, Ziyang, Sichuan 642350, P.R. China
| | - Jie Jiang
- Department of Respiration, Chongqing Sixth People's Hospital, Chongqing 404100, P.R. China
| | - Yang-Sheng Xiang
- Department of Gastroenterology, Anyue People's Hospital, Ziyang, Sichuan 642350, P.R. China
| | - Ling Wang
- Department of Gastroenterology, Anyue People's Hospital, Ziyang, Sichuan 642350, P.R. China
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12
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Saraiva-Esperón U, Ruibal A, Herranz M. The contrasting epigenetic role of RUNX3 when compared with that of MGMT and TIMP3 in glioblastoma multiforme clinical outcomes. J Neurol Sci 2014; 347:325-31. [DOI: 10.1016/j.jns.2014.10.043] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Revised: 10/25/2014] [Accepted: 10/29/2014] [Indexed: 02/02/2023]
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13
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Peng SL. Interactions of Fox proteins with inflammatory transcription-factor pathways. Expert Rev Clin Immunol 2014; 2:869-76. [DOI: 10.1586/1744666x.2.6.869] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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14
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Maccani JZJ, Koestler DC, Houseman EA, Marsit CJ, Kelsey KT. Placental DNA methylation alterations associated with maternal tobacco smoking at the RUNX3 gene are also associated with gestational age. Epigenomics 2013; 5:619-30. [PMID: 24283877 PMCID: PMC3982305 DOI: 10.2217/epi.13.63] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
AIMS The developmental origins of health and disease hypothesis states that later-life disease may be influenced by the quality of the in utero environment. Environmental toxicants can have detrimental effects on fetal development, potentially through effects on placental development and function. Maternal smoking during pregnancy is associated with low birth weight, preterm birth and other complications, and exposure to cigarette smoke in utero has been linked to gross pathologic and molecular changes to the placenta, including differential DNA methylation in placental tissue. The aim of this study was to investigate the relationship between maternal smoking during pregnancy, methylation changes in the placenta and gestational age. MATERIALS & METHODS We used Illumina(®)'s (CA, USA) Human Methylation27 BeadChip technology platform to investigate the methylation status of 21,551 autosomal, non-SNP-associated CpG loci in DNA extracted from 206 human placentas and examined loci whose variation in methylation was associated with maternal smoking during pregnancy. RESULTS We found that methylation patterns of a number of loci within the RUNX3 gene were significantly associated with smoking during pregnancy, and one of these loci was associated with decreased gestational age (p = 0.04). CONCLUSION Our findings, demonstrating maternal smoking-induced changes in DNA methylation at specific loci, suggest a mechanism by which in utero tobacco smoke exposure could exert its detrimental effects upon the health of the fetus.
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Affiliation(s)
- Jennifer ZJ Maccani
- Department of Pathology & Laboratory Medicine, Brown University, Providence, RI, USA
| | - Devin C Koestler
- Section of Biostatistics & Epidemiology, Department of Community & Family Medicine, Geisel School of Medicine at Dartmouth, Hanover, NH, USA
| | | | - Carmen J Marsit
- Section of Biostatistics & Epidemiology, Department of Community & Family Medicine, Geisel School of Medicine at Dartmouth, Hanover, NH, USA
- Department of Pharmacology & Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA
| | - Karl T Kelsey
- Department of Pathology & Laboratory Medicine, Brown University, Providence, RI, USA
- Department of Epidemiology, Brown University, Providence, RI, USA
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15
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Xu Y, Wang K, Gao W, Zhang C, Huang F, Wen S, Wang B. MicroRNA-106b regulates the tumor suppressor RUNX3 in laryngeal carcinoma cells. FEBS Lett 2013; 587:3166-74. [PMID: 23912048 DOI: 10.1016/j.febslet.2013.05.069] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Revised: 05/10/2013] [Accepted: 05/19/2013] [Indexed: 01/27/2023]
Abstract
Our study focuses on a set of laryngeal tumors that show reduced RUNX3 expression in the absence of transcriptional silencing of tumor suppressor gene RUNX3 by aberrant methylation of CpG islands. We report that the loss of expression of RUNX3 correlates with up-regulation of miR-106b in human laryngeal carcinoma tissue. The downregulation of RUNX3 is mediated by miR-106b through binding of its 3'UTR. Moreover, miR-106b can promote the proliferation and invasion of laryngeal carcinoma cells by directly targeting RUNX3, and RUXN3 knockdown can abolish this phenotype. These results shed a new insight into the mechanism of miRNA regulation in laryngeal carcinoma.
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Affiliation(s)
- Ying Xu
- Department of Otolaryngology, Head and Neck Surgery, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi, China
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16
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RUNX3 confers sensitivity to pheophorbide a-photodynamic therapy in human oral squamous cell carcinoma cell lines. Lasers Med Sci 2013; 30:499-507. [DOI: 10.1007/s10103-013-1350-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2013] [Accepted: 05/13/2013] [Indexed: 02/06/2023]
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17
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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: 326] [Impact Index Per Article: 25.1] [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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18
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Ottini L, Falchetti M, Nesi G. Gene Signatures in Gastric Cancer. DIAGNOSTIC, PROGNOSTIC AND THERAPEUTIC VALUE OF GENE SIGNATURES 2012:95-113. [DOI: 10.1007/978-1-61779-358-5_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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19
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He SY, Han SX, Jiang RF, Xiang YS. Significance of methylation and protein expression of the Runx3 gene in colon carcinogenesis. Shijie Huaren Xiaohua Zazhi 2011; 19:1860-1863. [DOI: 10.11569/wcjd.v19.i17.1860] [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] [Indexed: 02/06/2023] Open
Abstract
AIM: To detect the methylation and protein expression of the Runx3 gene in sporadic colorectal cancer (SCRC), colonic adenoma, and normal colon tissue and to evaluate their clinical significance in colorectal carcinogenesis.
METHODS: Thirty-four colonic cancer specimens, 34 colonic adenoma specimens, and 34 normal colonic tissue specimens were used in this study. The CpG island methylation status of the Runx3 gene was detected by methylation-specific PCR in these specimens. and the protein expression of Runx3 was detected by immunohistochemistry.
RESULTS: The rates of methylation of the Runx3 gene in colonic cancer and colonic adenoma were significantly higher than that in normal colonic tissue (23.5%, 20.6% vs 0.0%, both P < 0.05). There was no significant difference in the rate of methylation of the Runx3 gene between colonic adenoma and colonic cancer (P > 0.05). The positive rate of Runx3 protein expression was significantly lower in colonic cancer than in colonic adenoma and normal tissue (17.7% vs 61.8%, 76.5%, both P < 0.05).
CONCLUSION: Methylation of the promoter CpG islands of the Runx3 gene is an important genetic event of colon carcinogenesis and may be associated with altered protein expression of Runx3.
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20
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Wen J, Tao R, Ni L, Duan Q, Lu Q. Immunolocalization and expression of Runx2 in tertiary dentinogenesis. Hybridoma (Larchmt) 2010; 29:195-9. [PMID: 20568992 DOI: 10.1089/hyb.2009.0120] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Runx2 is a new transcription factor that takes part in odontoblast differentiation. This study is aimed at investigating the immunolocalization and expression of Runx2 in the process of dental pulp injury and repair using immunohistochemical technique. In normal dental pulp, positive staining can hardly be detected. In experimental groups, strong positive staining was detected at the site of the impaired pulp after 1 day, while only weak Runx2 staining was detected 3 days after operation. Five days later, a large number of stellate cells in the root apex expressed Runx2, and after 7 days, followed by the reparative dentinogenesis, Runx2 expression vanished slowly, then totally disappeared. Taken together, the expression of Runx2 has temporal and spatial specificity during different phases in rat tertiary dentinogenesis.
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Affiliation(s)
- Jun Wen
- Department of Operative Dentistry and Endodontics, College of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, China
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21
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Wu WKK, Lee CW, Cho CH, Fan D, Wu K, Yu J, Sung JJY. MicroRNA dysregulation in gastric cancer: a new player enters the game. Oncogene 2010; 29:5761-71. [PMID: 20802530 DOI: 10.1038/onc.2010.352] [Citation(s) in RCA: 235] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gastric carcinogenesis is a multistep process involving genetic and epigenetic alteration of protein-coding proto-oncogenes and tumor-suppressor genes. Recent discoveries have shed new light on the involvement of a class of noncoding RNA known as microRNA (miRNA) in gastric cancer. A substantial number of miRNAs show differential expression in gastric cancer tissues. Genes coding for these miRNAs have been characterized as novel proto-oncogenes and tumor-suppressor genes based on findings that these miRNAs control malignant phenotypes of gastric cancer cells. In this connection, miRNA dysregulation promotes cell-cycle progression, confers resistance to apoptosis, and enhances invasiveness and metastasis. Moreover, certain polymorphisms in miRNA genes are associated with increased risks for atrophic gastritis and gastric cancer, whereas circulating levels of miRNAs may serve as biomarkers for early diagnosis. Several miRNAs have also been shown to correlate with gastric cancer progression, and thus may be used as prognostic markers. Elucidating the biological aspects of miRNA dysregulation may help us better understand the pathogenesis of gastric cancer and promote the development of miRNA-directed therapeutics against this deadly disease.
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Affiliation(s)
- W K K Wu
- Department of Medicine and Therapeutics, Institute of Digestive Diseases, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, PR China
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22
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Wu WKK, Cho CH, Lee CW, Fan D, Wu K, Yu J, Sung JJY. Dysregulation of cellular signaling in gastric cancer. Cancer Lett 2010; 295:144-53. [PMID: 20488613 DOI: 10.1016/j.canlet.2010.04.025] [Citation(s) in RCA: 128] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2010] [Revised: 04/26/2010] [Accepted: 04/27/2010] [Indexed: 02/07/2023]
Abstract
The pathogenesis of gastric cancer is complex and related to multiple factors. Dysregulation of intracellular signaling pathways represents a common pathogenic mechanism and may be amenable to drug targeting. Multiple well-established oncogenic pathways, such as those mediated by cell cycle regulators, nuclear factor-kappaB, cyclooxygenase-2 and epidermal growth factor receptor are implicated in gastric carcinogenesis. Emerging evidence also underscores the importance of signaling pathways involved in the developmental process, including transforming growth factor-beta/bone morphogenetic protein signaling, Wnt/beta-catenin signaling, Hedgehog signaling and Notch signaling. Understanding their biological significance will provide a rational basis for drug development. Their relative importance and cross-talk in gastric carcinogenesis, however, are still not completely understood and warrant further investigation.
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Affiliation(s)
- William K K Wu
- LKS Institute of Health, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, China.
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23
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Lai KW, Koh KX, Loh M, Tada K, Subramaniam MM, Lim XY, Vaithilingam A, Salto-Tellez M, Iacopetta B, Ito Y, Soong R. MicroRNA-130b regulates the tumour suppressor RUNX3 in gastric cancer. Eur J Cancer 2010; 46:1456-63. [PMID: 20176475 DOI: 10.1016/j.ejca.2010.01.036] [Citation(s) in RCA: 118] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2009] [Revised: 01/20/2010] [Accepted: 01/26/2010] [Indexed: 02/07/2023]
Abstract
AIM Accumulating evidence indicates that RUNX3 is an important tumour suppressor that is inactivated in many cancer types. This study aimed to assess the role of microRNA (miRNA) in the regulation of RUNX3. METHODS Four bioinformatic algorithms were used to predict miRNA binding to RUNX3. The correlation between candidate miRNAs and RUNX3 expression in cell lines was determined by real-time reverse transcriptase quantitative PCR (RT-qPCR) and Western blot. Candidate miRNAs were tested for functional effects through transfection of miRNA precursors and inhibitors, and monitoring cell viability, apoptosis and Bim expression. miRNA and RUNX3 expression, RUNX3 methylation and RUNX3 protein levels were assessed in gastric tissue by RT-qPCR, Methylight analysis and immunohistochemistry, respectively. RESULTS Bioinformatics, gene and protein expression analysis in eight gastric cell lines identified miR-130b as the top candidate miRNA for RUNX3 binding. Overexpression of miR-130b increased cell viability, reduced cell death and decreased expression of Bim in TGF-beta mediated apoptosis, subsequent to the downregulation of RUNX3 protein expression. In 15 gastric tumours, miR-130b expression was significantly higher compared to matched normal tissue, and was inversely associated with RUNX3 hypermethylation. CONCLUSION Attenuation of RUNX3 protein levels by miRNA may reduce the growth suppressive potential of RUNX3 and contribute to tumourigenesis.
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Affiliation(s)
- Kin Wai Lai
- Cancer Science Institute of Singapore, Centre for Life Sciences #02-15, 28 Medical Drive, National University of Singapore, Singapore 117456, Singapore
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Beroukhim R, Brunet JP, Di Napoli A, Mertz KD, Seeley A, Pires MM, Linhart D, Worrell RA, Moch H, Rubin MA, Sellers WR, Meyerson M, Linehan WM, Kaelin WG, Signoretti S. Patterns of gene expression and copy-number alterations in von-hippel lindau disease-associated and sporadic clear cell carcinoma of the kidney. Cancer Res 2009; 69:4674-81. [PMID: 19470766 DOI: 10.1158/0008-5472.can-09-0146] [Citation(s) in RCA: 323] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Recent insights into the role of the von-Hippel Lindau (VHL) tumor suppressor gene in hereditary and sporadic clear-cell renal cell carcinoma (ccRCC) have led to new treatments for patients with metastatic ccRCC, although virtually all patients eventually succumb to the disease. We performed an integrated, genome-wide analysis of copy-number changes and gene expression profiles in 90 tumors, including both sporadic and VHL disease-associated tumors, in hopes of identifying new therapeutic targets in ccRCC. We identified 14 regions of nonrandom copy-number change, including 7 regions of amplification (1q, 2q, 5q, 7q, 8q, 12p, and 20q) and 7 regions of deletion (1p, 3p, 4q, 6q, 8p, 9p, and 14q). An analysis aimed at identifying the relevant genes revealed VHL as one of three genes in the 3p deletion peak, CDKN2A and CDKN2B as the only genes in the 9p deletion peak, and MYC as the only gene in the 8q amplification peak. An integrated analysis to identify genes in amplification peaks that are consistently overexpressed among amplified samples confirmed MYC as a potential target of 8q amplification and identified candidate oncogenes in the other regions. A comparison of genomic profiles revealed that VHL disease-associated tumors are similar to a subgroup of sporadic tumors and thus more homogeneous overall. Sporadic tumors without evidence of biallelic VHL inactivation fell into two groups: one group with genomic profiles highly dissimilar to the majority of ccRCC and a second group with genomic profiles that are much more similar to tumors with biallelic inactivation of VHL.
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Affiliation(s)
- Rameen Beroukhim
- Departments of Medical Oncology, Harvard Medical School, Boston, Massachusetts, USA.
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Runx2-mediated activation of the Bax gene increases osteosarcoma cell sensitivity to apoptosis. Oncogene 2008; 27:3605-14. [PMID: 18223689 DOI: 10.1038/sj.onc.1211020] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The Runx family of transcription factors regulate cell growth and differentiation, and control the expression of target genes involved in cell fate decisions. We examined the role of the bone-related member of this family, Runx2, in regulating apoptosis via modulation of the Bcl2 family of genes in the osteosarcoma cell line Saos2. Our data demonstrate that Runx2 directly binds to two Runx-specific regulatory elements on the human bax promoter thereby inducing Bax expression. Furthermore, bone morphogenetic protein-induced or vector-mediated expression of Runx2 resulted in upregulation of Bax expression, and subsequent increased sensitivity of Saos2 cells to apoptosis. Finally, the observed upregulation of Bax expression and increased apoptosis were Runx2 dependent as Runx2 loss of function abrogated these effects. Our study provides the first evidence for Bax as a direct target of Runx2, suggesting that Runx2 may act as a proapoptotic factor in osteosarcoma cells.
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26
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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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