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Liang X, Zhang C, Shen L, Ding L, Guo H. Role of non‑coding RNAs in UV‑induced radiation effects (Review). Exp Ther Med 2024; 27:262. [PMID: 38756908 PMCID: PMC11097301 DOI: 10.3892/etm.2024.12550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 04/04/2024] [Indexed: 05/18/2024] Open
Abstract
Ultraviolet (UV) is divided into UVA (long-wave, 320-400 nm), UVB (middle-wave, 280-320 nm) and UVC (short-wave, 100-280 nm) based on wavelength. UV radiation (UVR) from sunlight (UVA + UVB) is a major cause of skin photodamage including skin inflammation, aging and pigmentation. Accidental exposure to UVC burns the skin and induces skin cancer. In addition to the skin, UV radiation can also impair visual function. Non-coding RNAs (ncRNAs) are a class of functional RNAs that do not have coding activity but can control cellular processes at the post-transcriptional level, including microRNA (miRNA), long non-coding RNA (lncRNA) and circulatory RNA (circRNA). Through a review of the literature, it was determined that UVR can affect the expression of various ncRNAs, and that this regulation may be wavelength specific. Functionally, ncRNAs participate in the regulation of photodamage through various pathways and play pathogenic or protective regulatory roles. In addition, ncRNAs that are upregulated or downregulated by UVR can serve as biomarkers for UV-induced diseases, aiding in diagnosis and prognosis assessment. Therapeutic strategies targeting ncRNAs, including the use of natural drugs and their extracts, have shown protective effects against UV-induced photodamage. In the present review, an extensive summarization of previous studies was performed and the role and mechanism of ncRNAs in UV-induced radiation effects was reviewed to aid in the diagnosis and treatment of UV-related diseases.
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Affiliation(s)
- Xiaofei Liang
- Department of Laboratory Medicine, The First Hospital of Qiqihar, Qiqihar, Heilongjiang 161000, P.R. China
| | - Chao Zhang
- Department of Laboratory Medicine, The First Hospital of Qiqihar, Qiqihar, Heilongjiang 161000, P.R. China
| | - Lijuan Shen
- Department of Laboratory Medicine, Qiqihar MingZhu Hospital, Qiqihar, Heilongjiang 161000, P.R. China
| | - Ling Ding
- Department of Laboratory Medicine, The First Hospital of Qiqihar, Qiqihar, Heilongjiang 161000, P.R. China
| | - Haipeng Guo
- Department of Laboratory Medicine, The First Hospital of Qiqihar, Qiqihar, Heilongjiang 161000, P.R. China
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Li Y, Zeng ZW, Chen D, Gu ZC, Yan WL, Yue LY, Zhu RG, Zhao YL, Chen L, Zhao QJ, He B. Facilitated Drug Repurposing with Artemisinin-Derived PROTACs: Unveiling PCLAF as a Therapeutic Target. J Med Chem 2023; 66:11335-11350. [PMID: 37552639 DOI: 10.1021/acs.jmedchem.3c00824] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/10/2023]
Abstract
Artemisinin, a prominent anti-malaria drug, is being investigated for its potential as a repurposed cancer treatment. However, its effectiveness in tumor cell lines remains limited, and its mechanism of action is unclear. To make more progress, the PROteolysis-TArgeting chimera (PROTAC) technique has been applied to design and synthesize novel artemisinin derivatives in this study. Among them, AD4, the most potent compound, exhibited an IC50 value of 50.6 nM in RS4;11 cells, over 12-fold better than that of its parent compound, SM1044. This was supported by prolonged survival of RS4;11-transplanted NOD/SCID mice. Meanwhile, AD4 effectively degraded PCLAF in RS4;11 cells and thus activated the p21/Rb axis to exert antitumor activity by directly targeting PCLAF. The discovery of AD4 highlights the great potential of using PROTACs to improve the efficacy of natural products, identify therapeutic targets, and facilitate drug repurposing. This opens a promising avenue for transforming other natural products into effective therapies.
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Affiliation(s)
- Yan Li
- State Key Laboratory of Functions and Applications of Medicinal, Plants Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medical Science, Guizhou Medical University, Guiyang 550004, China
| | - Zi Wei Zeng
- State Key Laboratory of Functions and Applications of Medicinal, Plants Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medical Science, Guizhou Medical University, Guiyang 550004, China
| | - Di Chen
- State Key Laboratory of Functions and Applications of Medicinal, Plants Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medical Science, Guizhou Medical University, Guiyang 550004, China
| | - