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O'Reilly ML, Wulf MJ, Connors TM, Jin Y, Bearoff F, Hai N, Bouyer J, Kortagere S, Zhong Y, Bethea JR, Tom VJ. NF-κB inhibition attenuates sympathetic hyperreflexia and concomitant development of autonomic dysreflexia and immune dysfunction after spinal cord injury. Commun Biol 2025; 8:787. [PMID: 40404889 PMCID: PMC12098895 DOI: 10.1038/s42003-025-08237-y] [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: 07/13/2024] [Accepted: 05/15/2025] [Indexed: 05/24/2025] Open
Abstract
Heightened sympathetic reflexes (sympathetic hyperreflexia, SH) post-high-level spinal cord injury (SCI) detrimentally impact effector organs, resulting in peripheral immune dysfunction and cardiovascular disease, two leading causes of morbidity and mortality in SCI. We previously found that an activated neuroimmune system after SCI contributes to intraspinal plasticity in the spinal sympathetic reflex (SSR) circuit, underlying SH. We hypothesize that activation of NF-κB, a key regulator of inflammation, in spinal cord below-SCI contributes to driving SSR circuit plasticity, resulting in SH-associated autonomic dysreflexia (AD) and peripheral immune dysfunction. Here, we demonstrate inhibition of central NF-κB signaling via intrathecal delivery of dimethylamino parthenolide (DMAPT) significantly decreases SH post-complete transection of thoracic spinal segment 3 in adult rats. This included reduced AD severity that was associated with decreased interneuron recruitment into the SSR circuit after SCI. We also observed intrathecal DMAPT-treatment improved survival post-SCI that corresponded with normalized numbers of splenic regulatory T-cells. These findings underscore central NF-κB signaling as a key component driving SH after SCI.
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Affiliation(s)
- Micaela L O'Reilly
- Department of Neurobiology and Anatomy, Marion Murray Spinal Cord Research Center, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Mariah J Wulf
- Department of Neurobiology and Anatomy, Marion Murray Spinal Cord Research Center, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Theresa M Connors
- Department of Neurobiology and Anatomy, Marion Murray Spinal Cord Research Center, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Ying Jin
- Department of Neurobiology and Anatomy, Marion Murray Spinal Cord Research Center, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Frank Bearoff
- Department of Neurology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Nan Hai
- School of Biomedical Engineering Science and Health Systems, Drexel University, Philadelphia, PA, USA
| | - Julien Bouyer
- Department of Neurobiology and Anatomy, Marion Murray Spinal Cord Research Center, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Sandhya Kortagere
- Department of Microbiology & Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Yinghui Zhong
- School of Biomedical Engineering Science and Health Systems, Drexel University, Philadelphia, PA, USA
| | - John R Bethea
- Department of Anatomy and Cell Biology, George Washington University, Washington, DC, USA
| | - Veronica J Tom
- Department of Neurobiology and Anatomy, Marion Murray Spinal Cord Research Center, Drexel University College of Medicine, Philadelphia, PA, USA.
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Ogikubo K, Nishida J, Takahashi-Yamashiro K, Morikawa M, Ehata S, Watabe T, Miyazono K, Koinuma D. OCT-2 Is Associated With Pro-Metastatic Epigenomic Properties of Triple-Negative Breast Cancer Cells. Cancer Sci 2025. [PMID: 40364745 DOI: 10.1111/cas.70093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Revised: 04/18/2025] [Accepted: 04/26/2025] [Indexed: 05/15/2025] Open
Abstract
Triple-negative breast cancer (TNBC) is a malignant type of breast cancer. Owing to the lack of expression of receptors that serve as molecular targets for standard therapy for breast cancer, conventional cytotoxic chemotherapy is the primary treatment option for TNBC. However, TNBC exhibits a high degree of genomic heterogeneity, rendering it resistant to chemotherapy. Therefore, there is an urgent need to identify novel therapeutic targets for the treatment of TNBC. Advances in massively parallel sequencing technology have enabled the identification of cancer cell-specific gene expression patterns and epigenetic alterations that regulate their expression. Cancer cell-specific super-enhancers (SEs) have been identified as effective therapeutic targets for cancer. In this study, we identified the functional roles of epigenetic changes and their regulatory mechanisms in TNBC cells. TNBC cell-specific SEs were formed near several genes that contribute to malignant cancer cell acquisition. We found that the transcription factor OCT-2 (encoded by POU2F2) was responsible for the formation of SEs and the expression of genes encoded in the vicinity of the SE regions. Overexpression of POU2F2 enhances the metastasis of TNBC cells in mice, and its expression is highly correlated to poor prognosis of TNBC patients. Our findings provide a new insight into cancer cell-specific epigenetic changes induced by OCT-2, which trigger the progression of TNBC, and suggest possible candidates that could be targeted for the treatment of TNBC.
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Affiliation(s)
- Kazuki Ogikubo
- Department of Applied Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Jun Nishida
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA
- Department of Medicine, Harvard Medical School, Boston, USA
| | - Kei Takahashi-Yamashiro
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Chemistry, Faculty of Science, University of Alberta, Alberta, Canada
- Laboratory for Cancer Invasion and Metastasis, Institute for Medical Sciences, Yokohama, Japan
| | - Masato Morikawa
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Advanced Comprehensive Research Organization, Teikyo University, Tokyo, Japan
| | - Shogo Ehata
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Pathology, Wakayama Medical University, Wakayama, Japan
| | - Tetsuro Watabe
- Department of Biochemistry, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
| | - Kohei Miyazono
- Department of Applied Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Laboratory for Cancer Invasion and Metastasis, Institute for Medical Sciences, Yokohama, Japan
| | - Daizo Koinuma
- Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Hossain ME, Li H, Li Y, Zhang S, Wang X, Li B, Liu Y. Upregulation of PREX1 Expression by POU2F2 Promotes the Malignant Progression of Acute Myeloid Leukemia via the mTOR Pathway. J Biochem Mol Toxicol 2025; 39:e70286. [PMID: 40317800 DOI: 10.1002/jbt.70286] [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: 07/09/2024] [Revised: 01/19/2025] [Accepted: 04/23/2025] [Indexed: 05/07/2025]
Abstract
Acute myeloid leukemia (AML) is a hematologic neoplasm with heterologous cytology and short-term prognosis. In varying cancers, PREX1 and POU2F2 serve as oncogenes, but whether it influences AML malignant progression is elusive. This project attempted to unravel the influence of PREX1 and POU2F2 on AML malignant progression. Bioinformatics analysis of differential mRNAs in AML was carried out to identify target genes and predict upstream regulatory molecules. Bioinformatics analyzed PREX1 and POU2F2 expressions in AML. Kyoto Encyclopedia of Genes and Genomes (KEGG) analyzed the enriched pathway of PREX1. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was applied to examine the expressions of PREX1 and POU2F2. Dual-luciferase and Chromatin immunoprecipitation (ChIP) assays were applied to prove the regulatory relationship between PREX1 and POU2F2. Protein expression levels of POU2F2, PREX1, and mTOR in AML cells were examined by Western blot (WB). AML cell proliferation and viability were examined by colony formation assays and CCK-8, respectively. By Transwell assay, we assessed AML cell invasion and migration. The influence of the POU2F2/PREX1 axis on AML was evaluated by a xenograft tumor model. PREX1 was substantially upregulated in AML and enriched in the mTOR pathway. PREX1 knockdown noticeably hampered the proliferation, invasion, and migration of AML cells. Bioinformatics analysis unveiled that POU2F2, a potential upstream transcription factor (TF) of PREX1, was upregulated in AML cells. Dual-luciferase and ChIP proved the binding of PREX1 promoter region to POU2F2. In vivo and In Vitro experiments uncovered that PREX1 knockdown reversed the promoting influence conferred by POU2F2 overexpression on the mTOR pathway as well as the malignant progression of AML cells. POU2F2 modulates the mTOR pathway by upregulating the expression of PREX1 to stimulate the malignant progression of AML cells, suggesting POU2F2 and PREX1 as likely targets for AML therapy.
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Affiliation(s)
- Md Eamran Hossain
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Huanhuan Li
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yingcai Li
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Sidong Zhang
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaoyi Wang
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Bai Li
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yufeng Liu
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Shi H, Wang W, Luo J, Song G, Han R. POU2F2 + B cells enhance antitumor immunity and predict better survival in non small cell lung cancer. Sci Rep 2025; 15:6549. [PMID: 39994401 PMCID: PMC11850725 DOI: 10.1038/s41598-025-90817-3] [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: 08/17/2024] [Accepted: 02/17/2025] [Indexed: 02/26/2025] Open
Abstract
Immune checkpoint inhibitors are an effective adjuvant therapy for non-small cell lung cancer (NSCLC). Recent studies have highlighted the critical role of tumor-infiltrating B cells in tumor immunity. However, research specifically focusing on B cells in NSCLC is limited. This study aims to elucidate the role of POU2F2+ B cells in patient survival and immune cell infiltration in NSCLC. Pseudotime analysis was performed to identify B cell pseudotime-related gene sets from two single-cell RNA sequencing (scRNA-seq) datasets of NSCLC. Differentially expressed genes (DEGs) were identified from two NSCLC immunotherapy-related bulk RNA sequencing datasets. A Venn diagram was used to determine core genes shared between these datasets. Kaplan-Meier survival curves were utilized to analyze overall survival (OS). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed based on the differential genes between POU2F2+ and POU2F2- B cells. CIBERSORT analysis was conducted to compare the proportions of immune cell subpopulations between groups. Multiplex immunohistochemistry (mIHC) was used to localize POU2F2+ cells and measure distances between different immune cells. Three hallmark genes, POU2F2, CD2, and CST7, were identified as being associated with B cell maturation and immunotherapy efficacy in NSCLC. High expression of POU2F2 was associated with poorer OS in both LUAD and LUSC. However, the POU2F2+ B cell score specifically correlated with the OS of LUAD but not with LUSC. Further analysis using scRNA-seq and mIHC methods revealed that POU2F2 is predominantly expressed in B cells. In LUAD tumor tissues, POU2F2+ CD20+ B cells were spatially further from PD-1+ CD8+ T cells and CD206+ CD68+ macrophages compared to POU2F2- CD20+ B cells. In LUSC tumor tissues, POU2F2+ CD20+ B cells were spatially further from CD206+ CD68+ macrophages but showed no significant spatial difference from PD-1+ CD8+ T cells compared to POU2F2- CD20+ B cells. In patients with high POU2F2+ B cell scores, LUAD tissues showed an increased proportion of CD8+ T cells and M1 macrophages, and a decreased proportion of M2 macrophages. In contrast, in LUSC tissues, a high POU2F2+ B cell score was associated only with an increased proportion of M1 macrophages, with no significant differences in the proportions of CD8+ T cells or M2 macrophages between groups. This study elucidates the significant role of POU2F2+ B cells in influencing survival and immune cell infiltration in NSCLC. Our findings highlight POU2F2 as a novel target for NSCLC immunotherapy. Targeting POU2F2 may modulate the tumor immune microenvironment, enhance the infiltration and activity of critical immune cells, and ultimately improve patient survival.
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Affiliation(s)
- Hengchuan Shi
- Department of Laboratory Medicine, Jiangsu Province Geriatric Hospital, Geriatric Hospital of Nanjing Medical University, Nanjing, 210009, Jiangsu, China
| | - Wenqing Wang
- Department of Laboratory Medicine, Jiangsu Province Geriatric Hospital, Geriatric Hospital of Nanjing Medical University, Nanjing, 210009, Jiangsu, China
| | - Jun Luo
- Department of Central Laboratory, Jiangsu Health Vocational College, Nanjing, 210009, Jiangsu, China
| | - Guoxin Song
- Department of Pathology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210009, Jiangsu, China.
| | - Rongbo Han
- Department of Oncology, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 210009, Jiangsu, China.
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Gao W, Ma Y. Expression and Function of FAM72A Gene in Multiple MyelomaFAM72A. Curr Pharm Biotechnol 2025; 26:455-464. [PMID: 39129160 DOI: 10.2174/0113892010311258240729080309] [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: 02/19/2024] [Revised: 05/17/2024] [Accepted: 05/23/2024] [Indexed: 08/13/2024]
Abstract
AIMS This study aims to comprehensively investigate the role of Family Member A with sequence similarity 72-A (FAM72A) in multiple myeloma. BACKGROUND Multiple myeloma poses significant challenges. This study delves into FAM72A's impact on key cellular processes, shedding light on potential therapeutic targets and enhancing our understanding of multiple myeloma progression. OBJECTIVES Investigate the impact of FAM72A on the proliferation, apoptosis, and bortezomib sensitivity of multiple myeloma cell line U266. METHODS qRT-PCR analyzed FAM72A expression levels in bone marrow samples from 30 patients with multiple myeloma and 10 healthy donors at the Second Hospital of Shanxi Medical University. Cell lines overexpressing FAM72A were constructed, and Cell Counting Kit 8 (CCK-8) and flow cytometry were used to assess U266 cell proliferation, apoptosis, and sensitivity to bortezomib. Biological predictions for FAM72A were performed to find transcription factors binding to the FAM72A promoter region, verified using a luciferase assay. U266 cells were transfected with si-POU2F2 (POU class 2 homeobox 2), and the impact on cell proliferation was validated. Western blot analysis detected the expression of downstream proteins in the p53 signaling pathway. In vivo, experiments established a xenograft mouse model further to study the role of FAM72A in multiple myeloma. RESULTS FAM72A was upregulated in multiple myeloma bone marrow tissues. Compared to the OE-NC group, the OE-FAM72A group showed increased Mouse Double Minute 2 homolog (MDM2) expression, decreased p53 expression, increased cell proliferation, and decreased apoptosis. POU2F2 was identified as the upstream transcription factor for FAM72A. Compared to the si-NC group, the si-POU2F2 group exhibited decreased MDM2 expression, increased p53 expression, slowed cell proliferation, and increased apoptosis. Silencing POU2F2 could reverse the pro-proliferative effect of over-expressing FAM72A in U266 cells. In vivo experiments in a xenograft mouse model further studied the role of FAM72A in multiple myeloma. CONCLUSION Overexpression of FAM72A promotes U266 cell proliferation, inhibits apoptosis, and reduces sensitivity to bortezomib by regulating the POU2F2/FAM72A/p53 signaling pathway.
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Affiliation(s)
- Wenyu Gao
- Second Clinical Medical College, Shanxi Medical University, No.56, Xinjian South Road, Taiyuan City, Shanxi Province, 030000, China
| | - Yanping Ma
- Second Clinical Medical College, Shanxi Medical University, No.56, Xinjian South Road, Taiyuan City, Shanxi Province, 030000, China
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Markouli M, Papachristou A, Politis A, Boviatsis E, Piperi C. Emerging Role of the Slit/Roundabout (Robo) Signaling Pathway in Glioma Pathogenesis and Potential Therapeutic Options. Biomolecules 2024; 14:1231. [PMID: 39456164 PMCID: PMC11506736 DOI: 10.3390/biom14101231] [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: 07/31/2024] [Revised: 09/20/2024] [Accepted: 09/27/2024] [Indexed: 10/28/2024] Open
Abstract
Gliomas represent the most common primary Central Nervous System (CNS) tumors, characterized by increased heterogeneity, dysregulated intracellular signaling, extremely invasive properties, and a dismal prognosis. They are generally resistant to existing therapies and only a few molecular targeting options are currently available. In search of signal transduction pathways with a potential impact in glioma growth and immunotherapy, the Slit guidance ligands (Slits) and their Roundabout (Robo) family of receptors have been revealed as key regulators of tumor cells and their microenvironment. Recent evidence indicates the implication of the Slit/Robo signaling pathway in inflammation, cell migration, angiogenesis, and immune cell infiltration of gliomas, suppressing or promoting the expression of pivotal proteins, such as cell adhesion molecules, matrix metalloproteinases, interleukins, angiogenic growth factors, and immune checkpoints. Herein, we discuss recent data on the significant implication of the Slit/Robo signaling pathway in glioma pathology along with the respective targeting options, including immunotherapy, monoclonal antibody therapy, and protein expression modifiers.
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Affiliation(s)
- Mariam Markouli
- Department of Biological Chemistry, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece (A.P.); (A.P.)
- Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA 02118, USA
| | - Athina Papachristou
- Department of Biological Chemistry, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece (A.P.); (A.P.)
| | - Anastasios Politis
- Department of Biological Chemistry, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece (A.P.); (A.P.)
- Second Department of Neurosurgery, “Attikon” University Hospital, National and Kapodistrian University of Athens, 15772 Athens, Greece;
| | - Efstathios Boviatsis
- Second Department of Neurosurgery, “Attikon” University Hospital, National and Kapodistrian University of Athens, 15772 Athens, Greece;
| | - Christina Piperi
- Department of Biological Chemistry, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece (A.P.); (A.P.)
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Liu T, Feng YL, Wang RY, Yang S, Ge YL, Zhang TY, Li J, Li CY, Ruan Y, Luo B, Liang GY. Long-term MNNG exposure promotes gastric carcinogenesis by activating METTL3/m6A/miR1184 axis-mediated epithelial-mesenchymal transition. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 913:169752. [PMID: 38163601 DOI: 10.1016/j.scitotenv.2023.169752] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/12/2023] [Accepted: 12/26/2023] [Indexed: 01/03/2024]
Abstract
As the representative item of environmental chemical carcinogen, MNNG was closely associated with the onset of Gastric cancer (GC), while the underlying mechanisms remain largely unknown. Here, we comprehensively analyzed the potential clinical significance of METTL3 in multiple GC patient cohorts. Additionally, we demonstrated that long-term exposure to MNNG elevated METTL3 and EMT marker expression by in vitro and in vivo models. Furthermore, the depletion of METTL3 impacted the proliferation, migration, invasion, and tumorigenesis of MNNG malignant transformation cells and GC cells. By me-RIP sequencing, we identified a panel of vital miRNAs potentially regulated by METTL3 that aberrantly expressed in MNNG-induced GC cells. Mechanistically, we showed that METTL3 meditated miR-1184/TRPM2 axis by regulating the process of miRNA-118. Our results provide novel insights into critical epigenetic molecular events vital to MNNG-induced gastric carcinogenesis. These findings suggest the potential therapeutic targets of METTL3 for GC treatment.
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Affiliation(s)
- Tong Liu
- Institute of Occupational Health and Environmental Health, School of Public Health, Lanzhou University, Lanzhou, Gansu, PR China; Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, PR China
| | - Yan-Lu Feng
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, PR China
| | - Rui-Ying Wang
- Gansu Provincial Center for Disease Prevention and Control, Lanzhou, Gansu 730000, PR China
| | - Sheng Yang
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, PR China
| | - Yi-Ling Ge
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, PR China
| | - Tian-Yi Zhang
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, PR China
| | - Jie Li
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, PR China
| | - Cheng-Yun Li
- Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou, Gansu 730000, PR China
| | - Ye Ruan
- Institute of Occupational Health and Environmental Health, School of Public Health, Lanzhou University, Lanzhou, Gansu, PR China
| | - Bin Luo
- Institute of Occupational Health and Environmental Health, School of Public Health, Lanzhou University, Lanzhou, Gansu, PR China
| | - Ge-Yu Liang
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, PR China.
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Gao X, Li S, Wang W, Zhang X, Yu X, Fan C, Li W, Yang C, Wang L, Ji Q. Caspase-3 and gasdermin E mediate macrophage pyroptosis in periodontitis. J Periodontal Res 2024; 59:140-150. [PMID: 37885312 DOI: 10.1111/jre.13197] [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: 08/11/2023] [Revised: 10/09/2023] [Accepted: 10/12/2023] [Indexed: 10/28/2023]
Abstract
BACKGROUND AND OBJECTIVES Periodontitis is a chronic inflammatory disease linked to pyroptosis, an inflammatory cell death process. Macrophages are essential for maintaining microenvironment homeostasis, which is crucial for periodontal health. This study explores the mechanisms underlying the relationship between macrophage pyroptosis and periodontitis. METHODS Expression of the pyroptosis marker gasdermin E (GSDME) and the macrophage surface marker CD68 was examined by immunofluorescence double staining in healthy and periodontitis gingival tissues. In an in vitro pyroptosis model, RAW264.7 cells were irritated using Porphyromonas gingivalis-lipopolysaccharide (P. gingivalis-LPS) after treatment with either a nuclear factor kappa-B (NF-κB) agonist or inhibitor. The mRNA and protein levels of NF-κB, caspase-3, GSDME, and interleukin-1β (IL-1β) were evaluated through qRT-PCR, western blotting, and ELISA techniques. RESULTS GSDME and CD68 were heavily elevated in inflamed gingival tissues compared to healthy tissues and co-localized in the same region. Furthermore, exposure to P. gingivalis-LPS resulted in a significant upregulation of NF-κB, caspase-3, GSDME, and IL-1β at both the mRNA and protein levels in RAW264.7 cells. NF-κB agonist or inhibitor pretreatment enhanced or inhibited these effects. CONCLUSIONS GSDME-mediated macrophage pyroptosis is implicated in periodontitis. Based on in vitro experiments, P. gingivalis-LPS causes pyroptosis in RAW264.7 cells through the caspase-3/GSDME pathway. Furthermore, NF-κB regulates this pyroptotic pathway.
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Affiliation(s)
- Xiangru Gao
- Department of Periodontology, The Affiliated Hospital of Qingdao University, Qingdao, China
- School of Stomatology, Qingdao University, Qingdao, China
| | - Shuhan Li
- Department of Periodontology, The Affiliated Hospital of Qingdao University, Qingdao, China
- School of Stomatology, Qingdao University, Qingdao, China
| | - Wenxuan Wang
- Department of Stomatology, Qingdao West Coast New Area Central Hospital, Qingdao, China
| | - Xiangyan Zhang
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xinbo Yu
- Department of Periodontology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Chun Fan
- Department of Periodontology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wei Li
- Department of Periodontology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Caixiu Yang
- Department of Periodontology, The Affiliated Hospital of Qingdao University, Qingdao, China
- School of Stomatology, Qingdao University, Qingdao, China
| | - Lei Wang
- Department of Periodontology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qiuxia Ji
- Department of Periodontology, The Affiliated Hospital of Qingdao University, Qingdao, China
- School of Stomatology, Qingdao University, Qingdao, China
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Wang T, Wagner RT, Hlady RA, Pan X, Zhao X, Kim S, Wang L, Lee J, Luo H, Castle EP, Lake DF, Ho TH, Robertson KD. SETD2 loss in renal epithelial cells drives epithelial-to-mesenchymal transition in a TGF-β-independent manner. Mol Oncol 2024; 18:44-61. [PMID: 37418588 PMCID: PMC10766198 DOI: 10.1002/1878-0261.13487] [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: 04/21/2023] [Revised: 05/25/2023] [Accepted: 07/04/2023] [Indexed: 07/09/2023] Open
Abstract
Histone-lysine N-methyltransferase SETD2 (SETD2), the sole histone methyltransferase that catalyzes trimethylation of lysine 36 on histone H3 (H3K36me3), is often mutated in clear cell renal cell carcinoma (ccRCC). SETD2 mutation and/or loss of H3K36me3 is linked to metastasis and poor outcome in ccRCC patients. Epithelial-to-mesenchymal transition (EMT) is a major pathway that drives invasion and metastasis in various cancer types. Here, using novel kidney epithelial cell lines isogenic for SETD2, we discovered that SETD2 inactivation drives EMT and promotes migration, invasion, and stemness in a transforming growth factor-beta-independent manner. This newly identified EMT program is triggered in part through secreted factors, including cytokines and growth factors, and through transcriptional reprogramming. RNA-seq and assay for transposase-accessible chromatin sequencing uncovered key transcription factors upregulated upon SETD2 loss, including SOX2, POU2F2 (OCT2), and PRRX1, that could individually drive EMT and stemness phenotypes in SETD2 wild-type (WT) cells. Public expression data from SETD2 WT/mutant ccRCC support the EMT transcriptional signatures derived from cell line models. In summary, our studies reveal that SETD2 is a key regulator of EMT phenotypes through cell-intrinsic and cell-extrinsic mechanisms that help explain the association between SETD2 loss and ccRCC metastasis.
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Affiliation(s)
- Tianchu Wang
- Molecular Pharmacology and Experimental Therapeutics Graduate Program, Mayo Clinic Graduate School of Biomedical SciencesMayo ClinicRochesterMNUSA
- Department of Molecular Pharmacology and Experimental TherapeuticsMayo ClinicRochesterMNUSA
| | - Ryan T. Wagner
- Department of Molecular Pharmacology and Experimental TherapeuticsMayo ClinicRochesterMNUSA
| | - Ryan A. Hlady
- Department of Molecular Pharmacology and Experimental TherapeuticsMayo ClinicRochesterMNUSA
| | - Xiaoyu Pan
- Department of Molecular Pharmacology and Experimental TherapeuticsMayo ClinicRochesterMNUSA
| | - Xia Zhao
- Department of Molecular Pharmacology and Experimental TherapeuticsMayo ClinicRochesterMNUSA
| | - Sungho Kim
- Department of Molecular Pharmacology and Experimental TherapeuticsMayo ClinicRochesterMNUSA
| | - Liguo Wang
- Division of Biomedical Statistics and Informatics, Department of Health Science ResearchMayo ClinicRochesterMNUSA
| | - Jeong‐Heon Lee
- Epigenomics Development LaboratoryMayo ClinicRochesterMNUSA
- Department of Laboratory Medicine and PathologyMayo ClinicRochesterMNUSA
| | - Huijun Luo
- Division of Hematology and OncologyMayo Clinic ArizonaPhoenixAZUSA
| | | | | | - Thai H. Ho
- Division of Hematology and OncologyMayo Clinic ArizonaPhoenixAZUSA
| | - Keith D. Robertson
- Department of Molecular Pharmacology and Experimental TherapeuticsMayo ClinicRochesterMNUSA
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10
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Giriyappagoudar M, Vastrad B, Horakeri R, Vastrad C. Identification and Interaction Analysis of Molecular Markers in Pancreatic Ductal Adenocarcinoma by Bioinformatics and Next-Generation Sequencing Data Analysis. Bioinform Biol Insights 2023; 17:11779322231186719. [PMID: 37529485 PMCID: PMC10387711 DOI: 10.1177/11779322231186719] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 06/18/2023] [Indexed: 08/03/2023] Open
Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most common cancers worldwide. Intense efforts have been made to elucidate the molecular pathogenesis, but the molecular mechanisms of PDAC are still not well understood. The purpose of this study is to further explore the molecular mechanism of PDAC through integrated bioinformatics analysis. Methods To identify the candidate genes in the carcinogenesis and progression of PDAC, next-generation sequencing (NGS) data set GSE133684 was downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified, and Gene Ontology (GO) and pathway enrichment analyses were performed. The protein-protein interaction network (PPI) was constructed and the module analysis was performed using Integrated Interactions Database (IID) interactome database and Cytoscape. Subsequently, miRNA-DEG regulatory network and TF-DEG regulatory network were constructed using miRNet database, NetworkAnalyst database, and Cytoscape software. The expression levels of hub genes were validated based on Kaplan-Meier analysis, expression analysis, stage analysis, mutation analysis, protein expression analysis, immune infiltration analysis, and receiver operating characteristic (ROC) curve analysis. Results A total of 463 DEGs were identified, consisting of 232 upregulated genes and 233 downregulated genes. The enriched GO terms and pathways of the DEGs include vesicle organization, secretory vesicle, protein dimerization activity, lymphocyte activation, cell surface, transferase activity, transferring phosphorus-containing groups, hemostasis, and adaptive immune system. Four hub genes (namely, cathepsin B [CCNB1], four-and-a-half LIM domains 2 (FHL2), major histocompatibility complex, class II, DP alpha 1 (HLA-DPA1) and tubulin beta 1 class VI (TUBB1)) were obtained via taking interaction of different analysis results. Conclusions On the whole, the findings of this investigation enhance our understanding of the potential molecular mechanisms of PDAC and provide potential targets for further investigation.
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Affiliation(s)
| | - Basavaraj Vastrad
- Department of Pharmaceutical Chemistry, K.L.E. Society’s College of Pharmacy, Gadag, India
| | - Rajeshwari Horakeri
- Department of Computer Science, Government First Grade College, Hubballi, India
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11
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Lu G, Du R, Dong J, Sun Y, Zhou F, Feng F, Feng B, Han Y, Shang Y. Cancer associated fibroblast derived SLIT2 drives gastric cancer cell metastasis by activating NEK9. Cell Death Dis 2023; 14:421. [PMID: 37443302 PMCID: PMC10344862 DOI: 10.1038/s41419-023-05965-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 06/29/2023] [Accepted: 07/06/2023] [Indexed: 07/15/2023]
Abstract
The secretory properties of cancer-associated fibroblasts (CAFs) play predominant roles in shaping a pro-metastatic tumor microenvironment. The present study demonstrated that SLIT2, an axon guidance protein, produced by CAFs and promoted gastric cancer (GC) metastasis in two gastric cancer cell lines (AGS and MKN45) by binding to roundabout guidance receptor 1 (ROBO1). Mass-spectrometry analysis revealed that ROBO1 could interact with NEK9, a serine/threonine kinase. And their mutual binding activities were further enhanced by SLIT2. Domain analysis revealed the kinase domain of NEK9 was critical in its interaction with the intracellular domain (ICD) of ROBO1, and it also directly phosphorylated tripartite motif containing 28 (TRIM28) and cortactin (CTTN) in AGS and MKN45 cells. TRIM28 function as a transcriptional elongation factor, which directly facilitate CTTN activation. In addition, Bioinformatics analysis and experimental validation identified transcriptional regulation of STAT3 and NF-κB p100 by TRIM28, and a synergetic transcription of CTTN by STAT3 and NF-κB p100 was also observed in AGS and MKN45. Therefore, CAF-derived SLIT2 increased the expression and phosphorylation levels of CTTN, which induced cytoskeletal reorganization and GC cells metastasis. A simultaneous increase in the expression levels of NEK9, TRIM28 and CTTN was found in metastatic GC lesions compared with paired non-cancerous tissues and primary cancer lesions via IHC and Multiplex IHC. The analysis of the data from a cohort of patients with GC revealed that increased levels of NEK9, TRIM28 and CTTN were associated with a decreased overall survival rate. On the whole, these findings revealed the connections of CAFs and cancer cells through SLIT2/ROBO1 and inflammatory signaling, and the key molecules involved in this process may serve as potential biomarkers and therapeutic targets for GC.
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Affiliation(s)
- Guofang Lu
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China
- Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi'an, 710032, China
| | - Rui Du
- Institute for Biomedical Sciences of Pain, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Jiaqiang Dong
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China
| | - Yi Sun
- Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Fenli Zhou
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China
| | - Fan Feng
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China
| | - Bin Feng
- Department of Radiation Oncology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
| | - Ying Han
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China.
| | - Yulong Shang
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China.
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12
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Martínez-Zamudio RI, Stefa A, Nabuco Leva Ferreira Freitas JA, Vasilopoulos T, Simpson M, Doré G, Roux PF, Galan MA, Chokshi RJ, Bischof O, Herbig U. Escape from oncogene-induced senescence is controlled by POU2F2 and memorized by chromatin scars. CELL GENOMICS 2023; 3:100293. [PMID: 37082139 PMCID: PMC10112333 DOI: 10.1016/j.xgen.2023.100293] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 01/13/2023] [Accepted: 03/02/2023] [Indexed: 04/22/2023]
Abstract
Although oncogene-induced senescence (OIS) is a potent tumor-suppressor mechanism, recent studies revealed that cells could escape from OIS with features of transformed cells. However, the mechanisms that promote OIS escape remain unclear, and evidence of post-senescent cells in human cancers is missing. Here, we unravel the regulatory mechanisms underlying OIS escape using dynamic multidimensional profiling. We demonstrate a critical role for AP1 and POU2F2 transcription factors in escape from OIS and identify senescence-associated chromatin scars (SACSs) as an epigenetic memory of OIS detectable during colorectal cancer progression. POU2F2 levels are already elevated in precancerous lesions and as cells escape from OIS, and its expression and binding activity to cis-regulatory elements are associated with decreased patient survival. Our results support a model in which POU2F2 exploits a precoded enhancer landscape necessary for senescence escape and reveal POU2F2 and SACS gene signatures as valuable biomarkers with diagnostic and prognostic potential.
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Affiliation(s)
- Ricardo Iván Martínez-Zamudio
- Center for Cell Signaling, Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
- Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, USA
| | - Alketa Stefa
- Center for Cell Signaling, Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
- Graduate School of Biomedical and Health Sciences, Rutgers University, Newark, NJ 07103 USA
| | - José Américo Nabuco Leva Ferreira Freitas
- Sorbonne Université, UMR 8256, Biological Adaptation and Ageing – IBPS, 75005 Paris, France
- INSERM U1164, 75005 Paris, France
- IMRB, Mondor Institute for Biomedical Research, INSERM U955 – Université Paris Est Créteil, UPEC, Faculté de Médecine de Créteil 8, rue du Général Sarrail, 94010 Créteil, France
| | - Themistoklis Vasilopoulos
- Center for Cell Signaling, Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
- Graduate School of Biomedical and Health Sciences, Rutgers University, Newark, NJ 07103 USA
| | - Mark Simpson
- Center for Cell Signaling, Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
| | - Gregory Doré
- Institut Pasteur, Plasmodium RNA Biology Unit, 25 Rue du Docteur Roux, 75724 Cedex 15 Paris, France
| | - Pierre-François Roux
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut Régional du Cancer de Montpellier, Montpellier, France
| | - Mark A. Galan
- Department of Pathology and Laboratory Medicine, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
| | - Ravi J. Chokshi
- Department of Surgery, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
| | - Oliver Bischof
- IMRB, Mondor Institute for Biomedical Research, INSERM U955 – Université Paris Est Créteil, UPEC, Faculté de Médecine de Créteil 8, rue du Général Sarrail, 94010 Créteil, France
| | - Utz Herbig
- Center for Cell Signaling, Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA
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13
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Genome-wide CRISPR knockout screening identified G protein pathway suppressor 2 as a novel tumor suppressor for uveal melanoma metastasis. J Cancer Res Clin Oncol 2022:10.1007/s00432-022-04160-5. [PMID: 35941228 DOI: 10.1007/s00432-022-04160-5] [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: 05/05/2022] [Accepted: 06/16/2022] [Indexed: 10/15/2022]
Abstract
PURPOSE Uveal melanoma (UM) is the most common intraocular malignant tumor in adults. Due to the lack of effective treatments for metastatic UM, the survival of UM has not changed over the past 3 decades. Therefore, it is important to identify essential genes regulating the metastasis of UM. METHODS In this study, a genome-wide CRISPR knockout screen in an orthotopic mouse model of UM was performed to identify the regulatory genes conferring the metastatic phenotype. Loss-of-function analyses were performed to explore the function of G protein pathway suppressor 2 (GPS2) in UM metastasis in vitro and in vivo. RNA sequencing was performed to investigate the molecular mechanism underlying the function of GPS2 as a tumor suppressor in UM. RESULTS Among the highest-ranking genes, we found several validated tumor suppressors, such as SHPRH, GPS2, PRPH2, and hsa-mir-1229; GPS2 was chosen as the candidate gene for further studies. GPS2 was lower expressed in the tumor tissues of UM patients. Furthermore, knocking-down GPS2 promoted the proliferation and metastatic abilities of UM cells both in vivo and in vitro. Finally, analysis of the transcriptome data revealed that silencing GPS2 upregulates oncogenic signaling pathways MAPK and PI3K-Akt, and in the meantime downregulates tumor suppressor signaling pathway Slit/Robo in UM cells. CONCLUSION Altogether, our study proved that the GPS2 gene functions as a tumor suppressor and might be a novel potential therapeutic target for UM treatment.
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Su Z, Bao W, Yang G, Liu J, Zhao B. SOX12 Promotes Thyroid Cancer Cell Proliferation and Invasion by Regulating the Expression of POU2F1 and POU3F1. Yonsei Med J 2022; 63:591-600. [PMID: 35619584 PMCID: PMC9171662 DOI: 10.3349/ymj.2022.63.6.591] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 01/26/2022] [Accepted: 02/09/2022] [Indexed: 11/27/2022] Open
Abstract
PURPOSE SOX12 is overexpressed in many cancers, and we aimed to explore the biological function and mechanism of SOX12 in thyroid cancer. MATERIALS AND METHODS We first analyzed the expression of SOX12 in thyroid cancer using data in The Cancer Genome Atlas. Immunohistochemistry and qRT-PCR were performed to identify SOX12 expression in thyroid cancer tissue and cells. Thyroid cancer cells were transfected with small interfering RNA targeting SOX12, and cellular functional experiments, including CCK8, wound healing, and Transwell assays, were performed. Protein expression was examined by Western blot analysis. A xenograft model was developed to evaluate the effect of SOX12 on tumor growth in vivo. RESULTS SOX12 expression was increased in thyroid cancer tissue and cells. SOX12 promoted cell proliferation, migration, and invasion and accelerated tumor growth in vivo. The expression of PCNA, Cyclin D1, E-cadherin, Snail, MMP-2, and MMP-9 was affected by SOX12 knockdown. Bioinformatic analysis showed that SOX12 could interact with the POU family. SOX12 knockdown inhibited the expression of POU2F1, POU2F2, POU3F1 and POU3F2, and SOX12 expression showed a positive correlation with POU2F1, POU3F1, and POU3F2 expression in clinical data. POU2F1 and POU3F1 were able to reverse the effect of SOX12 knockdown on thyroid cancer cells. CONCLUSION SOX12 affects the progression of thyroid cancer by regulating epithelial-mesenchymal transition and interacting with POU2F1 and POU3F1, which may be novel targets for thyroid cancer molecular therapy.
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Affiliation(s)
- Zhenxi Su
- Department of General Surgery, Shanghai Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wenqing Bao
- Department of General Surgery, Shanghai Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guanghua Yang
- Department of General Surgery, Shanghai Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jianping Liu
- Department of General Surgery, Shanghai Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Bin Zhao
- Department of General Surgery, Shanghai Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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15
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Xu L, Li J, Tursun M, Hai Y, Tursun H, Mamtimin B, Hasim A. Receptor for activated C kinase 1 promotes cervical cancer lymph node metastasis via the glycolysis‑dependent AKT/mTOR signaling. Int J Oncol 2022; 61:83. [PMID: 35616137 PMCID: PMC9162043 DOI: 10.3892/ijo.2022.5373] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 05/06/2022] [Indexed: 12/01/2022] Open
Abstract
Cervical cancer (CC), an aggressive form of squamous cell carcinoma, is characterized by early-stage lymph node metastasis and an extremely poor prognosis. The authors have previously demonstrated that patients with CC have aberrant glycolysis. The upregulation of receptor for activated C kinase 1 (RACK1) is associated with CC lymph node metastasis (LNM). However, its role in mediating aerobic glycolysis in CC LNM remains unclear. In the present study, 1H nuclear magnetic resonance analysis revealed a significant association between RACK1 expression and the glycolysis/gluconeogenesis pathway. Additionally, RACK1 knockdown inhibited aerobic glycolysis and lymphangiogenesis in vitro and suppressed CC LNM in vivo. Furthermore, protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling was identified as a critical RACK1-regulated pathway that increased lymphangiogenesis in CC. Co-immunoprecipitation, immunofluorescence and western blot analysis revealed that RACK1 activated AKT/mTOR signaling by interacting with insulin-like growth factor 1 receptor (IGF1R). POU class 2 homeobox 2 (POU2F2) bound to the RACK1 promoter and regulated its transcription, thereby functionally contributing to glycolysis and lymphangiogenesis in CC. Of note, the admin-istration of 2-deoxy-D-glucose, which attenuates glycolysis, inhibited RACK1-induced lymphangiogenesis in CC. The correlations between RACK1, IGF1R, POU2F2 and hexokinase 2 were further confirmed in CC tissues. Thus, RACK1 plays a crucial role in CC tumor LNM by regulating glycolysis via IGF1R/AKT/mTOR signaling. Thus, the targeting of the POU2F2/RACK1/IGF1R/AKT/mTOR signaling pathway may provide a novel treatment strategy for CC.
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Affiliation(s)
- Lixiu Xu
- Department of Basic Medicine, Xinjiang Medical University and Xinjiang Key Laboratory of Molecular Biology of Endemic Diseases, Urumqi, Xinjiang 830017, P.R. China
| | - Jinqiu Li
- Department of Basic Medicine, Xinjiang Medical University and Xinjiang Key Laboratory of Molecular Biology of Endemic Diseases, Urumqi, Xinjiang 830017, P.R. China
| | - Mikrban Tursun
- Department of Basic Medicine, Xinjiang Medical University and Xinjiang Key Laboratory of Molecular Biology of Endemic Diseases, Urumqi, Xinjiang 830017, P.R. China
| | - Yan Hai
- Department of Basic Medicine, Xinjiang Medical University and Xinjiang Key Laboratory of Molecular Biology of Endemic Diseases, Urumqi, Xinjiang 830017, P.R. China
| | - Hatila Tursun
- Department of Basic Medicine, Xinjiang Medical University and Xinjiang Key Laboratory of Molecular Biology of Endemic Diseases, Urumqi, Xinjiang 830017, P.R. China
| | - Batur Mamtimin
- Department of Pharmacy, Xinjiang Medical University, Urumqi, Xinjiang 830017, P.R. China
| | - Ayshamgul Hasim
- Department of Basic Medicine, Xinjiang Medical University and Xinjiang Key Laboratory of Molecular Biology of Endemic Diseases, Urumqi, Xinjiang 830017, P.R. China
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16
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Tompkins VS, Rouse WB, O’Leary CA, Andrews RJ, Moss WN. Analyses of human cancer driver genes uncovers evolutionarily conserved RNA structural elements involved in posttranscriptional control. PLoS One 2022; 17:e0264025. [PMID: 35213597 PMCID: PMC8880891 DOI: 10.1371/journal.pone.0264025] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 02/01/2022] [Indexed: 12/02/2022] Open
Abstract
Experimental breakthroughs have provided unprecedented insights into the genes involved in cancer. The identification of such cancer driver genes is a major step in gaining a fuller understanding of oncogenesis and provides novel lists of potential therapeutic targets. A key area that requires additional study is the posttranscriptional control mechanisms at work in cancer driver genes. This is important not only for basic insights into the biology of cancer, but also to advance new therapeutic modalities that target RNA—an emerging field with great promise toward the treatment of various cancers. In the current study we performed an in silico analysis on the transcripts associated with 800 cancer driver genes (10,390 unique transcripts) that identified 179,190 secondary structural motifs with evidence of evolutionarily ordered structures with unusual thermodynamic stability. Narrowing to one transcript per gene, 35,426 predicted structures were subjected to phylogenetic comparisons of sequence and structural conservation. This identified 7,001 RNA secondary structures embedded in transcripts with evidence of covariation between paired sites, supporting structure models and suggesting functional significance. A select set of seven structures were tested in vitro for their ability to regulate gene expression; all were found to have significant effects. These results indicate potentially widespread roles for RNA structure in posttranscriptional control of human cancer driver genes.
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Affiliation(s)
- Van S. Tompkins
- Roy J. Carver Department of Biophysics, Biochemistry and Molecular Biology, Iowa State University, Ames, IA, United States of America
| | - Warren B. Rouse
- Roy J. Carver Department of Biophysics, Biochemistry and Molecular Biology, Iowa State University, Ames, IA, United States of America
| | - Collin A. O’Leary
- Roy J. Carver Department of Biophysics, Biochemistry and Molecular Biology, Iowa State University, Ames, IA, United States of America
| | - Ryan J. Andrews
- Roy J. Carver Department of Biophysics, Biochemistry and Molecular Biology, Iowa State University, Ames, IA, United States of America
| | - Walter N. Moss
- Roy J. Carver Department of Biophysics, Biochemistry and Molecular Biology, Iowa State University, Ames, IA, United States of America
- * E-mail:
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Hu Y, Gong C, Li Z, Liu J, Chen Y, Huang Y, Luo Q, Wang S, Hou Y, Yang S, Xiao Y. Demethylase ALKBH5 suppresses invasion of gastric cancer via PKMYT1 m6A modification. Mol Cancer 2022; 21:34. [PMID: 35114989 PMCID: PMC8812266 DOI: 10.1186/s12943-022-01522-y] [Citation(s) in RCA: 126] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 01/24/2022] [Indexed: 12/26/2022] Open
Abstract
Background Gastric cancer (GC) is one of the most pernicious tumors that seriously harm human healthcare. GC metastasis is one of the prime cause of failed cancer treatment, but correlation between N6-methyladenosine (m6A) and GC metastasis was less reported. Methods Methylated RNA immunoprecipitation sequencing (MeRIP-seq) of GC tissues was conducted. Quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry (IHC) were taken to determine the expression of ALKBH5 in GC tissues and cell lines. RNA-seq together with MeRIP-qRT-PCR was used to screen the target gene of ALKBH5. RNA pulldown, mass spectrometry and RNA immunoprecipitation (RIP) were used to search the “reader” protein of target gene. The mechanism was also validated via a tail vein injection method for lung metastasis model. Results Decreased expression of ALKBH5 was detected in GC samples, and it was correlated with clinical tumor distal metastasis and lymph node metastasis. ALKBH5 interference promoted metastasis of GC cells and this effect was closely related to the demethylase activity of ALKBH5. PKMYT1, as a downstream target of ALKBH5, promoted invasion and migration in GC. Caused by ALKBH5 knockdown or its demethylase activity mutation, upregulated expression of PKMYT1 indicated that ALKBH5 modulates expression of PKMYT1 in an m6A-dependent manner. IGF2BP3 helped stabilize the mRNA stability of PKMYT1 via its m6A modification site. Conclusions This study established an ALKBH5-PKMYT1-IGF2BP3 regulation system in metastasis, representing a new therapeutic target for GC metastasis. Supplementary Information The online version contains supplementary material available at 10.1186/s12943-022-01522-y.
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Affiliation(s)
- Yiyang Hu
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Chunli Gong
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Zhibin Li
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Jiao Liu
- Department of Endoscope, General Hospital of Northern Theater Command, Shenyang, Liaoning, 110016, China
| | - Yang Chen
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Yu Huang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Qiang Luo
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Sumin Wang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China
| | - Yu Hou
- Department of Hematology, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China. .,Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, China.
| | - Shiming Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
| | - Yufeng Xiao
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
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Zang M, Hou J, Huang Y, Wang J, Ding X, Zhang B, Wang Y, Xuan Y, Zhou Y. Crocetin suppresses angiogenesis and metastasis through inhibiting sonic hedgehog signaling pathway in gastric cancer. Biochem Biophys Res Commun 2021; 576:86-92. [PMID: 34482028 DOI: 10.1016/j.bbrc.2021.08.092] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 08/25/2021] [Accepted: 08/28/2021] [Indexed: 12/14/2022]
Abstract
Gastric cancer (GC) is one of the major causes of cancer-related deaths and chemoresistance is a key obstacle to the treatment of GC, particularly in advanced GC. As an active component of saffron stigma, crocetin has important therapeutic effects on various diseases including tumors. However, the therapeutic potential of crocetin targeting GC is still unclear and the underlying mechanisms are remained to be further explored. In this study, crocetin significantly inhibited angiogenesis in GC, including tubes of HUVECs and vasculogenic mimicry (VM) formation of GC cells. Crocetin also suppressed cell proliferation, migration and invasion. To explore which signaling pathway involving in crocetin, HIF-1α, Notch1, Sonic hedgehog (SHH) and VEGF were examined with crocetin treatment and we found that SHH significantly decreased. Crocetin suppressed SHH signaling with SHH, PTCH2, Sufu and Gli1 protein level decreased in western blot assay. In addition, crocetin suppressed SHH secretion in GC and HUVEC cells. The promoted effects on cell migration induced by secreted SHH were also inhibited by crocetin in GC and HUVEC cell co-culture system. Furthermore, recombinant SHH promoted angiogenesis as well as cell migration and proliferation. However, these promoted effects were reversed by crocetin treatment. These results revealed that crocetin suppressed GC angiogenesis and metastasis through SHH signaling pathway, indicating that crocetin may function as an effective therapeutic drug against GC.
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Affiliation(s)
- Mingde Zang
- Department of Gastric Cancer Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, PR China
| | - Junyi Hou
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, PR China
| | - Yakai Huang
- Department of Gastric Cancer Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, PR China
| | - Jiangli Wang
- Department of Gastric Cancer Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, PR China
| | - Xusheng Ding
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, PR China
| | - Baogui Zhang
- Affiliated Hospital of Jining Medical University, No. 89 Guhuai Road, Rencheng District, Jining City, 272000, PR China
| | - Yanong Wang
- Department of Gastric Cancer Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, PR China
| | - Yi Xuan
- Department of Gastric Cancer Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, PR China.
| | - Ye Zhou
- Department of Gastric Cancer Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, PR China.
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19
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Yuan C, Pang L, Wang W, Ouyang Y, Guo X, Liu K. POU2F2-IL-31 Autoregulatory Circuit Converts Hepatocytes into the Origin Cells of Hepatocellular Carcinoma. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2004683. [PMID: 37733361 PMCID: PMC10619474 DOI: 10.1002/advs.202004683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 02/07/2021] [Indexed: 09/22/2023]
Abstract
Hepatocellular carcinoma (HCC) originates from fully differentiated hepatocytes, but the decisive events for converting hepatocytes to the cells of origin for HCC are still unclear. Liver cancer stem cells (LCSCs) cause HCC but are not bona fide cells of origin. Here, the expressions of POU2F2 and IL-31 are identified in macroscopically normal livers of diethylnitrosamine-challenged mice. An autoregulatory circuit formed by mutual induction between POU2F2 and IL-31 drives hepatocytes to progress to LCSCs by acquiring stemness, as well as stimulates them to in vivo grow and malignantly progress. The development of the autoregulatory circuit is a decisive event for converting hepatocytes into the cells of origin, since hepatocytes expressing the circuit have acquired tumorigenic potential before progressing to LCSCs. Nonetheless, acquiring stemness is still required for the cells of origin to initiate hepatocarcinogenesis. The circuit also occurs in human cirrhotic tissues, partially elucidating how premalignant lesions progress to HCC.
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Affiliation(s)
- Chunwang Yuan
- Capital Medical University Affiliated to Beijing You An HospitalBeijing100069China
| | - Lijun Pang
- Capital Medical University Affiliated to Beijing You An HospitalBeijing100069China
- Beijing Institute of HepatologyBeijing100069China
| | - Wenjing Wang
- Capital Medical University Affiliated to Beijing You An HospitalBeijing100069China
- Beijing Institute of HepatologyBeijing100069China
| | - Yabo Ouyang
- Capital Medical University Affiliated to Beijing You An HospitalBeijing100069China
- Beijing Institute of HepatologyBeijing100069China
| | - Xianghua Guo
- Capital Medical University Affiliated to Beijing You An HospitalBeijing100069China
- Beijing Institute of HepatologyBeijing100069China
| | - Kai Liu
- Capital Medical University Affiliated to Beijing You An HospitalBeijing100069China
- Beijing Institute of HepatologyBeijing100069China
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20
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Weidle UH, Birzele F, Brinkmann U, Auslaender S. Gastric Cancer: Identification of microRNAs Inhibiting Druggable Targets and Mediating Efficacy in Preclinical In Vivo Models. Cancer Genomics Proteomics 2021; 18:497-514. [PMID: 34183383 DOI: 10.21873/cgp.20275] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/30/2021] [Accepted: 05/05/2021] [Indexed: 01/06/2023] Open
Abstract
In addition to chemotherapy, targeted therapies have been approved for treatment of locally advanced and metastatic gastric cancer. The therapeutic benefit is significant but more durable responses and improvement of survival should be achieved. Therefore, the identification of new targets and new approaches for clinical treatment are of paramount importance. In this review, we searched the literature for down-regulated microRNAs which interfere with druggable targets and exhibit efficacy in preclinical in vivo efficacy models. As druggable targets, we selected transmembrane receptors, secreted factors and enzymes. We identified 38 microRNAs corresponding to the criteria as outlined. A total of 13 miRs target transmembrane receptors, nine inhibit secreted proteins and 16 attenuate enzymes. These microRNAs are targets for reconstitution therapy of gastric cancer. Further target validation experiments are mandatory for all of the identified microRNAs.
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Affiliation(s)
- Ulrich H Weidle
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany;
| | - Fabian Birzele
- Pharmaceutical Sciences, Roche Pharma Research and Early Development (pRed), Roche Innovation Center Basel, Basel, Switzerland
| | - Ulrich Brinkmann
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany;
| | - Simon Auslaender
- Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany
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21
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Chen R, Yang M, Huang W, Wang B. Cascades between miRNAs, lncRNAs and the NF-κB signaling pathway in gastric cancer (Review). Exp Ther Med 2021; 22:769. [PMID: 34055068 PMCID: PMC8145527 DOI: 10.3892/etm.2021.10201] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 04/28/2021] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer is a common digestive tract malignancy that is mainly treated with surgery combined with perioperative adjuvant chemoradiotherapy and biological targeted therapy. However, the diagnosis rate of early gastric cancer is low and both postoperative recurrence and distant metastasis are thorny problems. Therefore, it is essential to study the pathogenesis of gastric cancer and search for more effective means of treatment. The nuclear factor-κB (NF-κB) signaling pathway has an important role in the occurrence and development of gastric cancer and recent studies have revealed that microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are able to regulate this pathway through a variety of mechanisms. Understanding these interrelated molecular mechanisms is helpful in guiding improvements in gastric cancer treatment. In the present review, the functional associations between miRNAs, lncRNAs and the NF-κB signaling pathway in the occurrence, development and prognosis of gastric cancer were discussed. It was concluded that miRNAs and lncRNAs have complex relations with the NF-κB signaling pathway in gastric cancer. miRNAs/target genes/NF-κB/target proteins, signaling molecules/NF-κB/miRNAs/target genes, lncRNAs/miRNAs/NF-κB/genes or mRNAs, lncRNAs/target genes/NF-Κb/target proteins, and lncRNAs/NF-κB/target proteins cascades are all important factors in the occurrence and development of gastric cancer.
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Affiliation(s)
- Risheng Chen
- Department of Anesthesiology, Affiliated Nanhua Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Mingxiu Yang
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology (2016TP1015), Cancer Research Institute, Hengyang Medical College of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Weiguo Huang
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology (2016TP1015), Cancer Research Institute, Hengyang Medical College of University of South China, Hengyang, Hunan 421001, P.R. China
| | - Baiyun Wang
- Department of Anesthesiology, Affiliated Nanhua Hospital of University of South China, Hengyang, Hunan 421001, P.R. China
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22
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Abstract
Gastric cancer (GC) is one of the most common malignant tumors. The mechanism of how GC develops is vague, and therapies are inefficient. The function of microRNAs (miRNAs) in tumorigenesis has attracted the attention from many scientists. During the development of GC, miRNAs function in the regulation of different phenotypes, such as proliferation, apoptosis, invasion and metastasis, drug sensitivity and resistance, and stem-cell-like properties. MiRNAs were evaluated for use in diagnostic and prognostic predictions and exhibited considerable accuracy. Although many problems exist for the application of therapy, current studies showed the antitumor effects of miRNAs. This paper reviews recent advances in miRNA mechanisms in the development of GC and the potential use of miRNAs in the diagnosis and treatment of GC.
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23
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Zhou L, Xu XL. Long Non-Coding RNA ARAP1-AS1 Facilitates the Progression of Cervical Cancer by Regulating miR-149-3p and POU2F2. Pathobiology 2021; 88:301-312. [PMID: 33965958 DOI: 10.1159/000507830] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 04/12/2020] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Emerging research has demonstrated that long non-coding RNAs (lncRNAs) attach great importance to the progression of cervical cancer (CC). LncRNA ARAP1-AS1 was involved in the development of several cancers; however, its role in CC is far from being elucidated. METHODS Real-time PCR (RT-PCR) was employed to detect ARAP1-AS1 and miR-149-3p expression in CC samples. CC cell lines (HeLa and C33A cells) were regarded as the cell models. The biological effect of ARAP1-AS1 on cancer cells was measured using CCK-8 assay, colony formation assay, flow cytometry, Transwell assay and wound healing assay in vitro, and subcutaneous xenotransplanted tumor model and tail vein injection model in vivo. Furthermore, interactions between ARAP1-AS1 and miR-149-3p, miR-149-3p and POU class 2 homeobox 2 (POU2F2) were determined by bioinformatics analysis, qRT-PCR, Western blot, luciferase reporter and RNA immunoprecipitation assay, respectively. RESULTS The expression of ARAP1-AS1 was enhanced in CC samples, while miR-149-3p was markedly suppressed. Additionally, ARAP1-AS1 overexpression enhanced the viability, migration, and invasion of CC cells. ARAP1-AS1 downregulated miR-149-3p via sponging it. ARAP1-AS1 and miR-149-3p exhibited a negative correlation in CC samples. On the other hand, ARAP1-AS1 enhanced the expression of POU2F2, which was validated as a target gene of miR-149-3p. CONCLUSION ARAP1-AS1 was abnormally upregulated in CC tissues and indirectly modulated the POU2F2 expression via reducing miR-149-3p expression. Our study identified a novel axis, ARAP1-AS1/miR-149-3p/POU2F2, in CC tumorigenesis.
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Affiliation(s)
- Ling Zhou
- Department of Obstetrics and Gynecology, Liyang People's Hospital, Liyang, China
| | - Xiao-Li Xu
- Department of Obstetrics and Gynecology, The First People's Hospital of Changzhou (The Third Affiliated Hospital of Suzhou University), Changzhou, China
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24
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Yang R, Wang M, Zhang G, Li Y, Wang L, Cui H. POU2F2 regulates glycolytic reprogramming and glioblastoma progression via PDPK1-dependent activation of PI3K/AKT/mTOR pathway. Cell Death Dis 2021; 12:433. [PMID: 33931589 PMCID: PMC8087798 DOI: 10.1038/s41419-021-03719-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 04/13/2021] [Accepted: 04/15/2021] [Indexed: 01/08/2023]
Abstract
The POU Class Homeobox 2 (POU2F2) is a member of POU transcription factors family, which involves in cell immune response by regulating B cell proliferation and differentiation genes. Recent studies have shown that POU2F2 acts as tumor-promoting roles in some cancers, but the underlying mechanism remains little known. Here, we identified that the highly expressed POU2F2 significantly correlated with poor prognosis of glioblastoma (GBM) patients. POU2F2 promoted cell proliferation and regulated glycolytic reprogramming. Mechanistically, the AKT/mTOR signaling pathway played important roles in the regulation of POU2F2-mediated aerobic glycolysis and cell growth. Furthermore, we demonstrated that POU2F2 activated the transcription of PDPK1 by directly binding to its promoter. Reconstituted the expression of PDPK1 in POU2F2-knockdown GBM cells reactivated AKT/mTOR pathway and recovered cell glycolysis and proliferation, whereas this effect was abolished by the PDPK1/AKT interaction inhibitor. In addition, we showed that POU2F2-PDPK1 axis promoted tumorigenesis by regulating glycolysis in vivo. In conclusion, our findings indicate that POU2F2 leads a metabolic shift towards aerobic glycolysis and promotes GBM progression in PDPK1-dependent activation of PI3K/AKT/mTOR pathway.
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Affiliation(s)
- Rui Yang
- Key Laboratory of Precision Oncology of Shandong Higher Education, Institute of Precision Medicine, Jining Medical University, Jining, China. .,State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.
| | - Mei Wang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
| | - Guanghui Zhang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.,Cancer center, Medical Research Institute, Southwest University, Chongqing, China
| | - Yanping Li
- Key Laboratory of Precision Oncology of Shandong Higher Education, Institute of Precision Medicine, Jining Medical University, Jining, China
| | - Lulin Wang
- Key Laboratory of Molecular Pharmacology, Liaocheng People's Hospital, Liaocheng, China
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China. .,Cancer center, Medical Research Institute, Southwest University, Chongqing, China.
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25
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Luo R, Zhuo Y, Du Q, Xiao R. POU2F2 promotes the proliferation and motility of lung cancer cells by activating AGO1. BMC Pulm Med 2021; 21:117. [PMID: 33832481 PMCID: PMC8034198 DOI: 10.1186/s12890-021-01476-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 03/23/2021] [Indexed: 01/11/2023] Open
Abstract
Background To detect and investigate the expression of POU domain class 2 transcription factor 2 (POU2F2) in human lung cancer tissues, its role in lung cancer progression, and the potential mechanisms. Methods Immunohistochemical (IHC) assays were conducted to assess the expression of POU2F2 in human lung cancer tissues. Immunoblot assays were performed to assess the expression levels of POU2F2 in human lung cancer tissues and cell lines. CCK-8, colony formation, and transwell-migration/invasion assays were conducted to detect the effects of POU2F2 and AGO1 on the proliferaion and motility of A549 and H1299 cells in vitro. CHIP and luciferase assays were performed for the mechanism study. A tumor xenotransplantation model was used to detect the effects of POU2F2 on tumor growth in vivo. Results We found POU2F2 was highly expressed in human lung cancer tissues and cell lines, and associated with the lung cancer patients’ prognosis and clinical features. POU2F2 promoted the proliferation, and motility of lung cancer cells via targeting AGO1 in vitro. Additionally, POU2F2 promoted tumor growth of lung cancer cells via AGO1 in vivo. Conclusion We found POU2F2 was highly expressed in lung cancer cells and confirmed the involvement of POU2F2 in lung cancer progression, and thought POU2F2 could act as a potential therapeutic target for lung cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s12890-021-01476-9.
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Affiliation(s)
- Ronggang Luo
- Department of Thoracic Surgery, The First Affiliated Hospital of Fujian Medical University, No.20 Chazhong Road, Fuzhou City, 350005, Fujian Province, China
| | - Yi Zhuo
- Department of Thoracic Surgery, The First Affiliated Hospital of Fujian Medical University, No.20 Chazhong Road, Fuzhou City, 350005, Fujian Province, China.
| | - Quan Du
- Department of Thoracic Surgery, The First Affiliated Hospital of Fujian Medical University, No.20 Chazhong Road, Fuzhou City, 350005, Fujian Province, China
| | - Rendong Xiao
- Department of Thoracic Surgery, The First Affiliated Hospital of Fujian Medical University, No.20 Chazhong Road, Fuzhou City, 350005, Fujian Province, China
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26
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Meier T, Timm M, Montani M, Wilkens L. Gene networks and transcriptional regulators associated with liver cancer development and progression. BMC Med Genomics 2021; 14:41. [PMID: 33541355 PMCID: PMC7863452 DOI: 10.1186/s12920-021-00883-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Accepted: 01/24/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Treatment options for hepatocellular carcinoma (HCC) are limited, and overall survival is poor. Despite the high frequency of this malignoma, its basic disease mechanisms are poorly understood. Therefore, the aim of this study was to use different methodological approaches and combine the results to improve our knowledge on the development and progression of HCC. METHODS Twenty-three HCC samples were characterized by histological, morphometric and cytogenetic analyses, as well as comparative genomic hybridization (aCGH) and genome-wide gene expression followed by a bioinformatic search for potential transcriptional regulators and master regulatory molecules of gene networks. RESULTS Histological evaluation revealed low, intermediate and high-grade HCCs, and gene expression analysis split them into two main sets: GE1-HCC and GE2-HCC, with a low and high proliferation gene expression signature, respectively. Array-based comparative genomic hybridization demonstrated a high level of chromosomal instability, with recurrent chromosomal gains of 1q, 6p, 7q, 8q, 11q, 17q, 19p/q and 20q in both HCC groups and losses of 1p, 4q, 6q, 13q and 18q characteristic for GE2-HCC. Gene expression and bioinformatics analyses revealed that different genes and gene regulatory networks underlie the distinct biological features observed in GE1-HCC and GE2-HCC. Besides previously reported dysregulated genes, the current study identified new candidate genes with a putative role in liver cancer, e.g. C1orf35, PAFAH1B3, ZNF219 and others. CONCLUSION Analysis of our findings, in accordance with the available published data, argues in favour of the notion that the activated E2F1 signalling pathway, which can be responsible for both inappropriate cell proliferation and initial chromosomal instability, plays a pivotal role in HCC development and progression. A dedifferentiation switch that manifests in exaggerated gene expression changes might be due to turning on transcriptional co-regulators with broad impact on gene expression, e.g. POU2F1 (OCT1) and NFY, as a response to accumulating cell stress during malignant development. Our findings point towards the necessity of different approaches for the treatment of HCC forms with low and high proliferation signatures and provide new candidates for developing appropriate HCC therapies.
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Affiliation(s)
- Tatiana Meier
- Institute of Pathology, Nordstadtkrankenhaus, Hanover, Germany.
| | - Max Timm
- Institute of Pathology, Nordstadtkrankenhaus, Hanover, Germany
- Clinic for Laryngology, Rhinology and Otology, Medical School Hanover, Hanover, Germany
| | - Matteo Montani
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Ludwig Wilkens
- Institute of Pathology, Nordstadtkrankenhaus, Hanover, Germany
- Institute of Human Genetics, Medical School Hanover, Hanover, Germany
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27
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Li H, Wang C, Lan L, Behrens A, Tomaschko M, Ruiz J, Su Q, Zhao G, Yuan C, Xiao X, Li B, Yan L, Wu W, Li W, Chen J, He Y, Zhang C. High expression of vinculin predicts poor prognosis and distant metastasis and associates with influencing tumor-associated NK cell infiltration and epithelial-mesenchymal transition in gastric cancer. Aging (Albany NY) 2021; 13:5197-5225. [PMID: 33535187 PMCID: PMC7950221 DOI: 10.18632/aging.202440] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 10/27/2020] [Indexed: 11/25/2022]
Abstract
In the process of epithelial-mesenchymal transition (EMT), epithelial cancer cells transdifferentiate into mesenchymal-like cells with high motility and aggressiveness, resulting in the spread of tumor cells. Immune cells and inflammation in the tumor microenvironment are the driving factors of EMT, but few studies have explored the core targets of the interaction between EMT and tumor immune cells. We analyzed thousands of cases of gastric cancer and gastric tissue specimens of TCGA, CPTAC, GTEx and analyzing QPCR and IHC data of 56 gastric cancer patients in SYSU Gastric Cancer Research Center. It was known that EMT has an important connection with the infiltration of NK cells, and that the expression of vinculin may be the target of the phenomenon. The increased expression of vinculin is closely related to the aggressiveness and distant metastasis of cancer, which affects the survival prognosis of the patient. Moreover, through in vitro experiments under 3D conditions, we found that vinculin, cell invasion and metastasis are clearly linked. VCL can affect EMT and tumor immunity by regulating EPCAM gene expression. The role and mechanism of action of vinculin have been controversial, but this molecule may downregulate EpCAM (epithelial cellular adhesion molecule) and its own role in gastric cancer through DNA methylation, causing NK cells to enrich into tumor cells and kill tumor cells. At the same time, it promotes the occurrence of EMT, which in turn causes tumor metastasis and thus poorer prognosis.
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Affiliation(s)
- Huafu Li
- Digestive Medicine Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China.,Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.,Adult Stem Cell Laboratory, The Francis Crick Institute, London, UK
| | - Chunming Wang
- Digestive Medicine Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China.,Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Linxiang Lan
- Adult Stem Cell Laboratory, The Francis Crick Institute, London, UK
| | - Axel Behrens
- Adult Stem Cell Laboratory, The Francis Crick Institute, London, UK
| | - Mona Tomaschko
- Adult Stem Cell Laboratory, The Francis Crick Institute, London, UK
| | - Josue Ruiz
- Adult Stem Cell Laboratory, The Francis Crick Institute, London, UK
| | - Qiao Su
- Animal Experiment Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Guangying Zhao
- Adult Stem Cell Laboratory, The Francis Crick Institute, London, UK
| | - Cheng Yuan
- Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Centre Singapore, Singapore
| | - Xing Xiao
- Digestive Medicine Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China.,Center of Scientific Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Bo Li
- Digestive Medicine Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China.,Center of Scientific Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Leping Yan
- Center of Scientific Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Wang Wu
- Digestive Medicine Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China.,Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Wuguo Li
- Animal Experiment Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Junzong Chen
- Digestive Medicine Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China
| | - Yulong He
- Digestive Medicine Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China.,Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Changhua Zhang
- Digestive Medicine Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China.,Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
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28
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Kanda M, Shimizu D, Sawaki K, Nakamura S, Umeda S, Miwa T, Tanaka H, Tanaka C, Hayashi M, Iguchi Y, Yamada S, Katsuno M, Kodera Y. Therapeutic monoclonal antibody targeting of neuronal pentraxin receptor to control metastasis in gastric cancer. Mol Cancer 2020; 19:131. [PMID: 32847597 PMCID: PMC7448342 DOI: 10.1186/s12943-020-01251-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 08/17/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Controlling metastasis is essential for improving the prognosis of patients with gastric cancer (GC). Here, we aimed to identify a molecule required for GC metastasis and to investigate its potential utility as a target for the development of therapeutic antibodies (Abs). METHODS Transcriptome and bioinformatics analyses of human GC cell lines identified the neuronal pentraxin receptor (NPTXR) as a candidate molecule. NPTXR function was probed by modulating its expression in GC cells and assessing the effects on intracellular signaling and malignant behaviors in vitro and in mouse xenograft models. We also generated anti-NPTXR Abs and Nptxr-/- mice, and assessed the clinical significance of NPTXR expression in GC specimens. RESULTS NPTXR mRNA expression in clinical specimens was associated with disease progression and was significantly higher in tissues from GC patients with distant metastasis compared with those without. NPTXR regulated expression of genes involved in metastatic behaviors as well as activation of the PI3K-AKT-mTOR, FAK-JNK, and YAP signaling pathways. NPTXR silencing promoted caspase-mediated apoptosis and attenuated GC cell proliferation, cell cycle progression, migration, invasion, adhesion, stem cell-like properties, and resistance to 5-fluorouracil in vitro, and also inhibited the tumorigenicity of GC cells in vivo. Anti-NPTXR Abs inhibited GC peritoneal metastasis in mice. Nptxr-/- mice showed no abnormalities in reproduction, development, metabolism, or motor function. CONCLUSIONS NPTXR plays an essential role in controlling the malignant behavior of GC cells in vitro and in vivo. NPTXR-targeting Abs may thus have utility as novel diagnostic tools and/or treatment modalities for GC.
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MESH Headings
- Animals
- Antibodies, Monoclonal/pharmacology
- Antineoplastic Agents, Immunological/pharmacology
- Biomarkers, Tumor
- CRISPR-Cas Systems
- Cell Line, Tumor
- Disease Models, Animal
- Gene Expression
- Gene Targeting
- Humans
- Mice
- Mice, Knockout
- Models, Biological
- Neoplasm Metastasis
- Neoplasm Staging
- Phenotype
- Prognosis
- Receptors, Cell Surface/antagonists & inhibitors
- Receptors, Cell Surface/genetics
- Receptors, Cell Surface/metabolism
- Signal Transduction/drug effects
- Stomach Neoplasms/drug therapy
- Stomach Neoplasms/genetics
- Stomach Neoplasms/metabolism
- Stomach Neoplasms/pathology
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Dai Shimizu
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Koichi Sawaki
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Shunsuke Nakamura
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Shinichi Umeda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Takashi Miwa
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Haruyoshi Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Chie Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Masamichi Hayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Yohei Iguchi
- Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Suguru Yamada
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Masahisa Katsuno
- Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
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29
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Zhang W, Zhao H, Chen K, Huang Y. Overexpressing of POU2F2 accelerates fracture healing via regulating HMGA1/Wnt/β-catenin signaling pathway. Biosci Biotechnol Biochem 2019; 84:491-499. [PMID: 31782345 DOI: 10.1080/09168451.2019.1695574] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
To elucidate the role of POU2F2 (POU class 2 homeobox 2) in fracture healing, 30 rats with femoral fracture were randomly grouped into three groups: FF group, LV-POU2F2 group and LV-scramble group. Rats were injected with PBS, lentivirus expressing POU2F2 or scramble lentivirus once a week for 4 weeks. Results showed that overexpressing of POU2F2 promoted fracture healing and callus growth. Besides, overexpressing of POU2F2 promoted protein and mRNA expression of Col10a1, Runx2, Osterix, and Osteocalcin. High Mobility Group AT-hook 1 (HMGA1) is a non-histone protein participating in chromatin remodeling of cells. Western blotting manifested HMGA1/Wnt/β-catenin pathway was activated in POU2F2 group. Moreover, in-vitro study of hMSCs cells supported the above data. In conclusion, POU2F2 promotes fracture healing via activating the HMGA1/Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Wei Zhang
- Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Hanke Zhao
- Department of Orthopedics, Changzhou Wujin People's Hospital, Changzhou, China
| | - Kun Chen
- Department of Orthopedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ye Huang
- Department of Orthopedics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Masgutova G, Harris A, Jacob B, Corcoran LM, Clotman F. Pou2f2 Regulates the Distribution of Dorsal Interneurons in the Mouse Developing Spinal Cord. Front Mol Neurosci 2019; 12:263. [PMID: 31787878 PMCID: PMC6853997 DOI: 10.3389/fnmol.2019.00263] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 10/16/2019] [Indexed: 12/20/2022] Open
Abstract
Spinal dorsal interneurons, which are generated during embryonic development, relay and process sensory inputs from the periphery to the central nervous system. Proper integration of these cells into neuronal circuitry depends on their correct positioning within the spinal parenchyma. Molecular cues that control neuronal migration have been extensively characterized but the genetic programs that regulate their production remain poorly investigated. Onecut (OC) transcription factors have been shown to control the migration of the dorsal interneurons (dINs) during spinal cord development. Here, we report that the OC factors moderate the expression of Pou2f2, a transcription factor essential for B-cell differentiation, in spinal dINs. Overexpression or inactivation of Pou2f2 leads to alterations in the differentiation of dI2, dI3 and Phox2a-positive dI5 populations and to defects in the distribution of dI2-dI6 interneurons. Thus, an OC-Pou2f2 genetic cascade regulates adequate diversification and distribution of dINs during embryonic development.
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Affiliation(s)
- Gauhar Masgutova
- Université catholique de Louvain, Institute of Neuroscience, Laboratory of Neural Differentiation, Brussels, Belgium
| | - Audrey Harris
- Université catholique de Louvain, Institute of Neuroscience, Laboratory of Neural Differentiation, Brussels, Belgium
| | - Benvenuto Jacob
- Université catholique de Louvain, Institute of Neuroscience, System and Cognition Division, Brussels, Belgium
| | - Lynn M Corcoran
- Molecular Immunology Division and Immunology Division, The Walter and Eliza Hall Institute, Parkville, VIC, Australia
| | - Frédéric Clotman
- Université catholique de Louvain, Institute of Neuroscience, Laboratory of Neural Differentiation, Brussels, Belgium
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Wang K, Zhao XH, Liu J, Zhang R, Li JP. Nervous system and gastric cancer. Biochim Biophys Acta Rev Cancer 2019; 1873:188313. [PMID: 31647986 DOI: 10.1016/j.bbcan.2019.188313] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 09/04/2019] [Accepted: 09/05/2019] [Indexed: 02/07/2023]
Abstract
The nervous system has been recently shown to exert impact on gastric cancer directly and indirectly. Gastric cancer cells invade nerve fibers to induce outgrowth and branching of neural cells, and nerve fibers in turn infiltrate into tumor microenvironment to promote progression of gastric cancer. Additionally, the neuro-immune interaction also plays an important role in gastric cancer development. The interplay of nerves and gastric cancer is mediated by many nervous system-associated factors, which can not only be synthesized and released by both cancer cells and nerve terminals, but also participate in regulation of many aspects of gastric cancer such as cell proliferation, angiogenesis, metastasis and recurrence. Furthermore, clinical researches indicate that some of these factors are significant diagnosis and prognosis biomarkers for gastric cancer. Herein, we reviewed recent advances and future prospects of the interaction between nervous system and gastric cancer.
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Affiliation(s)
- Ke Wang
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 710032 Xi'an, China; State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China
| | - Xin-Hui Zhao
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 710032 Xi'an, China; State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China
| | - Jun Liu
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China
| | - Rui Zhang
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China; State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, China.
| | - Ji-Peng Li
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 710032 Xi'an, China; Department of Experimental Surgery, Xijing Hospital, Fourth Military Medical University, 710032 Xi'an, China.
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Yue B, Song C, Yang L, Cui R, Cheng X, Zhang Z, Zhao G. METTL3-mediated N6-methyladenosine modification is critical for epithelial-mesenchymal transition and metastasis of gastric cancer. Mol Cancer 2019; 18:142. [PMID: 31607270 PMCID: PMC6790244 DOI: 10.1186/s12943-019-1065-4] [Citation(s) in RCA: 420] [Impact Index Per Article: 70.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 08/28/2019] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND As one of the most frequent chemical modifications in eukaryotic mRNAs, N6-methyladenosine (m6A) modification exerts important effects on mRNA stability, splicing, and translation. Recently, the regulatory role of m6A in tumorigenesis has been increasingly recognized. However, dysregulation of m6A and its functions in tumor epithelial-mesenchymal transition (EMT) and metastasis remain obscure. METHODS qRT-PCR and immunohistochemistry were used to evaluate the expression of methyltransferase-like 3 (METTL3) in gastric cancer (GC). The effects of METTL3 on GC metastasis were investigated through in vitro and in vivo assays. The mechanism of METTL3 action was explored through transcriptome-sequencing, m6A-sequencing, m6A methylated RNA immunoprecipitation quantitative reverse transcription polymerase chain reaction (MeRIP qRT-PCR), confocal immunofluorescent assay, luciferase reporter assay, co-immunoprecipitation, RNA immunoprecipitation and chromatin immunoprecipitation assay. RESULTS Here, we show that METTL3, a major RNA N6-adenosine methyltransferase, was upregulated in GC. Clinically, elevated METTL3 level was predictive of poor prognosis. Functionally, we found that METTL3 was required for the EMT process in vitro and for metastasis in vivo. Mechanistically, we unveiled the METTL3-mediated m6A modification profile in GC cells for the first time and identified zinc finger MYM-type containing 1 (ZMYM1) as a bona fide m6A target of METTL3. The m6A modification of ZMYM1 mRNA by METTL3 enhanced its stability relying on the "reader" protein HuR (also known as ELAVL1) dependent pathway. In addition, ZMYM1 bound to and mediated the repression of E-cadherin promoter by recruiting the CtBP/LSD1/CoREST complex, thus facilitating the EMT program and metastasis. CONCLUSIONS Collectively, our findings indicate the critical role of m6A modification in GC and uncover METTL3/ZMYM1/E-cadherin signaling as a potential therapeutic target in anti-metastatic strategy against GC.
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Affiliation(s)
- Ben Yue
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127 China
| | - Chenlong Song
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, 85 Wujin Road, Shanghai, 200080 China
| | - Linxi Yang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127 China
| | - Ran Cui
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127 China
| | - Xingwang Cheng
- Department of General Surgery, Shanghai Public Health Clinical Center, 2901 Caolang Road, Shanghai, 201508 China
| | - Zizhen Zhang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127 China
| | - Gang Zhao
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127 China
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Chen K, Liu H, Liu Z, Luo S, Patz EF, Moorman PG, Su L, Shen S, Christiani DC, Wei Q. Genetic variants in RUNX3, AMD1 and MSRA in the methionine metabolic pathway and survival in nonsmall cell lung cancer patients. Int J Cancer 2019; 145:621-631. [PMID: 30650190 PMCID: PMC6828159 DOI: 10.1002/ijc.32128] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 11/13/2018] [Accepted: 11/27/2018] [Indexed: 12/18/2022]
Abstract
Abnormal methionine dependence in cancer cells has led to methionine restriction as a potential therapeutic strategy. We hypothesized that genetic variants involved in methionine-metabolic genes are associated with survival in nonsmall cell lung cancer (NSCLC) patients. Therefore, we investigated associations of 16,378 common single-nucleotide polymorphisms (SNPs) in 97 methionine-metabolic pathway genes with overall survival (OS) in NSCLC patients using genotyping data from two published genome-wide association study (GWAS) datasets. In the single-locus analysis, 1,005 SNPs were significantly associated with NSCLC OS (p < 0.05 and false-positive report probability < 0.2) in the discovery dataset. Three SNPs (RUNX3 rs7553295 G > T, AMD1 rs1279590 G > A and MSRA rs73534533 C > A) were replicated in the validation dataset, and their meta-analysis showed an adjusted hazards ratio [HR] of 0.82 [95% confidence interval (CI) =0.75-0.89] and pmeta = 2.86 × 10-6 , 0.81 (0.73-0.91) and pmeta = 4.63 × 10-4 , and 0.77 (0.68-0.89) and pmeta = 2.07 × 10-4 , respectively). A genetic score of protective genotypes of these three SNPs revealed an increased OS in a dose-response manner (ptrend < 0.0001). Further expression quantitative trait loci (eQTL) analysis showed significant associations between these genotypes and mRNA expression levels. Moreover, differential expression analysis further supported a tumor-suppressive effect of MSRA, with lower mRNA levels in both lung squamous carcinoma and adenocarcinoma (p < 0.0001 and < 0.0001, respectively) than in adjacent normal tissues. Additionally, low mutation rates of these three genes indicated the critical roles of these functional SNPs in cancer progression. Taken together, these genetic variants of methionine-metabolic pathway genes may be promising predictors of survival in NSCLC patients.
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Affiliation(s)
- Ka Chen
- Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing 400038, P. R. China
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Population Health Sciences, Duke University School of Medicine, Durham, NC 27710, USA
| | - Hongliang Liu
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Population Health Sciences, Duke University School of Medicine, Durham, NC 27710, USA
| | - Zhensheng Liu
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Population Health Sciences, Duke University School of Medicine, Durham, NC 27710, USA
| | - Sheng Luo
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC 27710, USA
| | - Edward F. Patz
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Radiology, Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
| | - Patricia G. Moorman
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA
| | - Li Su
- Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA
| | - Sipeng Shen
- Departments of Environmental Health and Department of Epidemiology, Harvard School of Public Health, Boston, MA, 02115 USA
| | - David C. Christiani
- Departments of Environmental Health and Department of Epidemiology, Harvard School of Public Health, Boston, MA, 02115 USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Qingyi Wei
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Population Health Sciences, Duke University School of Medicine, Durham, NC 27710, USA
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
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Jiang M, Wu N, Xu B, Chu Y, Li X, Su S, Chen D, Li W, Shi Y, Gao X, Zhang H, Zhang Z, Du W, Nie Y, Liang J, Fan D. Fatty acid-induced CD36 expression via O-GlcNAcylation drives gastric cancer metastasis. Am J Cancer Res 2019; 9:5359-5373. [PMID: 31410220 PMCID: PMC6691574 DOI: 10.7150/thno.34024] [Citation(s) in RCA: 110] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 06/09/2019] [Indexed: 12/28/2022] Open
Abstract
Metastasis is the primary cause of death in patients with advanced cancer. Recently, a high-fat diet was shown to specifically promote the metastatic potential of specific cancer cells in a CD36-dependent manner. However, the molecular basis of the fatty acid (FA)-induced upregulation of CD36 has remained unclear. Methods: RT-qPCR, FACS analysis, immunoblotting and immunohistochemistry, as well as retrieving TCGA database, were carried out to quantitate CD36 expression in gastric cancer (GC) tissues and cell lines. Transwell assay and xenografts were used to assess cell metastasis abilities in vitro and in vivo after indicated treatment. Luciferase reporter assay was carried out to evaluate the changes in signaling pathways when O-GlcNAcylation level was increased in GC cells and in vitro O-GlcNAcylation assay was utilized for wild and mutant types of CD36 protein to explore the potential O-GlcNAcylation sites. Results: High CD36 expression is a predictor of poor survival and promotes metastasis of GC cells and the use of neutralizing antibodies to block CD36 inhibits GC metastasis in mice. FA or a HFD promotes the metastatic potential of GC cells by upregulating CD36 via increasing the O-GlcNAcylation level. Increased O-GlcNAcylation levels promote the transcription of CD36 by activating the NF-κB pathway and also increase its FA uptake activity by directly modifying CD36 at S468 and T470. Conclusion: FA-induced hyper-O-GlcNAcylation promotes the transcription and function of CD36 by activating the NF-κB pathway and directly modifying CD36 at S468 and T470, which drives GC metastasis.
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Orellana EA, Li C, Lisevick A, Kasinski AL. Identification and validation of microRNAs that synergize with miR-34a - a basis for combinatorial microRNA therapeutics. Cell Cycle 2019; 18:1798-1811. [PMID: 31258013 DOI: 10.1080/15384101.2019.1634956] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Efforts to search for better treatment options for cancer have been a priority, and due to these efforts, new alternative therapies have emerged. For instance, clinically relevant tumor-suppressive microRNAs that target key oncogenic drivers have been identified as potential anti-cancer therapeutics. MicroRNAs are small non-coding RNAs that negatively regulate gene expression at the posttranscriptional level. Aberrant microRNA expression, through misexpression of microRNA target genes, can have profound cellular effects leading to a variety of diseases, including cancer. While altered microRNA expression contributes to a cancerous state, restoration of microRNA expression has therapeutic benefits. For example, ectopic expression of microRNA-34a (miR-34a), a tumor suppressor gene that is a direct transcriptional target of p53 and thus is reduced in p53 mutant tumors, has clear effects on cell proliferation and survival in murine models of cancer. MicroRNA replacement therapies have recently been tested in combination with other agents, including other microRNAs, to simultaneously target multiple pathways to improve the therapeutic response. Thus, we reasoned that other microRNA combinations could collaborate to further improve treatment. To test this hypothesis miR-34a was used in an unbiased cell-based approach to identify combinatorial microRNA pairs with enhanced efficacy over miR-34a alone. This approach identified a subset of microRNAs that was able to enhance the miR-34a antiproliferative activity. These microRNA combinatorial therapeutics could offer superior tumor-suppressive abilities to suppress oncogenic properties compared to a monotherapeutic approach. Collectively these studies aim to address an unmet need of identifying, characterizing, and therapeutically targeting microRNAs for the treatment of cancer.
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Affiliation(s)
- Esteban A Orellana
- a Department of Biological Sciences , Purdue University , West Lafayette , IN , USA.,b Stem Cell Program, Boston Children's Hospital , Harvard Medical School , Boston , MA , USA
| | - Chennan Li
- a Department of Biological Sciences , Purdue University , West Lafayette , IN , USA
| | - Alexa Lisevick
- a Department of Biological Sciences , Purdue University , West Lafayette , IN , USA
| | - Andrea L Kasinski
- a Department of Biological Sciences , Purdue University , West Lafayette , IN , USA.,c Purdue Center for Cancer Research , Purdue University , West Lafayette , IN , USA
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Li K, Xu C, Du Y, Junaid M, Kaushik AC, Wei DQ. Comprehensive epigenetic analyses reveal master regulators driving lung metastasis of breast cancer. J Cell Mol Med 2019; 23:5415-5431. [PMID: 31215771 PMCID: PMC6653217 DOI: 10.1111/jcmm.14424] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 04/30/2019] [Accepted: 05/12/2019] [Indexed: 01/02/2023] Open
Abstract
The lung metastasis of breast cancer involves complicated regulatory changes driven by chromatin remodelling. However, the epigenetic reprogramming and regulatory mechanisms in lung metastasis of breast cancer remain unclear. Here, we generated and analysed genome‐wide profiles of multiple histone modifications (H3K4me3, H3K27ac, H3K27me3, H3K4me1 and H3K9me3), as well as transcriptome data in lung‐metastatic and non‐lung‐metastatic breast cancer cells. Our results showed that the expression changes were correlated with the enrichment of specific histone modifications in promoters and enhancers. Promoter and enhancer reprogramming regulated gene expression in a synergetic way, and involved in multiple important biological processes and pathways. In addition, lots of gained super‐enhancers were identified in lung‐metastatic cells. We also identified master regulators driving differential gene expression during lung metastasis of breast cancer. We found that the cooperations between regulators were much closer in lung‐metastatic cells. Moreover, regulators such as TFAP2C, GTF2I and LMO4 were found to have potential prognostic value for lung metastasis free (LMF) survival of breast cancer. Functional studies motivated by our data analyses uncovered an important role of LMO4 in regulating metastasis. This study provided comprehensive insights into regulatory mechanisms, as well as potential prognostic markers for lung metastasis of breast cancer.
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Affiliation(s)
- Kening Li
- State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.,State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai JiaoTong University, Shanghai, China
| | - Congling Xu
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai JiaoTong University, Shanghai, China
| | - Yuxin Du
- State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.,State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai JiaoTong University, Shanghai, China
| | - Muhammad Junaid
- State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Aman-Chandra Kaushik
- State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Dong-Qing Wei
- State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
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Tong M, Jun T, Nie Y, Hao J, Fan D. The Role of the Slit/Robo Signaling Pathway. J Cancer 2019; 10:2694-2705. [PMID: 31258778 PMCID: PMC6584916 DOI: 10.7150/jca.31877] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Accepted: 04/28/2019] [Indexed: 12/25/2022] Open
Abstract
The Slit family is a family of secreted proteins that play important roles in various physiologic and pathologic activities via interacting with Robo receptors. Slit/Robo signaling was first identified in the nervous system, where it functions in neuronal axon guidance; nevertheless, an increasing number of studies have shown that Slit/Robo signaling even regulates other activities, such as angiogenesis, inflammatory cell chemotaxis, tumor cell migration and metastasis. Although the precise role of the ligand-receptor in organisms has been obscure and the conclusions drawn are sometimes paradoxical, tremendous advances in understanding the Slit/Robo signaling pathway have been made. As such, our review summarizes the characteristics of the Slit/Robo signaling pathway and its role in various cell types.
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Affiliation(s)
- Mingfu Tong
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
- State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Tie Jun
- State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Yongzhan Nie
- State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Jianyu Hao
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Daiming Fan
- State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
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38
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Xia Y, Wang L, Xu Z, Kong R, Wang F, Yin K, Xu J, Li B, He Z, Wang L, Xu H, Zhang D, Yang L, Wu JY, Xu Z. Reduced USP33 expression in gastric cancer decreases inhibitory effects of Slit2-Robo1 signalling on cell migration and EMT. Cell Prolif 2019; 52:e12606. [PMID: 30896071 PMCID: PMC6536419 DOI: 10.1111/cpr.12606] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 01/26/2019] [Accepted: 02/26/2019] [Indexed: 01/05/2023] Open
Abstract
OBJECTIVES Gastric cancer (GC) is one of the most common cancers in the world, causing a large number of deaths every year. The Slit-Robo signalling pathway, initially discovered for its critical role in neuronal guidance, has recently been shown to modulate tumour invasion and metastasis in several human cancers. However, the role of Slit-Robo signalling and the molecular mechanisms underlying its role in the pathogenesis of gastric cancer remains to be elucidated. MATERIALS AND METHODS Slit2, Robo1 and USP33 expressions were analysed in datasets obtained from the Oncomine database and measured in human gastric cancer specimens. The function of Slit2-Robo1-USP33 signalling on gastric cancer cells migration and epithelial-mesenchymal transition (EMT) was studied both in vitro and in vivo. The mechanism of the interaction between Robo1 and USP33 was explored by co-IP and ubiquitination protein analysis. RESULTS The mRNA and protein levels of Slit2 and Robo1 are lower in GC tissues relative to those in adjacent healthy tissues. Importantly, Slit2 inhibits GC cell migration and suppresses EMT process in a Robo-dependent manner. The inhibitory function of Slit2-Robo1 is mediated by ubiquitin-specific protease 33 (USP33) via deubiquitinating and stabilizing Robo1. USP33 expression is decreased in GC tissues, and reduced USP33 level is correlated with poor patient survival. CONCLUSIONS Our study reveals the inhibitory function of Slit-Robo signalling in GC and uncovers a role of USP33 in suppressing cancer cell migration and EMT by enhancing Slit2-Robo1 signalling. USP33 represents a feasible choice as a prognostic biomarker for GC.
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MESH Headings
- Aged
- Animals
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Cell Line, Tumor
- Cell Movement
- Down-Regulation
- Epithelial-Mesenchymal Transition
- Female
- Gene Expression Regulation, Neoplastic
- Heterografts
- Humans
- Intercellular Signaling Peptides and Proteins/genetics
- Intercellular Signaling Peptides and Proteins/metabolism
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Middle Aged
- Models, Biological
- Neoplasm Transplantation
- Nerve Tissue Proteins/genetics
- Nerve Tissue Proteins/metabolism
- Prognosis
- Protein Stability
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- RNA, Small Interfering/genetics
- Receptors, Immunologic/genetics
- Receptors, Immunologic/metabolism
- Signal Transduction
- Stomach Neoplasms/genetics
- Stomach Neoplasms/metabolism
- Stomach Neoplasms/pathology
- Ubiquitin Thiolesterase/antagonists & inhibitors
- Ubiquitin Thiolesterase/genetics
- Ubiquitin Thiolesterase/metabolism
- Ubiquitination
- Roundabout Proteins
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Affiliation(s)
- Yiwen Xia
- Department of Gastric SurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Linjun Wang
- Department of Gastric SurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Zhipeng Xu
- Department of Gastric SurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Ruirui Kong
- State Key Laboratory of Brain and Cognitive Science, Institute of BiophysicsChinese Academy of SciencesBeijingChina
| | - Fei Wang
- State Key Laboratory of Brain and Cognitive Science, Institute of BiophysicsChinese Academy of SciencesBeijingChina
| | - Kai Yin
- Department of General SurgeryAffiliated Hospital of Jiangsu UniversityZhenjiangChina
| | - Jianghao Xu
- Department of Gastric SurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Bowen Li
- Department of Gastric SurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Zhongyuan He
- Department of Gastric SurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Lu Wang
- Department of Gastric SurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Hao Xu
- Department of Gastric SurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Diancai Zhang
- Department of Gastric SurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Li Yang
- Department of Gastric SurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Jane Y. Wu
- State Key Laboratory of Brain and Cognitive Science, Institute of BiophysicsChinese Academy of SciencesBeijingChina
- Department of Neurology, Center for Genetic MedicineNorthwestern University Feinberg School of MedicineChicagoIllinois
- Department of NeurologyCenter for Genetic MedicineLurie Cancer CenterChicagoIllinois
| | - Zekuan Xu
- Department of Gastric SurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and TreatmentJiangsu Collaborative Innovation Center for Cancer Personalized MedicineSchool of Publich HealthNanjing Medical UniversityNanjingChina
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Zhang H, Zhang N, Liu Y, Su P, Liang Y, Li Y, Wang X, Chen T, Song X, Sang Y, Duan Y, Zhang J, Wang L, Chen B, Zhao W, Guo H, Liu Z, Hu G, Yang Q. Epigenetic Regulation of NAMPT by NAMPT-AS
Drives Metastatic Progression in Triple-Negative Breast Cancer. Cancer Res 2019; 79:3347-3359. [PMID: 30940661 DOI: 10.1158/0008-5472.can-18-3418] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 02/26/2019] [Accepted: 03/29/2019] [Indexed: 11/16/2022]
Affiliation(s)
- Hanwen Zhang
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Ning Zhang
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Ying Liu
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Peng Su
- Department of Pathology, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Yiran Liang
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Yaming Li
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Xiaolong Wang
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Tong Chen
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Xiaojin Song
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Yuting Sang
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Yi Duan
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Jiashu Zhang
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Lijuan Wang
- Pathology Tissue Bank, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Bing Chen
- Pathology Tissue Bank, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Wenjing Zhao
- Pathology Tissue Bank, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Haiyang Guo
- Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada
| | - Zhaojian Liu
- Department of Cell Biology, Shandong University School of Medicine, Jinan, China
| | - Guohong Hu
- The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences, Shanghai, China
| | - Qifeng Yang
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China.
- Pathology Tissue Bank, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
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Liu H, Du F, Sun L, Wu Q, Wu J, Tong M, Wang X, Wang Q, Cao T, Gao X, Cao J, Wu N, Nie Y, Fan D, Lu Y, Zhao X. GATA6 suppresses migration and metastasis by regulating the miR-520b/CREB1 axis in gastric cancer. Cell Death Dis 2019; 10:35. [PMID: 30674866 PMCID: PMC6426848 DOI: 10.1038/s41419-018-1270-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 12/05/2018] [Accepted: 12/06/2018] [Indexed: 01/10/2023]
Abstract
Transcription factors (TFs) and microRNAs (miRNAs) are tightly linked to each other in tumor development and progression, but their interactions in gastric cancer (GC) metastasis remain elusive. Here we report a novel suppressive role of GATA6 in inhibiting GC metastasis by transactivating miR-520b. We found that GATA6 expression was significantly downregulated in metastatic GC cells and tissues and that its downregulation was correlated with a poor GC prognosis. Overexpression of GATA6 suppressed GC cell migration, invasion and metastasis both in vitro and in vivo. Luciferase reporter assays and chromatin immunoprecipitation assays demonstrated that miR-520b is a direct transcriptional target of GATA6. Moreover, miR-520b expression was positively correlated with GATA6 expression in GC tissues, and ectopic expression of miR-520b inhibited the migration and invasion of GC cells. Furthermore, cAMP responsive element binding protein 1 (CREB1) was identified as a direct and functional target of miR-520b, and GATA6 could suppress GC cell migration and metastasis via miR-520b-mediated repression of CREB1. Downregulation of GATA6 and miR-520b may partly account for the overexpression of CREB1 in GC. In conclusion, our results provide novel insight into the TF-miRNA regulatory network involved in GC metastasis. Targeting the GATA6/miR-520b/CREB1 axis may be an effective approach for GC treatment.
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Affiliation(s)
- Hao Liu
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Feng Du
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Lina Sun
- Department of Gastroenterology, Xi'an Children's Hospital, Xi'an, Shaanxi, China
| | - Qingfeng Wu
- Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Jian Wu
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Mingfu Tong
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Xin Wang
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Qi Wang
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Tianyu Cao
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xiaoliang Gao
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Jiayi Cao
- Faculty of Life Science, Northwest University, Xi'an, Shaanxi, China
| | - Nan Wu
- Faculty of Life Science, Northwest University, Xi'an, Shaanxi, China
| | - Yongzhan Nie
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Daiming Fan
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China.
| | - Yuanyuan Lu
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China.
| | - Xiaodi Zhao
- State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China.
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Zhang J, Wu Y, Jin HY, Guo S, Dong Z, Zheng ZC, Wang Y, Zhao Y. Prognostic value of sorting nexin 10 weak expression in stomach adenocarcinoma revealed by weighted gene co-expression network analysis. World J Gastroenterol 2018; 24:4906-4919. [PMID: 30487700 PMCID: PMC6250920 DOI: 10.3748/wjg.v24.i43.4906] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 10/17/2018] [Accepted: 10/21/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To detect significant clusters of co-expressed genes associated with tumorigenesis that might help to predict stomach adenocarcinoma (SA) prognosis.
METHODS The Cancer Genome Atlas database was used to obtain RNA sequences as well as complete clinical data of SA and adjacent normal tissues from patients. Weighted gene co-expression network analysis (WGCNA) was used to investigate the meaningful module along with hub genes. Expression of hub genes was analyzed in 362 paraffin-embedded SA biopsy tissues by immunohistochemical staining. Patients were classified into two groups (according to expression of hub genes): Weak expression and over-expression groups. Correlation of biomarkers with clinicopathological factors indicated patient survival.
RESULTS Whole genome expression level screening identified 6,231 differentially expressed genes. Twenty-four co-expressed gene modules were identified using WGCNA. Pearson’s correlation analysis showed that the tan module was the most relevant to tumor stage (r = 0.24, P = 7 × 10-6). In addition, we detected sorting nexin (SNX)10 as the hub gene of the tan module. SNX10 expression was linked to T category (P = 0.042, χ2 = 8.708), N category (P = 0.000, χ2 = 18.778), TNM stage (P = 0.001, χ2 = 16.744) as well as tumor differentiation (P = 0.000, χ2 = 251.930). Patients with high SNX10 expression tended to have longer disease-free survival (DFS; 44.97 mo vs 33.85 mo, P = 0.000) as well as overall survival (OS; 49.95 vs 40.84 mo, P = 0.000) in univariate analysis. Multivariate analysis showed that dismal prognosis could be precisely predicted clinicopathologically using SNX10 [DFS: P = 0.014, hazard ratio (HR) = 0.698, 95% confidence interval (CI): 0.524-0.930, OS: P = 0.017, HR = 0.704, 95%CI: 0.528-0.940].
CONCLUSION This study provides a new technique for screening prognostic biomarkers of SA. Weak expression of SNX10 is linked to poor prognosis, and is a suitable prognostic biomarker of SA.
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Affiliation(s)
- Jun Zhang
- Department of Gastric Cancer, Liaoning Cancer Hospital and Institute (Cancer Hospital of China Medical University), Shenyang 110042, Liaoning Province, China
| | - Yue Wu
- Department of Emergency, Sheng Jing Hospital of China Medical University, Shenyang 110042, Liaoning Province, China
| | - Hao-Yi Jin
- Pancreatic and Thyroid Surgery Department, Sheng Jing Hospital of China Medical University, Shenyang 110042, Liaoning Province, China
| | - Shuai Guo
- Department of Gastric Cancer, Liaoning Cancer Hospital and Institute (Cancer Hospital of China Medical University), Shenyang 110042, Liaoning Province, China
| | - Zhe Dong
- Department of Gastric Cancer, Liaoning Cancer Hospital and Institute (Cancer Hospital of China Medical University), Shenyang 110042, Liaoning Province, China
| | - Zhi-Chao Zheng
- Department of Gastric Cancer, Liaoning Cancer Hospital and Institute (Cancer Hospital of China Medical University), Shenyang 110042, Liaoning Province, China
| | - Yue Wang
- Department of Gastric Cancer, Liaoning Cancer Hospital and Institute (Cancer Hospital of China Medical University), Shenyang 110042, Liaoning Province, China
| | - Yan Zhao
- Department of Gastric Cancer, Liaoning Cancer Hospital and Institute (Cancer Hospital of China Medical University), Shenyang 110042, Liaoning Province, China
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Moirangthem A, Wang X, Yan IK, Patel T. Network analyses-based identification of circular ribonucleic acid-related pathways in intrahepatic cholangiocarcinoma. Tumour Biol 2018; 40:1010428318795761. [PMID: 30168369 DOI: 10.1177/1010428318795761] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Circular ribonucleic acids are non-coding ribonucleic acids that can be identified from genome sequencing studies. Although they can be readily detected, their regulation and functional role in human diseases such as cancer are unknown. Using a systematic approach, we analyzed ribonucleic acid-sequencing data from a well-characterized cohort of intrahepatic cholangiocarcinoma to identify genetic pathways related to circular ribonucleic acids. Although the expression of most circular ribonucleic acids was similar in both the cancer and non-cancer tissues, expression of circ2174 was significantly increased in cancer tissues. Network analysis of co-related genes identified several pathways associated with circ2174, and common regulatory mediators between genes in these pathways and circ2174. Among these, alterations in several genes involved in interleukin-16 signaling responses such Lck, interleukin-16, and macrophage inflammatory protein-1-beta were the most prominent. Octamer transcription factor (Oct)-2 was identified as a signal transducer that was common to both circ2174 and interleukin-16. Circ2174 has sequence complementarity to miR149 which can target Oct-2. These data suggest a mechanism whereby circ2174 can act as a sponge to regulate the expression of miR149, and thereby modulate Oct-2 and interleukin-16 signaling pathways in cholangiocarcinoma.
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Affiliation(s)
| | - Xue Wang
- 2 Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA
| | - Irene K Yan
- 1 Department of Transplantation, Mayo Clinic, Jacksonville, FL, USA
| | - Tushar Patel
- 1 Department of Transplantation, Mayo Clinic, Jacksonville, FL, USA.,3 Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
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Hu G, Lv Q, Yan J, Chen L, Du J, Zhao K, Xu W. MicroRNA-17 as a promising diagnostic biomarker of gastric cancer: An investigation combining TCGA, GEO, meta-analysis, and bioinformatics. FEBS Open Bio 2018; 8:1508-1523. [PMID: 30186751 PMCID: PMC6120248 DOI: 10.1002/2211-5463.12496] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 07/03/2018] [Accepted: 07/06/2018] [Indexed: 12/19/2022] Open
Abstract
Integrated studies of accumulated data can be performed to obtain more reliable information and more feasible measures for investigating potential diagnostic biomarkers of gastric cancer (GC) and to explore related molecular mechanisms. This study aimed to identify microRNAs involved in GC by integrating data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus. Through our analysis, we identified hsa‐miR‐17 (miR‐17) as a suitable candidate. We performed a meta‐analysis of published studies and analyzed clinical data from TCGA to evaluate the clinical significance and diagnostic value of miR‐17 in GC. miR‐17 was found to be upregulated in GC tissues and exhibited a favorable value in diagnosing GC. In addition, we predicted that 288 target genes of miR‐17 participate in GC‐related pathways. Enrichment of Kyoto Encyclopedia of Genes and Genomes pathway, Gene Ontology analysis, and protein–protein interaction analysis of the 288 target genes of miR‐17 were also performed. Through this study, we identified possible core pathways and genes that may play an important role in GC. The possible core pathways include the cAMP, phosphoinositide‐3‐kinase–Akt, Rap1, and mitogen‐activated protein kinase signaling pathways. miR‐17 may be involved in several biological processes, including DNA template transcription, the regulation of transcription from RNA polymerase II promoters, and cell adhesion. In addition, cellular components (such as cytoplasm and plasma membrane) and molecular functions (such as protein binding and metal ion binding) also seemed to be regulated by miR‐17.
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Affiliation(s)
- GaoFeng Hu
- Department of Clinical Laboratory The First Hospital of Jilin University Changchun China
| | - QianWen Lv
- Department of Clinical Laboratory The First Hospital of Jilin University Changchun China
| | - JiaXiu Yan
- Department of Neonatology The First Hospital of Jilin University Changchun China
| | - LiJun Chen
- Department of Clinical Laboratory The First Hospital of Jilin University Changchun China
| | - Juan Du
- Institute of Virology and AIDS Research The First Hospital of Jilin University Changchun China
| | - Ke Zhao
- Institute of Virology and AIDS Research The First Hospital of Jilin University Changchun China
| | - Wei Xu
- Department of Clinical Laboratory The First Hospital of Jilin University Changchun China
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44
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Hu L, Wu H, Wan X, Liu L, He Y, Zhu L, Liu S, Yao H, Zhu Z. MicroRNA-585 suppresses tumor proliferation and migration in gastric cancer by directly targeting MAPK1. Biochem Biophys Res Commun 2018; 499:52-58. [DOI: 10.1016/j.bbrc.2018.03.116] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Accepted: 03/14/2018] [Indexed: 02/07/2023]
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45
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Li X, Jiang M, Chen D, Xu B, Wang R, Chu Y, Wang W, Zhou L, Lei Z, Nie Y, Fan D, Shang Y, Wu K, Liang J. miR-148b-3p inhibits gastric cancer metastasis by inhibiting the Dock6/Rac1/Cdc42 axis. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:71. [PMID: 29587866 PMCID: PMC5872400 DOI: 10.1186/s13046-018-0729-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 03/08/2018] [Indexed: 12/19/2022]
Abstract
Background Our previous work showed that some Rho GTPases, including Rho, Rac1 and Cdc42, play critical roles in gastric cancer (GC); however, how they are regulated in GC remains largely unknown. In this study, we aimed to investigate the roles and molecular mechanisms of Dock6, an atypical Rho guanine nucleotide exchange factor (GEF), in GC metastasis. Methods The expression levels of Dock6 and miR-148b-3p in GC tissues and paired nontumor tissues were determined by immunohistochemistry (IHC) and in situ hybridization (ISH), respectively. The correlation between Dock6/miR-148b-3p expression and the overall survival of GC patients was calculated by the Kaplan-Meier method and log-rank test. The roles of Dock6 and miR-148b-3p in GC were investigated by in vitro and in vivo functional studies. Rac1 and Cdc42 activation was investigated by GST pull-down assays. The inhibition of Dock6 transcription by miR-148b-3p was determined by luciferase reporter assays. Results A significant increase in Dock6 expression was found in GC tissues compared with nontumor tissues, and its positive expression was associated with lymph node metastasis and a higher TNM stage. Patients with positive Dock6 expression exhibited shorter overall survival periods than patients with negative Dock6 expression. Dock6 promoted GC migration and invasion by increasing the activation of Rac1 and Cdc42. miR-148b-3p expression was negatively correlated with Dock6 expression in GC, and it decreased the motility of GC cells by inhibiting the Dock6/Rac1/Cdc42 axis. Conclusions Dock6 was over-expressed in GC tissues, and its positive expression was associated with GC metastasis and indicated poor prognosis of GC patients. Targeting of Dock6 by miR-148b-3p could activate Rac1 and Cdc42, directly affecting the motility of GC cells. Targeting the Dock6-Rac1/Cdc42 axis could serve as a new therapeutic strategy for GC treatment. Electronic supplementary material The online version of this article (10.1186/s13046-018-0729-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xiaowei Li
- State Key Laboratory of Cancer Biology & National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, Shaanxi, 710032, China
| | - Mingzuo Jiang
- State Key Laboratory of Cancer Biology & National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, Shaanxi, 710032, China
| | - Di Chen
- State Key Laboratory of Cancer Biology & National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, Shaanxi, 710032, China
| | - Bing Xu
- State Key Laboratory of Cancer Biology & National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, Shaanxi, 710032, China.,Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710004, China
| | - Rui Wang
- National-Local Joint Engineering Research Center of Biodiagnostics & Biotheraphy, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710032, China
| | - Yi Chu
- State Key Laboratory of Cancer Biology & National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, Shaanxi, 710032, China
| | - Weijie Wang
- State Key Laboratory of Cancer Biology & National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, Shaanxi, 710032, China
| | - Lin Zhou
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Zhijie Lei
- State Key Laboratory of Cancer Biology & National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, Shaanxi, 710032, China
| | - Yongzhan Nie
- State Key Laboratory of Cancer Biology & National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, Shaanxi, 710032, China
| | - Daiming Fan
- State Key Laboratory of Cancer Biology & National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, Shaanxi, 710032, China
| | - Yulong Shang
- State Key Laboratory of Cancer Biology & National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, Shaanxi, 710032, China.
| | - Kaichun Wu
- State Key Laboratory of Cancer Biology & National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, Shaanxi, 710032, China.
| | - Jie Liang
- State Key Laboratory of Cancer Biology & National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, Shaanxi, 710032, China.
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Sun G, Peng B, Xie Q, Ruan J, Liang X. Upregulation of ZBTB7A exhibits a tumor suppressive role in gastric cancer cells. Mol Med Rep 2017; 17:2635-2641. [PMID: 29207095 DOI: 10.3892/mmr.2017.8104] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 07/25/2017] [Indexed: 11/06/2022] Open
Abstract
Gastric cancer presents as a complex solid tumor and is the third leading cause of global cancer‑associated mortality. The genetic alterations in gastric cancer remain unclear and deserve further investigation. Mining The Cancer Genome Atlas gastric adenocarcinoma dataset identified a frequent loss of the zinc finger and BTB domain containing 7A (ZBTB7A) gene locus and a significant correlation between low ZBTB7A expression and poor patient survival. ZBTB7A belongs to the POZ/BTB and Kruppel transcription factor family. In the present study, overexpression of ZBTB7A in a gastric cancer cell line induced cell cycle arrest at the S phase. Upregulation of ZBTB7A also promoted apoptosis and repressed cell migration. The results of the present study indicated that ZBTB7A functions as a tumor suppressor in gastric cancer cells. Understanding the role of ZBTB7A in gastric cancer may provide important clinical insight for treatment.
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Affiliation(s)
- Guang Sun
- Department of Gastroenterology Surgery, Haikou Municipal People's Hospital, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou, Hainan 570208, P.R. China
| | - Bo Peng
- Department of Gastroenterology Surgery, Haikou Municipal People's Hospital, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou, Hainan 570208, P.R. China
| | - Quan Xie
- Department of Gastroenterology Surgery, Haikou Municipal People's Hospital, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou, Hainan 570208, P.R. China
| | - Jianwen Ruan
- Department of Gastroenterology Surgery, Haikou Municipal People's Hospital, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou, Hainan 570208, P.R. China
| | - Xianwen Liang
- Department of Gastroenterology Surgery, Haikou Municipal People's Hospital, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou, Hainan 570208, P.R. China
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Peng Z, Wang J, Shan B, Yuan F, Li B, Dong Y, Peng W, Shi W, Cheng Y, Gao Y, Zhang C, Duan C. Genome-wide analyses of long noncoding RNA expression profiles in lung adenocarcinoma. Sci Rep 2017; 7:15331. [PMID: 29127420 PMCID: PMC5681506 DOI: 10.1038/s41598-017-15712-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 10/31/2017] [Indexed: 01/01/2023] Open
Abstract
LncRNAs have emerged as a novel class of critical regulators of cancer. We aimed to construct a landscape of lncRNAs and their potential target genes in lung adenocarcinoma. Genome-wide expression of lncRNAs and mRNAs was determined using microarray. qRT-PCR was performed to validate the expression of the selected lncRNAs in a cohort of 42 tumor tissues and adjacent normal tissues. R and Bioconductor were used for data analysis. A total of 3045 lncRNAs were differentially expressed between the paired tumor and normal tissues (1048 up and 1997 down). Meanwhile, our data showed that the expression NONHSAT077036 was associated with N classification and clinical stage. Further, we analyzed the potential co-regulatory relationship between the lncRNAs and their potential target genes using the ‘cis’ and ‘trans’ models. In the 25 related transcription factors (TFs), our analysis of The Cancer Genome Atlas database (TCGA) found that patients with lower expression of POU2F2 and higher expression of TRIM28 had a shorter overall survival time. The POU2F2 and TRIM28 co-expressed lncRNA landscape characterized here may shed light into normal biology and lung adenocarcinoma pathogenesis, and be valuable for discovery of biomarkers.
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Affiliation(s)
- Zhenzi Peng
- Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, 410008, P. R. China
| | - Jun Wang
- Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, 410008, P. R. China
| | - Bin Shan
- Washington State University, Elison S Floyd College of Medicine, P.O. Box 1495, Spokane, WA, 99210-1495, USA
| | - Fulai Yuan
- Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, 410008, P. R. China
| | - Bin Li
- Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, 410008, P. R. China
| | - Yeping Dong
- Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, 410008, P. R. China
| | - Wei Peng
- Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, 410008, P. R. China
| | - Wenwen Shi
- Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, 410008, P. R. China
| | - Yuanda Cheng
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, P. R. China
| | - Yang Gao
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, P. R. China
| | - Chunfang Zhang
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, P. R. China
| | - Chaojun Duan
- Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, 410008, P. R. China. .,Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, P. R. China.
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Zhang X, Dong J, He Y, Zhao M, Liu Z, Wang N, Jiang M, Zhang Z, Liu G, Liu H, Nie Y, Fan D, Tie J. miR-218 inhibited tumor angiogenesis by targeting ROBO1 in gastric cancer. Gene 2017; 615:42-49. [PMID: 28323002 DOI: 10.1016/j.gene.2017.03.022] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Revised: 02/22/2017] [Accepted: 03/16/2017] [Indexed: 12/20/2022]
Abstract
Aberrant expression of miRNAs is involved in several carcinogenic processes, including tumor growth, metastasis and angiogenesis. The aim of this study was to determine the role of miR-218 in gastric cancer angiogenesis. In situ hybridization was performed on a set of tissue microarray samples to assess the difference in miR-218 expression in vessels between tumor tissues and normal gastric mucosa. In vitro, ectopic expression of miR-218 disturbed the tubular structure and inhibited the migration of endothelial cells. Motility and tube formation were rescued when miR-218 was downregulated. Moreover, miR-218 suppressed endothelial cell sprouting in a fibrin bead sprouting assay. Subsequently, we identified ROBO1 as a target of miR-218 in endothelial cells and determined it was responsible for the effect of miR-218 on tumor angiogenesis. In vivo, local injection of mature miR-218 in xenografted tumors disrupted the vessel plexus and thus inhibited tumor growth. Taken together, our study demonstrated an anti-angiogenic role of miR-218 in gastric cancer and indicated that delivery of miR-218 may be a potential therapeutic strategy to inhibit tumor angiogenesis.
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Affiliation(s)
- Xiangyuan Zhang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Jiaqiang Dong
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Yan He
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Ming Zhao
- Yan'an University, Yan'an 716000, China
| | - Zhen Liu
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Na Wang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Mingzuo Jiang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Zhe Zhang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Gang Liu
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Haiming Liu
- College of Computer Science and Technology, Jilin University, Changchun 120012, China
| | - Yongzhan Nie
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Daiming Fan
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
| | - Jun Tie
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
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49
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Xiang Z, Zhou ZJ, Xia GK, Zhang XH, Wei ZW, Zhu JT, Yu J, Chen W, He Y, Schwarz RE, Brekken RA, Awasthi N, Zhang CH. A positive crosstalk between CXCR4 and CXCR2 promotes gastric cancer metastasis. Oncogene 2017; 36:5122-5133. [PMID: 28481874 DOI: 10.1038/onc.2017.108] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Revised: 02/16/2017] [Accepted: 03/14/2017] [Indexed: 02/07/2023]
Abstract
The molecular mechanism underlying gastric cancer (GC) invasion and metastasis is still poorly understood. In this study, we tried to investigate the roles of CXCR4 and CXCR2 signalings in gastric cancer metastasis. A highly invasive gastric cancer cell model was established. Chemokines receptors were profiled to search for the accountable ones. Then the underlying molecular mechanism was investigated using both in vitro and in vivo techniques, and the clinical relevance of CXCR4 and CXCR2 expression was studied in gastric cancer samples. CXCR4 and CXCR2 were highly expressed in a high invasive gastric cancer cell model and in gastric cancer tissues. Overexpression of CXCR4 and CXCR2 was associated with more advanced tumor stage and poorer survival for GC patients. CXCR4 and CXCR2 expression strongly correlated with each other in the way that CXCR2 expression changed accordingly with the activity of CXCR4 signaling and CXCR4 expression also changed in agreement with CXCR2 activity. Further studies demonstrated CXCR4 and CXCR2 can both activated NF-κB and STAT3 signaling, while NF-κBp65 can then transcriptionally activate CXCR4 and STAT3 can activate CXCR2 expression. This crosstalk between CXCR4 and CXCR2 contributed to EMT, migration and invasion of gastric cancer. Finally, Co-inhibition of CXCR4 and CXCR2 is more effective in reducing gastric cancer metastasis. Our results demonstrated that CXCR4 and CXCR2 cross-activate each other to promote the metastasis of gastric cancer.
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Affiliation(s)
- Z Xiang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.,Gastric Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Z-J Zhou
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.,Gastric Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - G-K Xia
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.,Gastric Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - X-H Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.,Gastric Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Z-W Wei
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.,Gastric Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - J-T Zhu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.,Gastric Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - J Yu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.,Gastric Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - W Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.,Gastric Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Y He
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.,Gastrointestinal Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - R E Schwarz
- Indiana University School of Medicine, South Bend, and IU Health Goshen Center for Cancer Care, Goshen, IN, USA
| | - R A Brekken
- Division of Surgical Oncology, Department of Surgery, and the Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - N Awasthi
- Indiana University School of Medicine, South Bend, and IU Health Goshen Center for Cancer Care, Goshen, IN, USA
| | - C-H Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.,Gastric Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China
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50
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Tie J, Zhang X, Fan D. Epigenetic roles in the malignant transformation of gastric mucosal cells. Cell Mol Life Sci 2016; 73:4599-4610. [PMID: 27464701 PMCID: PMC5097112 DOI: 10.1007/s00018-016-2308-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Revised: 06/10/2016] [Accepted: 07/08/2016] [Indexed: 12/14/2022]
Abstract
Gastric carcinogenesis occurs when gastric epithelial cells transition through the initial, immortal, premalignant, and malignant stages of transformation. Epigenetic regulations contribute to this multistep process. Due to the critical role of epigenetic modifications , these changes are highly likely to be of clinical use in the future as new biomarkers and therapeutic targets for the early detection and treatment of cancers. Here, we summarize the recent findings on how epigenetic modifications, including DNA methylation, histone modifications, and non-coding RNAs, regulate gastric carcinogenesis, and we discuss potential new strategies for the diagnosis and treatments of gastric cancer. The strategies may be helpful in the further understanding of epigenetic regulation in human diseases.
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Affiliation(s)
- Jun Tie
- State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, No. 127, West Chang-Le Road, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Xiangyuan Zhang
- State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, No. 127, West Chang-Le Road, Xi'an, Shaanxi, 710032, People's Republic of China
| | - Daiming Fan
- State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, No. 127, West Chang-Le Road, Xi'an, Shaanxi, 710032, People's Republic of China.
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