|
1
|
Li D, Chu X, Liu W, Ma Y, Tian X, Yang Y. The regulatory roles of RNA-binding proteins in the tumour immune microenvironment of gastrointestinal malignancies. RNA Biol 2025; 22:1-14. [PMID: 39718205 DOI: 10.1080/15476286.2024.2440683] [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] [Revised: 11/03/2024] [Accepted: 12/04/2024] [Indexed: 12/25/2024] Open
Abstract
The crosstalk between the tumour immune microenvironment (TIME) and tumour cells promote immune evasion and resistance to immunotherapy in gastrointestinal (GI) tumours. Post-transcriptional regulation of genes is pivotal to GI tumours progression, and RNA-binding proteins (RBPs) serve as key regulators via their RNA-binding domains. RBPs may exhibit either anti-tumour or pro-tumour functions by influencing the TIME through the modulation of mRNAs and non-coding RNAs expression, as well as post-transcriptional modifications, primarily N6-methyladenosine (m6A). Aberrant regulation of RBPs, such as HuR and YBX1, typically enhances tumour immune escape and impacts prognosis of GI tumour patients. Further, while targeting RBPs offers a promising strategy for improving immunotherapy in GI cancers, the mechanisms by which RBPs regulate the TIME in these tumours remain poorly understood, and the therapeutic application is still in its early stages. This review summarizes current advances in exploring the roles of RBPs in regulating genes expression and their effect on the TIME of GI tumours, then providing theoretical insights for RBP-targeted cancer therapies.
Collapse
Affiliation(s)
- Dongqi Li
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, China
| | - Xiangyu Chu
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Weikang Liu
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, China
| | - Yongsu Ma
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, China
| | - Xiaodong Tian
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, China
| | - Yinmo Yang
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, China
| |
Collapse
|
|
2
|
Jones M, Norman M, Tiet AM, Lee J, Lee MH. C. elegans Germline as Three Distinct Tumor Models. BIOLOGY 2024; 13:425. [PMID: 38927305 PMCID: PMC11200432 DOI: 10.3390/biology13060425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 06/04/2024] [Accepted: 06/07/2024] [Indexed: 06/28/2024]
Abstract
Tumor cells display abnormal growth and division, avoiding the natural process of cell death. These cells can be benign (non-cancerous growth) or malignant (cancerous growth). Over the past few decades, numerous in vitro or in vivo tumor models have been employed to understand the molecular mechanisms associated with tumorigenesis in diverse regards. However, our comprehension of how non-tumor cells transform into tumor cells at molecular and cellular levels remains incomplete. The nematode C. elegans has emerged as an excellent model organism for exploring various phenomena, including tumorigenesis. Although C. elegans does not naturally develop cancer, it serves as a valuable platform for identifying oncogenes and the underlying mechanisms within a live organism. In this review, we describe three distinct germline tumor models in C. elegans, highlighting their associated mechanisms and related regulators: (1) ectopic proliferation due to aberrant activation of GLP-1/Notch signaling, (2) meiotic entry failure resulting from the loss of GLD-1/STAR RNA-binding protein, (3) spermatogenic dedifferentiation caused by the loss of PUF-8/PUF RNA-binding protein. Each model requires the mutations of specific genes (glp-1, gld-1, and puf-8) and operates through distinct molecular mechanisms. Despite these differences in the origins of tumorigenesis, the internal regulatory networks within each tumor model display shared features. Given the conservation of many of the regulators implicated in C. elegans tumorigenesis, it is proposed that these unique models hold significant potential for enhancing our comprehension of the broader control mechanisms governing tumorigenesis.
Collapse
Affiliation(s)
- Mariah Jones
- Division of Hematology/Oncology, Department of Internal Medicine, Brody School of Medicine at East Carolina University, Greenville, NC 27834, USA; (M.J.); (M.N.)
| | - Mina Norman
- Division of Hematology/Oncology, Department of Internal Medicine, Brody School of Medicine at East Carolina University, Greenville, NC 27834, USA; (M.J.); (M.N.)
| | - Alex Minh Tiet
- Neuroscience Program, East Carolina University, Greenville, NC 27858, USA;
- Department of Biology, East Carolina University, Greenville, NC 27858, USA
| | - Jiwoo Lee
- Department of Biology, East Carolina University, Greenville, NC 27858, USA
| | - Myon Hee Lee
- Division of Hematology/Oncology, Department of Internal Medicine, Brody School of Medicine at East Carolina University, Greenville, NC 27834, USA; (M.J.); (M.N.)
- Department of Biology, East Carolina University, Greenville, NC 27858, USA
| |
Collapse
|
|
3
|
Zhao B, Che H, Li L, Hu L, Yi W, Xiao L, Liu S, Hou Z. Asperuloside regulates the proliferation, apoptosis, and differentiation of chronic myeloid leukemia cell line K562 through the RAS/MEK/ERK pathway. Heliyon 2024; 10:e23580. [PMID: 38226258 PMCID: PMC10788273 DOI: 10.1016/j.heliyon.2023.e23580] [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: 08/13/2023] [Revised: 12/06/2023] [Accepted: 12/06/2023] [Indexed: 01/17/2024] Open
Abstract
Context Chronic myeloid leukemia (CML) is a malignant hematopoietic stem cell disease caused by excessive proliferation and abnormal differentiation of hematopoietic stem cells. Asperuloside (ASP) is considered to have good biological activity and may be a good anti-CML drug. Objective This study aimed to explore the effects and possible mechanisms of ASP on the biological behavior of K562 cells based on RNA-seq. Materials and methods The IC50 of ASP in K562 cells was calculated by the concentration-effect curve. Cell viability, apoptosis, and differentiation were detected by CCK8, flow cytometry, benzidine staining, and WB analysis, respectively. Further, RNA-seq was used to analyze the possible mechanism of ASP regulating K562 cells. Results ASP significantly inhibited the proliferation, and promoted apoptosis and differentiation of K562 cells. A total of 117 differentially expressed genes were screened by RNA-seq, mainly involved in the RAS/MEK/ERK pathway. PD98059 was used to inhibit the RAS/MEK/ERK pathway in K562 cells, and results confirmed that PD98059 could not only inhibit the RAS/MEK/ERK pathway, but also inhibit the regulation of ASP on the proliferation and differentiation of K562 cells. Conclusion ASP inhibited the proliferation, promoted apoptosis and differentiation of K562 cells by regulating the RAS/MEK/ERK pathway, and played a good anti-CML role.
Collapse
Affiliation(s)
| | | | - Linlin Li
- Department of Hematology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Lian Hu
- Department of Hematology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Wenjing Yi
- Department of Hematology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Li Xiao
- Department of Hematology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Songshan Liu
- Department of Hematology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Zhufa Hou
- Department of Hematology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| |
Collapse
|
|
4
|
Li X, Tibenda JJ, Nan Y, Huang SC, Ning N, Chen GQ, Du YH, Yang YT, Meng FD, Yuan L. MiR-204-3p overexpression inhibits gastric carcinoma cell proliferation by inhibiting the MAPK pathway and RIP1/MLK1 necroptosis pathway to promote apoptosis. World J Gastroenterol 2023; 29:4542-4556. [PMID: 37621755 PMCID: PMC10445008 DOI: 10.3748/wjg.v29.i29.4542] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 05/24/2023] [Accepted: 07/05/2023] [Indexed: 08/02/2023] Open
Abstract
BACKGROUND Gastric carcinoma (GC) is the third most frequent cause of cancer-related death, highlighting the pressing need for novel clinical treatment options. In this regard, microRNAs (miRNAs) have emerged as a promising therapeutic strategy. Studies have shown that miRNAs can regulate related signaling pathways, acting as tumor suppressors or tumor promoters. AIM To explore the effect of miR-204-3p on GC cells. METHODS We measured the expression levels of miR-204-3p in GC cells using quantitative real-time polymerase chain reaction, followed by the delivery of miR-204-3p overexpression and miR-204-3p knockdown vectors into GC cells. CCK-8 was used to detect the effect of miR-204-3p on the proliferation of GC cells, and the colony formation ability of GC cells was detected by the clonal formation assay. The effects of miR-204-3p on GC cell cycle and apoptosis were detected by flow cytometry. The BABL/c nude mouse subcutaneous tumor model using MKN-45 cells was constructed to verify the effect of miR-204-3p on the tumorigenicity of GC cells. Furthermore, the study investigated the effects of miR-204-3p on various proteins related to the MAPK signaling pathway, necroptosis signaling pathway and apoptosis signaling pathway on GC cells using Western blot techniques. RESULTS Firstly, we found that the expression of miR-204-3p in GC was low. When treated with the lentivirus overexpression vector, miR-204-3p expression significantly increased, but the lentivirus knockout vector had no significant effect on miR-204-3p. In vitro experiments confirmed that miR-204-3p overexpression inhibited GC cell viability, promoted cell apoptosis, blocked the cell cycle, and inhibited colony formation ability. In vivo animal experiments confirmed that miR-204-3p overexpression inhibited subcutaneous tumorigenesis ability in BABL/c nude mice. Simultaneously, our results verified that miR-204-3p overexpression can inhibit GC cell proliferation by inhibiting protein expression levels of KRAS and p-ERK1/2 in the MAPK pathway, as well as inhibiting protein expression levels of p-RIP1 and p-MLK1 in the necroptosis pathway to promote the BCL-2/BAX/Caspase-3 apoptosis pathway. CONCLUSION MiR-204-3p overexpression inhibited GC cell proliferation by inhibiting the MAPK pathway and necroptosis pathway to promote apoptosis of GC cells. Thus, miR-204-3p may represent a new potential therapeutic target for GC.
Collapse
Affiliation(s)
- Xia Li
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
- Ningxia Chinese Medicine Reserch Center, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Joanna J Tibenda
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Yi Nan
- Key Laboratory of Hui Ethnic Medicine Modernization of Ministry of Education, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
- Traditional Chinese Medicine College, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Shi-Cong Huang
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Na Ning
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Guo-Qing Chen
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Yu-Hua Du
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Ya-Ting Yang
- Traditional Chinese Medicine College, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Fan-Di Meng
- Key Laboratory of Hui Ethnic Medicine Modernization of Ministry of Education, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Ling Yuan
- College of Pharmacy, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| |
Collapse
|
|
5
|
Vershinina YS, Krasnov GS, Garbuz DG, Shaposhnikov MV, Fedorova MS, Pudova EA, Katunina IV, Kornev AB, Zemskaya NV, Kudryavtsev AA, Bulavkina EV, Matveeva AA, Ulyasheva NS, Guvatova ZG, Anurov AA, Moskalev AA, Kudryavtseva AV. Transcriptomic Analysis of the Effect of Torin-2 on the Central Nervous System of Drosophila melanogaster. Int J Mol Sci 2023; 24:ijms24109095. [PMID: 37240439 DOI: 10.3390/ijms24109095] [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: 02/02/2023] [Revised: 04/24/2023] [Accepted: 05/16/2023] [Indexed: 05/28/2023] Open
Abstract
Torin-2, a synthetic compound, is a highly selective inhibitor of both TORC1 and TORC2 (target of rapamycin) complexes as an alternative to the well-known immunosuppressor, geroprotector, and potential anti-cancer natural compound rapamycin. Torin-2 is effective at hundreds of times lower concentrations and prevents some negative side effects of rapamycin. Moreover, it inhibits the rapamycin-resistant TORC2 complex. In this work, we evaluated transcriptomic changes in D. melanogaster heads induced with lifetime diets containing Torin-2 and suggested possible neuroprotective mechanisms of Torin-2. The analysis included D. melanogaster of three ages (2, 4, and 6 weeks old), separately for males and females. Torin-2, taken at the lowest concentration being tested (0.5 μM per 1 L of nutrient paste), had a slight positive effect on the lifespan of D. melanogaster males (+4% on the average) and no positive effect on females. At the same time, RNA-Seq analysis revealed interesting and previously undiscussed effects of Torin-2, which differed between sexes as well as in flies of different ages. Among the cellular pathways mostly altered by Torin-2 at the gene expression level, we identified immune response, protein folding (heat shock proteins), histone modification, actin cytoskeleton organization, phototransduction and sexual behavior. Additionally, we revealed that Torin-2 predominantly reduced the expression of Srr gene responsible for the conversion of L-serine to D-serine and thus regulating activity of NMDA receptor. Via western blot analysis, we showed than in old males Torin-2 tends to increase the ratio of the active phosphorylated form of ERK, the lowest node of the MAPK cascade, which may play a significant role in neuroprotection. Thus, the complex effect of Torin-2 may be due to the interplay of the immune system, hormonal background, and metabolism. Our work is of interest for further research in the field of NMDA-mediated neurodegeneration.
Collapse
Affiliation(s)
- Yulia S Vershinina
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - George S Krasnov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - David G Garbuz
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | | | - Maria S Fedorova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Elena A Pudova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Irina V Katunina
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Alexey B Kornev
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Nadezhda V Zemskaya
- Institute of Biology, Komi Science Center, Ural Branch of RAS, 167000 Syktyvkar, Russia
| | - Alexander A Kudryavtsev
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Elizaveta V Bulavkina
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Anna A Matveeva
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Natalia S Ulyasheva
- Institute of Biology, Komi Science Center, Ural Branch of RAS, 167000 Syktyvkar, Russia
| | - Zulfiya G Guvatova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Artemiy A Anurov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Alexey A Moskalev
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Anna V Kudryavtseva
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| |
Collapse
|
|
6
|
Lin Z, Lin J. Circ_0004585 Facilitates Tumorigenesis of Colorectal Cancer Via Modulating the miR-338-3p/ZFX Axis and Activating the MEK/ERK Pathway. Cell Mol Bioeng 2023; 16:159-171. [PMID: 37096071 PMCID: PMC10121944 DOI: 10.1007/s12195-022-00756-6] [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: 02/17/2022] [Accepted: 12/06/2022] [Indexed: 01/22/2023] Open
Abstract
Background Colorectal cancer (CRC) is a common malignant tumor in the digestive tract. Circular RNAs (circRNAs) have been identified as crucial regulators of tumorigenesis. However, the role and potential mechanism of circ_0004585 in CRC are poorly understood. Methods The expression of circ_0004585, microRNA-338-3p (miR-338-3p), and zinc finger protein X-linked (ZFX) was detected by quantitative real-time PCR and Western blot. Cell proliferation, cell cycle arrest, apoptosis, and angiogenesis were evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), 5-Ethynyl-2'-deoxyuridine (EdU), flow cytometry and tube formation assays. Western blot assay was applied to detect the expression of epithelial-mesenchymal transition (EMT)-related proteins and MEK/ERK signaling pathway-related proteins. A xenograft model was used to analyze tumor growth in vivo. The targeted relationship between miR-338-3p and circ_0004585/ZFX was verified by a dual-luciferase reporter assay. Results Circ_0004585 and ZFX were up-regulated, while miR-338-3p was down-regulated in CRC tissues and cells. Silencing of circ_0004585 inhibited proliferation, angiogenesis, and EMT and triggered apoptosis in CRC cells. Consistently, circ_0004585 depletion blocked tumor growth in vivo. Circ_0004585 contributed to CRC cell development via sequestering miR-338-3p. Also, miR-338-3p hindered the malignant progression of CRC cells by targeting ZFX. Circ_0004585 activated MEK/ERK pathway via regulating ZFX. Conclusion Circ_0004585 facilitated CRC progression through modulating miR-338-3p/ZFX/MEK/ERK pathway, which might provide a potential therapeutic target for CRC. Supplementary Information The online version contains supplementary material available at 10.1007/s12195-022-00756-6.
