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Hong Y, An Q, Wang Z, Hu B, Yang Y, Zeng R, Yao Y. Multi-omics Analysis Reveals the Propagation Mechanism of Ferroptosis in Acute Kidney Injury. Inflammation 2025:10.1007/s10753-025-02311-7. [PMID: 40358793 DOI: 10.1007/s10753-025-02311-7] [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: 12/19/2024] [Revised: 04/01/2025] [Accepted: 04/28/2025] [Indexed: 05/15/2025]
Abstract
Acute kidney injury (AKI) is a prevalent and critical clinical condition characterized by high morbidity and mortality. Recently, numerous studies have implicated ferroptosis, an iron-dependent programmed cell death process, in the pathophysiology of AKI. Despite this, the mechanism underlying the widespread occurrence of ferroptosis in AKI remains elusive. To address this, our study analyzed snRNA-seq data from AKI and healthy renal tissues. The analysis revealed notable differences in ferroptosis activity within proximal tubule (PT) cells of AKI patients, specifically highlighting a strong correlation between ferroptosis and the expression of genes GPX4, FTH1, and FTL. Spatial transcriptomics confirmed that the genes GPX4, FTH1, and FTL play a crucial role in driving ferroptosis propagation in AKI. Furthermore, utilizing a mouse model of bilateral renal ischemia-reperfusion injury, we validated the emergence of ferroptosis mediated by these key genes following AKI. The findings from our in vivo experiments were consistent with the spatial transcriptomics data. Chromatin accessibility and transcription factor analysis identified KLF6 as a repressor of ferroptosis-related genes. An in-depth analysis of PT revealed a subpopulation closely associated with ferroptosis. The cellular microenvironment within this subpopulation may regulate ferroptosis through the SPP1 signaling pathway, ultimately influencing the outcome of PT following AKI. In conclusion, this study elucidates the crucial role of GPX4, FTH1, and FTL in ferroptosis propagation during AKI and underscores the potential therapeutic benefits of targeting ferroptosis in the management of AKI.
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Affiliation(s)
- Yu Hong
- Department of Nephrology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Qi An
- Department of Nephrology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Zheng Wang
- Department of Nephrology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Bin Hu
- Department of Nephrology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Yi Yang
- Department of Public Health, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Rui Zeng
- Department of Nephrology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
- Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, China.
| | - Ying Yao
- Department of Nephrology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
- Department of Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
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Ver Heul AM, Mack M, Zamidar L, Tamari M, Yang TL, Trier AM, Kim DH, Janzen-Meza H, Van Dyken SJ, Hsieh CS, Karo JM, Sun JC, Kim BS. RAG suppresses group 2 innate lymphoid cells. eLife 2025; 13:RP98287. [PMID: 40326866 PMCID: PMC12055012 DOI: 10.7554/elife.98287] [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] [Indexed: 05/07/2025] Open
Abstract
Antigen specificity is the central trait distinguishing adaptive from innate immune function. Assembly of antigen-specific T cell and B cell receptors occurs through V(D)J recombination mediated by the Recombinase Activating Gene endonucleases RAG1 and RAG2 (collectively called RAG). In the absence of RAG, mature T and B cells do not develop and thus RAG is critically associated with adaptive immune function. In addition to adaptive T helper 2 (Th2) cells, group 2 innate lymphoid cells (ILC2s) contribute to type 2 immune responses by producing cytokines like Interleukin-5 (IL-5) and IL-13. Although it has been reported that RAG expression modulates the function of innate natural killer (NK) cells, whether other innate immune cells such as ILC2s are affected by RAG remains unclear. We find that in RAG-deficient mice, ILC2 populations expand and produce increased IL-5 and IL-13 at steady state and contribute to increased inflammation in atopic dermatitis (AD)-like disease. Furthermore, we show that RAG modulates ILC2 function in a cell-intrinsic manner independent of the absence or presence of adaptive T and B lymphocytes. Lastly, employing multiomic single cell analyses of RAG1 lineage-traced cells, we identify key transcriptional and epigenomic ILC2 functional programs that are suppressed by a history of RAG expression. Collectively, our data reveal a novel role for RAG in modulating innate type 2 immunity through suppression of ILC2s.
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Affiliation(s)
- Aaron M Ver Heul
- Division of Allergy and Immunology, Department of Medicine, Washington University School of MedicineSt. LouisUnited States
| | - Madison Mack
- Immunology and Inflammation Research Therapeutic Area, SanofiCambridgeUnited States
| | - Lydia Zamidar
- Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
- Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount SinaiNew YorkUnited States
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount SinaiNew YorkUnited States
- Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Masato Tamari
- Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
- Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount SinaiNew YorkUnited States
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount SinaiNew YorkUnited States
- Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Ting-Lin Yang
- Division of Dermatology, Department of Medicine, Washington University School of MedicineSt. LouisUnited States
| | - Anna M Trier
- Division of Dermatology, Department of Medicine, Washington University School of MedicineSt. LouisUnited States
| | - Do-Hyun Kim
- Department of Pathology and Immunology, Washington University School of MedicineSt. LouisUnited States
- Department of Life Science, College of Natural Sciences, Hanyang UniversitySeoulRepublic of Korea
| | - Hannah Janzen-Meza
- Division of Allergy and Immunology, Department of Medicine, Washington University School of MedicineSt. LouisUnited States
| | - Steven J Van Dyken
- Department of Pathology and Immunology, Washington University School of MedicineSt. LouisUnited States
| | - Chyi-Song Hsieh
- Division of Rheumatology, Department of Medicine, Washington University School of MedicineSt. LouisUnited States
| | - Jenny M Karo
- Immunology and Microbial Pathogenesis Program, Graduate School of Medical Sciences, Weill Cornell Medical CollegeNew YorkUnited States
- Immunology Program, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
| | - Joseph C Sun
- Immunology and Microbial Pathogenesis Program, Graduate School of Medical Sciences, Weill Cornell Medical CollegeNew YorkUnited States
- Immunology Program, Memorial Sloan Kettering Cancer CenterNew YorkUnited States
| | - Brian S Kim
- Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
- Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount SinaiNew YorkUnited States
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount SinaiNew YorkUnited States
- Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNew YorkUnited States
- Allen Discovery Center for Neuroimmune Interactions, Icahn School of Medicine at Mount SinaiNew YorkUnited States
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3
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Sahoo R, Pattnaik S, Mohanty B, Mir SA, Behera B. Aryl hydrocarbon receptor (AHR) signalling: A double-edged sword guiding both cancer progression and cancer therapy. Biochim Biophys Acta Gen Subj 2025; 1869:130805. [PMID: 40222634 DOI: 10.1016/j.bbagen.2025.130805] [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: 12/20/2024] [Revised: 02/21/2025] [Accepted: 04/05/2025] [Indexed: 04/15/2025]
Abstract
Aryl Hydrocarbon Receptor (AHR) reported to be associated with major carcinogenic signalling cascades which cause cell proliferations, metastasis and invasion as well as immune imbalance. AHR Participates in cellular processes not only through genomic pathways to cause genomic alterations but also via nongenomic pathways to alter various cytoplasmic proteins. In addition, AHR senses a wide range of ligands that modulate its downstream mechanisms that are intricated in cancer induction and prevention. Thus, AHR functions as a two-sided sword where some AHR ligands contribute to enhance cancer whereas few are useful for cancer treatment. Therefore, AHR represent as a regulatory point in cancer progression and treatment. There is a need to reinvestigate the regulatory role of AHR in major intracellular pathways and to explore the potential of AHR ligand for the design of cancer therapeutics. This review emphasizes the interaction of AHR with pro-carcinogenic signalling pathways that modulate cancer induction and progression. Furthermore, it also discusses about the current discovery of AHR ligands for cancer initiation or inhibition. This information could be useful for development of therapeutic strategies for the management of cancer by targeting AHR.
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Affiliation(s)
- Rahul Sahoo
- Department of Biotechnology and Bioinformatics, Sambalpur University, Jyoti Vihar, Burla, Odisha 768019, India
| | - Sriya Pattnaik
- Department of Biotechnology and Bioinformatics, Sambalpur University, Jyoti Vihar, Burla, Odisha 768019, India
| | - Biswajit Mohanty
- Department of Biotechnology and Bioinformatics, Sambalpur University, Jyoti Vihar, Burla, Odisha 768019, India
| | - Showkat Ahmad Mir
- School of Life Sciences, Sambalpur University, Jyoti Vihar, Burla, Odisha 768019, India
| | - Birendra Behera
- Department of Biotechnology and Bioinformatics, Sambalpur University, Jyoti Vihar, Burla, Odisha 768019, India.
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4
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Soukar I, Fisher RJ, Bhagavatula S, Collard M, Cole PA, Alani RM. The CoREST complex is a therapeutic vulnerability in malignant peripheral nerve sheath tumors. Sci Rep 2025; 15:10128. [PMID: 40128216 PMCID: PMC11933703 DOI: 10.1038/s41598-025-94517-w] [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: 11/26/2024] [Accepted: 03/14/2025] [Indexed: 03/26/2025] Open
Abstract
Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive sarcoma that may be seen in patients with neurofibromatosis type 1 (NF1) or occur sporadically. While surgery is the primary treatment for localized MPNST with a 61.9% overall survival rate, metastatic disease is often fatal due to resistance to systemic therapies which underscores the urgent need for effective treatments. MPNSTs frequently harbor inactivating driver mutations in the PRC2 epigenetic repressor complex suggesting epigenetic therapies may represent a specific vulnerability in these tumors. Here, we investigate the role of the LSD1-HDAC1-CoREST (LHC) repressor complex in mediating MPNST tumor growth and progression. Our findings demonstrate that the LHC small molecule inhibitor, corin, induces apoptosis and significantly inhibits proliferation in MPNST cells. Transcriptomic analysis of corin-treated MPNST cells demonstrates specific increases in genes associated with axonogenesis and neuronal differentiation as well as altered extracellular matrix; additionally, corin treatment is shown to inhibit MPNST invasion in vitro. These results underscore the critical role of the LHC complex in facilitating MPNST growth and progression and suggest that targeting the LHC complex represents a promising therapeutic approach for this aggressive malignancy.
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Affiliation(s)
- Imad Soukar
- Department of Dermatology, Boston University Chobanian and Avedisian School of Medicine, 609 Albany Street, J-507, Boston, MA, 02118, USA
| | - Robert J Fisher
- Department of Dermatology, Boston University Chobanian and Avedisian School of Medicine, 609 Albany Street, J-507, Boston, MA, 02118, USA
| | - Sanjana Bhagavatula
- Department of Dermatology, Boston University Chobanian and Avedisian School of Medicine, 609 Albany Street, J-507, Boston, MA, 02118, USA
| | - Marianne Collard
- Department of Dermatology, Boston University Chobanian and Avedisian School of Medicine, 609 Albany Street, J-507, Boston, MA, 02118, USA
| | - Philip A Cole
- Division of Genetics, Departments of Medicine and Biological Chemistry and Molecular Pharmacology, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA
| | - Rhoda M Alani
- Department of Dermatology, Boston University Chobanian and Avedisian School of Medicine, 609 Albany Street, J-507, Boston, MA, 02118, USA.
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5
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Wang K, Lan Z, Zhou H, Fan R, Chen H, Liang H, You Q, Liang X, Zeng G, Deng R, Lan Y, Shen S, Chen P, Hou J, Bu P, Sun J. Long-chain acylcarnitine deficiency promotes hepatocarcinogenesis. Acta Pharm Sin B 2025; 15:1383-1396. [PMID: 40370557 PMCID: PMC12069247 DOI: 10.1016/j.apsb.2025.01.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 01/04/2025] [Accepted: 01/10/2025] [Indexed: 05/16/2025] Open
Abstract
Despite therapy with potent antiviral agents, chronic hepatitis B (CHB) patients remain at high risk of hepatocellular carcinoma (HCC). While metabolites have been rediscovered as active drivers of biological processes including carcinogenesis, the specific metabolites modulating HCC risk in CHB patients are largely unknown. Here, we demonstrate that baseline plasma from CHB patients who later developed HCC during follow-up exhibits growth-promoting properties in a case-control design nested within a large-scale, prospective cohort. Metabolomics analysis reveals a reduction in long-chain acylcarnitines (LCACs) in the baseline plasma of patients with HCC development. LCACs preferentially inhibit the proliferation of HCC cells in vitro at a physiological concentration and prevent the occurrence of HCC in vivo without hepatorenal toxicity. Uptake and metabolism of circulating LCACs increase the intracellular level of acetyl coenzyme A, which upregulates histone H3 Lys14 acetylation at the promoter region of KLF6 gene and thereby activates KLF6/p21 pathway. Indeed, blocking LCAC metabolism attenuates the difference in KLF6/p21 expression induced by baseline plasma of HCC/non-HCC patients. The deficiency of circulating LCACs represents a driver of HCC in CHB patients with viral control. These insights provide a promising direction for developing therapeutic strategies to reduce HCC risk further in the antiviral era.
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Affiliation(s)
- Kaifeng Wang
- State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China, Ministry of Education; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Provincial Key Laboratory of Viral Hepatitis Research; Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Zhixian Lan
- State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China, Ministry of Education; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Provincial Key Laboratory of Viral Hepatitis Research; Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Heqi Zhou
- State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China, Ministry of Education; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Provincial Key Laboratory of Viral Hepatitis Research; Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Rong Fan
- State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China, Ministry of Education; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Provincial Key Laboratory of Viral Hepatitis Research; Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Huiyi Chen
- State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China, Ministry of Education; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Provincial Key Laboratory of Viral Hepatitis Research; Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Hongyan Liang
- State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China, Ministry of Education; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Provincial Key Laboratory of Viral Hepatitis Research; Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Qiuhong You
- State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China, Ministry of Education; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Provincial Key Laboratory of Viral Hepatitis Research; Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Xieer Liang
- State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China, Ministry of Education; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Provincial Key Laboratory of Viral Hepatitis Research; Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Ge Zeng
- State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China, Ministry of Education; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Provincial Key Laboratory of Viral Hepatitis Research; Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Rui Deng
- State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China, Ministry of Education; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Provincial Key Laboratory of Viral Hepatitis Research; Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yu Lan
- State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China, Ministry of Education; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Provincial Key Laboratory of Viral Hepatitis Research; Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Sheng Shen
- State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China, Ministry of Education; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Provincial Key Laboratory of Viral Hepatitis Research; Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Peng Chen
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China, Ministry of Education; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Provincial Key Laboratory of Viral Hepatitis Research; Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Pengcheng Bu
- Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jian Sun
- State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China, Ministry of Education; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Provincial Key Laboratory of Viral Hepatitis Research; Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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6
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Su X, Hu P, Li D, Zhao B, Niu Z, Herget T, Yu PS, Hu L. Interpretable identification of cancer genes across biological networks via transformer-powered graph representation learning. Nat Biomed Eng 2025; 9:371-389. [PMID: 39789329 DOI: 10.1038/s41551-024-01312-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 11/01/2024] [Indexed: 01/12/2025]
Abstract
Graph representation learning has been leveraged to identify cancer genes from biological networks. However, its applicability is limited by insufficient interpretability and generalizability under integrative network analysis. Here we report the development of an interpretable and generalizable transformer-based model that accurately predicts cancer genes by leveraging graph representation learning and the integration of multi-omics data with the topologies of homogeneous and heterogeneous networks of biological interactions. The model allows for the interpretation of the respective importance of multi-omic and higher-order structural features, achieved state-of-the-art performance in the prediction of cancer genes across biological networks (including networks of interactions between miRNA and proteins, transcription factors and proteins, and transcription factors and miRNA) in pan-cancer and cancer-specific scenarios, and predicted 57 cancer-gene candidates (including three genes that had not been identified by other models) among 4,729 unlabelled genes across 8 pan-cancer datasets. The model's interpretability and generalization may facilitate the understanding of gene-related regulatory mechanisms and the discovery of new cancer genes.
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Affiliation(s)
- Xiaorui Su
- Xinjiang Technical Institutes of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, China
- University of Chinese Academy of Sciences, Beijing, China
- Department of Computer Science, University of Illinois Chicago, Chicago, IL, USA
| | - Pengwei Hu
- Xinjiang Technical Institutes of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Dongxu Li
- Xinjiang Technical Institutes of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Bowei Zhao
- Xinjiang Technical Institutes of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Zhaomeng Niu
- Department of Health Informatics, Rutgers School of Health Professions, Piscataway, NJ, USA
| | | | - Philip S Yu
- Department of Computer Science, University of Illinois Chicago, Chicago, IL, USA
| | - Lun Hu
- Xinjiang Technical Institutes of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, China.
- University of Chinese Academy of Sciences, Beijing, China.
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7
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Dollinger E, Hernandez-Davies J, Felgner J, Jain A, Hwang M, Strahsburger E, Nakajima R, Jasinskas A, Nie Q, Pone EJ, Othy S, Davies DH. Combination adjuvant improves influenza virus immunity by downregulation of immune homeostasis genes in lymphocytes. Immunohorizons 2025; 9:vlae007. [PMID: 39849993 PMCID: PMC11841980 DOI: 10.1093/immhor/vlae007] [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: 10/23/2024] [Accepted: 10/23/2024] [Indexed: 01/30/2025] Open
Abstract
Adjuvants play a central role in enhancing the immunogenicity of otherwise poorly immunogenic vaccine antigens. Combining adjuvants has the potential to enhance vaccine immunogenicity compared with single adjuvants, although the cellular and molecular mechanisms of combination adjuvants are not well understood. Using the influenza virus hemagglutinin H5 antigen, we define the immunological landscape of combining CpG and MPLA (TLR-9 and TLR-4 agonists, respectively) with a squalene nanoemulsion (AddaVax) using immunologic and transcriptomic profiling. Mice immunized and boosted with recombinant H5 in AddaVax, CpG+MPLA, or AddaVax plus CpG+MPLA (IVAX-1) produced comparable levels of neutralizing antibodies and were equally well protected against the H5N1 challenge. However, after challenge with H5N1 virus, H5/IVAX-1-immunized mice had 100- to 300-fold lower virus lung titers than mice receiving H5 in AddaVax or CpG+MPLA separately. Consistent with enhanced viral clearance, unsupervised expression analysis of draining lymph node cells revealed the combination adjuvant IVAX-1 significantly downregulated immune homeostasis genes, and induced higher numbers of antibody-producing plasmablasts than either AddaVax or CpG+MPLA. IVAX-1 was also more effective after single-dose administration than either AddaVax or CpG+MPLA. These data reveal a novel molecular framework for understanding the mechanisms of combination adjuvants, such as IVAX-1, and highlight their potential for the development of more effective vaccines against respiratory viruses.
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Affiliation(s)
- Emmanuel Dollinger
- Department of Mathematics, University of California Irvine, Irvine, CA, United States
| | - Jenny Hernandez-Davies
- Vaccine Research & Development Center, Department of Physiology & Biophysics, University of California Irvine, Irvine, CA 92697, United States
| | - Jiin Felgner
- Vaccine Research & Development Center, Department of Physiology & Biophysics, University of California Irvine, Irvine, CA 92697, United States
| | - Aarti Jain
- Vaccine Research & Development Center, Department of Physiology & Biophysics, University of California Irvine, Irvine, CA 92697, United States
| | - Michael Hwang
- Vaccine Research & Development Center, Department of Physiology & Biophysics, University of California Irvine, Irvine, CA 92697, United States
| | - Erwin Strahsburger
- Vaccine Research & Development Center, Department of Physiology & Biophysics, University of California Irvine, Irvine, CA 92697, United States
| | - Rie Nakajima
- Vaccine Research & Development Center, Department of Physiology & Biophysics, University of California Irvine, Irvine, CA 92697, United States
| | - Algimantas Jasinskas
- Vaccine Research & Development Center, Department of Physiology & Biophysics, University of California Irvine, Irvine, CA 92697, United States
| | - Qing Nie
- Department of Mathematics, University of California Irvine, Irvine, CA, United States
| | - Egest James Pone
- Vaccine Research & Development Center, Department of Physiology & Biophysics, University of California Irvine, Irvine, CA 92697, United States
| | - Shivashankar Othy
- Vaccine Research & Development Center, Department of Physiology & Biophysics, University of California Irvine, Irvine, CA 92697, United States
| | - David Huw Davies
- Vaccine Research & Development Center, Department of Physiology & Biophysics, University of California Irvine, Irvine, CA 92697, United States
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8
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Li J, Tian J, Cai T. Integrated analysis of miRNAs and mRNAs in thousands of single cells. Sci Rep 2025; 15:1636. [PMID: 39794399 PMCID: PMC11724058 DOI: 10.1038/s41598-025-85612-z] [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: 07/28/2024] [Accepted: 01/03/2025] [Indexed: 01/13/2025] Open
Abstract
The simultaneous sequencing of multiple types of biomolecules can facilitate understanding various forms of regulation occurring in cells. Cosequencing of miRNA and mRNA at single-cell resolution is challenging, and to date, only a few such studies (examining a quite limited number of cells) have been reported. Here, we developed a parallel single-cell small RNA and mRNA coprofiling method (PSCSR-seq V2) that enables miRNA and mRNA coexpression analysis in many cells. The PSCSR-seq V2 method is highly sensitive for miRNA analysis, and it also provides rich mRNA information about the examined cells at the same time. We employed PSCSR-seq V2 to profile miRNA and mRNA in 2310 cultured cells, and detected an average of 181 miRNA species and 7354 mRNA species per cell. An integrated analysis of miRNA and mRNA profiles linked miRNA functions with the negative regulation of tumor suppressor and reprogramming of cellular metabolism. We coprofiled miRNA and mRNA in 9403 lung cells and generated a coexpression atlas for known cell populations in mouse lungs, and detected conserved expression patterns of miRNAs among lineage-related cells. Based on this information, we identified informative age-associated miRNAs in mouse and human lung cells including miR-29, which can be understood as a conserved marker for immunosenescence. PSCSR-seq V2 offers unique functionality to users conducting functional studies of miRNAs in clinical and basic biological research.
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Affiliation(s)
- Jia Li
- National Institute of Biological Sciences, Beijing, China
| | - Jing Tian
- National Institute of Biological Sciences, Beijing, China
| | - Tao Cai
- National Institute of Biological Sciences, Beijing, China.
- Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua, China.
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Vitale E, Manicardi V, Gugnoni M, Torricelli F, Donati B, Muccioli S, Salviato E, Rossi T, Manzotti G, Piana S, Ciarrocchi A. Exploring the transcriptional cooperation between RUNX2 and its associated elncRNA RAIN. Cell Death Dis 2024; 15:673. [PMID: 39271656 PMCID: PMC11399121 DOI: 10.1038/s41419-024-07058-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 08/30/2024] [Accepted: 09/04/2024] [Indexed: 09/15/2024]
Abstract
Recent insights into the mechanisms controlling gene expression identified enhancer-associated long non-coding RNAs (elncRNAs) as master players of transcription in cancers. RUNX2, a mammalian RUNT-related transcription factor, is increasingly recognized in cancer biology for its role in supporting survival and progression also in thyroid cancer (TC). We recently identified, within the RUNX2 locus, a novel elncRNA that we named RAIN (RUNX2 associated intergenic lncRNA). We showed that RAIN and RUNX2 expression correlate in TC, both in vitro and in vivo, and that RAIN promotes RUNX2 expression by interacting with and affecting the activity of the RUNX2 P2 promoter through two distinct mechanisms. Here, we took forward these observations to explore the genome-wide transcriptional function of RAIN and its contribution to the RUNX2-dependent gene expression program in TC. By combining multiple omics data, we demonstrated that RAIN functionally cooperates with RUNX2 to the regulation of a subset of functionally related genes involved in promoting matrix remodeling, migration, and loss of differentiation. We showed that RAIN interacts with RUNX2 and its expression is required for the efficient recruitment of this TF to its target regulatory regions. In addition, our data revealed that besides RUNX2, RAIN governs a hierarchically organized complex transcriptional program by controlling a core of cancer-associated TFs that, in turn, orchestrate the expression of downstream genes. This evidence indicates that the functional cooperation observed between RAIN and RUNX2 can be a diffuse work mechanism for this elncRNA.
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Affiliation(s)
- Emanuele Vitale
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
- Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy
| | - Veronica Manicardi
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Mila Gugnoni
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Federica Torricelli
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Benedetta Donati
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Silvia Muccioli
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Elisa Salviato
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Teresa Rossi
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Gloria Manzotti
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Simonetta Piana
- Pathology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Alessia Ciarrocchi
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy.
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10
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Fu M, Du Y, Liu F, Xiao J, Zhang L, Zeng Y, Yang Y, Yan Y. Prognostic value of KLFs family genes in renal clear cell carcinoma. Sci Rep 2024; 14:20204. [PMID: 39215019 PMCID: PMC11364764 DOI: 10.1038/s41598-024-69892-5] [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: 02/19/2024] [Accepted: 08/09/2024] [Indexed: 09/04/2024] Open
Abstract
Numerous studies have shown that the Krüppel-like factors (KLFs) family of transcription factors regulate various eukaryotic physiological processes including the proliferation, differentiation, senescence, death, and carcinogenesis of animal cells. In addition, they are involved in the regulation of key biological processes such as cell cycle, DNA repair, and immune response. Current studies focus on investigating the role of KLFs in normal physiological conditions and the incidence and development of diseases. However002C the significance of KLFs family genes in clear cell renal cell carcinoma (ccRCC) remains partly understood; therefore, an in-depth investigation of their role and clinical value in this cancer is desired. The study aimed to investigate the role of KLF family genes in the incidence, development, and prognosis of ccRCC, and to identify the related potential biomarkers and therapeutic targets. The expression of KLFs in the RNA sequencing data of 613 ccRCCs from the TCGA database was analyzed using R software, and UALCAN and GEPIA assessed the expression of KLF genes in ccRCC. Real-time fluorescence quantitative PCR analysis was performed using 10 pairs of paired ccRCC sample tissues and renal cancer cell lines from the First Affiliated Hospital of Nanchang University. Overall survival (OS), progression-free interval (PFI), and disease-specific survival (DSS) of Kidney Clear Cell Carcinoma (KIRC) samples at differential expressions of KLFs in the TCGA database were analyzed using the R software, followed by generating a nomogram prediction model. GSCALite assessed the interactions of KLF genes with miRNAs and generated network maps. Protein interaction network maps of 50 neighboring genes associated with KLF mutations were analyzed using STRING with GO and KEGG functional enrichment analyses. The cBioPortal determined the probability of KLF gene mutations and their impact on OS and disease-free survival (DFS) in patients with ccRCC. Immune cell infiltration of KLFs was analyzed using TIMER. Finally, GSCALite was used to analyze the drug sensitivity and associated pathways of action of KLFs. Correlation validation using cellular experiments. KLF3/5/9/15 were significantly downregulated in ccRCC tissues, whereas KLF16/17 were upregulated compared with the adjacent tissues. Patients with high mRNA levels of KLF16/17 showed significantly lower OS, PFI, and DSS, whereas KLF3/5/9 showed a reverse trend. In patients with ccRCC, a significant correlation was observed between KLF mutations and OS and DSS. Furthermore, the correlation of KLF3/5/9 with immune cell infiltration was stronger than that of KLF15/16, while KLF17 was significantly associated with the Epithelial-Mesenchymal Transition (EMT) pathway. Overexpression of KLF5 inhibits the proliferative and migratory capacity of renal cancer cells (786-O and OS-RC-2), as well as their sensitivity to relevant small molecule drugs. Our research revealed the expression levels and biological significance of KLF genes in ccRCC, particularly highlighting the potential of KLF5 as a promising biomarker and therapeutic target for effective prognosis and diagnosis of ccRCC.
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Affiliation(s)
- MengRu Fu
- Department of Nephrology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330000, Jiangxi Province, China
- Key Laboratory of Urinary System Diseases of Jiangxi Province, Nanchang, China
| | - YuanZhuo Du
- Key Laboratory of Urinary System Diseases of Jiangxi Province, Nanchang, China
- Department of Urology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China, 330000
| | - Fei Liu
- Department of Nephrology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330000, Jiangxi Province, China
- Key Laboratory of Urinary System Diseases of Jiangxi Province, Nanchang, China
| | - Jun Xiao
- Department of Nephrology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330000, Jiangxi Province, China
| | - Li Zhang
- Department of Nephrology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330000, Jiangxi Province, China
| | - Yan Zeng
- Department of Nephrology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330000, Jiangxi Province, China
| | - YuJuan Yang
- Department of Nephrology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330000, Jiangxi Province, China
| | - Yan Yan
- Department of Nephrology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330000, Jiangxi Province, China.
- Key Laboratory of Urinary System Diseases of Jiangxi Province, Nanchang, China.
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11
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Soukar I, Fisher R, Bhagavatula S, Collard M, Cole PA, Alani RM. The CoREST complex is a therapeutic vulnerability in malignant peripheral nerve sheath tumors. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.17.607802. [PMID: 39229179 PMCID: PMC11370389 DOI: 10.1101/2024.08.17.607802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive sarcoma that may be seen in patients with neurofibromatosis type 1 (NF1) or occur sporadically. While surgery is the primary treatment for localized MPNST with a 61.9% overall survival rate, metastatic disease is often fatal due to resistance to systemic therapies which underscores the urgent need for effective treatments. MPNSTs frequently harbor inactivating driver mutations in the PRC2 epigenetic repressor complex suggesting epigenetic therapies may represent a specific vulnerability in these tumors. Here, we investigate the role of the LSD1-HDAC1-CoREST (LHC) repressor complex in mediating MPNST tumor growth and progression. Our findings demonstrate that the LHC small molecule inhibitor, corin, induces apoptosis and significantly inhibits proliferation in MPNST cells. Transcriptomic analysis of corin-treated MPNST cells demonstrates specific increases in genes associated with axonogenesis and neuronal differentiation as well as altered extracellular matrix; additionally, corin treatment is shown to inhibit MPNST invasion in vitro. These results underscore the critical role of the LHC complex in facilitating MPNST growth and progression and suggest that targeting the LHC complex represents a promising therapeutic approach for this aggressive malignancy.
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12
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Shi J, Jing W, He Y, Huang Y. Decreased expression of KLF6 in ectopic endometrial stromal cells contributes to endometriosis progression by targeting CTNNB1. Cell Signal 2024; 120:111230. [PMID: 38761988 DOI: 10.1016/j.cellsig.2024.111230] [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: 12/28/2023] [Revised: 05/13/2024] [Accepted: 05/15/2024] [Indexed: 05/20/2024]
Abstract
Despite decades of research, endometriosis remains a mysterious gynecological disease with unknown etiology and pathogenesis. Krüppel-like Factor 6 (KLF6), a transcription factor, has a wide expression profile and regulates a variety of biological processes. Here, we investigated the expression and function of KLF6 and its possible regulatory mechanisms in endometriosis. To determine the function of KLF6, knockdown and overexpression experiments were performed in eutopic endometrial stromal cells (EU-ESCs) and ectopic endometrial stromal cells (EC-ESCs), respectively. Cell viability, apoptosis, migration, invasion, and angiogenesis assays were conducted in ESCs. ChIP-sequencing and mRNA-sequencing were performed to investigate the functional mechanism of KLF6 in regulating ESCs. We found that KLF6 was highly expressed in eutopic endometrium of endometriosis patients, compared with ectopic endometrium. Similarly, the same was true in EU-ESCs, which was compared with EC-ESCs. Overexpression of KLF6 significantly suppressed EC-ESC proliferation, migration and invasion and induced cell apoptosis, while knockdown of KLF6 resulted in the opposite effects on EU-ESCs. Overexpression of KLF6 significantly inhibited EC-ESC angiogenesis. Mechanistically, the results of ChIP sequencing and mRNA sequencing revealed that CTNNB1 may be a transcriptional target regulated by KLF6. Reintroduction of KLF6 reversed the effects of KLF6 knockdown on EU-ESCs. KLF6 inhibited the proliferation, migration and angiogenesis of EC-ESCs by inhibiting the expression of CTNNB1. Our findings provided a new perspective on the role of KLF6 in endometriosis progression and inspire potential targeted therapeutic strategies.
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Affiliation(s)
- Jingwen Shi
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang 110004, PR China
| | - Wenda Jing
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang 110004, PR China
| | - Yueyun He
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang 110004, PR China
| | - Ying Huang
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang 110004, PR China.
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13
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Lin J, Liu P, Sun K, Jiang L, Liu Y, Huang Y, Liu J, Shi M, Zhang J, Wang T, Shen B. Comprehensive analysis of KLF family reveals KLF6 as a promising prognostic and immune biomarker in pancreatic ductal adenocarcinoma. Cancer Cell Int 2024; 24:177. [PMID: 38773440 PMCID: PMC11106939 DOI: 10.1186/s12935-024-03369-3] [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: 01/27/2024] [Accepted: 05/11/2024] [Indexed: 05/23/2024] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumors worldwide, with extremely aggressive and complicated biology. Krüppel-like factors (KLFs) encode a series of transcriptional regulatory proteins and play crucial roles in a variety of processes, including tumor cell differentiation and proliferation. However, the potential biological functions and possible pathways of KLFs in the progression of PDAC remain elusive. METHODS We systematically evaluated the transcriptional variations and expression patterns of KLFs in pancreatic cancer from the UCSC Xena. Based on difference analysis, the non-negative matrix factorization (NMF) algorithm was utilized to identify the immune characteristics and clinical significance of two different subtypes. The multivariate Cox regression was used to construct the risk model and then explore the differences in tumor immune microenvironment (TIME) and drug sensitivity between high and low groups. Through single-cell RNA sequencing (scRNA-seq) analysis, we screened KLF6 and further investigated its biological functions in pancreatic cancer and pan-cancer. RESULTS The KLFs exhibited differential expression and mutations in the transcriptomic profile of PDAC. According to the expression of KLFs, patients were classified into two distinct subtypes, each exhibiting significant differences in prognosis and TIME. Moreover, the KLF signature was developed using univariate Cox and Lasso regression, which proved to be a reliable and effective prognostic model. Furthermore, the KLF_Score was closely associated with immune infiltration, response to immunotherapy, and drug sensitivity and we screened small molecule compounds targeting prognostic genes separately. Through scRNA-seq analysis, KLF6 was selected to further demonstrate its role in the malignance of PC in vitro. Finally, pan-cancer analysis emphasized the biological significance of KLF6 in multiple types of tumors and its clinical utility in assessing cancer prognosis. CONCLUSION This study elucidated the pivotal role of KLF family genes in the malignant development of PC through comprehensive analysis and revealed that KLF6 would be a novel diagnostic biomolecule marker and potential therapeutic target for PDAC.
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Affiliation(s)
- Jiayu Lin
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Neoplasms Translational Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiaotong University, Shanghai, China
- Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Pengyi Liu
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Neoplasms Translational Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiaotong University, Shanghai, China
- Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Keyan Sun
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Neoplasms Translational Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiaotong University, Shanghai, China
- Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Lingxi Jiang
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Neoplasms Translational Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiaotong University, Shanghai, China
- Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yang Liu
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Neoplasms Translational Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiaotong University, Shanghai, China
- Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yishu Huang
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Neoplasms Translational Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiaotong University, Shanghai, China
- Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jia Liu
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Neoplasms Translational Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiaotong University, Shanghai, China
- Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Minmin Shi
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Neoplasms Translational Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiaotong University, Shanghai, China
- Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jun Zhang
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pancreatic Neoplasms Translational Medicine, Shanghai, China
- Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiaotong University, Shanghai, China
- Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Ting Wang
- Department of Pathology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Baiyong Shen
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
- Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
- State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, People's Republic of China.
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14
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Lai C, Xu L, Dai S. The nuclear export protein exportin-1 in solid malignant tumours: From biology to clinical trials. Clin Transl Med 2024; 14:e1684. [PMID: 38783482 PMCID: PMC11116501 DOI: 10.1002/ctm2.1684] [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: 12/07/2023] [Revised: 04/15/2024] [Accepted: 04/19/2024] [Indexed: 05/25/2024] Open
Abstract
BACKGROUND Exportin-1 (XPO1), a crucial protein regulating nuclear-cytoplasmic transport, is frequently overexpressed in various cancers, driving tumor progression and drug resistance. This makes XPO1 an attractive therapeutic target. Over the past few decades, the number of available nuclear export-selective inhibitors has been increasing. Only KPT-330 (selinexor) has been successfully used for treating haematological malignancies, and KPT-8602 (eltanexor) has been used for treating haematologic tumours in clinical trials. However, the use of nuclear export-selective inhibitors for the inhibition of XPO1 expression has yet to be thoroughly investigated in clinical studies and therapeutic outcomes for solid tumours. METHODS We collected numerous literatures to explain the efficacy of XPO1 Inhibitors in preclinical and clinical studies of a wide range of solid tumours. RESULTS In this review, we focus on the nuclear export function of XPO1 and results from clinical trials of its inhibitors in solid malignant tumours. We summarized the mechanism of action and therapeutic potential of XPO1 inhibitors, as well as adverse effects and response biomarkers. CONCLUSION XPO1 inhibition has emerged as a promising therapeutic strategy in the fight against cancer, offering a novel approach to targeting tumorigenic processes and overcoming drug resistance. SINE compounds have demonstrated efficacy in a wide range of solid tumours, and ongoing research is focused on optimizing their use, identifying response biomarkers, and developing effective combination therapies. KEY POINTS Exportin-1 (XPO1) plays a critical role in mediating nucleocytoplasmic transport and cell cycle. XPO1 dysfunction promotes tumourigenesis and drug resistance within solid tumours. The therapeutic potential and ongoing researches on XPO1 inhibitors in the treatment of solid tumours. Additional researches are essential to address safety concerns and identify biomarkers for predicting patient response to XPO1 inhibitors.
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Affiliation(s)
- Chuanxi Lai
- Department of Colorectal SurgerySir Run Run Shaw HospitalSchool of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Biotherapy of Zhejiang ProvinceHangzhouChina
| | - Lingna Xu
- Department of Colorectal SurgerySir Run Run Shaw HospitalSchool of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Biotherapy of Zhejiang ProvinceHangzhouChina
| | - Sheng Dai
- Department of Colorectal SurgerySir Run Run Shaw HospitalSchool of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Biotherapy of Zhejiang ProvinceHangzhouChina
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15
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Kypraios A, Bennour J, Imbert V, David L, Calvo J, Pflumio F, Bonnet R, Couralet M, Magnone V, Lebrigand K, Barbry P, Rohrlich PS, Peyron JF. Identifying Candidate Gene Drivers Associated with Relapse in Pediatric T-Cell Acute Lymphoblastic Leukemia Using a Gene Co-Expression Network Approach. Cancers (Basel) 2024; 16:1667. [PMID: 38730619 PMCID: PMC11083586 DOI: 10.3390/cancers16091667] [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: 01/18/2024] [Revised: 04/22/2024] [Accepted: 04/23/2024] [Indexed: 05/13/2024] Open
Abstract
Pediatric T-cell Acute Lymphoblastic Leukemia (T-ALL) relapses are still associated with a dismal outcome, justifying the search for new therapeutic targets and relapse biomarkers. Using single-cell RNA sequencing (scRNAseq) data from three paired samples of pediatric T-ALL at diagnosis and relapse, we first conducted a high-dimensional weighted gene co-expression network analysis (hdWGCNA). This analysis highlighted several gene co-expression networks (GCNs) and identified relapse-associated hub genes, which are considered potential driver genes. Shared relapse-expressed genes were found to be related to antigen presentation (HLA, B2M), cytoskeleton remodeling (TUBB, TUBA1B), translation (ribosomal proteins, EIF1, EEF1B2), immune responses (MIF, EMP3), stress responses (UBC, HSP90AB1/AA1), metabolism (FTH1, NME1/2, ARCL4C), and transcriptional remodeling (NF-κB family genes, FOS-JUN, KLF2, or KLF6). We then utilized sparse partial least squares discriminant analysis to select from a pool of 481 unique leukemic hub genes, which are the genes most discriminant between diagnosis and relapse states (comprising 44, 35, and 31 genes, respectively, for each patient). Applying a Cox regression method to these patient-specific genes, along with transcriptomic and clinical data from the TARGET-ALL AALL0434 cohort, we generated three model gene signatures that efficiently identified relapsed patients within the cohort. Overall, our approach identified new potential relapse-associated genes and proposed three model gene signatures associated with lower survival rates for high-score patients.
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Affiliation(s)
- Anthony Kypraios
- Université Côte d’Azur, Inserm C3M, 06200 Nice, France (V.I.); (L.D.); (R.B.); (P.S.R.)
- Team#4: “Fundamental to Translational Research on Dysregulated Hematopoiesis—DysHema”, Centre Méditerranéen de Médecine Moléculaire-C3M-Inserm U1065, Bâtiment Universitaire ARCHIMED, 151 Route Saint Antoine de Ginestière, BP 2 3194, CEDEX 3, 06204 Nice, France
| | - Juba Bennour
- Université Côte d’Azur, Inserm C3M, 06200 Nice, France (V.I.); (L.D.); (R.B.); (P.S.R.)
- Team#4: “Fundamental to Translational Research on Dysregulated Hematopoiesis—DysHema”, Centre Méditerranéen de Médecine Moléculaire-C3M-Inserm U1065, Bâtiment Universitaire ARCHIMED, 151 Route Saint Antoine de Ginestière, BP 2 3194, CEDEX 3, 06204 Nice, France
| | - Véronique Imbert
- Université Côte d’Azur, Inserm C3M, 06200 Nice, France (V.I.); (L.D.); (R.B.); (P.S.R.)
- Team#4: “Fundamental to Translational Research on Dysregulated Hematopoiesis—DysHema”, Centre Méditerranéen de Médecine Moléculaire-C3M-Inserm U1065, Bâtiment Universitaire ARCHIMED, 151 Route Saint Antoine de Ginestière, BP 2 3194, CEDEX 3, 06204 Nice, France
| | - Léa David
- Université Côte d’Azur, Inserm C3M, 06200 Nice, France (V.I.); (L.D.); (R.B.); (P.S.R.)
- Team#4: “Fundamental to Translational Research on Dysregulated Hematopoiesis—DysHema”, Centre Méditerranéen de Médecine Moléculaire-C3M-Inserm U1065, Bâtiment Universitaire ARCHIMED, 151 Route Saint Antoine de Ginestière, BP 2 3194, CEDEX 3, 06204 Nice, France
| | - Julien Calvo
- Team#4: “Fundamental to Translational Research on Dysregulated Hematopoiesis—DysHema”, Centre Méditerranéen de Médecine Moléculaire-C3M-Inserm U1065, Bâtiment Universitaire ARCHIMED, 151 Route Saint Antoine de Ginestière, BP 2 3194, CEDEX 3, 06204 Nice, France
| | - Françoise Pflumio
- Team#4: “Fundamental to Translational Research on Dysregulated Hematopoiesis—DysHema”, Centre Méditerranéen de Médecine Moléculaire-C3M-Inserm U1065, Bâtiment Universitaire ARCHIMED, 151 Route Saint Antoine de Ginestière, BP 2 3194, CEDEX 3, 06204 Nice, France
| | - Raphaël Bonnet
- Université Côte d’Azur, Inserm C3M, 06200 Nice, France (V.I.); (L.D.); (R.B.); (P.S.R.)
- Team#4: “Fundamental to Translational Research on Dysregulated Hematopoiesis—DysHema”, Centre Méditerranéen de Médecine Moléculaire-C3M-Inserm U1065, Bâtiment Universitaire ARCHIMED, 151 Route Saint Antoine de Ginestière, BP 2 3194, CEDEX 3, 06204 Nice, France
| | - Marie Couralet
- Université de Paris, Inserm, CEA, 92260 Fontenay-aux-Roses, France
- Université Côte d’Azur, CNRS, IPMC, 06560 Valbonne, France; (M.C.); (V.M.); (K.L.)
| | - Virginie Magnone
- Université de Paris, Inserm, CEA, 92260 Fontenay-aux-Roses, France
- Université Côte d’Azur, CNRS, IPMC, 06560 Valbonne, France; (M.C.); (V.M.); (K.L.)
| | - Kevin Lebrigand
- Université de Paris, Inserm, CEA, 92260 Fontenay-aux-Roses, France
- Université Côte d’Azur, CNRS, IPMC, 06560 Valbonne, France; (M.C.); (V.M.); (K.L.)
| | - Pascal Barbry
- Université Côte d’Azur, Inserm C3M, 06200 Nice, France (V.I.); (L.D.); (R.B.); (P.S.R.)
- Team#4: “Fundamental to Translational Research on Dysregulated Hematopoiesis—DysHema”, Centre Méditerranéen de Médecine Moléculaire-C3M-Inserm U1065, Bâtiment Universitaire ARCHIMED, 151 Route Saint Antoine de Ginestière, BP 2 3194, CEDEX 3, 06204 Nice, France
- CHU de Nice, Hôpital de l’Archet, 06000 Nice, France
| | - Pierre S. Rohrlich
- Université Côte d’Azur, Inserm C3M, 06200 Nice, France (V.I.); (L.D.); (R.B.); (P.S.R.)
- Team#4: “Fundamental to Translational Research on Dysregulated Hematopoiesis—DysHema”, Centre Méditerranéen de Médecine Moléculaire-C3M-Inserm U1065, Bâtiment Universitaire ARCHIMED, 151 Route Saint Antoine de Ginestière, BP 2 3194, CEDEX 3, 06204 Nice, France
- CHU de Nice, Hôpital de l’Archet, 06000 Nice, France
| | - Jean-François Peyron
- Université Côte d’Azur, Inserm C3M, 06200 Nice, France (V.I.); (L.D.); (R.B.); (P.S.R.)
- CHU de Nice, Hôpital de l’Archet, 06000 Nice, France
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16
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Jha K, Kumar A, Bhatnagar K, Patra A, Bhavesh NS, Singh B, Chaudhary S. Modulation of Krüppel-like factors (KLFs) interaction with their binding partners in cancers through acetylation and phosphorylation. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2024; 1867:195003. [PMID: 37992989 DOI: 10.1016/j.bbagrm.2023.195003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 09/05/2023] [Accepted: 11/16/2023] [Indexed: 11/24/2023]
Abstract
Post-translational modifications (PTMs) of transcription factors regulate transcriptional activity and play a key role in essentially all biological processes and generate indispensable insight towards biological function including activity state, subcellular localization, protein solubility, protein folding, substrate trafficking, and protein-protein interactions. Amino acids modified chemically via PTMs, function as molecular switches and affect the protein function and characterization and increase the proteome complexity. Krüppel-like transcription factors (KLFs) control essential cellular processes including proliferation, differentiation, migration, programmed cell death and various cancer-relevant processes. We investigated the interactions of KLF group-2 members with their binding partners to assess the role of acetylation and phosphorylation in KLFs on their binding affinity. It was observed that acetylation and phosphorylation at different positions in KLFs have a variable effect on binding with specific partners. KLF2-EP300, KLF4-SP1, KLF6-ATF3, KLF6-JUN, and KLF7-JUN show stabilization upon acetylation or phosphorylation at variable positions. On the other hand, KLF4-CBP, KLF4-EP300, KLF5-CBP, KLF5-WWP1, KLF6-SP1, and KLF7-ATF3 show stabilization or destabilization due to acetylation or phosphorylation at variable positions in KLFs. This provides a molecular explanation of the experimentally observed dual role of KLF group-2 members as a suppressor or activator of cancers in a PTM-dependent manner.
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Affiliation(s)
- Kanupriya Jha
- Department of Biotechnology, School of Engineering and Applied Sciences, Bennett University, Plot Nos. 8-11, Tech Zone 2, Greater Noida, Uttar Pradesh 201310, India.
| | - Amit Kumar
- Department of Biotechnology, School of Engineering and Applied Sciences, Bennett University, Plot Nos. 8-11, Tech Zone 2, Greater Noida, Uttar Pradesh 201310, India.
| | - Kartik Bhatnagar
- Department of Biotechnology, School of Engineering and Applied Sciences, Bennett University, Plot Nos. 8-11, Tech Zone 2, Greater Noida, Uttar Pradesh 201310, India.
| | - Anupam Patra
- Transcription Regulation Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi 110067, India.
| | - Neel Sarovar Bhavesh
- Transcription Regulation Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi 110067, India.
| | - Bipin Singh
- Department of Biotechnology, School of Engineering and Applied Sciences, Bennett University, Plot Nos. 8-11, Tech Zone 2, Greater Noida, Uttar Pradesh 201310, India; Centre for Life Sciences, Mahindra University, Bahadurpally, Jeedimetla, Hyderabad, Telangana 500043, India.
| | - Sarika Chaudhary
- Department of Biotechnology, School of Engineering and Applied Sciences, Bennett University, Plot Nos. 8-11, Tech Zone 2, Greater Noida, Uttar Pradesh 201310, India.
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17
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Shen W, Yuan L, Hao B, Xiang J, Cheng F, Wu Z, Li X. KLF3 promotes colorectal cancer growth by activating WNT1. Aging (Albany NY) 2024; 16:2475-2493. [PMID: 38305787 PMCID: PMC10911342 DOI: 10.18632/aging.205494] [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: 08/17/2023] [Accepted: 12/26/2023] [Indexed: 02/03/2024]
Abstract
OBJECTIVE The function of Kruppel-like factor 3 (KLF3) remains largely unexplored in colorectal cancer (CRC). METHODS KLF3 expression in CRC was assessed through qPCR, western blotting, immunohistochemical assays, and The Cancer Genome Atlas (TCGA) database. The tumor-promoting capacity of KLF3 was explored by performing in vitro functional experiments using CRC cells. A subcutaneous nude mouse tumor assay was employed to evaluate tumor growth. To further elucidate the interaction between KLF3 and other factors, luciferase reporter assay, agarose gel electrophoresis, and ChIP analysis were performed. RESULTS KLF3 was downregulated in CRC tissue and cells. Silencing of KLF3 increased the potential of CRC cells for proliferation, migration, and invasion, while its activation decreased these processes. Downregulated KLF3 was associated with accelerated tumor growth in vivo. Mechanistically, KLF3 was discovered to target the promoter sequence of WNT1. Consequently, the diminished expression of KLF3 led to the buildup of WNT1 and the WNT/β-catenin pathway activation, consequently stimulating the progression of CRC. CONCLUSIONS This investigation suggests that the involvement of KLF3/WNT1 regulatory pathway contributes to the progression of CRC, thereby emphasizing its promise as an important focus for future therapies aimed at treating CRC.
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Affiliation(s)
- Wei Shen
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Lebin Yuan
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Boyu Hao
- General Medicine, First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Jiajia Xiang
- Laboratory of Molecular Center, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Fei Cheng
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Zhao Wu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Xiaodong Li
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
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18
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Malin J, Martinez-Ruiz GU, Zhao Y, Shissler SC, Cowan JE, Ding Y, Morales-Sanchez A, Ishikawa M, Lavaert M, Das A, Butcher D, Warner AC, Kallarakal M, Chen J, Kedei N, Kelly M, Brinster LR, Allman D, Bhandoola A. Expression of the transcription factor Klf6 by thymic epithelial cells is required for thymus development. SCIENCE ADVANCES 2023; 9:eadg8126. [PMID: 37967174 PMCID: PMC10651122 DOI: 10.1126/sciadv.adg8126] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 10/16/2023] [Indexed: 11/17/2023]
Abstract
Thymic epithelial cells (TEC) control T cell development and play essential roles in establishing self-tolerance. By using Foxn1-Cre-driven ablation of Klf6 gene in TEC, we identified Klf6 as a critical factor in TEC development. Klf6 deficiency resulted in a hypoplastic thymus-evident from fetal stages into adulthood-in which a dramatic increase in the frequency of apoptotic TEC was observed. Among cortical TEC (cTEC), a previously unreported cTEC population expressing the transcription factor Sox10 was relatively expanded. Within medullary TEC (mTEC), mTEC I and Tuft-like mTEC IV were disproportionately decreased. Klf6 deficiency altered chromatin accessibility and affected TEC chromatin configuration. Consistent with these defects, naïve conventional T cells and invariant natural killer T cells were reduced in the spleen. Late stages of T cell receptor-dependent selection of thymocytes were affected, and mice exhibited autoimmunity. Thus, Klf6 has a prosurvival role and affects the development of specific TEC subsets contributing to thymic function.
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Affiliation(s)
- Justin Malin
- Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Gustavo Ulises Martinez-Ruiz
- Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Research Division, Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
- Children’s Hospital Federico Gomez, Mexico City, Mexico
| | - Yongge Zhao
- Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Susannah C. Shissler
- Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jennifer E. Cowan
- Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Institute of Immunity and Transplantation, University College London, London, UK
| | - Yi Ding
- Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Abigail Morales-Sanchez
- Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Children’s Hospital Federico Gomez, Mexico City, Mexico
| | - Masaki Ishikawa
- Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Marieke Lavaert
- Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Arundhoti Das
- Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Donna Butcher
- Molecular Histopathology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Andrew C. Warner
- Molecular Histopathology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Melissa Kallarakal
- Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jingqiu Chen
- Office of Science and Technology Resources, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- ACROBiosystems, Newark, DE, USA
| | - Noemi Kedei
- Office of Science and Technology Resources, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Michael Kelly
- Single Cell Analysis Facility, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Lauren R. Brinster
- Division of Veterinary Resources, Office of Research Services, National Institutes of Health, Bethesda, MD, USA
| | - David Allman
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Avinash Bhandoola
- Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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Bajpai VK, Swigut T, Mohammed J, Naqvi S, Arreola M, Tycko J, Kim TC, Pritchard JK, Bassik MC, Wysocka J. A genome-wide genetic screen uncovers determinants of human pigmentation. Science 2023; 381:eade6289. [PMID: 37561850 PMCID: PMC10901463 DOI: 10.1126/science.ade6289] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 06/28/2023] [Indexed: 08/12/2023]
Abstract
Skin color, one of the most diverse human traits, is determined by the quantity, type, and distribution of melanin. In this study, we leveraged the light-scattering properties of melanin to conduct a genome-wide screen for regulators of melanogenesis. We identified 169 functionally diverse genes that converge on melanosome biogenesis, endosomal transport, and gene regulation, of which 135 represented previously unknown associations with pigmentation. In agreement with their melanin-promoting function, the majority of screen hits were up-regulated in melanocytes from darkly pigmented individuals. We further unraveled functions of KLF6 as a transcription factor that regulates melanosome maturation and pigmentation in vivo, and of the endosomal trafficking protein COMMD3 in modulating melanosomal pH. Our study reveals a plethora of melanin-promoting genes, with broad implications for human variation, cell biology, and medicine.
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Affiliation(s)
- Vivek K. Bajpai
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- School of Chemical, Biological, and Materials Engineering, The University of Oklahoma, Norman, OK, 73019, USA
| | - Tomek Swigut
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Jaaved Mohammed
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Sahin Naqvi
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Department of Genetics, Stanford University, Stanford, CA 94305, USA
| | - Martin Arreola
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Josh Tycko
- Department of Genetics, Stanford University, Stanford, CA 94305, USA
| | - Tayne C. Kim
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Jonathan K. Pritchard
- Department of Genetics, Stanford University, Stanford, CA 94305, USA
- Department of Biology, Stanford University, Stanford, CA 94305, USA
| | - Michael C. Bassik
- Department of Genetics, Stanford University, Stanford, CA 94305, USA
- Chemistry, Engineering, and Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA 94305, USA
- Program in Cancer Biology, Stanford University School of Medicine, Stanford, CA 94305 USA
| | - Joanna Wysocka
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
- Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
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20
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Lu H, Ma J, Li Y, Zhang J, An Y, Du W, Cai X. Bioinformatic and systems biology approach revealing the shared genes and molecular mechanisms between COVID-19 and non-alcoholic hepatitis. Front Mol Biosci 2023; 10:1164220. [PMID: 37405258 PMCID: PMC10315682 DOI: 10.3389/fmolb.2023.1164220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 06/01/2023] [Indexed: 07/06/2023] Open
Abstract
Introduction: Coronavirus disease 2019 (COVID-19) has become a global pandemic and poses a serious threat to human health. Many studies have shown that pre-existing nonalcoholic steatohepatitis (NASH) can worsen the clinical symptoms in patients suffering from COVID-19. However, the potential molecular mechanisms between NASH and COVID-19 remain unclear. To this end, key molecules and pathways between COVID-19 and NASH were herein explored by bioinformatic analysis. Methods: The common differentially expressed genes (DEGs) between NASH and COVID-19 were obtained by differential gene analysis. Enrichment analysis and protein-protein interaction (PPI) network analysis were carried out using the obtained common DEGs. The key modules and hub genes in PPI network were obtained by using the plug-in of Cytoscape software. Subsequently, the hub genes were verified using datasets of NASH (GSE180882) and COVID-19 (GSE150316), and further evaluated by principal component analysis (PCA) and receiver operating characteristic (ROC). Finally, the verified hub genes were analyzed by single-sample gene set enrichment analysis (ssGSEA) and NetworkAnalyst was used for the analysis of transcription factor (TF)-gene interactions, TF-microRNAs (miRNA) coregulatory network, and Protein-chemical Interactions. Results: A total of 120 DEGs between NASH and COVID-19 datasets were obtained, and the PPI network was constructed. Two key modules were obtained via the PPI network, and enrichment analysis of the key modules revealed the common association between NASH and COVID-19. In total, 16 hub genes were obtained by five algorithms, and six of them, namely, Kruppel-like factor 6 (KLF6), early growth response 1 (EGR1), growth arrest and DNA-damage-inducible 45 beta (GADD45B), JUNB, FOS, and FOS-like antigen 1 (FOSL1) were confirmed to be closely related to NASH and COVID-19. Finally, the relationship between hub genes and related pathways was analyzed, and the interaction network of six hub genes was constructed with TFs, miRNAs, and compounds. Conclusion: This study identified six hub genes related to COVID-19 and NASH, providing a new perspective for disease diagnosis and drug development.
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21
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Santos MVC, Feltrin AS, Costa-Amaral IC, Teixeira LR, Perini JA, Martins DC, Larentis AL. Network Analysis of Biomarkers Associated with Occupational Exposure to Benzene and Malathion. Int J Mol Sci 2023; 24:ijms24119415. [PMID: 37298367 DOI: 10.3390/ijms24119415] [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: 03/01/2023] [Revised: 04/21/2023] [Accepted: 05/03/2023] [Indexed: 06/12/2023] Open
Abstract
Complex diseases are associated with the effects of multiple genes, proteins, and biological pathways. In this context, the tools of Network Medicine are compatible as a platform to systematically explore not only the molecular complexity of a specific disease but may also lead to the identification of disease modules and pathways. Such an approach enables us to gain a better understanding of how environmental chemical exposures affect the function of human cells, providing better perceptions about the mechanisms involved and helping to monitor/prevent exposure and disease to chemicals such as benzene and malathion. We selected differentially expressed genes for exposure to benzene and malathion. The construction of interaction networks was carried out using GeneMANIA and STRING. Topological properties were calculated using MCODE, BiNGO, and CentiScaPe, and a Benzene network composed of 114 genes and 2415 interactions was obtained. After topological analysis, five networks were identified. In these subnets, the most interconnected nodes were identified as: IL-8, KLF6, KLF4, JUN, SERTAD1, and MT1H. In the Malathion network, composed of 67 proteins and 134 interactions, HRAS and STAT3 were the most interconnected nodes. Path analysis, combined with various types of high-throughput data, reflects biological processes more clearly and comprehensively than analyses involving the evaluation of individual genes. We emphasize the central roles played by several important hub genes obtained by exposure to benzene and malathion.
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Affiliation(s)
- Marcus Vinicius C Santos
- Studies Center of Worker's Health and Human Ecology (CESTEH), Sergio Arouca National School of Public Health (ENSP), Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro 21041-210, RJ, Brazil
| | - Arthur S Feltrin
- Center for Mathematics, Computation and Cognition, Federal University of ABC, Santo André 09210-580, SP, Brazil
| | - Isabele C Costa-Amaral
- Studies Center of Worker's Health and Human Ecology (CESTEH), Sergio Arouca National School of Public Health (ENSP), Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro 21041-210, RJ, Brazil
| | - Liliane R Teixeira
- Studies Center of Worker's Health and Human Ecology (CESTEH), Sergio Arouca National School of Public Health (ENSP), Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro 21041-210, RJ, Brazil
| | - Jamila A Perini
- Research Laboratory of Pharmaceutical Sciences (LAPESF), State University of Rio de Janeiro (West Zone-UERJ-ZO), Rio de Janeiro 23070-200, RJ, Brazil
| | - David C Martins
- Center for Mathematics, Computation and Cognition, Federal University of ABC, Santo André 09210-580, SP, Brazil
| | - Ariane L Larentis
- Studies Center of Worker's Health and Human Ecology (CESTEH), Sergio Arouca National School of Public Health (ENSP), Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro 21041-210, RJ, Brazil
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22
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Yedla P, Babalghith AO, Andra VV, Syed R. PROTACs in the Management of Prostate Cancer. Molecules 2023; 28:molecules28093698. [PMID: 37175108 PMCID: PMC10179857 DOI: 10.3390/molecules28093698] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/15/2023] [Accepted: 04/17/2023] [Indexed: 05/15/2023] Open
Abstract
Cancer treatments with targeted therapy have gained immense interest due to their low levels of toxicity and high selectivity. Proteolysis-Targeting Chimeras (PROTACs) have drawn special attention in the development of cancer therapeutics owing to their unique mechanism of action, their ability to target undruggable proteins, and their focused target engagement. PROTACs selectively degrade the target protein through the ubiquitin-proteasome system, which describes a different mode of action compared to conventional small-molecule inhibitors or even antibodies. Among different cancer types, prostate cancer (PC) is the most prevalent non-cutaneous cancer in men. Genetic alterations and the overexpression of several genes, such as FOXA1, AR, PTEN, RB1, TP53, etc., suppress the immune response, resulting in drug resistance to conventional drugs in prostate cancer. Since the progression of ARV-110 (PROTAC for PC) into clinical phases, the focus of research has quickly shifted to protein degraders targeting prostate cancer. The present review highlights an overview of PROTACs in prostate cancer and their superiority over conventional inhibitors. We also delve into the underlying pathophysiology of the disease and explain the structural design and linkerology strategies for PROTAC molecules. Additionally, we touch on the various targets for PROTAC in prostate cancer, including the androgen receptor (AR) and other critical oncoproteins, and discuss the future prospects and challenges in this field.
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Affiliation(s)
- Poornachandra Yedla
- Department of Pharmacogenomics, Institute of Translational Research, Asian Healthcare Foundation, Asian Institute of Gastroenterology Hospitals, Gachibowli, Hyderabad 500082, India
| | - Ahmed O Babalghith
- Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah 21955, Saudi Arabia
| | - Vindhya Vasini Andra
- Department of Medical Oncology, Omega Hospitals, Gachibowli, Hyderabad 500032, India
| | - Riyaz Syed
- Department of Chemiinformatics, Centella Scientific, JHUB, Jawaharlal Nehru Technological University, Hyderabad 500085, India
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MiRNA-21-5p Accelerates EMT and Inhibits Apoptosis of Laryngeal Carcinoma via Inhibiting KLF6 Expression. Biochem Genet 2023; 61:101-115. [PMID: 35761154 DOI: 10.1007/s10528-022-10246-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 06/07/2022] [Indexed: 01/24/2023]
Abstract
The incidence of laryngeal carcinoma accounts for 1 to 5% of systemic malignancies and ranks second among head and neck malignancies. Screening more effective targets are meaningful for the treatment of laryngeal carcinoma. The purpose was to research the action of miR-21-5p in the occurrence of laryngeal carcinoma. Genecards combined with g:profiler was used for cluster analysis to predict gene-related miRNAs. Q-PCR assay was performed for measuring the level of miR-21-5p and Kruppel-like factor 6 (KLF6). miR-21-5p-mimic, miR-21-5p-inhibitor and sh-KLF6 were transfected using LipofectamineTM 2000. Both CCK-8 and EdU experiments were undertaken to detect cell proliferation ability. Western blot was used to detect apoptosis and epithelial-mesenchymal transition (EMT) related proteins. Wound healing assay and transwell assay were undertaken for migration and invasion, respectively. Three online software (ENCORI, miRWalk, and miRDB) were applied to screen the downstream of miR-21-5p. At the same time, a dual-luciferase reporter experiment was processed to verify the binding. Finally, a rescue experiment was applied to reveal the mediating role of miR-21-5p and KLF6. MiR-21-5p expressed highly in laryngeal carcinoma tissues and cell lines. Knockdown of miR-21-5p reduced the EMT, while enhancing apoptosis of laryngeal carcinoma cell lines. MiR-21-5p targeted KLF6 with negative relationships. The rescue assay results confirmed that sh-KLF6 rescued the action of miR-21-5p knockdown in developing laryngeal carcinoma cells. MiR-21-5p promotes the occurrence and development of laryngeal cancer by targeting KLF6. This finding may provide new insights into miRNA as a biomarker for diagnosing and treating laryngeal carcinoma in the future.
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24
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Krüppel-like Factor 6 Suppresses the Progression of Pancreatic Cancer by Upregulating Activating Transcription Factor 3. J Clin Med 2022; 12:jcm12010200. [PMID: 36615000 PMCID: PMC9821328 DOI: 10.3390/jcm12010200] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 12/19/2022] [Accepted: 12/23/2022] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND As a member of the Krüppel-like factor (KLFs) family, Krüppel-like factor 6 (KLF6) plays a critical role in regulating key cellular functions. Presently, scholars have proved the important role of KLF6 in the tumorigenesis of certain cancers through a large number of experiments. However, gaps still remain in our knowledge of the role of KLF6 in pancreatic cancer (PAAD). Therefore, this paper mainly investigates the role of KLF6 in the progression of pancreatic cancer. METHODS The expression pattern of KLF6 in pancreatic cancer was explored in pancreatic cancer tissues and cell lines. Then, we investigated the prognostic value of KLF6 in pancreatic cancer by immunohistochemical assays. Next, Cell Counting Kit-8 (CCK8) and clone information assays were employed to explore the proliferation of PAAD affected by KLF6. The metastasis and epithelial-mesenchymal transition (EMT) abilities affected by KLF6 were identified through transwell invasion as well as migration assays and western blots. Finally, the TRRUST tool was used to analyze the potential targeted genes of KLF6. The results were verified by Quantificational Real-time Polymerase Chain Reaction (qRT-PCR), western blot and rescue assays. RESULTS KLF6 expresses lowly in pancreatic cancer compared to corresponding normal tissues and relates to poor survival times. Overexpression of KLF6 inhibits the proliferation, metastasis, and EMT progression in pancreatic cancer cells. Further studies suggest that KLF6 could upregulate ATF3 in PAAD. CONCLUSIONS Our results suggest that KLF6 can be a useful factor in predicting the prognosis of PAAD patients and that it inhibits the progression of pancreatic cancer by upregulating activating transcription factor 3 (ATF3).
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25
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Kruppel-like Factors in Skeletal Physiology and Pathologies. Int J Mol Sci 2022; 23:ijms232315174. [PMID: 36499521 PMCID: PMC9741390 DOI: 10.3390/ijms232315174] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 11/28/2022] [Accepted: 11/30/2022] [Indexed: 12/11/2022] Open
Abstract
Kruppel-like factors (KLFs) belong to a large group of zinc finger-containing transcription factors with amino acid sequences resembling the Drosophila gap gene Krüppel. Since the first report of molecular cloning of the KLF family gene, the number of KLFs has increased rapidly. Currently, 17 murine and human KLFs are known to play crucial roles in the regulation of transcription, cell proliferation, cellular differentiation, stem cell maintenance, and tissue and organ pathogenesis. Recent evidence has shown that many KLF family molecules affect skeletal cells and regulate their differentiation and function. This review summarizes the current understanding of the unique roles of each KLF in skeletal cells during normal development and skeletal pathologies.
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Meyer E, Chaung K, Dehghannasiri R, Salzman J. ReadZS detects cell type-specific and developmentally regulated RNA processing programs in single-cell RNA-seq. Genome Biol 2022; 23:226. [PMID: 36284317 PMCID: PMC9594907 DOI: 10.1186/s13059-022-02795-8] [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: 04/15/2022] [Accepted: 10/13/2022] [Indexed: 11/13/2022] Open
Abstract
RNA processing, including splicing and alternative polyadenylation, is crucial to gene function and regulation, but methods to detect RNA processing from single-cell RNA sequencing data are limited by reliance on pre-existing annotations, peak calling heuristics, and collapsing measurements by cell type. We introduce ReadZS, an annotation-free statistical approach to identify regulated RNA processing in single cells. ReadZS discovers cell type-specific RNA processing in human lung and conserved, developmentally regulated RNA processing in mammalian spermatogenesis-including global 3' UTR shortening in human spermatogenesis. ReadZS also discovers global 3' UTR lengthening in Arabidopsis development, highlighting the usefulness of this method in under-annotated transcriptomes.
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Affiliation(s)
- Elisabeth Meyer
- Department of Biochemistry, Stanford University, Stanford, CA, 94305, USA
- Department of Biomedical Data Science, Stanford University, Stanford, CA, 94305, USA
| | - Kaitlin Chaung
- Department of Biochemistry, Stanford University, Stanford, CA, 94305, USA
- Department of Biomedical Data Science, Stanford University, Stanford, CA, 94305, USA
| | - Roozbeh Dehghannasiri
- Department of Biochemistry, Stanford University, Stanford, CA, 94305, USA
- Department of Biomedical Data Science, Stanford University, Stanford, CA, 94305, USA
| | - Julia Salzman
- Department of Biochemistry, Stanford University, Stanford, CA, 94305, USA.
- Department of Biomedical Data Science, Stanford University, Stanford, CA, 94305, USA.
- Department of Statistics (by courtesy), Stanford University, Stanford, CA, 94305, USA.
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Miranda AL, Kourdova LT, Racca AC, Cruz Del Puerto M, Rojas ML, Marques ALX, Silva ECO, Fonseca EJS, Gazzoni Y, Gruppi A, Borbely AU, Genti‐Raimondi S, Panzetta‐Dutari GM. Krüppel‐like factor 6 participates in extravillous trophoblast cell differentiation and its expression is reduced in abnormally invasive placenta. FEBS Lett 2022; 596:1700-1719. [DOI: 10.1002/1873-3468.14367] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 03/30/2022] [Accepted: 04/22/2022] [Indexed: 11/10/2022]
Affiliation(s)
- Andrea L. Miranda
- Universidad Nacional de Córdoba Facultad de Ciencias Químicas Departamento de Bioquímica Clínica Ciudad Universitaria X5000HUA Córdoba Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI) Ciudad Universitaria X5000HUA Córdoba Argentina
| | - Lucille T. Kourdova
- Universidad Nacional de Córdoba Facultad de Ciencias Químicas Departamento de Bioquímica Clínica Ciudad Universitaria X5000HUA Córdoba Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI) Ciudad Universitaria X5000HUA Córdoba Argentina
| | - Ana C. Racca
- Universidad Nacional de Córdoba Facultad de Ciencias Químicas Departamento de Bioquímica Clínica Ciudad Universitaria X5000HUA Córdoba Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI) Ciudad Universitaria X5000HUA Córdoba Argentina
| | - Mariano Cruz Del Puerto
- Universidad Nacional de Córdoba Facultad de Ciencias Químicas Departamento de Bioquímica Clínica Ciudad Universitaria X5000HUA Córdoba Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI) Ciudad Universitaria X5000HUA Córdoba Argentina
| | - Maria L. Rojas
- Universidad Nacional de Córdoba Facultad de Ciencias Químicas Departamento de Bioquímica Clínica Ciudad Universitaria X5000HUA Córdoba Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI) Ciudad Universitaria X5000HUA Córdoba Argentina
| | - Aldilane L. X. Marques
- Cell Biology Laboratory Institute of Health and Biological Sciences Federal University of Alagoas Maceio Brazil
| | - Elaine C. O. Silva
- Optics and Nanoscopy Group Physics Institute Federal University of Alagoas Maceio Brazil
| | - Eduardo J. S. Fonseca
- Optics and Nanoscopy Group Physics Institute Federal University of Alagoas Maceio Brazil
| | - Yamila Gazzoni
- Universidad Nacional de Córdoba Facultad de Ciencias Químicas Departamento de Bioquímica Clínica Ciudad Universitaria X5000HUA Córdoba Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI) Ciudad Universitaria X5000HUA Córdoba Argentina
| | - Adriana Gruppi
- Universidad Nacional de Córdoba Facultad de Ciencias Químicas Departamento de Bioquímica Clínica Ciudad Universitaria X5000HUA Córdoba Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI) Ciudad Universitaria X5000HUA Córdoba Argentina
| | - Alexandre U. Borbely
- Cell Biology Laboratory Institute of Health and Biological Sciences Federal University of Alagoas Maceio Brazil
| | - Susana Genti‐Raimondi
- Universidad Nacional de Córdoba Facultad de Ciencias Químicas Departamento de Bioquímica Clínica Ciudad Universitaria X5000HUA Córdoba Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI) Ciudad Universitaria X5000HUA Córdoba Argentina
| | - Graciela M. Panzetta‐Dutari
- Universidad Nacional de Córdoba Facultad de Ciencias Químicas Departamento de Bioquímica Clínica Ciudad Universitaria X5000HUA Córdoba Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI) Ciudad Universitaria X5000HUA Córdoba Argentina
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Chen Z, Wu W, Zheng C, Lan Y, Xie H, Xie Z. KLF6 facilitates differentiation of odontoblasts through modulating the expression of P21 in vitro. Int J Oral Sci 2022; 14:20. [PMID: 35422483 PMCID: PMC9010434 DOI: 10.1038/s41368-022-00172-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 03/08/2022] [Accepted: 03/21/2022] [Indexed: 12/03/2022] Open
Abstract
Multiple signaling pathways are involved in the regulation of cell proliferation and differentiation in odontogenesis and dental tissue renewal, but the details of these mechanisms remain unknown. Here, we investigated the expression patterns of a transcription factor, Krüppel-like factor 6 (KLF6), during the development of murine tooth germ and its function in odontoblastic differentiation. KLF6 was almost ubiquitously expressed in odontoblasts at various stages, and it was co-expressed with P21 (to varying degrees) in mouse dental germ. To determine the function of Klf6, overexpression and knockdown experiments were performed in a mouse dental papilla cell line (iMDP-3). Klf6 functioned as a promoter of odontoblastic differentiation and inhibited the proliferation and cell cycle progression of iMDP-3 through p21 upregulation. Dual-luciferase reporter assay and chromatin immunoprecipitation showed that Klf6 directly activates p21 transcription. Additionally, the in vivo study showed that KLF6 and P21 were also co-expressed in odontoblasts around the reparative dentin. In conclusion, Klf6 regulates the transcriptional activity of p21, thus promoting the cell proliferation to odontoblastic differentiation transition in vitro. This study provides a theoretical basis for odontoblast differentiation and the formation of reparative dentine regeneration.
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Expression and Prognosis Value of the KLF Family Members in Colorectal Cancer. JOURNAL OF ONCOLOGY 2022; 2022:6571272. [PMID: 35345512 PMCID: PMC8957442 DOI: 10.1155/2022/6571272] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 01/03/2022] [Accepted: 01/07/2022] [Indexed: 12/17/2022]
Abstract
Krüppel-like factors (KLFs) are some kind of transcriptional regulator that regulates a broad range of cellular functions and has been linked to the development of certain malignancies. KLF expression patterns and prognostic values in colorectal cancer (CRC) have, however, been investigated rarely. To investigate the differential expression, predictive value, and gene mutations of KLFs in CRC patients, we used various online analytic tools, including ONCOMINE, TCGA, cBioPortal, and the TIMER database. KLF2-6, KLF8-10, KLF12-15, and KLF17 mRNA expression levels were dramatically downregulated in CRC tissues, but KLF1, KLF7, and KLF16 mRNA expression levels were significantly elevated in CRC tissues. According to the findings of Cox regression analysis, upregulation of KLF3, KLF5, and KLF6 and downregulation of KLF15 were linked with a better prognosis in CRC. For functional enrichment, our findings revealed that KLF members are involved in a variety of cancer-related biological processes. In colon cancer and rectal cancer, KLFs were also shown to be associated with a variety of immune cells. The findings of this research reveal that KLF family members' mRNA expression levels are possible prognostic indicators for patients with CRC.
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Kum Chol Ri, Ri MR, Kim KH, Choe SI, Ri JH, Kim JH, Ri JH. KLF6 Super-enhancer Regulates Cell Proliferation by Recruiting GATA2 and SOX10 in Human Hepatoma Cells. Mol Biol 2022. [DOI: 10.1134/s0026893322030116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Su Y, Hou W, Zhang C, Ji P, Hu R, Zhang Q, Wang Y, Li P, Zhang H, Chen Y, Zhang X, Zhang M. Long non-coding RNA ZFAS1 regulates cell proliferation and invasion in cervical cancer via the miR-190a-3p/KLF6 axis. Bioengineered 2022; 13:3840-3851. [PMID: 35112985 PMCID: PMC8973928 DOI: 10.1080/21655979.2021.2022265] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Long non-coding RNA (lncRNA) ZFAS1 (zinc finger antisense 1) was demonstrated to play critical roles in various cancer progression. However, the functions of ZFAS in cervical cancers (CC) are unclear. Human CC cell lines were used for in vitro experiments. RT-qPCR (Real Time Quantitative PCR) was performed to detect the expression of ZFAS1, microRNA-190a-3p (miR-190a-3p) and Kruppel-like factor 6 (KLF6). Cell proliferation, invasion and migration assays were used to investigate biological behaviors of CC cells related to CC progression. The relationship of KLF6 to ZFAS1 and miR-190a-3p was analyzed by circRIP and luciferase reporter assay. In addition, in vivo experiment was carried out to explore the function of ZFAS1 in tumor growth of CC. The expression levels of ZFAS1 and KLF6 were both significantly elevated, while the expression of miR-190a-3p was inhibited in CC tumor tissues. In addition, ZFAS1 influenced CC tumor growth through miR-190a-3p. KLF6 was a target of miR-190a-3p and inhibited miR-190a-3p-induced CC tumor growth. Furthermore, KLF6 was negatively regulated by miR-190a-3p, but positively regulated by ZFAS1. Overexpression of ZFAS1 and inhibition of miR-190a-3p significantly increased the expression levels of KLF6. Finally, in vitro assays demonstrated that inhibition of ZFAS1 reduced CC tumor growth and the expression levels of KLF6, but increased the expression levels of miR-190a-3p. ZFAS1 could regulate CC pathogenesis via regulating the miR-190a-3p/KLF6 axis, which might be considered as new CC therapeutic targets.
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Affiliation(s)
- Yuehui Su
- Department of Gynaecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR. China
| | - Wenjing Hou
- Department of Gynaecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR. China
| | - Chunyan Zhang
- Department of Gynaecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR. China
| | - Pengcheng Ji
- Department of Gynaecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR. China
| | - Rui Hu
- Department of Gynaecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR. China
| | - Qiongying Zhang
- Department of Gynaecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR. China
| | - Yao Wang
- Department of Gynaecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR. China
| | - Panpan Li
- Department of Gynaecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR. China
| | - Huiping Zhang
- Department of Gynaecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR. China
| | - Yueyue Chen
- Department of Gynaecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR. China
| | - Xiaodong Zhang
- Department of Gynaecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR. China
| | - Mengzhen Zhang
- Department of Gynaecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR. China
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Zeng B, Lin J, Cai X, Che L, Zeng W, Liu S. Krüppel-Like Factor 6 Downregulation Is Connected with a Poor Prognosis and Tumor Growth in Non-Small-Cell Lung Cancer. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:3193553. [PMID: 35136416 PMCID: PMC8818409 DOI: 10.1155/2022/3193553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/20/2021] [Accepted: 01/04/2022] [Indexed: 11/17/2022]
Abstract
PURPOSE Research in this article was performed to explore the biological role and clinical significance of Krüppel-like transcription factor 6 (KLF6) in non-small-cell lung cancer (NSCLC). METHODS KLF6 expression in NSCLC cell lines was analyzed using reverse transcription PCR and Western blot. The expressed KLF6 protein was examined in 50 surgical NSCLC tissues using immunohistochemistry. Statistical analyses were employed for clinical association examinations. CCK8 assay and Annexin V/PI analysis were used to execute cell proliferation and apoptosis in KLF6-overexpression cell lines and the control groups. Cleaved caspase-3 expression was also detected in KLF6-overexpression cells and NSCLC tissues. KLF6 expression correlation with cleaved caspase-3 was also examined. RESULTS It was discovered that downregulation of KLF6 was seen in human NSCLC cell lines. Low KLF6 expression in NSCLC tissues was correlated with poor patient prognosis (P < 0.005); patients with less KLF6 expression possessed a lower cumulative 5-year survival rate. Multivariate analysis showed KLF6 expression as an independent prognostic indicator for NSCLC individuals. Expression levels of KLF6 were associated with NSCLC tumor size (P = 0.041). Overexpression of KLF6 inhibited cell proliferation and stimulated A549 and H322 cell line apoptosis. Cleaved caspase-3 protein had higher expression levels in KLF6-overexpressed cells than in the control group. The KLF6 expression levels were positively related to the cleaved caspase-3 protein expression in NSCLC tissues (r = 0.689, P = 0.001). CONCLUSIONS The results indicate that downregulation of KLF6 is a significant NSCLC progression marker. KLF6 prevents cell growth and promotes cell apoptosis, possibly caspase-3 activations.
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Affiliation(s)
- Binbin Zeng
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, China
- Department of Pulmonary and Critical Care Medicine, Huadu District People's Hospital of Guangzhou, Guangzhou, China
| | - Jiaxin Lin
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Xingdong Cai
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Li Che
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Wei Zeng
- Department of Anatomy, School of Medical College, Jinan University, Guangzhou, China
| | - Shengming Liu
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, China
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Guo F, Du J, Liu L, Gou Y, Zhang M, Sun W, Yu H, Fu X. lncRNA OR3A4 Promotes the Proliferation and Metastasis of Ovarian Cancer Through KLF6 Pathway. Front Pharmacol 2021; 12:727876. [PMID: 34776953 PMCID: PMC8578722 DOI: 10.3389/fphar.2021.727876] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Accepted: 08/26/2021] [Indexed: 12/11/2022] Open
Abstract
Aim: Ovarian cancer is a collaborative malignant tumor of the female reproductive system in clinical research. Some clinical studies have shown that OR3A4, which is a cancer-causing lncRNA, plays a major role in promoting the occurrence and development of a variety of tumors. And we also expressed the view that it expressed in ovarian tissue. However, the function of OR3A4 in ovarian cancer remains unclear. Methods and Results: To further verify the function of lncRNA OR3A4 in ovarian cancer, we established the xenograft model in the zebra fish. In this study, cells transformed with OR3A4 shRNA plasmids were transplanted into the zebra fish, and the cell proliferation and migration ability were significantly reduced compared to the empty vector. While knocking out OR3A4, we further downregulated its expression by siRNA of KLF6. Our study found that the knocked out OR3A4 resulted in a decrease in cell proliferation and migration level, which can be found in the downregulated expression of KLF6. We also verify the relationship between OR3A4 and circulating tumor cells in the zebra fish xenograft model, the results indicate that lncRNA OR3A4 may be involved in the resistance of ovarian cancer to complain. Conclusion: lncRNA OR3A4 promotes the proliferation and metastasis of ovarian cancer through the KLF6 pathway.
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Affiliation(s)
- Fangfang Guo
- Edmond H. Fischer Signal Transduction Laboratory, College of Life Sciences, Jilin University, Changchun, China.,Department of Gynecology, Xinhua Hospital Affiliated to Dalian University, Dalian, China
| | - Jianan Du
- Department of Molecular Biology, College of Basic Medical Sciences Jilin University, Changchun, China.,Jilin Province Zebrafish Genetic Engineering Laboratory, Jilin Provincial Development and Reform Commission, Changchun, China
| | - Lingling Liu
- Department of Molecular Biology, College of Basic Medical Sciences Jilin University, Changchun, China.,Jilin Province Zebrafish Genetic Engineering Laboratory, Jilin Provincial Development and Reform Commission, Changchun, China
| | - Yawei Gou
- Department of Molecular Biology, College of Basic Medical Sciences Jilin University, Changchun, China.,Jilin Province Zebrafish Genetic Engineering Laboratory, Jilin Provincial Development and Reform Commission, Changchun, China
| | - Mingming Zhang
- Department of Molecular Biology, College of Basic Medical Sciences Jilin University, Changchun, China.,Jilin Province Zebrafish Genetic Engineering Laboratory, Jilin Provincial Development and Reform Commission, Changchun, China
| | - Wei Sun
- Department of Molecular Biology, College of Basic Medical Sciences Jilin University, Changchun, China.,Jilin Province Zebrafish Genetic Engineering Laboratory, Jilin Provincial Development and Reform Commission, Changchun, China
| | - Hongmei Yu
- Department of Blood Transfusion, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Xueqi Fu
- Edmond H. Fischer Signal Transduction Laboratory, College of Life Sciences, Jilin University, Changchun, China
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Liu S, Qiao W, Sun Q, Luo Y. Chromosome Region Maintenance 1 (XPO1/CRM1) as an Anticancer Target and Discovery of Its Inhibitor. J Med Chem 2021; 64:15534-15548. [PMID: 34669417 DOI: 10.1021/acs.jmedchem.1c01145] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Chromosome region maintenance 1 (CRM1) is a major nuclear export receptor protein and contributes to cell homeostasis by mediating the transport of cargo from the nucleus to the cytoplasm. CRM1 is a therapeutic target comprised of several tumor types, including osteosarcoma, multiple myeloma, gliomas, and pancreatic cancer. In the past decade, dozens of CRM1 inhibitors have been discovered and developed, including KPT-330, which received FDA approval for multiple myeloma (MM) and diffuse large B-cell lymphoma (DLBCL) in 2019 and 2020, respectively. This review summarizes the biological functions of CRM1, the current understanding of the role CRM1 plays in cancer, the discovery of CRM1 small-molecule inhibitors, preclinical and clinical studies on KPT-330, and other recently developed inhibitors. A new CRM1 inhibition mechanism and structural dynamics are discussed. Through this review, we hope to guide the future design and optimization of CRM1 inhibitors.
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Affiliation(s)
- Song Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Wenliang Qiao
- Lung Cancer Center, Laboratory of Lung Cancer, West China Medical School, Sichuan University, Chengdu 610041, China
| | - Qingxiang Sun
- State Key Laboratory of Biotherapy, Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Youfu Luo
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
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Song C, Fang X, Yang Z, Wang Q, Meng F, Chen Y, Chen J, Zhao B, Wang Y, Fang X, Gu L, Zhang C. miR-152 Regulates Bovine Myoblast Proliferation by Targeting KLF6. Animals (Basel) 2021; 11:ani11103001. [PMID: 34680020 PMCID: PMC8532817 DOI: 10.3390/ani11103001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 10/13/2021] [Accepted: 10/16/2021] [Indexed: 01/03/2023] Open
Abstract
Though miRNAs have been reported to regulate bovine myoblast proliferation, but many miRNAs still need to be further explored. Specifically, miR-152 is a highly expressed miRNA in cattle skeletal muscle tissues, but its function in skeletal muscle development is unknown. Herein, we aimed to investigate the role of miR-152 in regulating bovine myoblast proliferation. Functionally, RT-qPCR, Western blotting, EdU assay, and flow cytometry detection results showed that miR-152 inhibited bovine myoblast proliferation. Mechanistically, we demonstrated transcription factor KLF6 was a target gene of miR-152 by means of bioinformatics software prediction and dual-luciferase report analysis, which had been demonstrated to be favorable for myoblast proliferation. Collectively, our research suggested that miR-152 inhibits bovine myoblast proliferation via targeting KLF6.
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Affiliation(s)
- Chengchuang Song
- Institute of Cellular and Molecular Biology, School of Life Science, Jiangsu Normal University, Xuzhou 221116, China; (C.S.); (X.F.); (Q.W.); (F.M.); (Y.C.); (J.C.); (B.Z.); (Y.W.); (X.F.)
| | - Xue Fang
- Institute of Cellular and Molecular Biology, School of Life Science, Jiangsu Normal University, Xuzhou 221116, China; (C.S.); (X.F.); (Q.W.); (F.M.); (Y.C.); (J.C.); (B.Z.); (Y.W.); (X.F.)
| | - Zhaoxin Yang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China;
| | - Qi Wang
- Institute of Cellular and Molecular Biology, School of Life Science, Jiangsu Normal University, Xuzhou 221116, China; (C.S.); (X.F.); (Q.W.); (F.M.); (Y.C.); (J.C.); (B.Z.); (Y.W.); (X.F.)
| | - Fantong Meng
- Institute of Cellular and Molecular Biology, School of Life Science, Jiangsu Normal University, Xuzhou 221116, China; (C.S.); (X.F.); (Q.W.); (F.M.); (Y.C.); (J.C.); (B.Z.); (Y.W.); (X.F.)
| | - Yaqi Chen
- Institute of Cellular and Molecular Biology, School of Life Science, Jiangsu Normal University, Xuzhou 221116, China; (C.S.); (X.F.); (Q.W.); (F.M.); (Y.C.); (J.C.); (B.Z.); (Y.W.); (X.F.)
| | - Junhao Chen
- Institute of Cellular and Molecular Biology, School of Life Science, Jiangsu Normal University, Xuzhou 221116, China; (C.S.); (X.F.); (Q.W.); (F.M.); (Y.C.); (J.C.); (B.Z.); (Y.W.); (X.F.)
| | - Bei Zhao
- Institute of Cellular and Molecular Biology, School of Life Science, Jiangsu Normal University, Xuzhou 221116, China; (C.S.); (X.F.); (Q.W.); (F.M.); (Y.C.); (J.C.); (B.Z.); (Y.W.); (X.F.)
| | - Yanhong Wang
- Institute of Cellular and Molecular Biology, School of Life Science, Jiangsu Normal University, Xuzhou 221116, China; (C.S.); (X.F.); (Q.W.); (F.M.); (Y.C.); (J.C.); (B.Z.); (Y.W.); (X.F.)
| | - Xingtang Fang
- Institute of Cellular and Molecular Biology, School of Life Science, Jiangsu Normal University, Xuzhou 221116, China; (C.S.); (X.F.); (Q.W.); (F.M.); (Y.C.); (J.C.); (B.Z.); (Y.W.); (X.F.)
| | - Lihong Gu
- Institute of Animal Science & Veterinary Medicine, Hainan Academy of Agricultural Sciences, Haikou 571100, China;
| | - Chunlei Zhang
- Institute of Cellular and Molecular Biology, School of Life Science, Jiangsu Normal University, Xuzhou 221116, China; (C.S.); (X.F.); (Q.W.); (F.M.); (Y.C.); (J.C.); (B.Z.); (Y.W.); (X.F.)
- Correspondence:
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36
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Mann-Nüttel R, Ali S, Petzsch P, Köhrer K, Alferink J, Scheu S. The transcription factor reservoir and chromatin landscape in activated plasmacytoid dendritic cells. BMC Genom Data 2021; 22:37. [PMID: 34544361 PMCID: PMC8454182 DOI: 10.1186/s12863-021-00991-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 08/29/2021] [Indexed: 12/13/2022] Open
Abstract
Background Transcription factors (TFs) control gene expression by direct binding to regulatory regions of target genes but also by impacting chromatin landscapes and modulating DNA accessibility for other TFs. In recent years several TFs have been defined that control cell fate decisions and effector functions in the immune system. Plasmacytoid dendritic cells (pDCs) are an immune cell type with the unique capacity to produce high amounts of type I interferons quickly in response to contact with viral components. Hereby, this cell type is involved in anti-infectious immune responses but also in the development of inflammatory and autoimmune diseases. To date, the global TF reservoir in pDCs early after activation remains to be fully characterized. Results To fill this gap, we have performed a comprehensive analysis in naïve versus TLR9-activated murine pDCs in a time course study covering early timepoints after stimulation (2 h, 6 h, 12 h) integrating gene expression (RNA-Seq) and chromatin landscape (ATAC-Seq) studies. To unravel the biological processes underlying the changes in TF expression on a global scale gene ontology (GO) analyses were performed. We found that 70% of all genes annotated as TFs in the mouse genome (1014 out of 1636) are expressed in pDCs for at least one stimulation time point and are covering a wide range of TF classes defined by their specific DNA binding mechanisms. GO analysis revealed involvement of TLR9-induced TFs in epigenetic modulation, NFκB and JAK-STAT signaling, and protein production in the endoplasmic reticulum. pDC activation predominantly “turned on” the chromatin regions associated with TF genes. Our in silico analyses pointed at the AP-1 family of TFs as less noticed but possibly important players in these cells after activation. AP-1 family members exhibit (1) increased gene expression, (2) enhanced chromatin accessibility in their promoter region, and (3) a TF DNA binding motif that is globally enriched in genomic regions that were found more accessible in pDCs after TLR9 activation. Conclusions In this study we define the complete set of TLR9-regulated TFs in pDCs. Further, this study identifies the AP-1 family of TFs as potentially important but so far less well characterized regulators of pDC function. Supplementary Information The online version contains supplementary material available at 10.1186/s12863-021-00991-2.
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Affiliation(s)
- Ritu Mann-Nüttel
- Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, Düsseldorf, Germany
| | - Shafaqat Ali
- Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, Düsseldorf, Germany.,Cells in Motion Interfaculty Centre, Münster, Germany.,Department of Mental Health, University of Münster, Münster, Germany
| | - Patrick Petzsch
- Biological and Medical Research Center (BMFZ), Medical Faculty, University of Düsseldorf, Düsseldorf, Germany
| | - Karl Köhrer
- Biological and Medical Research Center (BMFZ), Medical Faculty, University of Düsseldorf, Düsseldorf, Germany
| | - Judith Alferink
- Cells in Motion Interfaculty Centre, Münster, Germany.,Department of Mental Health, University of Münster, Münster, Germany
| | - Stefanie Scheu
- Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, Düsseldorf, Germany.
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Cardinali G, Flori E, Mastrofrancesco A, Mosca S, Ottaviani M, Dell'Anna ML, Truglio M, Vento A, Zaccarini M, Zouboulis CC, Picardo M. Anti-Inflammatory and Pro-Differentiating Properties of the Aryl Hydrocarbon Receptor Ligands NPD-0614-13 and NPD-0614-24: Potential Therapeutic Benefits in Psoriasis. Int J Mol Sci 2021; 22:ijms22147501. [PMID: 34299118 PMCID: PMC8304622 DOI: 10.3390/ijms22147501] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/06/2021] [Accepted: 07/10/2021] [Indexed: 12/13/2022] Open
Abstract
The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor expressed in all skin cell types, plays a key role in physiological and pathological processes. Several studies have shown that this receptor is involved in the prevention of inflammatory skin diseases, e.g., psoriasis, atopic dermatitis, representing a potential therapeutic target. We tested the safety profile and the biological activity of NPD-0614-13 and NPD-0614-24, two new synthetic AhR ligands structurally related to the natural agonist FICZ, known to be effective in psoriasis. NPD-0614-13 and NPD-0614-24 did not alter per se the physiological functions of the different skin cell populations involved in the pathogenesis of inflammatory skin diseases. In human primary keratinocytes stimulated with tumor necrosis factor-α or lipopolysaccharide the compounds were able to counteract the altered proliferation and to dampen inflammatory signaling by reducing the activation of p38MAPK, c-Jun, NF-kBp65, and the release of cytokines. Furthermore, the molecules were tested for their beneficial effects in human epidermal and full-thickness reconstituted skin models of psoriasis. NPD-0614-13 and NPD-0614-24 recovered the psoriasis skin phenotype exerting pro-differentiating activity and reducing the expression of pro-inflammatory cytokines and antimicrobial peptides. These data provide a rationale for considering NPD-0614-13 and NPD-0614-24 in the management of psoriasis.
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Affiliation(s)
- Giorgia Cardinali
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy
| | - Enrica Flori
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy
| | - Arianna Mastrofrancesco
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy
| | - Sarah Mosca
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy
| | - Monica Ottaviani
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy
| | - Maria Lucia Dell'Anna
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy
| | - Mauro Truglio
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy
| | - Antonella Vento
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy
| | - Marco Zaccarini
- Genetic Research, Molecular Biology and Dermatopathology Unit, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy
| | - Christos C Zouboulis
- Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical School Theodore Fontane and Faculty of Health Sciences Brandenburg, 06847 Dessau, Germany
| | - Mauro Picardo
- Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy
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Predictive value of transcriptional expression of Krüppel-like factor-6 (KLF6) in head and neck carcinoma patients treated with radiotherapy. Clin Transl Oncol 2021; 23:2507-2512. [PMID: 34061320 DOI: 10.1007/s12094-021-02651-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 05/20/2021] [Indexed: 12/21/2022]
Abstract
PURPOSE To analyse the relationship between the transcriptional expression of Krüppel-like factor-6 (KLF6) and local response to treatment with radiotherapy in patients with head and neck squamous cell carcinoma (HNSCC). METHODS We determined the transcriptional expression of KLF6 in tumour biopsies obtained before treatment with radiotherapy in 83 HNSCC patients. The KLF6 expression was categorized according to the local control of the disease with a recursive partitioning analysis. RESULTS During the follow-up period, 27 patients (32.5%) had a local recurrence of the tumour. Patients with local recurrence had significantly higher levels of KLF6 expression than patients in which radiotherapy achieved local control of the disease (P = 0.029). Five-year local recurrence-free survival for patients with a high transcriptional expression of KLF6 (n = 46) was 51.1% (95% CI 36.4-66.2%), and for patients with low expression it was 85.6% (95% CI 73.9-97.3%) (P = 0.0001). The results of a multivariate analysis showed that patients with a high KLF6 expression had a 3.8 times higher risk of local recurrence after treatment with radiotherapy (95% CI 1.4-10.5, P = 0.008). CONCLUSION Transcriptional expression of KLF6 was significantly related to local control in HNSCC patients treated with radiotherapy. Patients with high levels of KLF6 expression had a significantly higher risk of local recurrence after treatment.
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MicroRNA-543-3p down-regulates inflammation and inhibits periodontitis through KLF6. Biosci Rep 2021; 41:228588. [PMID: 33955459 PMCID: PMC8144941 DOI: 10.1042/bsr20210138] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 04/22/2021] [Accepted: 05/04/2021] [Indexed: 11/17/2022] Open
Abstract
MicroRNA-543-3p (miR-543-3p) has been reported to be involved in many human disease’s progression, but its role in inflammation is still unclear. After bacterial infection, innate immune cells are activated to trigger inflammation by recognizing lipopolysaccharide (LPS) on the bacterial outer membrane. In our research, it showed that miR-543-3p was down-regulated in LPS-treated periodontal ligament cells (PDLCs). And it mediated the apoptosis of PDLC induced by LPS, which may be involved in periodontitis development. Besides, up-regulation of miR-543-3p alleviated the inflammatory damage induced by LPS. Furthermore, our research demonstrated Kruppel-like factor 6 (KLF6) served as a direct downstream target of miR-543-3p to play a vital role in periodontitis. Simply put, these findings suggest that miR-543-3p could down-regulate inflammation and inhibit periodontitis by targeting KLF6, and it provides a new insight into the molecular mechanism of periodontitis, which may be helpful for the early diagnosis and treatment of this disease.
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Wang S, Tong X, Li C, Jin E, Su Z, Sun Z, Zhang W, Lei Z, Zhang HT. Quaking 5 suppresses TGF-β-induced EMT and cell invasion in lung adenocarcinoma. EMBO Rep 2021; 22:e52079. [PMID: 33769671 PMCID: PMC8183405 DOI: 10.15252/embr.202052079] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 02/28/2021] [Accepted: 03/08/2021] [Indexed: 01/01/2023] Open
Abstract
Quaking (QKI) proteins belong to the signal transduction and activation of RNA (STAR) family of RNA-binding proteins that have multiple functions in RNA biology. Here, we show that QKI-5 is dramatically decreased in metastatic lung adenocarcinoma (LUAD). QKI-5 overexpression inhibits TGF-β-induced epithelial-mesenchymal transition (EMT) and invasion, whereas QKI-5 knockdown has the opposite effect. QKI-5 overexpression and silencing suppresses and promotes TGF-β-stimulated metastasis in vivo, respectively. QKI-5 inhibits TGF-β-induced EMT and invasion in a TGFβR1-dependent manner. KLF6 knockdown increases TGFβR1 expression and promotes TGF-β-induced EMT, which is partly abrogated by QKI-5 overexpression. Mechanistically, QKI-5 directly interacts with the TGFβR1 3' UTR and causes post-transcriptional degradation of TGFβR1 mRNA, thereby inhibiting TGF-β-induced SMAD3 phosphorylation and TGF-β/SMAD signaling. QKI-5 is positively regulated by KLF6 at the transcriptional level. In LUAD tissues, KLF6 is lowly expressed and positively correlated with QKI-5 expression, while TGFβR1 expression is up-regulated and inversely correlated with QKI-5 expression. We reveal a novel mechanism by which KLF6 transcriptionally regulates QKI-5 and suggest that targeting the KLF6/QKI-5/TGFβR1 axis is a promising targeting strategy for metastatic LUAD.
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Affiliation(s)
- Shengjie Wang
- Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, China.,Department of Genetics, School of Biology and Basic Medical Sciences, Medical College of Soochow University, Suzhou, China.,Department of Basic Medicine, Kangda College of Nanjing Medical University, Lianyungang, China
| | - Xin Tong
- Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, China.,Department of Genetics, School of Biology and Basic Medical Sciences, Medical College of Soochow University, Suzhou, China
| | - Chang Li
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Medical College of Soochow University, Suzhou, China
| | - Ersuo Jin
- Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, China.,Department of Genetics, School of Biology and Basic Medical Sciences, Medical College of Soochow University, Suzhou, China
| | - Zhiyue Su
- Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, China.,Department of Genetics, School of Biology and Basic Medical Sciences, Medical College of Soochow University, Suzhou, China
| | - Zelong Sun
- Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, China.,Department of Genetics, School of Biology and Basic Medical Sciences, Medical College of Soochow University, Suzhou, China
| | - Weiwei Zhang
- Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, China.,Department of Genetics, School of Biology and Basic Medical Sciences, Medical College of Soochow University, Suzhou, China
| | - Zhe Lei
- Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, China.,Department of Genetics, School of Biology and Basic Medical Sciences, Medical College of Soochow University, Suzhou, China
| | - Hong-Tao Zhang
- Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, China.,Department of Genetics, School of Biology and Basic Medical Sciences, Medical College of Soochow University, Suzhou, China.,Suzhou Key Laboratory for Molecular Cancer Genetics, Suzhou, Jiangsu, China
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Hu K, Zheng QK, Ma RJ, Ma C, Sun ZG, Zhang N. Krüppel-Like Factor 6 Splice Variant 1: An Oncogenic Transcription Factor Involved in the Progression of Multiple Malignant Tumors. Front Cell Dev Biol 2021; 9:661731. [PMID: 33816511 PMCID: PMC8017371 DOI: 10.3389/fcell.2021.661731] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 02/23/2021] [Indexed: 01/03/2023] Open
Abstract
Krüppel-like factor 6 (KLF6) is one of the most studied members of the specificity protein/Krüppel-like factor (SP/KLF) transcription factor family. It has a typical zinc finger structure and plays a pivotal role in regulating the biological processes of cells. Recently, it has been considered to play a role in combatting cancer. Krüppel-like factor 6 splice variant 1 (KLF6-SV1), being one of the alternative KLF6 splicing isoforms, participates in tumor occurrence and development and has the potential to become a new target for molecular targeted therapy, although its action mechanism remains to be determined. The purpose of this article is to provide a comprehensive and systematic review of the important role of KLF6-SV1 in human malignant tumors to provide novel insights for oncotherapy.
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Affiliation(s)
- Kang Hu
- School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Qing-Kang Zheng
- School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Rui-Jie Ma
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chao Ma
- School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Zhi-Gang Sun
- Department of Thoracic Surgery, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Nan Zhang
- Department of Oncology, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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Single-cell profiling identifies pre-existing CD19-negative subclones in a B-ALL patient with CD19-negative relapse after CAR-T therapy. Nat Commun 2021; 12:865. [PMID: 33558546 PMCID: PMC7870924 DOI: 10.1038/s41467-021-21168-6] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 01/14/2021] [Indexed: 01/16/2023] Open
Abstract
Chimeric antigen receptor T cell (CAR-T) targeting the CD19 antigen represents an innovative therapeutic approach to improve the outcome of relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). Yet, despite a high initial remission rate, CAR-T therapy ultimately fails for some patients. Notably, around half of relapsing patients develop CD19 negative (CD19neg) B-ALL allowing leukemic cells to evade CD19-targeted therapy. Herein, we investigate leukemic cells of a relapsing B-ALL patient, at two-time points: before (T1) and after (T2) anti-CD19 CAR-T treatment. We show that at T2, the B-ALL relapse is CD19 negative due to the expression of a non-functional CD19 transcript retaining intron 2. Then, using single-cell RNA sequencing (scRNAseq) approach, we demonstrate that CD19neg leukemic cells were present before CAR-T cell therapy and thus that the relapse results from the selection of these rare CD19neg B-ALL clones. In conclusion, our study shows that scRNAseq profiling can reveal pre-existing CD19neg subclones, raising the possibility to assess the risk of targeted therapy failure. CD19-negative relapses are observed in patients with B-cell acute lymphoblastic leukemia (B-ALL) treated with anti-CD19 CAR-T cells. Here, by single-cell RNA sequencing of leukemic cells in a patient with B-ALL, the authors show that pre-existing CD19 negative leukemic subclones are present before CAR-T cell therapy and can account for the relapse.
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Chen Z, Xie H, Yuan J, Lan Y, Xie Z. Krüppel-like factor 6 promotes odontoblastic differentiation through regulating the expression of dentine sialophosphoprotein and dentine matrix protein 1 genes. Int Endod J 2021; 54:572-584. [PMID: 33200415 DOI: 10.1111/iej.13447] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 11/12/2020] [Indexed: 12/21/2022]
Abstract
AIM To investigate the potential role of Krüppel-like factor 6 (KLF6) in the odontoblastic differentiation of immortalized dental papilla mesenchymal cells (iMDP-3) cells. METHODOLOGY Alizarin Red S (ARS) and Alkaline phosphatase (ALP) staining was used to examine the mineralization effect of iMDP-3 cells after odontoblastic induction. Real-time PCR and Western blotting were employed to analyse dentine sialophosphoprotein (DSPP), dentine matrix protein 1 (DMP1), RUNX family transcription factor 2 (RUNX2), ALP and KLF6 expression during this process. Co-expression of the KLF6 with DMP1, DSPP and RUNX2 was detected by double immunofluorescence staining to explore their local relationship in the cell. To further investigate KLF6 functions, Klf6 gain- and loss-of-function assays followed by ARS and ALP stainings, real-time PCR and Western blotting were performed using Klf6-overexpression plasmids and Klf6 siRNA to investigate whether changes in Klf6 expression affect the odontoblastic differentiation of iMDP-3 cells. Dual-luciferase reporter assays were used to elucidate the mechanistic regulation of Dspp and Dmp1 expression by Klf6. Means were compared using the unpaired t-test and Kruskal-Wallis one-way anova with P < 0.05 and P < 0.01 defined as statistical significance levels. RESULTS The expression levels of Klf6 (P < 0.01), Dspp (P < 0.05), Dmp1 (P < 0.01), Runx2 (P < 0.01) and Alp (P < 0.01) were significantly elevated during odontoblastic differentiation of iMDP-3 cells. KLF6 was co-localized with DSPP, DMP1 and RUNX2 in the cytoplasm and nucleus of iMDP-3 cells. Overexpression of Klf6 promoted the odontoblastic differentiation of iMDP-3, whereas the inhibition of Klf6 prevented this procession. Dual-luciferase assays revealed that Klf6 upregulates Dspp and Dmp1 transcription in iMDP-3 cells during odontoblastic differentiation. CONCLUSION Klf6 promoted odontoblastic differentiation by targeting the transcription promoter of Dmp1 and Dspp. This study may offer novel insights into strategies for treating injuries to dental pulp tissue.
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Affiliation(s)
- Z Chen
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, and Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, China
| | - H Xie
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, and Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, China
| | - J Yuan
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, and Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, China
| | - Y Lan
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, and Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, China
| | - Z Xie
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, and Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, China
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Syafruddin SE, Mohtar MA, Wan Mohamad Nazarie WF, Low TY. Two Sides of the Same Coin: The Roles of KLF6 in Physiology and Pathophysiology. Biomolecules 2020; 10:biom10101378. [PMID: 32998281 PMCID: PMC7601070 DOI: 10.3390/biom10101378] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 09/26/2020] [Accepted: 09/26/2020] [Indexed: 12/12/2022] Open
Abstract
The Krüppel-like factors (KLFs) family of proteins control several key biological processes that include proliferation, differentiation, metabolism, apoptosis and inflammation. Dysregulation of KLF functions have been shown to disrupt cellular homeostasis and contribute to disease development. KLF6 is a relevant example; a range of functional and expression assays suggested that the dysregulation of KLF6 contributes to the onset of cancer, inflammation-associated diseases as well as cardiovascular diseases. KLF6 expression is either suppressed or elevated depending on the disease, and this is largely due to alternative splicing events producing KLF6 isoforms with specialised functions. Hence, the aim of this review is to discuss the known aspects of KLF6 biology that covers the gene and protein architecture, gene regulation, post-translational modifications and functions of KLF6 in health and diseases. We put special emphasis on the equivocal roles of its full-length and spliced variants. We also deliberate on the therapeutic strategies of KLF6 and its associated signalling pathways. Finally, we provide compelling basic and clinical questions to enhance the knowledge and research on elucidating the roles of KLF6 in physiological and pathophysiological processes.
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Affiliation(s)
- Saiful E. Syafruddin
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (M.A.M.); (T.Y.L.)
- Correspondence: ; Tel.: +60-3-9145-9040
| | - M. Aiman Mohtar
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (M.A.M.); (T.Y.L.)
| | - Wan Fahmi Wan Mohamad Nazarie
- Biotechnology Programme, Faculty of Science and Natural Resources, Universiti Malaysia Sabah, Kota Kinabalu 88400, Malaysia;
| | - Teck Yew Low
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (M.A.M.); (T.Y.L.)
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Al-Qarni R, Iqbal M, Al-Otaibi M, Al-Saif F, Alfadda AA, Alkhalidi H, Bamehriz F, Hassanain M. Validating candidate biomarkers for different stages of non-alcoholic fatty liver disease. Medicine (Baltimore) 2020; 99:e21463. [PMID: 32898995 PMCID: PMC7478685 DOI: 10.1097/md.0000000000021463] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common chronic condition caused by the accumulation of fat in the liver. NAFLD may range from simple steatosis to advanced cirrhosis, and affects more than 1 billion people around the world. To date, there has been no effective treatment for NAFLD. In this study, we evaluated the expression of 4 candidate NAFLD biomarkers to assess their possible applicability in the classification and treatment of the disease.Twenty-six obese subjects, who underwent bariatric surgery, were recruited and their liver biopsies obtained. Expression of 4 candidate biomarker genes, PNPLA3, COL1A1, PPP1R3B, and KLF6 were evaluated at gene and protein levels by RT-qPCR and enzyme-linked immunosorbent assay (ELISA), respectively.A significant increase in the levels of COL1A1 protein (P = .03) and PNPLA3 protein (P = .03) were observed in patients with fibrosis-stage NAFLD compared to that in patients with steatosis-stage NAFLD. However, no significant differences were found in abundance of PPP1R3B and KLF6 proteins or at the gene level for any of the candidate.This is the first study, to our knowledge, to report on the expression levels of candidate biomarker genes for NAFLD in the Saudi population. Although PNPLA3 and PPP1R3B had been previously suggested as biomarkers for steatosis and KLF6 as a possible marker for the fibrosis stage of NAFLD, our results did not support these findings. However, other studies that had linked PNPLA3 to fibrosis in advanced NAFLD supported our current finding of high PNPLA3 protein in patients with fibrosis. Additionally, our results support COL1A1 protein as a potential biomarker for the fibrosis stage of NAFLD, and indicate its use in the screening of patients with NAFLD. Further studies are required to validate the use of COL1A1 as a biomarker for advanced NAFLD in a larger cohort.
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Affiliation(s)
| | | | | | - Faisal Al-Saif
- Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | | | | | - Fahad Bamehriz
- Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Mazen Hassanain
- Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- Department of Oncology, McGill University, Montreal, Quebec, Canada
- Liver Disease Research Center, King Saud University, Riyadh, Saudi Arabia
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Sun S, Chen H, Sun L, Wang M, Wu X, Xiao ZXJ. Hotspot mutant p53-R273H inhibits KLF6 expression to promote cell migration and tumor metastasis. Cell Death Dis 2020; 11:595. [PMID: 32733026 PMCID: PMC7393383 DOI: 10.1038/s41419-020-02814-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 07/08/2020] [Accepted: 07/08/2020] [Indexed: 12/13/2022]
Abstract
Hotspot p53 mutant proteins often gain novel functions in promoting tumor metastases. However, the molecular mechanisms by which mutant p53 exerts gain-of-function in cancer are not totally understood. In this study, we demonstrate that hotspot mutant p53, p53-R273H, promotes cell scattering growth and migration via inhibiting the expression of Krupple-like factor 6 (KLF6), a Zinc finger transcription factor and a documented tumor suppressor. Restoration of KLF6 increases the expression of E-cadherin downregulated by p53-R273H and inhibits p53-R273H-induced cell migration and tumor metastasis. Further, p53-R273H reduces KLF6 transcription by upregulating EGFR expression which in turn activates AKT–FOXO1 axis. Pharmacological inhibitor of AKT, MK2206, rescues KLF6 expression and suppresses p53-R273H-induced cell migration. Clinical analyses reveal that KLF6 expression is decreased in human breast cancer specimens harboring p53 mutations, and negatively correlated with EGFR expression in human breast cancer. In addition, low expression of KLF6 is associated with poor overall survival (OS) and relapse-free survival (RFS) in p53 mutated human breast cancer patients. Together, these results reveal an important role for EGFR–AKT–FOXO1–KLF6–E-cadherin axis in mutant p53-induced cell migration and tumor metastasis.
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Affiliation(s)
- Shengnan Sun
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610064, China
| | - Hu Chen
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610064, China.
| | - Lijuan Sun
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610064, China
| | - Miao Wang
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610064, China
| | - Xianqiang Wu
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610064, China
| | - Zhi-Xiong Jim Xiao
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610064, China.
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Vianna R, Secco D, Hanhoerderster L, Motta J, Cardoso J, Porto LC. An
NGS
‐based
HLA
haplotype analysis and population comparison between two cities in Rio de Janeiro, Brazil. HLA 2020; 96:268-276. [DOI: 10.1111/tan.13940] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 04/10/2020] [Accepted: 05/15/2020] [Indexed: 02/02/2023]
Affiliation(s)
- Romulo Vianna
- Histocompatibility and Cryopreservation LaboratoryRio de Janeiro State University Rio de Janeiro Brazil
| | - Danielle Secco
- Histocompatibility and Cryopreservation LaboratoryRio de Janeiro State University Rio de Janeiro Brazil
| | - Leonardo Hanhoerderster
- Histocompatibility and Cryopreservation LaboratoryRio de Janeiro State University Rio de Janeiro Brazil
| | - Juliana Motta
- Histocompatibility and Cryopreservation LaboratoryRio de Janeiro State University Rio de Janeiro Brazil
| | - Juliana Cardoso
- Histocompatibility and Cryopreservation LaboratoryRio de Janeiro State University Rio de Janeiro Brazil
| | - Luís Cristóvão Porto
- Histocompatibility and Cryopreservation LaboratoryRio de Janeiro State University Rio de Janeiro Brazil
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Belluti S, Rigillo G, Imbriano C. Transcription Factors in Cancer: When Alternative Splicing Determines Opposite Cell Fates. Cells 2020; 9:E760. [PMID: 32244895 PMCID: PMC7140685 DOI: 10.3390/cells9030760] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 03/05/2020] [Accepted: 03/17/2020] [Indexed: 02/08/2023] Open
Abstract
Alternative splicing (AS) is a finely regulated mechanism for transcriptome and proteome diversification in eukaryotic cells. Correct balance between AS isoforms takes part in molecular mechanisms that properly define spatiotemporal and tissue specific transcriptional programs in physiological conditions. However, several diseases are associated to or even caused by AS alterations. In particular, multiple AS changes occur in cancer cells and sustain the oncogenic transcriptional program. Transcription factors (TFs) represent a key class of proteins that control gene expression by direct binding to DNA regulatory elements. AS events can generate cancer-associated TF isoforms with altered activity, leading to sustained proliferative signaling, differentiation block and apoptosis resistance, all well-known hallmarks of cancer. In this review, we focus on how AS can produce TFs isoforms with opposite transcriptional activities or antagonistic functions that severely impact on cancer biology. This summary points the attention to the relevance of the analysis of TFs splice variants in cancer, which can allow patients stratification despite the presence of interindividual genetic heterogeneity. Recurrent TFs variants that give advantage to specific cancer types not only open the opportunity to use AS transcripts as clinical biomarkers but also guide the development of new anti-cancer strategies in personalized medicine.
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Affiliation(s)
| | | | - Carol Imbriano
- Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 213/D, 41125 Modena, Italy; (S.B.); (G.R.)
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Jiang X, Zhu Q, Wu P, Zhou F, Chen J. Upregulated Long Noncoding RNA LINC01234 Predicts Unfavorable Prognosis for Colorectal Cancer and Negatively Correlates With KLF6 Expression. Ann Lab Med 2020; 40:155-163. [PMID: 31650732 PMCID: PMC6822002 DOI: 10.3343/alm.2020.40.2.155] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 07/12/2019] [Accepted: 10/10/2019] [Indexed: 12/13/2022] Open
Abstract
Background LINC01234, a long noncoding RNA (lncRNA), is overexpressed in several cancers, including colorectal cancer (CRC). We investigated the role of LINC01234 in CRC development and confirmed its correlation with Krüppel-like factor 6 (KLF6), a tumor suppressor gene that is dysregulated in CRC. Methods We tested mRNA levels using quantitative reverse transcription PCR (qRT-PCR). Tissue samples from patients with CRC, inflammatory bowel disease (IBD), hyperplastic polyp, and adenoma were included. Correlations between clinicopathological parameters, overall survival (OS) rate, and LINC01234 were analyzed using Kruskal-Wallis H test. Additionally, cell proliferation, apoptosis, and tumor formation in nude mice were tested to investigate the mechanism of LINC01234. Western blotting was used to determine protein levels. Results LINC01234 expression was significantly upregulated in CRC tissues and CRC cell lines than in non-tumor tissues and normal epithelial cells, respectively. LINC01234 was associated with high tumor stage, larger tumor size, and metastasis. Patients with higher LINC01234 expression showed reduced OS. Cell proliferation was inhibited by LINC01234 knockdown, whereas apoptosis was enhanced. Mice injected with SW480 cells with LINC01234 knockdown displayed decreased tumor volume, weight, and Ki-67 levels compared with those injected with control cells. KLF6 was negatively regulated by LINC01234. Overexpression of KLF6 showed effects similar to those observed following LINC01234 knockdown on cell proliferation and apoptosis. Conclusions LINC01234 could be a prognostic biomarker in CRC patients. Upregulation of LINC01234 in CRC promotes tumor development through negative regulation of KLF6.
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Affiliation(s)
- Xiao Jiang
- Department of Ultrasound, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, China
| | - Qiaoying Zhu
- Department of Ultrasound, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, China.
| | - Pengxi Wu
- Department of Ultrasound, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, China
| | - Fengsheng Zhou
- Department of Ultrasound, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, China
| | - Jun Chen
- Department of Ultrasound, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, China
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Tian F, Zhao J, Bu S, Teng H, Yang J, Zhang X, Li X, Dong L. KLF6 Induces Apoptosis in Human Lens Epithelial Cells Through the ATF4-ATF3-CHOP Axis. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:1041-1055. [PMID: 32210535 PMCID: PMC7069589 DOI: 10.2147/dddt.s218467] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 12/01/2019] [Indexed: 12/18/2022]
Abstract
Background Many studies have confirmed that high myopia is related to the high prevalence of cataracts, which results from apoptosis of lens epithelial cells (LECs) due to endoplasmic reticulum stress. Krüppel-like factor 6 (KLF6) is a tumor suppressor that is involved in the regulation of cell proliferation and apoptosis. Purpose In this study, our purpose was to find the relationship between KLF6-induced apoptosis in LECs and ATF4 (activating transcription factor 4)-ATF3 (activating transcription factor 3)-CHOP (C/EBP homologous protein) signaling pathway. Methods KLF6, ATF4, ATF3, and CHOP were ectopically expressed using cDNAs subcloned into the pCDNA3.1+ vector. ATF4, ATF3, and CHOP knockdown were performed by small interfering RNA (siRNA). Expression of relative gene was tested using QT-PCR and western-blot. Then, accompanied by UVB stimulation, cell viability was measured by CCK-8 assay; The cell damage was examined by live & dead staining; The apoptotic markers Bax and Bcl-2 were detected by immunoblotting; Quantitative apoptotic levels were measured with the Apoptosis Detection Kit; The expression level of reactive oxygen-free radical (ROS) was analyzed by DCFH-DA` probe. Results Ectopically expressed ATF4, ATF3, and CHOP-induced apoptosis in cells, whereas ATF4, ATF3, and CHOP knockdown by small interfering RNA (siRNA) blocked KLF6-induced apoptosis. In addition, we determined that ATF4 regulates ATF3 and CHOP expression and that ATF3 silencing reduces CHOP upregulation without changing ATF4 levels; however, ATF4 and ATF3 expression was unaffected by blockade of CHOP, suggesting that KLF6 triggers endoplasmic reticulum stress in LECs by mediating the ATF4-ATF3/CHOP axis. Besides, KLF6 overexpression significantly induced LEC apoptosis under UV radiation, as demonstrated by the elevated Bax/Bcl-2 ratio. Conclusion The ATF4-ATF3-CHOP pathway plays an important role in KLF6-induced apoptosis in HLECs. Our results increase our understanding of the mechanisms that regulate LEC apoptosis and contribute to the development of a new preventative strategy for cataract.
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Affiliation(s)
- Fang Tian
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Medical University Eye Hospital, Tianjin, People's Republic of China
| | - Jinzhi Zhao
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Medical University Eye Hospital, Tianjin, People's Republic of China
| | - Shaochong Bu
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Medical University Eye Hospital, Tianjin, People's Republic of China
| | - He Teng
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Medical University Eye Hospital, Tianjin, People's Republic of China
| | - Jun Yang
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Medical University Eye Hospital, Tianjin, People's Republic of China
| | - Xiaomin Zhang
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Medical University Eye Hospital, Tianjin, People's Republic of China
| | - Xiaorong Li
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Medical University Eye Hospital, Tianjin, People's Republic of China
| | - Lijie Dong
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Medical University Eye Hospital, Tianjin, People's Republic of China
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