Collapse
Affiliation(s)
- Zenghai Lin
- Department of General Surgery, Guangdong Province, The First Affiliated Hospital of Shantou University Medical College, No. 57 Changping Road, Shantou City, 515041 Guangdong China
| | - Jianwei Lin
- Department of General Surgery, Guangdong Province, The First Affiliated Hospital of Shantou University Medical College, No. 57 Changping Road, Shantou City, 515041 Guangdong China
| |
Collapse
|
|
7
|
Siddiqui SH, Khan M, Park J, Lee J, Choe H, Shim K, Kang D. COPA3 peptide supplementation alleviates the heat stress of chicken fibroblasts. Front Vet Sci 2023; 10:985040. [PMID: 36908511 PMCID: PMC9998527 DOI: 10.3389/fvets.2023.985040] [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: 07/03/2022] [Accepted: 02/07/2023] [Indexed: 03/14/2023] Open
Abstract
Heat stress inhibits cellular proliferation and differentiation through the production of reactive oxygen species. Under stress conditions, antioxidant drugs promote stable cellular function by reducing the stress level. We sought to demonstrate 9-mer disulfide dimer peptide (COPA3) supplementation stabilizes fibroblast proliferation and differentiation even under heat stress conditions. In our study, fibroblasts were assigned to two different groups based on the temperature, like 38°C group presented as Control - and 43°C group presented as Heat Stress-. Each group was subdivided into two groups depending upon COPA3 treatment, like 38°C + COPA3 group symbolized Control+ and the 43°C + COPA3 group symbolized as Heat Stress+. Heat stress was observed to decrease the fibroblast viability and function and resulted in alterations in the fibroblast shape and cytoskeleton structure. In contrast, COPA3 stabilized the fibroblast viability, shape, and function. Moreover, heat stress and COPA3 were found to have opposite actions with respect to energy production, which facilitates the stabilization of cellular functions by increasing the heat tolerance capacity. The gene expression levels of antioxidant and heat shock proteins were higher after heat stress. Additionally, heat stress promotes the mitogen-activated protein kinase/ extracellular signal-regulated kinase-nuclear factor erythroid 2-related factor 2 (MAPK/ERK-Nrf2). COPA3 maintained the MAPK/ERK-Nrf2 gene expressions that promote stable fibroblast proliferation, and differentiation as well as suppress apoptosis. These findings suggest that COPA3 supplementation increases the heat tolerance capacity, viability, and functional activity of fibroblasts.
Collapse
Affiliation(s)
- Sharif Hasan Siddiqui
- Center for Musculoskeletal Research, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY, United States.,Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States
| | - Mousumee Khan
- Department of Biomedical Sciences and Institute for Medical Science, Jeonbuk National University Medical School, Jeonju, Republic of Korea
| | - Jinryong Park
- Department of Animal Biotechnology, Jeonbuk National University, Jeonju, Republic of Korea.,Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul, Republic of Korea.,3D Tissue Culture Research Center, Konkuk University, Seoul, Republic of Korea
| | - Jeongeun Lee
- Department of Agricultural Convergence Technology, Jeonbuk National University, Jeonju, Republic of Korea
| | - Hosung Choe
- Department of Animal Biotechnology, Jeonbuk National University, Jeonju, Republic of Korea
| | - Kwanseob Shim
- Department of Animal Biotechnology, Jeonbuk National University, Jeonju, Republic of Korea.,Department of Agricultural Convergence Technology, Jeonbuk National University, Jeonju, Republic of Korea
| | - Darae Kang
- Department of Animal Biotechnology, Jeonbuk National University, Jeonju, Republic of Korea
| |
Collapse
|
|
8
|
Liu B, Guan Y, Wang M, Han Y, Wang W, Wang Y, Wu P. ABRACL as a potential prognostic biomarker and correlates with immune infiltration in low-grade gliomas. INTERDISCIPLINARY NEUROSURGERY 2022. [DOI: 10.1016/j.inat.2022.101618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022] Open
|
|
9
|
Ou J, Liu Q, Bian Y, Luan X, Meng Y, Dong H, Cao M, Zhang B, Wang Z, Zhao W. Integrated analysis of mRNA and microRNA transcriptome related to immunity and autophagy in shrimp hemocytes infected with Spiroplasma eriocheiris. FISH & SHELLFISH IMMUNOLOGY 2022; 130:436-452. [PMID: 36184970 DOI: 10.1016/j.fsi.2022.09.035] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 09/13/2022] [Accepted: 09/15/2022] [Indexed: 06/16/2023]
Abstract
In recent years, the industry in charge of the cultivation of Macrobrachium nipponense (M.nipponense) has suffered significant economic losses due to an infectious pathogen called Spiroplasma eriocheiris (S.eriocheiris). There has therefore been a need to identify the key immune and autophagy genes that respond to M.nipponense's infection with S. eriocheiris to analyze its immune response mechanism and the regulation of related microRNAs (miRNAs). In this study, the mRNA and miRNA transcriptome of M.nipponense's hemocytes were analyzed at different stages of infection. This analysis employed the second and third-generation sequencing technologies. In the mRNA transcriptome, 1656 genes were expressed in healthy and susceptible M.nipponense. 892 of these were significantly up-regulated, while 764 were down-regulated. 118 genes with significant differences in autophagy, endocytosis, lysosome, Toll, IMD, and VEGF pathways were obtained from the transcriptome. In the miRNA transcriptome, 312 miRNAs (Conserved: 112, PN-type: 18, PC-type: 182) were sequenced. 74 were significantly up-regulated, and 57 were down-regulated. There were 25 miRNAs involved in regulating the Toll and IMD pathways, 41 in endocytosis, 30 in lysosome, and 12 in the VEGF pathway. An integrated analysis of immune-related miRNAs and mRNAs showed that miRNAs with significant differences (P < 0.05) such as ame-miR-29b-3p, dpu-miR-1and PC-3p-945_4074, had corresponding regulatory relationships with 118 important immune genes such as Relish, Dorsal, Caspase-3, and NF-κB. This study obtained the key immune and autophagy-related genes and corresponding regulatory miRNAs in M. nipponense's hemocytes in response to an infection by S.eriocheiris. The results can provide vital data that further reveals the defense mechanism of M.nipponense's immune system against S.eriocheiris. It can also help further comprehension and interpretation of M.nipponense's resistance mechanism to the invading S.eriocheiris, and provide molecular research information for the realization of host-directed therapies (HDT) for M.nipponense.
Collapse
Affiliation(s)
- Jiangtao Ou
- Jiangsu Key Laboratory of Biochemistry and Biotechnology of Marine Wetland, School of Marine and Biological Engineering, Yancheng Institute of Technology, Yancheng, 224051, Province Jiangsu, China.
| | - Qiao Liu
- Jiangsu Key Laboratory of Biochemistry and Biotechnology of Marine Wetland, School of Marine and Biological Engineering, Yancheng Institute of Technology, Yancheng, 224051, Province Jiangsu, China; The Key Laboratory of Biotechnology for Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, 221116, Province Jiangsu, China
| | - Yunxia Bian
- Jiangsu Key Laboratory of Biochemistry and Biotechnology of Marine Wetland, School of Marine and Biological Engineering, Yancheng Institute of Technology, Yancheng, 224051, Province Jiangsu, China
| | - Xiaoqi Luan
- Jiangsu Key Laboratory of Biochemistry and Biotechnology of Marine Wetland, School of Marine and Biological Engineering, Yancheng Institute of Technology, Yancheng, 224051, Province Jiangsu, China; Jiangsu Key Laboratory for Biodiversity & Biotechnology and Jiangsu Key Laboratory for Aquatic Crustacean Diseases, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Nanjing, 210023, China
| | - Yusuo Meng
- Jiangsu Key Laboratory of Biochemistry and Biotechnology of Marine Wetland, School of Marine and Biological Engineering, Yancheng Institute of Technology, Yancheng, 224051, Province Jiangsu, China
| | - Huizi Dong
- Jiangsu Key Laboratory of Biochemistry and Biotechnology of Marine Wetland, School of Marine and Biological Engineering, Yancheng Institute of Technology, Yancheng, 224051, Province Jiangsu, China
| | - Miao Cao
- Jiangsu Key Laboratory of Biochemistry and Biotechnology of Marine Wetland, School of Marine and Biological Engineering, Yancheng Institute of Technology, Yancheng, 224051, Province Jiangsu, China
| | - Benhou Zhang
- Jiangsu Key Laboratory of Biochemistry and Biotechnology of Marine Wetland, School of Marine and Biological Engineering, Yancheng Institute of Technology, Yancheng, 224051, Province Jiangsu, China
| | - Zisheng Wang
- Jiangsu Key Laboratory of Biochemistry and Biotechnology of Marine Wetland, School of Marine and Biological Engineering, Yancheng Institute of Technology, Yancheng, 224051, Province Jiangsu, China
| | - Weihong Zhao
- Jiangsu Key Laboratory of Biochemistry and Biotechnology of Marine Wetland, School of Marine and Biological Engineering, Yancheng Institute of Technology, Yancheng, 224051, Province Jiangsu, China
| |
Collapse
|
|
10
|
Zhang Q, Liu L, Hu Y, Shen L, Li L, Wang Y. Kv1.3 Channel Is Involved In Ox-LDL-induced Macrophage Inflammation Via ERK/NF-κB signaling pathway. Arch Biochem Biophys 2022; 730:109394. [PMID: 36100082 DOI: 10.1016/j.abb.2022.109394] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 08/30/2022] [Accepted: 09/06/2022] [Indexed: 11/29/2022]
Abstract
Macrophage inflammatory response is crucial for the initiation and progression of atherosclerosis. The voltage-gated potassium channel Kv1.3 plays an important role in the modulation of macrophage function. The aim of this study was to investigate the effect and possible mechanism of Kv1.3 on inflammation in oxidized low-density lipoprotein (ox-LDL)-induced RAW264.7 macrophages. Treatment with Kv1.3-siRNA attenuated the expression of IL-6 and TNF-α and reduced the phosphorylation of ERK1/2 and NF-κB in ox-LDL-induced macrophages. In contrast, overexpression of Kv1.3 with Lv-Kv1.3 promoted the expression of IL-6 and TNF-α, and increased ERK1/2 and NF-κB phosphorylation in macrophages. PD-98059, a specific inhibitor of ERK, reversed the expression of IL-6 and TNF-α in ox-LDL-treated macrophages. Kv1.3-siRNA did not inhibit inflammation any further when cells were treated with PD-98059. This suggests that ERK acts as a downstream regulator of the Kv1.3 channel. In conclusion, Kv1.3 may be an indispensable membrane protein in ox-LDL-induced RAW264.7 macrophage inflammation in atherosclerosis through the ERK/NF-κB pathway.
Collapse
Affiliation(s)
- Qiujie Zhang
- Department of Geriatric Medicine, Qilu Hospital of Shandong University, China; Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital of Shandong University, China
| | - Lin Liu
- Department of Geriatric Medicine, Qilu Hospital of Shandong University, China; Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital of Shandong University, China
| | - Yanyan Hu
- Department of Geriatric Medicine, Qilu Hospital of Shandong University, China; Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital of Shandong University, China
| | - Lin Shen
- Department of Geriatric Medicine, Qilu Hospital of Shandong University, China; Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital of Shandong University, China
| | - Li Li
- Key Laboratory of Cardiovascular Remodeling and Function Research, Department of Cardiology, Qilu Hospital of Shandong University, China
| | - Yuanyuan Wang
- Department of Geriatric Medicine, Qilu Hospital of Shandong University, China; Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital of Shandong University, China.
| |
Collapse
|
|
11
|
Duan XH, Chen R, Li DS, Luo AH, Guo LL. HuR affects chemoresistance of small cell lung cancer by regulating FGFRL1 expression. Exp Ther Med 2022; 24:638. [PMID: 36160905 PMCID: PMC9468853 DOI: 10.3892/etm.2022.11575] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 06/06/2022] [Indexed: 11/06/2022] Open
Abstract
Human antigen R (HuR), an RNA-binding protein, has been demonstrated to serve an oncogenic role in various types of cancer. Fibroblast growth factor receptor-like 1 (FGFRL1) has been shown to regulate small cell lung cancer (SCLC) chemoresistance. In the present study, the role of HuR in chemoresistance of SCLC, as well as its possible molecular mechanism involving FGFRL1, was explored by reverse transcription-quantitative PCR, western blotting, Cell Counting Kit-8 assay, flow cytometry and RNA immunoprecipitation. The results revealed that HuR expression levels were markedly upregulated in drug-resistant SCLC cell lines (H69AR and H446DDP) compared with in the parental cell lines (H69 and H446). Knockdown of HuR in drug-resistant SCLC cells enhanced drug sensitivity, cell apoptosis and cell cycle arrest. Furthermore, molecular mechanism studies indicated that HuR could bind and regulate FGFRL1 expression levels to increase FGFRL1 mRNA stability. Taken together, the present study suggested that HuR may mediate chemoresistance of SCLC by regulating FGFRL1 expression. HuR may represent a prognostic predictor and a potential target for overcoming chemoresistance in SCLC.
Collapse
Affiliation(s)
- Xun-Huang Duan
- Department of Oncology, Jiujiang No. 1 People's Hospital, Jiujiang, Jiangxi 332000, P.R. China
| | - Rui Chen
- Department of Oncology, Jiujiang No. 1 People's Hospital, Jiujiang, Jiangxi 332000, P.R. China
| | - Dao-Sheng Li
- Department of Oncology, Jiujiang No. 1 People's Hospital, Jiujiang, Jiangxi 332000, P.R. China
| | - Ai-Hua Luo
- Department of Pathology, Gaozhou People's Hospital, Gaozhou, Guangdong 525200, P.R. China
| | - Lin-Lang Guo
- Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510220, P.R. China
| |
Collapse
|
|
12
|
Blagden SP. Targeting MAPK in recurrent, low-grade serous ovarian cancer. Lancet 2022; 399:499-501. [PMID: 35123677 DOI: 10.1016/s0140-6736(21)02338-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Accepted: 10/18/2021] [Indexed: 02/06/2023]
Affiliation(s)
- Sarah P Blagden
- Department of Oncology, University of Oxford, Oxford OX3 7DG, UK.
| |
Collapse
|
|
13
|
Bitaraf A, Razmara E, Bakhshinejad B, Yousefi H, Vatanmakanian M, Garshasbi M, Cho WC, Babashah S. The oncogenic and tumor suppressive roles of RNA-binding proteins in human cancers. J Cell Physiol 2021; 236:6200-6224. [PMID: 33559213 DOI: 10.1002/jcp.30311] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 01/14/2021] [Accepted: 01/22/2021] [Indexed: 12/17/2022]
Abstract
Posttranscriptional regulation is a mechanism for the cells to control gene regulation at the RNA level. In this process, RNA-binding proteins (RBPs) play central roles and orchestrate the function of RNA molecules in multiple steps. Accumulating evidence has shown that the aberrant regulation of RBPs makes contributions to the initiation and progression of tumorigenesis via numerous mechanisms such as genetic changes, epigenetic alterations, and noncoding RNA-mediated regulations. In this article, we review the effects caused by RBPs and their functional diversity in the malignant transformation of cancer cells that occurs through the involvement of these proteins in various stages of RNA regulation including alternative splicing, stability, polyadenylation, localization, and translation. Besides this, we review the various interactions between RBPs and other crucial posttranscriptional regulators such as microRNAs and long noncoding RNAs in the pathogenesis of cancer. Finally, we discuss the potential approaches for targeting RBPs in human cancers.
Collapse
Affiliation(s)
- Amirreza Bitaraf
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ehsan Razmara
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Babak Bakhshinejad
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hassan Yousefi
- Department of Biochemistry and Molecular Biology, LSUHSC School of Medicine, New Orleans, Louisiana, USA
| | - Mousa Vatanmakanian
- Department of Biochemistry and Molecular Biology, LSUHSC School of Medicine, New Orleans, Louisiana, USA
| | - Masoud Garshasbi
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - William C Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong
| | - Sadegh Babashah
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| |
Collapse
|
|
14
|
Wei R, Li X, Wang X, Wang Y, Zhang X, Zhang N, Wang J, Yang J, Zhang X, Gong P, Li J. Trypanosoma evansi triggered neutrophil extracellular traps formation dependent on myeloperoxidase, neutrophil elastase, and extracellular signal-regulated kinase 1/2 signaling pathways. Vet Parasitol 2021; 296:109502. [PMID: 34214944 DOI: 10.1016/j.vetpar.2021.109502] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 06/06/2021] [Accepted: 06/16/2021] [Indexed: 10/21/2022]
Abstract
Trypanosoma evansi infects a wide range of hosts to cause huge economic losses in livestock industry. In recent years, it has been demonstrated that neutrophils extracellular traps (NETs) play a critical role in combating parasite infections. However, the role of NETs in the resistance to T. evansi infection is still unclear. In this study, T. evansi induced NETs were observed and their components were determined. The effect of NETs on the viability and motility of T. evansi were estimated. The production of reactive oxygen species (ROS) and Lactate dehydrogenase (LDH) activity in the process of T. evansi-induced NETs formation were detected. The effect of ERK1/2 signaling pathway, neutrophil elastase (NE), myeloperoxidase (MPO), store-operated Ca(2+) entry (SOCE) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase on T. evansi triggered NETs formation were determined. The results showed that neutrophils could release ETs after being stimulated with T. evansi and the structures of NETs mainly consisted of DNA decorated with histone 3 (H3), NE, and MPO. NETs could reduce the parasite motility without affecting the parasite viability. T. evansi-induced NETs formation was dose and time-dependent and was accompanied by ROS production. Inhibitor assays suggested that the formation of NETs induced by T. evansi was dependent on MPO, NE and ERK1/2 signaling pathway but independent on NADPH oxidase and SOCE. In addition, there was no significant changes in LDH activity during NETs formation. This study is the first report of T. evansi-induced NETs formation.
Collapse
Affiliation(s)
- Ran Wei
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xian Road, Changchun, 130062, Jilin, China.
| | - Xin Li
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xian Road, Changchun, 130062, Jilin, China.
| | - Xiaocen Wang
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xian Road, Changchun, 130062, Jilin, China.
| | - Yuru Wang
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xian Road, Changchun, 130062, Jilin, China.
| | - Xu Zhang
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xian Road, Changchun, 130062, Jilin, China.
| | - Nan Zhang
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xian Road, Changchun, 130062, Jilin, China.
| | - Jingsen Wang
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xian Road, Changchun, 130062, Jilin, China.
| | - Ju Yang
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xian Road, Changchun, 130062, Jilin, China.
| | - Xichen Zhang
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xian Road, Changchun, 130062, Jilin, China.
| | - Pengtao Gong
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xian Road, Changchun, 130062, Jilin, China.
| | - Jianhua Li
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xian Road, Changchun, 130062, Jilin, China.
| |
Collapse
|
|
15
|
Kelaini S, Chan C, Cornelius VA, Margariti A. RNA-Binding Proteins Hold Key Roles in Function, Dysfunction, and Disease. BIOLOGY 2021; 10:biology10050366. [PMID: 33923168 PMCID: PMC8146904 DOI: 10.3390/biology10050366] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/21/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023]
Abstract
RNA-binding proteins (RBPs) are multi-faceted proteins in the regulation of RNA or its RNA splicing, localisation, stability, and translation. Amassing proof from many recent and dedicated studies reinforces the perception of RBPs exerting control through differing expression levels, cellular localization and post-transcriptional alterations. However, since the regulation of RBPs is reliant on the micro-environment and events like stress response and metabolism, their binding affinities and the resulting RNA-RBP networks may be affected. Therefore, any misregulation and disruption in the features of RNA and its related homeostasis can lead to a number of diseases that include diabetes, cardiovascular disease, and other disorders such as cancer and neurodegenerative diseases. As such, correct regulation of RNA and RBPs is crucial to good health as the effect RBPs exert through loss of function can cause pathogenesis. In this review, we will discuss the significance of RBPs and their typical function and how this can be disrupted in disease.
Collapse
|
|
16
|
Ding K, Lai Z, Yang G, Zeng L. MiR-140-5p targets Prox1 to regulate the proliferation and differentiation of neural stem cells through the ERK/MAPK signaling pathway. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:671. [PMID: 33987369 PMCID: PMC8106095 DOI: 10.21037/atm-21-597] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 04/04/2021] [Indexed: 12/25/2022]
Abstract
BACKGROUND The expression of miR-140-5p increased in the brain tissue of a bilateral common carotid artery ligation model, while the overexpression of miR-140-5p significantly decreased the number of neurons. The luciferase report experiment in the previous study proved that miR-140-5p negatively regulated one of the potential targets of Prospero-related homeobox 1 (Prox1). Therefore, we want to investigate the effect of miR-140-5p on the proliferation and differentiation of neural stem cells (NSCs) and the underlying mechanism. METHODS Primary NSCs were extracted from pregnant ICR mice aged 16-18 days and induced to differentiate. After transient transfection with miR-140-5p mimic and inhibitor into NSCs, the cells were divided into five groups: blank, mimic normal control, mimic, inhibitor normal control, and inhibitor. Cell Counting Kit-8 (CCK-8) and 5-Bromo-2-deoxyUridine (BrDU), Ki-67 were used, and the diameter of neural spheres was measured to observe proliferation ability 48 h later. Doublecortin (DCX), glial fibrillary acidic protein (GFAP), microtubule-associated proteins 2 (MAP-2), synapsin I (SYN1), and postsynaptic density protein-95 (PSD-95) were stained to identify the effect of miR-140-5p on the differentiation ability of NSCs into neural precursor cells, astrocytes, and neurons and the expression of synapse-associated proteins. The expression of miR-140-5p, Prox1, p-ERK1/2, and ERK1/2 was analyzed by real time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. RESULTS While the expression of miR-140-5p decreased after NSC differentiation (P<0.05), the results of CCK-8, BrDU, and Ki-67 staining showed no significant difference in cell viability and the percentage of NSCs with proliferation ability (P>0.05). However, the neural spheres were shorter in the miR-140-5p overexpression group (P<0.05) and the expression of DCX, MAP2, synapsin I, and PSD-95 decreased, while the expression of GFAP increased after differentiation in the mimic group (P<0.05). In addition, the expression of Prox1 decreased and the expression of p-ERK1/2 protein increased (P<0.05), but the expression of ERK1/2 showed no significant difference (P>0.05) in the miR-140-5p overexpression group. CONCLUSIONS MiR-140-5p reduced the proliferation rate of NSCs, inhibited their differentiation into neurons, produced synapse-associated proteins, and promoted their differentiation into astrocytes. MiR-140-5p negatively regulated downstream target Prox1 and activated the ERK/MAPK signaling pathway.
Collapse
Affiliation(s)
- Kaiqi Ding
- Department of Neurology and Institute of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zehua Lai
- Department of Neurology and Institute of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Guoyuan Yang
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Lili Zeng
- Department of Neurology and Institute of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|
|
17
|
Han L, Li W, Hu Y, Zhang H, Ma J, Ma K, Xiao B, Fei G, Zeng Y, Tian L, Chen L. Model for the prediction of mechanical asphyxia as the cause of death based on four biological indexes in human cardiac tissue. Sci Justice 2021; 61:221-226. [PMID: 33985670 DOI: 10.1016/j.scijus.2021.02.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 02/01/2021] [Accepted: 02/21/2021] [Indexed: 11/17/2022]
Abstract
Determination of mechanical asphyxia as the cause of death has always been difficult for forensic pathologists, particularly when signs of asphyxia are not obvious on the body. Currently, depending on only physical examination of corpses, pathologists must be cautious when making cause-of-death appraisals. In a previous study, four biomarkers-dual-specificity phosphatase 1 (DUSP1), potassium voltage-gated channel subfamily J member 2 (KCNJ2), miR-122, and miR-3185-were screened in human cardiac tissue from cadavers that died from mechanical asphyxia compared with those that died from craniocerebral injury, hemorrhagic shock, or other causes. Expression of the markers correlated with death from mechanical asphyxia regardless of age, environmental temperature, and postmortem interval. However, a single biological index is not an accurate basis for the identification of the cause of death. In this study, receiver operating characteristic curves of the ΔCq values of the four indexes were generated. The diagnostic accuracy of the indexes was judged according to their area under the curve (DUSP1: 0.773, KCNJ2: 0.775, miR-122: 0.667, and miR-3185: 0.801). Finally, a nomogram was generated, and single blind experiment was conducted to verify the cause of death of mechanical asphyxia.
Collapse
Affiliation(s)
- Liujun Han
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Wencan Li
- Institute of Criminal Scientific Technology, Shanghai Public Security Bureau Pudong Branch, Shanghai 200125, China
| | - Yikai Hu
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Heng Zhang
- Department of Pathology, Anhui Medical University, Hefei 230032, China
| | - Jianlong Ma
- Criminal Investigation Department of Shenzhen Public Security Bureau, Shenzhen Institute of Criminal Science and Technology, Shenzhen 518000, China
| | - Kaijun Ma
- Forensic Lab, Criminal Science and Technology Institute, Shanghai Public Security Bureau, Shanghai 200082, China
| | - Bi Xiao
- Forensic Lab, Criminal Science and Technology Institute, Shanghai Public Security Bureau, Shanghai 200082, China
| | - Geng Fei
- Shanghai Police College, Shanghai 200137, China
| | - Yan Zeng
- Children's Hospital of Fudan University, Shanghai 201102, China
| | - Lu Tian
- Institute of Criminal Scientific Technology, Shanghai Public Security Bureau Pudong Branch, Shanghai 200125, China.
| | - Long Chen
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
| |
Collapse
|
|
18
|
Liu Z, Fan P, Chen M, Xu Y, Zhao D. miRNAs and Leukotrienes in Respiratory Syncytial Virus Infection. Front Pediatr 2021; 9:602195. [PMID: 33996675 PMCID: PMC8116547 DOI: 10.3389/fped.2021.602195] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 03/17/2021] [Indexed: 01/03/2023] Open
Abstract
MicroRNAs (miRNAs) are small, non-coding RNAs that regulate posttranscription by binding to 3'-untranslated regions of target mRNAs. Recent functional studies have elucidated mechanisms that miRNAs regulate leukotriene synthesis by perturbing arachidonic acid metabolism. Both microarrays and high-throughput sequencing revealed distinct differential expression of miRNAs in children with respiratory syncytial virus (RSV) infection compared with healthy controls. Abnormal miRNA expression may contribute to higher leukotriene levels, which is associated with airway hyperreactivity. Targeting miRNAs may benefit to restore the homeostasis of inflammatory reaction and provide new strategies to alleviate airway hyperreactivity induced by RSV. In this article, we provide an overview of the current knowledge about miRNAs modulating leukotrienes through regulation of arachidonic acid metabolism with a special focus on miRNAs aberrantly expressed in children with RSV infection.
Collapse
Affiliation(s)
- Zhi Liu
- Department of Pediatrics, Children's Digital Health and Data Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Panpan Fan
- Department of Pediatrics, Children's Digital Health and Data Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Ming Chen
- Department of Pediatrics, Children's Digital Health and Data Center, Zhongnan Hospital of Wuhan University, Wuhan, China.,Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China
| | - Yueshi Xu
- Department of Pediatrics, Children's Digital Health and Data Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Dongchi Zhao
- Department of Pediatrics, Children's Digital Health and Data Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| |
Collapse
|
|
19
|
Yuan X, Guo Q, Bai H, Jiang Y, Zhang Y, Liang W, Wang Z, Xu Q, Chang G, Chen G. Identification of key genes and pathways associated with duck ( Anas platyrhynchos) embryonic skin development using weighted gene co-expression network analysis. Genome 2020; 63:615-628. [PMID: 32956594 DOI: 10.1139/gen-2020-0054] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Skin and feather follicle morphogenesis are important processes for duck development; however, the mechanisms underlying morphogenesis at the embryonic stage remain unclear. To improve the understanding of these processes, we used transcriptome and weighted gene co-expression network analyses to identify the critical genes and pathways involved in duck skin development. Five modules were found to be the most related to five key stages in skin development that span from embryonic day 8 (E8) to postnatal day 7 (D7). Using STEM software, 6519 genes from five modules were clustered into 10 profiles to reveal key genes. Above all, we obtained several key module genes including WNT3A, NOTCH1, SHH, BMP2, NOG, SMAD3, and TGFβ2. Furthermore, we revealed that several pathways play critical roles throughout the skin development process, including the Wnt pathway and cytoskeletal rearrangement-related pathways, whereas others are involved in specific stages of skin development, such as the Notch, Hedgehog, and TGF-beta signaling pathways. Overall, this study identified the pathways and genes that play critical roles in skin development, which may provide a basis for high-quality down-type meat duck breeding.
Collapse
Affiliation(s)
- Xiaoya Yuan
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, China
| | - Qixin Guo
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, China
| | - Hao Bai
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Institutes of Agricultural Science and Technology Development, Yangzhou University, Yangzhou, 225009, China
| | - Yong Jiang
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, China
| | - Yi Zhang
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, China
| | - Wenshuang Liang
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, China
| | - Zhixiu Wang
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, China
| | - Qi Xu
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, China
| | - Guobin Chang
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Institutes of Agricultural Science and Technology Development, Yangzhou University, Yangzhou, 225009, China
| | - Guohong Chen
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Institutes of Agricultural Science and Technology Development, Yangzhou University, Yangzhou, 225009, China
| |
Collapse
|
|
20
|
Wu X, Ouyang Y, Wang B, Lin J, Bai Y. Hypermethylation of the IRAK3-Activated MAPK Signaling Pathway to Promote the Development of Glioma. Cancer Manag Res 2020; 12:7043-7059. [PMID: 32848462 PMCID: PMC7425661 DOI: 10.2147/cmar.s252772] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Accepted: 06/25/2020] [Indexed: 12/21/2022] Open
Abstract
Objective This study aimed to elucidate the molecular mechanism underlying the involvement of abnormal DNA methylation in the development of glioma and identify potential new targets for glioma therapy. Methods The GSE79122 chip achieved from the Gene Expression Omnibus (GEO) database containing 69 glioma samples and 9 normal samples was analyzed. Methylation-specific polymerase chain reaction (MS-PCR or MSP), reverse transcription-PCR, and Western blot analysis were used to confirm the methylation level and expression level of the interleukin receptor-associated kinase (IRAK3) gene in glioma cells, 36 glioma samples, and the corresponding normal samples. In vitro, the proliferation, apoptosis rate, migration, and invasion abilities of glioma cells were detected by Cell Counting Kit-8 assay, Transwell assay, enzyme-linked immunosorbent assay, and flow cytometry, respectively. Besides, the xenograft assay of nude mice was used to confirm the effect of the IRAK3 on glioma in vivo. Results Microarray analysis showed that the IRAK3 was one of the most hypermethylated genes in glioma, and the related mitogen-activated protein kinase (MAPK) signaling pathway was activated. More experiments supported the higher methylation level and lower expression level of the IRAK3 in glioma tissues and cell lines. The viability, migration, and invasion ability of glioma cells significantly reduced and the apoptosis rate increased with the overexpression and demethylation of the IRAK3 in vitro. Besides, treatment with the MAPK signaling pathway inhibitor PD325901 alone or the overexpression or demethylation of the IRAK3 had a similar effect as the overexpression or demethylation of the IRAK3 alone in glioma cells. In vivo, xenotransplantation experiments in nude mice confirmed that the overexpression and demethylation of the IRAK3 and suppression of the MAPK signaling pathway inhibited the development of glioma. Conclusion IRAK3 inhibited the development of glioma progression through the MAPK signaling pathway.
Collapse
Affiliation(s)
- Xinghai Wu
- Department of Neurosurgery, Zhangye People's Hospital Affiliated to Hexi University, Gansu, People's Republic of China
| | - Yian Ouyang
- Department of Neurosurgery, First Affiliated Hospital of Gannan Medical College, Jiangxi, People's Republic of China
| | - Bin Wang
- Department of Neurosurgery, Zhangye People's Hospital Affiliated to Hexi University, Gansu, People's Republic of China
| | - Jian Lin
- Department of Neurosurgery, Zhangye People's Hospital Affiliated to Hexi University, Gansu, People's Republic of China
| | - Yun Bai
- Department of Neurosurgery, Zhangye People's Hospital Affiliated to Hexi University, Gansu, People's Republic of China
| |
Collapse
|
|
21
|
Wu PK, Becker A, Park JI. Growth Inhibitory Signaling of the Raf/MEK/ERK Pathway. Int J Mol Sci 2020; 21:ijms21155436. [PMID: 32751750 PMCID: PMC7432891 DOI: 10.3390/ijms21155436] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 07/28/2020] [Indexed: 12/14/2022] Open
Abstract
In response to extracellular stimuli, the Raf/MEK/extracellular signal-regulated kinase (ERK) pathway regulates diverse cellular processes. While mainly known as a mitogenic signaling pathway, the Raf/MEK/ERK pathway can mediate not only cell proliferation and survival but also cell cycle arrest and death in different cell types. Growing evidence suggests that the cell fate toward these paradoxical physiological outputs may be determined not only at downstream effector levels but also at the pathway level, which involves the magnitude of pathway activity, spatial-temporal regulation, and non-canonical functions of the molecular switches in this pathway. This review discusses recent updates on the molecular mechanisms underlying the pathway-mediated growth inhibitory signaling, with a major focus on the regulation mediated at the pathway level.
Collapse
Affiliation(s)
- Pui-Kei Wu
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
- Correspondence: (P.-K.W.); (J.-I.P.)
| | - Andrew Becker
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
| | - Jong-In Park
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
- Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Correspondence: (P.-K.W.); (J.-I.P.)
| |
Collapse
|
|
22
|
Swarup V, Chang TS, Duong DM, Dammer EB, Dai J, Lah JJ, Johnson ECB, Seyfried NT, Levey AI, Geschwind DH. Identification of Conserved Proteomic Networks in Neurodegenerative Dementia. Cell Rep 2020; 31:107807. [PMID: 32579933 PMCID: PMC8221021 DOI: 10.1016/j.celrep.2020.107807] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 04/27/2020] [Accepted: 06/03/2020] [Indexed: 12/11/2022] Open
Abstract
Data-driven analyses are increasingly valued in modern medicine. We integrate quantitative proteomics and transcriptomics from over 1,000 post-mortem brains from six cohorts representing Alzheimer's disease (AD), asymptomatic AD, progressive supranuclear palsy (PSP), and control patients from the Accelerating Medicines Partnership - Alzheimer's Disease consortium. We define robust co-expression trajectories related to disease progression, including early neuronal, microglial, astrocyte, and immune response modules, and later mRNA splicing and mitochondrial modules. The majority of, but not all, modules are conserved at the transcriptomic level, including module C3, which is only observed in proteome networks and enriched in mitogen-activated protein kinase (MAPK) signaling. Genetic risk enriches in modules changing early in disease and indicates that AD and PSP have distinct causal biological drivers at the pathway level, despite aspects of similar pathology, including synaptic loss and glial inflammatory changes. The conserved, high-confidence proteomic changes enriched in genetic risk represent targets for drug discovery.
Collapse
Affiliation(s)
- Vivek Swarup
- Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Timothy S Chang
- Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Duc M Duong
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Eric B Dammer
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Jingting Dai
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, China
| | - James J Lah
- Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Erik C B Johnson
- Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Nicholas T Seyfried
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Allan I Levey
- Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Daniel H Geschwind
- Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Institute of Precision Health, University of California, Los Angeles, Los Angeles, CA 90095, USA.
| |
Collapse
|
|
23
|
Jia T, Ren Y, Wang F, Zhao R, Qiao B, Xing L, Ou L, Guo B. MiR-148a inhibits oral squamous cell carcinoma progression through ERK/MAPK pathway via targeting IGF-IR. Biosci Rep 2020; 40:BSR20182458. [PMID: 32202300 PMCID: PMC7174276 DOI: 10.1042/bsr20182458] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 02/04/2020] [Accepted: 03/19/2020] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE The current study aimed to investigate the functional roles and clinical significance of microRNA-148a (miR-148a) in the progression of oral squamous cell carcinoma (OSCC). METHODS Relative expression of miR-148a in OSCC cells and tissues were detected using quantitative real-time polymerase chain reaction (qRT-PCR). Chi-square test was performed to estimate the relationship between miR-148a expression and clinical characteristics of OSCC patients. Cell transfection was carried out using Lipofectamine® 2000. Biological behaviors of tumor cells were detected using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and transwell assays. Bioinformatics analysis and luciferase reporter assay were used to identify the target genes of miR-148a. Protein expression was detected through Western blot analysis. RESULTS MiR-148a expression was obviously decreased in OSCC tissues and cells, and such down-regulation was closely correlated with lymph node metastasis (P=0.027) and tumor node metastasis (TNM) stage (P=0.001) of OSCC patients. miR-148a overexpression could significantly impair OSCC cell proliferation, migration and invasion in vitro (P<0.05 for all). Insulin-like growth factor-I receptor (IGF-IR) was a potential target of miR-148a. MiR-148a could inhibit ERK/MAPK signaling pathway through targeting IGF-IR. CONCLUSION MiR-148a plays an anti-tumor role in OSCC and inhibits OSCC progression through suppressing ERK/MAPK pathway via targeting IGF-IR.
Collapse
Affiliation(s)
- Tingting Jia
- Department of Oral and Maxillofacial Surgery, The Chinese PLA General Hospital, Haidian District, Beijing, China
| | - Yipeng Ren
- Department of Oral and Maxillofacial Surgery, The Chinese PLA General Hospital, Haidian District, Beijing, China
| | - Fengze Wang
- Department of Stomatology, The 316th Hospital of Chinese People’s Liberation Army, Haidian District, Beijing, China
| | - Rui Zhao
- Department of Oral and Maxillofacial Surgery, The Chinese PLA General Hospital, Haidian District, Beijing, China
| | - Bo Qiao
- Department of Oral and Maxillofacial Surgery, The Chinese PLA General Hospital, Haidian District, Beijing, China
| | - Lejun Xing
- Department of Oral and Maxillofacial Surgery, The Chinese PLA General Hospital, Haidian District, Beijing, China
| | - Long Ou
- Department of Oral and Maxillofacial Surgery, The Chinese PLA General Hospital, Haidian District, Beijing, China
| | - Bin Guo
- Department of Oral and Maxillofacial Surgery, The Chinese PLA General Hospital, Haidian District, Beijing, China
| |
Collapse
|
|
24
|
Han L, Zhang H, Zeng Y, Lv Y, Tao L, Ma J, Xu H, Ma K, Shi Q, Xiao B, Chen L. Identification of the miRNA-3185/CYP4A11 axis in cardiac tissue as a biomarker for mechanical asphyxia. Forensic Sci Int 2020; 311:110293. [PMID: 32320934 DOI: 10.1016/j.forsciint.2020.110293] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Revised: 04/01/2020] [Accepted: 04/03/2020] [Indexed: 12/19/2022]
Abstract
Death by mechanical asphyxia is one of the most difficult conclusions to make in forensic science, especially in corpses displaying slight or no trauma to the surface of the body. Therefore, death by mechanical asphyxia is difficult to prove in medico-legal practice. MicroRNAs (miRNAs) are a class of small, non-coding RNAs involved in the regulation of numerous physiological and pathological cellular processes. In the present study, we demonstrate that significantly increased expression of miR-3185 in cardiac tissues was detected among cases of mechanical asphyxia compared to case of craniocerebral injury, hemorrhagic shock, sudden cardiac death and poisoning. We observed no correlation between the expression of miR-3185 and postmortem interval, age or temperature. Further work indicated that CYP4A11 is a putative target gene of miR-3185 and expressed at a relatively low level in cardiac tissue specimens from cases of mechanical asphyxia compared with specimens from cases of craniocerebral injury, hemorrhagic shock, sudden cardiac death and poisoning. Our results suggest that the miRNA-3185/CYP4A11 axis is associated with mechanical asphyxia-induced death and may provide new insight into asphyxial death investigations.
Collapse
Affiliation(s)
- Liujun Han
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Heng Zhang
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Yan Zeng
- Children's Hospital of Fudan University, Shanghai 201102, China
| | - Yehui Lv
- Shanghai University of Medicine & Health Sciences, Shanghai 201318, China
| | - Li Tao
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Jianlong Ma
- Criminal Investigation Department of Shenzhen Public Security Bureau, Shenzhen Institute of Criminal Science and Technology, Shenzhen 518000, China
| | - Hongmei Xu
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Kaijun Ma
- Forensic Lab, Criminal Science and Technology Institute, Shanghai Public Security Bureau, Shanghai 200082, China
| | - Qun Shi
- Forensic Lab, Criminal Science and Technology Institute, Shanghai Public Security Bureau, Shanghai 200082, China
| | - Bi Xiao
- Forensic Lab, Criminal Science and Technology Institute, Shanghai Public Security Bureau, Shanghai 200082, China.
| | - Long Chen
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
| |
Collapse
|
|
25
|
Takashima Y, Kawaguchi A, Iwadate Y, Hondoh H, Fukai J, Kajiwara K, Hayano A, Yamanaka R. miR-101, miR-548b, miR-554, and miR-1202 are reliable prognosis predictors of the miRNAs associated with cancer immunity in primary central nervous system lymphoma. PLoS One 2020; 15:e0229577. [PMID: 32101576 PMCID: PMC7043771 DOI: 10.1371/journal.pone.0229577] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 02/11/2020] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) inhibit protein function by silencing the translation of target mRNAs. However, in primary central nervous system lymphoma (PCNSL), the expression and functions of miRNAs are inadequately known. Here, we examined the expression of 847 miRNAs in 40 PCNSL patients with a microarray and investigated for the miRNA predictors associated with cancer immunity-related genes such as T helper cell type 1/2 (Th-1/Th-2) and regulatory T cell (T-reg) status, and stimulatory and inhibitory checkpoint genes, for prognosis prediction in PCNSL. The aim of this study is to find promising prognosis markers based on the miRNA expression in PCNSL. We detected 334 miRNAs related to 66 cancer immunity-related genes in the microarray profiling. Variable importance measured by the random survival forest analysis and Cox proportional hazards regression model elucidated that 11 miRNAs successfully constitute the survival formulae dividing the Kaplan-Meier curve of the respective PCNSL subgroups. On the other hand, univariate analysis shortlisted 23 miRNAs for overall survival times, with four miRNAs clearly dividing the survival curves-miR-101/548b/554/1202. These miRNAs regulated Th-1/Th-2 status, T-reg cell status, and immune checkpoints. The miRNAs were also associated with gene ontology terms as Ras/MAP-kinase, ubiquitin ligase, PRC2 and acetylation, CDK, and phosphorylation, and several diseases including acquired immunodeficiency syndrome, glioma, and those related to blood and hippocampus with statistical significance. In conclusion, the results demonstrated that the four miRNAs comprising miR-101/548b/554/1202 associated with cancer immunity can be a useful prognostic marker in PCNSL and would help us understand target pathways for PCNSL treatments.
Collapse
Affiliation(s)
- Yasuo Takashima
- Laboratory of Molecular Target Therapy for Cancer, Graduate School for Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Atsushi Kawaguchi
- Center for Comprehensive Community Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Yasuo Iwadate
- Department of Neurosurgery, Graduate School of Medical Sciences, Chiba University, Chiba, Japan
| | - Hiroaki Hondoh
- Departments of Neurosurgery, Toyama Prefectural Central Hospital, Toyama, Japan
| | - Junya Fukai
- Department of Neurological Surgery, Wakayama Medical University School of Medicine, Wakayama, Japan
| | - Koji Kajiwara
- Department of Neurosurgery, Graduate School of Medical Sciences, Yamaguchi University, Ube, Yamaguchi, Japan
| | - Azusa Hayano
- Laboratory of Molecular Target Therapy for Cancer, Graduate School for Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Ryuya Yamanaka
- Laboratory of Molecular Target Therapy for Cancer, Graduate School for Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
- * E-mail:
| |
Collapse
|
|
26
|
Wang S, Ran Y, Chen X, Li C, Cheng S, Liu J. Pleiotropic Effects of Simvastatin on the Regulation of Potassium Channels in Monocytes. Front Pharmacol 2020; 11:101. [PMID: 32153409 PMCID: PMC7046754 DOI: 10.3389/fphar.2020.00101] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 01/28/2020] [Indexed: 12/17/2022] Open
Abstract
Purpose The underlying mechanism of pleiotropic effects of statins on atherosclerosis is still unclear. Kv1.3 and KCa3.1 are two potassium channels that might be involved in monocyte migration and atherosclerosis formation. The aim of this study was to investigate the effect of simvastatin on the Kv1.3 and KCa3.1 in monocyte. Methods and Results In human monocytic THP-1 cells, simvastatin significantly inhibited Kv1.3 mRNA and protein expression by real-time quantitative PCR analysis and western blotting. However, simvastatin had no effects on KCa3.1 mRNA and protein expression. By whole-cell patch clamp, simvastatin (10 μM) remarkably inhibited the current intensity of Kv1.3, but had no effect on KCa3.1. Simvastatin (10 μM) treatment significantly reduced the monocyte chemoattractant protein 1 (MCP-1)-induced monocyte migration. This inhibition was only partially reversed by mevalonate (1mM). In human peripheral blood mononuclear cells (PBMCs), both Kv1.3 and KCa3.1 mRNA expression were increased in patients with coronary artery diseases (CAD) (n = 20) compared to healthy controls (n = 22). However, simvastatin (40 mg per day) significantly inhibited the Kv1.3 but not KCa3.1 mRNA expression after 1 month and 3 months therapy in CAD patients. Conclusion Our data suggested Kv1.3 in monocytes was a potential molecular target of the pleiotropic effects of statins. KCa3.1 might be another marker of CAD, but not associated with statins treatment.
Collapse
Affiliation(s)
- Shaoping Wang
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China
| | - Yuhua Ran
- Department of New Drug Evaluation, State Key Laboratory of Toxicology Medical Courtermeasures, Institute of Pharmacology and Toxicology, Beijing, China
| | - Xuejun Chen
- Research Institute of Chemical Defense, Beijing, China
| | - Chungang Li
- No. 926 Hospital, Joint Logistics Support, Force of PLA, Yunan, China
| | - Shujuan Cheng
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China
| | - Jinghua Liu
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China
| |
Collapse
|
|
27
|
Park Y, O'Rourke S, Taki FA, Alfhili MA, Lee MH. Dose-Dependent Effects of GLD-2 and GLD-1 on Germline Differentiation and Dedifferentiation in the Absence of PUF-8. Front Cell Dev Biol 2020; 8:5. [PMID: 32039211 PMCID: PMC6992537 DOI: 10.3389/fcell.2020.00005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 01/08/2020] [Indexed: 11/29/2022] Open
Abstract
PUMILIO/FBF (PUF) proteins have a conserved function in stem cell regulation. Caenorhabditis elegans PUF-8 protein inhibits the translation of target mRNAs by interacting with PUF binding element (PBE) in the 3′ untranslated region (3′ UTR). In this work, an in silico analysis has identified gld-2 [a poly(A) polymerase] as a putative PUF-8 target. Biochemical and reporter analyses showed that PUF-8 specifically binds to a PBE in gld-2 3′ UTR and represses a GFP reporter gene carrying gld-2 3′ UTR in the C. elegans mitotic germ cells. GLD-2 enhances meiotic entry at least in part by activating GLD-1 (a KH motif-containing RNA-binding protein). Our genetic analyses also demonstrated that heterozygous gld-2(+/−) gld-1(+/−) genes in the absence of PUF-8 are competent for meiotic entry (early differentiation), but haplo-insufficient for the meiotic division (terminal differentiation) of spermatocytes. Indeed, the arrested spermatocytes return to mitotic cells via dedifferentiation, which results in germline tumors. Since these regulators are broadly conserved, we thus suggest that similar molecular mechanisms may control differentiation, dedifferentiation, and tumorigenesis in other organisms, including humans.
Collapse
Affiliation(s)
- Youngyong Park
- Department of Internal Medicine, Division of Hematology/Oncology, Brody School of Medicine at East Carolina University, Greenville, NC, United States
| | - Samuel O'Rourke
- Department of Internal Medicine, Division of Hematology/Oncology, Brody School of Medicine at East Carolina University, Greenville, NC, United States
| | - Faten A Taki
- Department of Pharmacology, Weill Cornell Medical College, New York, NY, United States
| | - Mohammad A Alfhili
- Department of Internal Medicine, Division of Hematology/Oncology, Brody School of Medicine at East Carolina University, Greenville, NC, United States.,Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Myon Hee Lee
- Department of Internal Medicine, Division of Hematology/Oncology, Brody School of Medicine at East Carolina University, Greenville, NC, United States
| |
Collapse
|
|
28
|
Liu X, Chu Y, Wang D, Weng Y, Jia Z. MAPK-mediated upregulation of fibrinogen-like protein 2 promotes proliferation, migration, and invasion of colorectal cancer cells. Cell Biol Int 2019; 43:1483-1491. [PMID: 31286589 DOI: 10.1002/cbin.11198] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 07/05/2019] [Indexed: 01/24/2023]
Abstract
Fibrinogen-like protein 2 (FGL2) has been reported to play a key role in the development of human cancers. However, it is still unmasked whether FGL2 plays a potential role in colorectal carcinogenesis. In this study, the messenger RNA and protein expression levels were measured by quantitative real-time polymerase chain reaction and western blot. Cell counting kit-8 assay, transwell migration, and invasion assay were carried out to evaluate the proliferation, migration, and invasion of LOVO and SW620 cells. FGL2 was upregulated in colorectal cancer (CRC) tissues, as well as cell lines. Mitogen-activated protein kinase (MAPK) signaling was activated in CRC tissues and cell lines. FGL2 was confirmed to be downregulated by MAPK signaling inhibitor U0126. Further, we determined that knockdown of FGL2 caused a reduction of proliferation, migration, and invasion in LOVO and SW620 cells. Consistently, treatment of LOVO and SW620 cells with U0126 led to a decrease in cell proliferation, migration, and invasion. However, these changes initiated by U0126 were abolished by FGL2 overexpression. To conclude, MAPK-mediated upregulation of FGL2 promotes the proliferation, migration, and invasion of CRC cells.
Collapse
Affiliation(s)
- Xiaochuan Liu
- Department of Gastroenterology, Meitan General Hospital, 100028 Peking, China
| | - Yunxiang Chu
- Department of Gastroenterology, Meitan General Hospital, 100028 Peking, China
| | - Dongsheng Wang
- Department of Gastroenterology, Meitan General Hospital, 100028 Peking, China
| | - Yan Weng
- Department of Gastroenterology, Meitan General Hospital, 100028 Peking, China
| | - Zhiwei Jia
- Department of Gastroenterology, Meitan General Hospital, 100028 Peking, China
| |
Collapse
|
|
29
|
Yin Y, Li B, Mou K, Khan MT, Kaushik AC, Wei D, Zhang YJ. Stoichioproteomics reveal oxygen usage bias, key proteins and pathways in glioma. BMC Med Genomics 2019; 12:125. [PMID: 31464612 PMCID: PMC6716898 DOI: 10.1186/s12920-019-0571-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Accepted: 08/12/2019] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The five-year survival rate and therapeutic effect of malignant glioma is low. Identification of key/associated proteins and pathways in glioma is necessary for developing effective diagnosis and targeted therapy of glioma. In addition, Glioma involves hypoxia-specific microenvironment, whether hypoxia restriction influences the stoichioproteomic characteristics of expressed proteins is unknown. METHODS In this study, we analyzed the most comprehensive immunohistochemical data from 12 human glioma samples and 4 normal cell types of cerebral cortex, identified differentially expressed proteins (DEPs), and researched the oxygen contents of DEPs, highly and lowly expressed proteins. Further we located key genes on human genome to determine their locations and enriched them for key functional pathways. RESULTS Our results showed that although no difference was detected on whole proteome, the average oxygen content of highly expressed proteins is 6.65% higher than that of lowly expressed proteins in glioma. A total of 1480 differentially expressed proteins were identified in glioma, including 226 up regulated proteins and 1254 down regulated proteins. The average oxygen content of up regulated proteins is 2.56% higher than that of down regulated proteins in glioma. The localization of differentially expressed genes on human genome showed that most genes were on chromosome 1 and least on Y. The up regulated proteins were significantly enriched in pathways including cell cycle, pathways in cancer, oocyte meiosis, DNA replication etc. Functional dissection of the up regulated proteins with high oxygen contents showed that 51.28% of the proteins were involved in cell cycle and cyclins. CONCLUSIONS Element signature of oxygen limitation could not be detected in glioma, just as what happened in plants and microbes. Unsaved use of oxygen by the highly expressed proteins and DEPs were adapted to the fast division of glioma cells. This study can help to reveal the molecular mechanism of glioma, and provide a new approach for studies of cancer-related biomacromolecules. In addition, this study lays a foundation for application of stoichioproteomics in precision medicine.
Collapse
Affiliation(s)
- Yongqin Yin
- Chongqing Key Laboratory of Vector Insects, Institute of Entomology and Molecular Biology, College of Life Sciences, Chongqing Normal University, Shapingba, University City, Chongqing, 401331 People’s Republic of China
| | - Bo Li
- Chongqing Key Laboratory of Vector Insects, Institute of Entomology and Molecular Biology, College of Life Sciences, Chongqing Normal University, Shapingba, University City, Chongqing, 401331 People’s Republic of China
| | - Kejie Mou
- Department of Neurosurgery, Bishan Hospital, Bishan, Chongqing, 402760 China
| | - Muhammad T. Khan
- Shanghai Jiao Tong University, Shanghai, China
- Capital University of Science & Technology, Islamabad, Pakistan
| | | | - Dongqing Wei
- Shanghai Jiao Tong University, Shanghai, China
- Peng Cheng Laboratory, Vanke Cloud City Phase I Building 8, Xili Street, Nanshan District, Shenzhen, Guangdong 518055 China
| | - Yu-Juan Zhang
- Chongqing Key Laboratory of Vector Insects, Institute of Entomology and Molecular Biology, College of Life Sciences, Chongqing Normal University, Shapingba, University City, Chongqing, 401331 People’s Republic of China
| |
Collapse
|
|
30
|
Liu YS, Wei B. Over-expression of Bcl2-associated athanogene 2 in oral cancer promotes cellular proliferation and is associated with poor prognosis. Arch Oral Biol 2019; 102:164-170. [PMID: 31055249 DOI: 10.1016/j.archoralbio.2019.04.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 04/24/2019] [Accepted: 04/26/2019] [Indexed: 12/17/2022]
Abstract
OBJECTIVE The aim of the present study was to state the role of BAG2 in oral squamous cell carcinomas (OSCC). DESIGN Expression data of BAG2 in OSCC tissues were extracted from Oncomine and TCGA database. Expression levels of BAG2 mRNA and protein were examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot assay. The Kaplan-Meier method was conducted to evaluate the overall survival of OSCC patients. Small interfering RNAs (siRNAs) strategy was used to confirm the effect of BAG2 expression on proliferative, invasive, migrated capacities of OSCC cells by Cell Counting kit-8 (CCK-8), colon formation assay, wound healing and transwell assay. RESULTS Our results showed that BAG2 expression was up-regulated in oral squamous cell carcinomas tissues. Compared with OSCC patients with low BAG2 expression, poorer overall survival rate was found in OSCC patients with high BAG2 expression. Furthermore, proliferation, invasion and migration of HO-1-N-1 cells were significantly inhibited because of the knockdown of BAG2. Transfection of si-BAG2 has no impacts on proliferation in HNOEC cells. Inhibition of BAG2 downregulated the expression of relevant proteins, such as proliferating cell nuclear antigen (PCNA), c-Myc, matrix metalloproteinase-2 (MMP-2) and Vimentin. Additionally, the expression levels of the important protein phosphorylation (p-ERK1/2 and p-MEK) in mitogen-activated protein kinase (MAPK) pathway were reduced in HO-1-N-1 cells transfected with si-BAG2. CONCLUSIONS High-regulated BAG2 is related to poor prognosis and could promote proliferation, invasion and migration of OSCC cells by activating the MAPK signaling pathway. Thus, BAG2 may be a potential target for OSCC therapy.
Collapse
Affiliation(s)
- Yi-Song Liu
- Dental Department, Daqing Oilfield General Hospital, Daqing City, Heilongjiang Province, 163001, China
| | - Bing Wei
- Endocrine Department, Daqing Oilfield General Hospital, Daqing City, Heilongjiang Province, 163001, China.
| |
Collapse
|
|
31
|
Wang J, Luo Z, Yao T, Li W, Pu J. LINC00707 promotes hepatocellular carcinoma progression through activating ERK/JNK/AKT pathway signaling pathway. J Cell Physiol 2018; 234:6908-6916. [PMID: 30317590 DOI: 10.1002/jcp.27449] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 08/27/2018] [Indexed: 12/21/2022]
Abstract
Increasing evidence has demonstrated that abnormal expression of lncRNA is correlated with various malignant tumors, including hepatocellular carcinoma (HCC). Our current study was aimed to investigate the role of LINC00707 in HCC development. We observed that LINC00707 was upregulated in HCC cell lines compared with normal liver cell lines. Then, Hep3B cells and SNU449 cells were infected with LV-shLINC00707 and LV-LINC00707. LINC00707 silencing could greatly repress the proliferation and colony formation of HCC cells in vitro. On the contrary, overexpression of LINC00707 induced HCC cell proliferation and colony formation. In addition, HCC cell apoptosis was significantly enhanced and HCC cell cycle was blocked in G1 phase by LV-shLINC00707. Hep3B cells and SNU449 cell invasion capacity was restrained by the knockdown of LINC00707, whereas upregulation of LINC00707 exhibited an opposite phenomenon. Accumulating evidence has reported that ERK/JNK/AKT signaling is involved in multiple cancers, including HCC. Here, in our study, we identified that ERK/JNK/AKT signaling was dramatically restrained by silencing of LINC00707 while activated by LV-LINC00707 in HCC cells. Subsequently, an in vivo experiment was conducted, and it demonstrated that LINC00707 could modulate HCC development through activating ERK/JNK/AKT signaling. Taking the above results together, it was implied in our study that LINC00707 contributed to HCC progression through modulating the ERK/JNK/AKT pathway.
Collapse
Affiliation(s)
- Jianchu Wang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, China
| | - Zongjiang Luo
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, China
| | - Tianwei Yao
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, China
| | - Wenchuan Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, China
| | - Jian Pu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, China
| |
Collapse
|
|
32
|
Yang C, Kelaini S, Caines R, Margariti A. RBPs Play Important Roles in Vascular Endothelial Dysfunction Under Diabetic Conditions. Front Physiol 2018; 9:1310. [PMID: 30294283 PMCID: PMC6158626 DOI: 10.3389/fphys.2018.01310] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Accepted: 08/30/2018] [Indexed: 12/17/2022] Open
Abstract
Diabetes is one of the major health care problems worldwide leading to huge suffering and burden to patients and society. Diabetes is also considered as a cardiovascular disorder because of the correlation between diabetes and an increased incidence of cardiovascular disease. Vascular endothelial cell dysfunction is a major mediator of diabetic vascular complications. It has been established that diabetes contributes to significant alteration of the gene expression profile of vascular endothelial cells. Post-transcriptional regulation by RNA binding proteins (RBPs) plays an important role in the alteration of gene expression profile under diabetic conditions. The review focuses on the roles and mechanisms of critical RBPs toward diabetic vascular endothelial dysfunction. Deeper understanding of the post- transcriptional regulation by RBPs could lead to new therapeutic strategies against diabetic manifestation in the future.
Collapse
Affiliation(s)
- Chunbo Yang
- Centre for Experimental Medicine, Queens University Belfast, Belfast, United Kingdom
| | - Sophia Kelaini
- Centre for Experimental Medicine, Queens University Belfast, Belfast, United Kingdom
| | - Rachel Caines
- Centre for Experimental Medicine, Queens University Belfast, Belfast, United Kingdom
| | - Andriana Margariti
- Centre for Experimental Medicine, Queens University Belfast, Belfast, United Kingdom
| |
Collapse
|
|
33
|
Alleviating airway inflammation by inhibiting ERK-NF-κB signaling pathway by blocking Kv1.3 channels. Int Immunopharmacol 2018; 63:110-118. [PMID: 30077824 DOI: 10.1016/j.intimp.2018.07.009] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Revised: 06/29/2018] [Accepted: 07/10/2018] [Indexed: 11/22/2022]
Abstract
Allergic asthma is a chronic inflammatory disease of the airways. T lymphocytes play an important role in the pathogenesis of asthma. The voltage-gated Kv1.3 potassium channel is a target for the preferential inhibition of TEM cells. In this study, we investigate the effects of PAP-1, a selective inhibitor of Kv1.3 channel, on the treatment of the neutrophilic asthma model. PAP-1 (40 mg/kg) was injected intraperitoneally into ovalbumin (OVA)-lipopolysaccharide (LPS)-challenged BALB/c mice. We found that the expression of the Kv1.3 channel in the lung tissues, and the intensity of the Kv current in the asthmatic mice increased clearly compared with those in normal control. PAP-1 significantly reduced airway hyperresponsiveness (AHR), inflammatory cell count in the bronchoalveolar lavage fluids (BALF) and serum, and attenuated airway inflammation in a histological examination of the asthmatic mice. Moreover, PAP-1 inhibited the OVA-LPS-induced imbalance of Th1/Th2, Treg/Th17 lymphocytes, and reduced levels of IL-4 and IL-17, inducing an increase in the production of IFN-γ and IL-10. Furthermore, the activation of the extracellular signal-regulated kinase (ERK)/nuclear factor-κB (NF-κB) pathway in the lungs of the asthmatic mice was suppressed by PAP-1. We also found that PD-98059, an inhibitor of ERK, had a similar effect with PAP-1 in terms of regulating the imbalance of Th1/Th2, Treg/Th17 cytokines. However, PD-98059 could not further influence cytokine changes when the cells were treated with PAP-1. The results suggest that ERK acts as a downstream regulator of inhibitors of the Kv1.3 channel in neutrophilic asthma. In conclusion, the inhibitor of the Kv1.3 channel has therapeutic potential for treating asthma.
Collapse
|
|
34
|
Zhao B, Chen Y, Mu L, Hu S, Wu X. Identification and profiling of microRNA between back and belly Skin in Rex rabbits (Oryctolagus cuniculus). WORLD RABBIT SCIENCE 2018. [DOI: 10.4995/wrs.2018.7058] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
Skin is an important trait for Rex rabbits and skin development is influenced by many processes, including hair follicle cycling, keratinocyte differentiation and formation of coat colour and skin morphogenesis. We identified differentially expressed microRNAs (miRNAs) between the back and belly skin in Rex rabbits. In total, 211 miRNAs (90 upregulated miRNAs and 121 downregulated miRNAs) were identified with a |log<sub>2</sub> (fold change)|>1 and <em>P</em>-value<0.05. Using target gene prediction for the miRNAs, differentially expressed predicted target genes were identified and the functional enrichment and signalling pathways of these target genes were processed to reveal their biological functions. A number of differentially expressed miRNAs were found to be involved in regulation of the cell cycle, skin epithelium differentiation, keratinocyte proliferation, hair follicle development and melanogenesis. In addition, target genes regulated by miRNAs play key roles in the activities of the Hedgehog signalling pathway, Wnt signalling pathway, Osteoclast differentiation and MAPK pathway, revealing mechanisms of skin development. Nine candidate miRNAs and 5 predicted target genes were selected for verification of their expression by quantitative reverse transcription polymerase chain reaction. A regulation network of miRNA and their target genes was constructed by analysing the GO enrichment and signalling pathways. Further studies should be carried out to validate the regulatory relationships between candidate miRNAs and their target genes.
Collapse
|
|
35
|
Long-term ethanol exposure: Temporal pattern of microRNA expression and associated mRNA gene networks in mouse brain. PLoS One 2018; 13:e0190841. [PMID: 29315347 PMCID: PMC5760035 DOI: 10.1371/journal.pone.0190841] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 12/20/2017] [Indexed: 01/05/2023] Open
Abstract
Long-term alcohol use can result in lasting changes in brain function, ultimately leading to alcohol dependence. These functional alterations arise from dysregulation of complex gene networks, and growing evidence implicates microRNAs as key regulators of these networks. We examined time- and brain region-dependent changes in microRNA expression after chronic intermittent ethanol (CIE) exposure in C57BL/6J mice. Animals were sacrificed at 0, 8, and 120h following the last exposure to four weekly cycles of CIE vapor and we measured microRNA expression in prefrontal cortex (PFC), nucleus accumbens (NAC), and amygdala (AMY). The number of detected (395–419) and differentially expressed (DE, 42–47) microRNAs was similar within each brain region. However, the DE microRNAs were distinct among brain regions and across time within each brain region. DE microRNAs were linked with their DE mRNA targets across each brain region. In all brain regions, the greatest number of DE mRNA targets occurred at the 0 or 8h time points and these changes were associated with microRNAs DE at 0 or 8h. Two separate approaches (discrete temporal association and hierarchical clustering) were combined with pathway analysis to further characterize the temporal relationships between DE microRNAs and their 120h DE targets. We focused on targets dysregulated at 120h as this time point represents a state of protracted withdrawal known to promote an increase in subsequent ethanol consumption. Discrete temporal association analysis identified networks with highly connected genes including ERK1/2 (mouse equivalent Mapk3, Mapk1), Bcl2 (in AMY networks) and Srf (in PFC networks). Similarly, the cluster-based analysis identified hub genes that include Bcl2 (in AMY networks) and Srf in PFC networks, demonstrating robust microRNA-mRNA network alterations in response to CIE exposure. In contrast, datasets utilizing targets from 0 and 8h microRNAs identified NF-kB-centered networks (in NAC and PFC), and Smad3-centered networks (in AMY). These results demonstrate that CIE exposure results in dynamic and complex temporal changes in microRNA-mRNA gene network structure.
Collapse
|
|
36
|
Zhao B, Chen Y, Yan X, Hao Y, Zhu J, Weng Q, Wu X. Gene expression profiling analysis reveals fur development in rex rabbits (Oryctolagus cuniculus). Genome 2017; 60:1060-1067. [PMID: 28850794 DOI: 10.1139/gen-2017-0003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Fur is an important economic trait in rabbits. The identification of genes that influence fur development and knowledge regarding the actions of these genes provides useful tools for improving fur quality. However, the mechanism of fur development is unclear. To obtain candidate genes related to fur development, the transcriptomes of tissues from backs and bellies of Chinchilla rex rabbits were compared. Of the genes analyzed, 336 showed altered expression in the two groups (285 upregulated and 51 downregulated, P ≤ 0.05, fold-change ≥2 or ≤0.5). Using GO and KEGG to obtain gene classes that were differentially enriched, we found several genes to be involved in many important biological processes. In addition, we identified several signaling pathways involved in fur development, including the Wnt and MAPK signaling pathways, revealing mechanisms of skin and hair follicle development, and epidermal cell and keratinocytes differentiation. The obtained rabbit transcriptome and differentially expressed gene profiling data provided comprehensive gene expression information for SFRP2, FRZB, CACNG1, SLC25A4, and SLC16A3. To validate the RNA-seq data, the expression levels of eight differentially expressed genes involved in fur development were confirmed by qRT-PCR. The results of rabbit transcriptomic profiling provide a basis for understanding the molecular mechanisms of fur development.
Collapse
Affiliation(s)
- BoHao Zhao
- a The Key Laboratory of Animal Genetics & Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Yang Chen
- a The Key Laboratory of Animal Genetics & Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - XiaoRong Yan
- a The Key Laboratory of Animal Genetics & Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Ye Hao
- a The Key Laboratory of Animal Genetics & Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Jie Zhu
- a The Key Laboratory of Animal Genetics & Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - QiaoQing Weng
- b Zhejiang Yuyao Xinnong Rabbit Industry Co., Ltd., Yuyao, Zhejiang 315400, China
| | - XinSheng Wu
- a The Key Laboratory of Animal Genetics & Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| |
Collapse
|
|
37
|
Martínez M, Sorzano COS, Pascual-Montano A, Carazo JM. Gene signature associated with benign neurofibroma transformation to malignant peripheral nerve sheath tumors. PLoS One 2017; 12:e0178316. [PMID: 28542306 PMCID: PMC5443557 DOI: 10.1371/journal.pone.0178316] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Accepted: 05/11/2017] [Indexed: 11/19/2022] Open
Abstract
Benign neurofibromas, the main phenotypic manifestations of the rare neurological disorder neurofibromatosis type 1, degenerate to malignant tumors associated to poor prognosis in about 10% of patients. Despite efforts in the field of (epi)genomics, the lack of prognostic biomarkers with which to predict disease evolution frustrates the adoption of appropriate early therapeutic measures. To identify potential biomarkers of malignant neurofibroma transformation, we integrated four human experimental studies and one for mouse, using a gene score-based meta-analysis method, from which we obtained a score-ranked signature of 579 genes. Genes with the highest absolute scores were classified as promising disease biomarkers. By grouping genes with similar neurofibromatosis-related profiles, we derived panels of potential biomarkers. The addition of promoter methylation data to gene profiles indicated a panel of genes probably silenced by hypermethylation. To identify possible therapeutic treatments, we used the gene signature to query drug expression databases. Trichostatin A and other histone deacetylase inhibitors, as well as cantharidin and tamoxifen, were retrieved as putative therapeutic means to reverse the aberrant regulation that drives to malignant cell proliferation and metastasis. This in silico prediction corroborated reported experimental results that suggested the inclusion of these compounds in clinical trials. This experimental validation supported the suitability of the meta-analysis method used to integrate several sources of public genomic information, and the reliability of the gene signature associated to the malignant evolution of neurofibromas to generate working hypotheses for prognostic and drug-responsive biomarkers or therapeutic measures, thus showing the potential of this in silico approach for biomarker discovery.
Collapse
Affiliation(s)
- Marta Martínez
- Biocomputing Unit, Nacional Center for Biotechnology (CSIC), Campus Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain
- * E-mail:
| | - Carlos O. S. Sorzano
- Biocomputing Unit, Nacional Center for Biotechnology (CSIC), Campus Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain
- Bioengineering Lab., Universidad CEU San Pablo, Campus Urb. Montepríncipe, Boadilla del Monte, Madrid, Spain
| | - Alberto Pascual-Montano
- Biocomputing Unit, Nacional Center for Biotechnology (CSIC), Campus Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain
| | - Jose M. Carazo
- Biocomputing Unit, Nacional Center for Biotechnology (CSIC), Campus Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain
| |
Collapse
|
|
38
|
Yang W, Wang XM, Yuan HY, Liu ZH, Gao S, Peng L. Exploring the mechanism of WWOX growth inhibitory effects on oral squamous cell carcinoma. Oncol Lett 2017; 13:3198-3204. [PMID: 28521426 DOI: 10.3892/ol.2017.5850] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2015] [Accepted: 01/17/2017] [Indexed: 12/14/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) is one of the most common types of head and neck neoplasms in the world. Patients diagnosed with OSCC exhibit a poor prognosis. WW domain-containing oxidoreductase (WWOX), as a candidate tumor-suppressor gene, is involved in the genesis and progression of tumors. The deletion of the WWOX gene has been identified in OSCC and oral leukoplakia, but the function and mechanism of WWOX in OSCC remain unknown. Therefore, the present study investigated the role of WWOX in oral squamous carcinoma cells. The results revealed that an elevation of WWOX expression had an inhibitory effect on the growth of three types of oral squamous carcinoma cells, with the most evident effect occurring in Tca8113 cells. Also, in the Tca8113 cells, WWOX overexpression significantly inhibited colony formation, and induced apoptosis and cell cycle arrest. Microarray analysis, reverse transcription-quantitative polymerase chain reaction and western blotting methods detected that WWOX overexpression contributed to the differential expression of the genes involved in mediating the extracellular-signal regulated protein kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathway. These results suggest that the tumor-suppressor function of the WWOX gene may be associated with the modulation of the ERK/MAPK signaling pathway, thus providing a novel target for OSCC therapy.
Collapse
Affiliation(s)
- Wei Yang
- School of Laboratory Medicine, Beihua University, Jilin City, Jilin 132013, P.R. China
| | - Xiao-Ming Wang
- Department of Pathology, Jilin Province People's Hospital, Changchun, Jilin 132001, P.R. China
| | - Hong-Yan Yuan
- Department of Immunology, College of Basic Medical Science, Jilin University, Changchun, Jilin 132001, P.R. China
| | - Zhi-Hui Liu
- Department of Stomatology, Taizhou Municipal Hospital, Taizhou, Zhejiang 318000, P.R. China
| | - Shuang Gao
- School of Laboratory Medicine, Beihua University, Jilin City, Jilin 132013, P.R. China
| | - Liang Peng
- School of Laboratory Medicine, Beihua University, Jilin City, Jilin 132013, P.R. China
| |
Collapse
|
|
39
|
Chen P, Xu W, Luo Y, Zhang Y, He Y, Yang S, Yuan Z. MicroRNA 543 suppresses breast cancer cell proliferation, blocks cell cycle and induces cell apoptosis via direct targeting of ERK/MAPK. Onco Targets Ther 2017; 10:1423-1431. [PMID: 28331335 PMCID: PMC5348068 DOI: 10.2147/ott.s118366] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Breast cancer affects millions of people with a high mortality rate throughout the world; microRNA 543 (miR-543) has been reported to suppress progression in some kinds of cancers, but has not been reported in breast cancer. Thus, the purpose of this study is to investigate the function of miR-543 in breast cancer cells. METHODS Two cell lines, MCF-7 and MDA-MB-231, were selected to be the research objects; the miR-543 overexpression and knockdown models were established in the study by transforming miR-543 mimics and miR-543 inhibitor. Real-time polymerase chain reaction, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, Western blot, clone formation and cell flow cytometer assay were used to test the miR-543's function. Dual-luciferase assay was used for the detection of miR-543 and ERK2 targeting relationship. RESULTS The results showed that the cell proliferation and cell cycle were inhibited, and the capability of cell apoptosis was upregulated when miR-543 was overexpressed; we found that there was a target relationship between ERK2 and miR-543. Furthermore, downstream factors of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase-2 (ERK2) pathway, including RSK2 and MSK1, were decreased in miR-543 overexpression model. CONCLUSION This study provides series evidences to support that breast cancer progression was inhibited by miR-543 via direct targeting of ERK2 in MAPK/ERK signal pathway, which may provide a molecular basis for better treatment for patients.
Collapse
Affiliation(s)
- Po Chen
- Department of Medical Oncology, Hunan Cancer Hospital, Changsha
| | - Wentao Xu
- Clinical Medical College of An Hui Medical University, Hefei
| | - Yi Luo
- Department of Medical Oncology, Hunan Cancer Hospital, Changsha
| | - Yi Zhang
- Department of Breast Surgery, Hunan Cancer Hospital, Changsha, China
| | - Yi He
- Department of Medical Oncology, Hunan Cancer Hospital, Changsha
| | - Shuo Yang
- Department of Medical Oncology, Hunan Cancer Hospital, Changsha
| | - Zhijun Yuan
- Department of Medical Oncology, Hunan Cancer Hospital, Changsha
| |
Collapse
|
|
40
|
Cochrane A, Kelaini S, Tsifaki M, Bojdo J, Vilà-González M, Drehmer D, Caines R, Magee C, Eleftheriadou M, Hu Y, Grieve D, Stitt AW, Zeng L, Xu Q, Margariti A. Quaking Is a Key Regulator of Endothelial Cell Differentiation, Neovascularization, and Angiogenesis. Stem Cells 2017; 35:952-966. [PMID: 28207177 PMCID: PMC5396345 DOI: 10.1002/stem.2594] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 01/10/2017] [Accepted: 01/24/2017] [Indexed: 12/28/2022]
Abstract
The capability to derive endothelial cell (ECs) from induced pluripotent stem cells (iPSCs) holds huge therapeutic potential for cardiovascular disease. This study elucidates the precise role of the RNA‐binding protein Quaking isoform 5 (QKI‐5) during EC differentiation from both mouse and human iPSCs (hiPSCs) and dissects how RNA‐binding proteins can improve differentiation efficiency toward cell therapy for important vascular diseases. iPSCs represent an attractive cellular approach for regenerative medicine today as they can be used to generate patient‐specific therapeutic cells toward autologous cell therapy. In this study, using the model of iPSCs differentiation toward ECs, the QKI‐5 was found to be an important regulator of STAT3 stabilization and vascular endothelial growth factor receptor 2 (VEGFR2) activation during the EC differentiation process. QKI‐5 was induced during EC differentiation, resulting in stabilization of STAT3 expression and modulation of VEGFR2 transcriptional activation as well as VEGF secretion through direct binding to the 3′ UTR of STAT3. Importantly, mouse iPS‐ECs overexpressing QKI‐5 significantly improved angiogenesis and neovascularization and blood flow recovery in experimental hind limb ischemia. Notably, hiPSCs overexpressing QKI‐5, induced angiogenesis on Matrigel plug assays in vivo only 7 days after subcutaneous injection in SCID mice. These results highlight a clear functional benefit of QKI‐5 in neovascularization, blood flow recovery, and angiogenesis. Thus, they provide support to the growing consensus that elucidation of the molecular mechanisms underlying EC differentiation will ultimately advance stem cell regenerative therapy and eventually make the treatment of cardiovascular disease a reality. The RNA binding protein QKI‐5 is induced during EC differentiation from iPSCs. RNA binding protein QKI‐5 was induced during EC differentiation in parallel with the EC marker CD144. Immunofluorescence staining showing that QKI‐5 is localized in the nucleus and stained in parallel with CD144 in differentiated ECs (scale bar = 50 µm). stemcells2017 Stem Cells2017;35:952–966
Collapse
Affiliation(s)
- Amy Cochrane
- The Wellcome-Wolfson Building, Centre for Experimental Medicine, Queen's University Belfast, United Kingdom
| | - Sophia Kelaini
- The Wellcome-Wolfson Building, Centre for Experimental Medicine, Queen's University Belfast, United Kingdom
| | - Marianna Tsifaki
- The Wellcome-Wolfson Building, Centre for Experimental Medicine, Queen's University Belfast, United Kingdom
| | - James Bojdo
- The Wellcome-Wolfson Building, Centre for Experimental Medicine, Queen's University Belfast, United Kingdom
| | - Marta Vilà-González
- The Wellcome-Wolfson Building, Centre for Experimental Medicine, Queen's University Belfast, United Kingdom
| | - Daiana Drehmer
- The Wellcome-Wolfson Building, Centre for Experimental Medicine, Queen's University Belfast, United Kingdom
| | - Rachel Caines
- The Wellcome-Wolfson Building, Centre for Experimental Medicine, Queen's University Belfast, United Kingdom
| | - Corey Magee
- The Wellcome-Wolfson Building, Centre for Experimental Medicine, Queen's University Belfast, United Kingdom
| | - Magdalini Eleftheriadou
- The Wellcome-Wolfson Building, Centre for Experimental Medicine, Queen's University Belfast, United Kingdom
| | - Yanhua Hu
- Cardiovascular Division, King's College London, London, United Kingdom
| | - David Grieve
- The Wellcome-Wolfson Building, Centre for Experimental Medicine, Queen's University Belfast, United Kingdom
| | - Alan W Stitt
- The Wellcome-Wolfson Building, Centre for Experimental Medicine, Queen's University Belfast, United Kingdom
| | - Lingfang Zeng
- Cardiovascular Division, King's College London, London, United Kingdom
| | - Qingbo Xu
- Cardiovascular Division, King's College London, London, United Kingdom
| | - Andriana Margariti
- The Wellcome-Wolfson Building, Centre for Experimental Medicine, Queen's University Belfast, United Kingdom
| |
Collapse
|
|
41
|
Song MH, Kim YR, Bae JH, Shin DH, Lee SY. A cancer/testis antigen, NY-SAR-35, induces EpCAM, CD44, and CD133, and activates ERK in HEK293 cells. Biochem Biophys Res Commun 2017; 484:298-303. [PMID: 28126340 DOI: 10.1016/j.bbrc.2017.01.105] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 01/21/2017] [Indexed: 12/19/2022]
Abstract
The cancer/testis (CT) antigen NY-SAR-35 gene is located on the X chromosome and is aberrantly expressed in various cancers but not in normal tissues, other than testes. Previously, we reported the expression of NY-SAR-35 enhanced cell growth, proliferation, and invasion in HEK293 and cancer cells. To extend understanding of the NY-SAR-35 gene, we used a next generation sequencing (NGS) approach. NY-SAR-35 expression induced growth, proliferation, metastasis, and stemness genes, as indicated by the up-regulations of CXCR4, EpCAM, CD133, and CD44, at the mRNA and protein levels. The expression of NY-SAR-35 in HEK293 cells significantly increased ERK phosphorylation, but not the phosphorylation of AKT. In HEK293/NY-SAR-35 cells, the expressions of pro-apoptotic proteins, including p53, Bax, and p21, were reduced and that of cyclin E was increased. Also, NY-SAR-35 increased the expressions of pluripotency genes (Nanog, Oct-4, and Sox2) and the ability of HEK293 cells to form colonies. Taken together, the present study indicates NY-SAR-35 functions as a CT antigen that triggers oncogenesis and self-renewal.
Collapse
Affiliation(s)
- Myung-Ha Song
- Department of Biochemistry, School of Medicine, Pusan National University, Yangsan, 626-870, Gyeongsangnam-do, Republic of Korea
| | - Ye-Rin Kim
- Department of Biochemistry, School of Medicine, Pusan National University, Yangsan, 626-870, Gyeongsangnam-do, Republic of Korea
| | - Jae-Ho Bae
- Department of Biochemistry, School of Medicine, Pusan National University, Yangsan, 626-870, Gyeongsangnam-do, Republic of Korea
| | - Dong-Hoon Shin
- Department of Pathology, School of Medicine, Pusan National University, Yangsan, 626-870, Gyeongsangnam-do, Republic of Korea
| | - Sang-Yull Lee
- Department of Biochemistry, School of Medicine, Pusan National University, Yangsan, 626-870, Gyeongsangnam-do, Republic of Korea.
| |
Collapse
|
|
42
|
Lee MH, Yoon DS. A Phenotype-Based RNAi Screening for Ras-ERK/MAPK Signaling-Associated Stem Cell Regulators in C. elegans. Methods Mol Biol 2017; 1622:207-221. [PMID: 28674811 DOI: 10.1007/978-1-4939-7108-4_15] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Stem cells have the ability to self-renew and to generate differentiated cell types. A regulatory network that controls this balance is critical for stem cell homeostasis and normal animal development. Particularly, Ras-ERK/MAPK signaling pathway is critical for stem cell self-renewal and differentiation in mammals, including humans. Aberrant regulation of Ras-ERK/MAPK signaling pathway results in either stem cell or overproliferation. Therefore, the identification of Ras-ERK/MAPK signaling pathway-associated regulators is critical to understand the mechanism of stem cell (possibly cancer stem cell) control. In this report, using the nematode C. elegans mutants, we developed a methodology for a phenotype-based RNAi screening that identifies stem cell regulator genes associated with Ras-ERK/MAPK signaling within the context of a whole organism. Importantly, this phenotype-based RNAi screening can be applied for other stem cell-associated signaling pathways such as Wnt/β-catenin and Notch using the C. elegans.
Collapse
Affiliation(s)
- Myon-Hee Lee
- Division of Hematology/Oncology, Department of Medicine, Brody School of Medicine at East Carolina University, Greenville, NC, 27834, USA.
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA.
| | - Dong Suk Yoon
- Division of Hematology/Oncology, Department of Medicine, Brody School of Medicine at East Carolina University, Greenville, NC, 27834, USA
| |
Collapse
|
|
43
|
Lee MH, Mamillapalli SS, Keiper BD, Cha DS. A systematic mRNA control mechanism for germline stem cell homeostasis and cell fate specification. BMB Rep 2016; 49:93-8. [PMID: 26303971 PMCID: PMC4915122 DOI: 10.5483/bmbrep.2016.49.2.135] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Indexed: 11/20/2022] Open
Abstract
Germline stem cells (GSCs) are the best understood adult stem cell types in the nematode Caenorhabditis elegans, and have provided an important model system for studying stem cells and their cell fate in vivo, in mammals. In this review, we propose a mechanism that controls GSCs and their cell fate through selective activation, repression and mobilization of the specific mRNAs. This mechanism is acutely controlled by known signal transduction pathways (e.g., Notch signaling and Ras-ERK MAPK signaling pathways) and P granule (analogous to mammalian germ granule)-associated mRNA regulators (FBF-1, FBF-2, GLD-1, GLD-2, GLD-3, RNP-8 and IFE-1). Importantly, all regulators are highly conserved in many multi-cellular animals. Therefore, GSCs from a simple animal may provide broad insight into vertebrate stem cells (e.g., hematopoietic stem cells) and their cell fate specification. [BMB Reports 2016; 49(2): 93-98]
Collapse
Affiliation(s)
- Myon-Hee Lee
- Department of Medicine, Hematology/Oncology Division, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA; Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599, USA
| | - Srivalli Swathi Mamillapalli
- Department of Medicine, Hematology/Oncology Division, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
| | - Brett D Keiper
- Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
| | - Dong Seok Cha
- Department of Oriental Pharmacy, College of Pharmacy, Woosuk University, Jeonju 55338, Korea
| |
Collapse
|
|
44
|
Zhu GH, Dai HP, Shen Q, Ji O, Zhang Q, Zhai YL. Curcumin induces apoptosis and suppresses invasion through MAPK and MMP signaling in human monocytic leukemia SHI-1 cells. PHARMACEUTICAL BIOLOGY 2016; 54:1303-1311. [PMID: 26134921 DOI: 10.3109/13880209.2015.1060508] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
CONTEXT Curcumin is a polyphenolic compound extracted from rhizomes of the tropical plant Curcuma longa L. (Zingiberaceae) and it has antitumor, antioxidative, and anti-inflammatory effects. However, its effects on leukemia cell proliferation and invasion are not clear. OBJECTIVE This study investigates the effects of curcumin on acute monocytic leukemia SHI-1 cells at the molecular level. MATERIALS AND METHODS The effects of SHI-1 cells treated with 6.25-25 μM curcumin for 12-48 h were measured by MTT assay, flow cytometry, and Matrigel transwell assay; the underlying molecular mechanisms were assessed by quantitative PCR, Western blotting, and gelatin zymography. RESULTS Treatment of SHI-1 cells with curcumin inhibited cell proliferation in a dose- and time-dependent manner, and the IC50 values at 12, 24, and 48 h were 32.40, 14.13, and 9.67 μM. Curcumin inhibited SHI-1 cell proliferation by arresting the cells in the S-phase, increasing the number of Annexin V-FITC(+)/PI(-) cells and promoting the loss of △Ψm. The results of PCR and Western blotting showed that curcumin increased the FasL mRNA level; inhibited Bcl-2, NF-κB, and ERK expression; and activated P38 MAPK, JNK, and caspase-3. Additionally, curcumin partially suppressed SHI-1 cell invasion and attenuated the mRNA transcription and secretion of MMP-2 and MMP-9. DISCUSSION AND CONCLUSION This study demonstrates that curcumin not only induces SHI-1 cell apoptosis, possibly via both intrinsic and extrinsic pathways triggered by JNK, P38 MAPK and ERK signaling, but also partially suppresses SHI-1 cell invasion, likely by reducing the levels of transcription and secretion of MMP-2 and MMP-9.
Collapse
MESH Headings
- Antineoplastic Agents, Phytogenic/pharmacology
- Apoptosis/drug effects
- Apoptosis Regulatory Proteins/metabolism
- Cell Line, Tumor
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- Curcumin/pharmacology
- Dose-Response Relationship, Drug
- Gene Expression Regulation, Enzymologic
- Gene Expression Regulation, Neoplastic
- Humans
- Inhibitory Concentration 50
- Leukemia, Monocytic, Acute/drug therapy
- Leukemia, Monocytic, Acute/enzymology
- Leukemia, Monocytic, Acute/genetics
- Leukemia, Monocytic, Acute/pathology
- Matrix Metalloproteinase 2/genetics
- Matrix Metalloproteinase 2/metabolism
- Matrix Metalloproteinase 9/genetics
- Matrix Metalloproteinase 9/metabolism
- Membrane Potential, Mitochondrial/drug effects
- Mitogen-Activated Protein Kinases/metabolism
- NF-kappa B/metabolism
- Neoplasm Invasiveness
- S Phase Cell Cycle Checkpoints/drug effects
- Signal Transduction/drug effects
- Time Factors
Collapse
Affiliation(s)
- Guo-Hua Zhu
- a First Clinical College, Nanjing University of Chinese Medicine , Nanjing , China
| | - Hai-Ping Dai
- b Leukemia Research Unit, Jiangsu Institute of Hematology, 1st Affiliated Hospital of Soochow University , Suzhou , China , and
| | - Qun Shen
- a First Clinical College, Nanjing University of Chinese Medicine , Nanjing , China
- c Department of Hematology , 1st Affiliated Hospital of Nanjing University of Chinese Medicine , Nanjing , China
| | - Ou Ji
- a First Clinical College, Nanjing University of Chinese Medicine , Nanjing , China
| | - Qi Zhang
- a First Clinical College, Nanjing University of Chinese Medicine , Nanjing , China
| | - Yun-Liang Zhai
- a First Clinical College, Nanjing University of Chinese Medicine , Nanjing , China
| |
Collapse
|
|
45
|
Ayush O, Jin ZW, Kim HK, Shin YR, Im SY, Lee HK. Glutamine up-regulates MAPK phosphatase-1 induction via activation of Ca 2+→ ERK cascade pathway. Biochem Biophys Rep 2016; 7:10-19. [PMID: 28955885 PMCID: PMC5613282 DOI: 10.1016/j.bbrep.2016.05.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Revised: 05/09/2016] [Accepted: 05/11/2016] [Indexed: 11/25/2022] Open
Abstract
The non-essential amino acid L-glutamine (Gln) displays potent anti-inflammatory activity by deactivating p38 mitogen activating protein kinase and cytosolic phospholipase A2 via induction of MAPK phosphatase-1 (MKP-1) in an extracellular signal-regulated kinase (ERK)-dependent way. In this study, the mechanism of Gln-mediated ERK-dependency in MKP-1 induction was investigated. Gln increased ERK phosphorylation and activity, and phosphorylations of Ras, c-Raf, and MEK, located in the upstream pathway of ERK, in response to lipopolysaccharidein vitro and in vivo. Gln-induced dose-dependent transient increases in intracellular calcium ([Ca2+]i) in MHS macrophage cells. Ionomycin increased [Ca2+]i and activation of Ras → ERK pathway, and MKP-1 induction, in the presence, but not in the absence, of LPS. The Gln-induced pathways involving Ca2+→ MKP-1 induction were abrogated by a calcium blocker. Besides Gln, other amino acids including L-phenylalanine and l-cysteine (Cys) also induced Ca2+ response, activation of Ras → ERK, and MKP-1 induction, albeit to a lesser degree. Gln and Cys were comparable in suppression against 2, 4-dinitrofluorobenzene-induced contact dermatitis. Gln-mediated, but not Cys-mediated, suppression was abolished by MKP-1 small interfering RNA. These data indicate that Gln induces MKP-1 by activating Ca2+→ ERK pathway, which plays a key role in suppression of inflammatory reactions.
Collapse
Key Words
- AP-1, activating protein 1
- Ala, alanine
- Asp, aspartate
- BAPTA, 1,2-bis(o-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid tetraacetoxymethylester
- CD, contact dermatitis
- CaM, calmodulin
- CaR, Ca2+-sensing receptor
- DMSO, dimethyl sulfoxide
- DNFB, 1-fluoro-2,4-dinitrobenzene
- ERK, extracellular signal-regulated kinase
- ESR, ear swelling response
- Gln, L-glutamine
- Glu, glutamate
- Gly, glycine
- H&E, hematoxylin and eosin
- JNK, c-Jun N-terminal kinase
- L-Glutamine
- LPS, lipopolysaccharides
- MAPK Phosphatase-1
- MAPK, mitogen activated protein kinase
- MKP-1, MAPK phosphatase-1
- Mitogen-activated protein kinase
- PEI, polyethyleneimine
- Ras/c-Raf/MEK/ERK, extracellular-signal-regulated kinase
- [Ca2+]i, intracellular calcium concentration
- cPLA2, cytoplasmic phospholipase A2
- siRNA, small interfering RNA
Collapse
Affiliation(s)
- Otgonzaya Ayush
- Department of Dermatology, Medical University, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Zhe Wu Jin
- Department of Anatomy and Histology and Embryology, Yanbian University Medical College, YanJi City, Jilin Province, China
| | - Hae-Kyoung Kim
- Departments of Immunology and Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Republic of Korea
| | - Yu-Rim Shin
- Biofoods Story, Inc, 477 Jeonjucheon-seoro, Wansan-gu, Jeonju, Jeonbuk 560-821, Republic of Korea
| | - Suhn-Young Im
- Department of Biological Sciences, College of Natural Sciences, Chonnam National University, Gwangju, Republic of Korea
| | - Hern-Ku Lee
- Departments of Immunology and Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Republic of Korea
| |
Collapse
|
|
46
|
Atorvastatin Prevents Glutamate Uptake Reduction Induced by Quinolinic Acid Via MAPKs Signaling. Neurochem Res 2016; 41:2017-28. [DOI: 10.1007/s11064-016-1913-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Revised: 04/04/2016] [Accepted: 04/08/2016] [Indexed: 10/21/2022]
|
|
47
|
Porter K, Day B. From filaments to function: The role of the plant actin cytoskeleton in pathogen perception, signaling and immunity. JOURNAL OF INTEGRATIVE PLANT BIOLOGY 2016; 58:299-311. [PMID: 26514830 DOI: 10.1111/jipb.12445] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Accepted: 10/28/2015] [Indexed: 05/23/2023]
Abstract
The eukaryotic actin cytoskeleton is required for numerous cellular processes, including cell shape, development and movement, gene expression and signal transduction, and response to biotic and abiotic stress. In recent years, research in both plants and animal systems have described a function for actin as the ideal surveillance platform, linking the function and activity of primary physiological processes to the immune system. In this review, we will highlight recent advances that have defined the regulation and breadth of function of the actin cytoskeleton as a network required for defense signaling following pathogen infection. Coupled with an overview of recent work demonstrating specific targeting of the plant actin cytoskeleton by a diversity of pathogens, including bacteria, fungi and viruses, we will highlight the importance of actin as a key signaling hub in plants, one that mediates surveillance of cellular homeostasis and the activation of specific signaling responses following pathogen perception. Based on the studies highlighted herein, we propose a working model that posits changes in actin filament organization is in and of itself a highly specific signal, which induces, regulates and physically directs stimulus-specific signaling processes, most importantly, those associated with response to pathogens.
Collapse
Affiliation(s)
- Katie Porter
- Graduate Program in Cell and Molecular Biology, Michigan State University, East Lansing, MI, 48823, USA
| | - Brad Day
- Graduate Program in Cell and Molecular Biology, Michigan State University, East Lansing, MI, 48823, USA
- Department of Plant, Soil and Microbial Sciences, Michigan State University, East Lansing, MI, 48823, USA
- Graduate Program in Genetics, Michigan State University, East Lansing, MI, 48823, USA
| |
Collapse
|
|
48
|
Kv1.3 potassium channel mediates macrophage migration in atherosclerosis by regulating ERK activity. Arch Biochem Biophys 2016; 591:150-6. [DOI: 10.1016/j.abb.2015.12.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2015] [Revised: 12/05/2015] [Accepted: 12/29/2015] [Indexed: 12/30/2022]
|
|
49
|
Duan J, Kodali VK, Gaffrey MJ, Guo J, Chu RK, Camp DG, Smith RD, Thrall BD, Qian WJ. Quantitative Profiling of Protein S-Glutathionylation Reveals Redox-Dependent Regulation of Macrophage Function during Nanoparticle-Induced Oxidative Stress. ACS NANO 2016; 10:524-38. [PMID: 26700264 PMCID: PMC4762218 DOI: 10.1021/acsnano.5b05524] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
Engineered nanoparticles (ENPs) are increasingly utilized for commercial and medical applications; thus, understanding their potential adverse effects is an important societal issue. Herein, we investigated protein S-glutathionylation (SSG) as an underlying regulatory mechanism by which ENPs may alter macrophage innate immune functions, using a quantitative redox proteomics approach for site-specific measurement of SSG modifications. Three high-volume production ENPs (SiO2, Fe3O4, and CoO) were selected as representatives which induce low, moderate, and high propensity, respectively, to stimulate cellular reactive oxygen species (ROS) and disrupt macrophage function. The SSG modifications identified highlighted a broad set of redox sensitive proteins and specific Cys residues which correlated well with the overall level of cellular redox stress and impairment of macrophage phagocytic function (CoO > Fe3O4 ≫ SiO2). Moreover, our data revealed pathway-specific differences in susceptibility to SSG between ENPs which induce moderate versus high levels of ROS. Pathways regulating protein translation and protein stability indicative of ER stress responses and proteins involved in phagocytosis were among the most sensitive to SSG in response to ENPs that induce subcytoxic levels of redox stress. At higher levels of redox stress, the pattern of SSG modifications displayed reduced specificity and a broader set pathways involving classical stress responses and mitochondrial energetics (e.g., glycolysis) associated with apoptotic mechanisms. An important role for SSG in regulation of macrophage innate immune function was also confirmed by RNA silencing of glutaredoxin, a major enzyme which reverses SSG modifications. Our results provide unique insights into the protein signatures and pathways that serve as ROS sensors and may facilitate cellular adaption to ENPs, versus intracellular targets of ENP-induced oxidative stress that are linked to irreversible cell outcomes.
Collapse
Affiliation(s)
- Jicheng Duan
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352, United States
| | - Vamsi K. Kodali
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352, United States
| | - Matthew J. Gaffrey
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352, United States
| | - Jia Guo
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352, United States
| | - Rosalie K. Chu
- Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, Washington 99352, United States
| | - David G. Camp
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352, United States
| | - Richard D. Smith
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352, United States
- Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, Washington 99352, United States
| | - Brian D. Thrall
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352, United States
- Corresponding Authors: .
| | - Wei-Jun Qian
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352, United States
- Corresponding Authors: .
| |
Collapse
|
|
50
|
Prindull G. Potential Gene Interactions in the Cell Cycles of Gametes, Zygotes, Embryonic Stem Cells and the Development of Cancer. Front Oncol 2015; 5:200. [PMID: 26442212 PMCID: PMC4585297 DOI: 10.3389/fonc.2015.00200] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Accepted: 08/31/2015] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES This review is to explore whether potential gene interactions in the cell cycles of gametes, zygotes, and embryonic stem (ES) cells are associated with the development of cancer. METHODS MEDPILOT at the Central Library of the University of Cologne, Germany (Zentralbibliothek Köln) that covers 5,800 international medical journals and 4,300 E-journals was used to collect data. The initial searches were done in December 2012 and additional searches in October 2013-May 2015. The search terms included "cancer development," "gene interaction," and "ES cells," and the time period was between 1998 and 2015. A total of 147 articles in English language only were included in this review. RESULTS Transgenerational gene translation is implemented in the zygote through interactions of epigenetic isoforms of transcription factors (TFs) from parental gametes, predominantly during the first two zygote cleavages. Pluripotent transcription factors may provide interacting links with mutated genes during zygote-to-ES cell switches. Translation of post-transcriptional carcinogenic genes is implemented by abnormally spliced, tumor-specific isoforms of gene-encoded mRNA/non-coding RNA variants of TFs employing de novo gene synthesis and neofunctionalization. Post-translationally, mutated genes are preserved in pre-neoplastic ES cell subpopulations that can give rise to overt cancer stem cells. Thus, TFs operate as cell/disease-specific epigenetic messengers triggering clinical expression of neoplasms. CONCLUSION Potential gene interactions in the cell cycle of gametes, zygotes, and ES cells may play some roles in the development of cancer.
Collapse
Affiliation(s)
- Gregor Prindull
- Medical Faculty, University of Göttingen , Göttingen , Germany
| |
Collapse
|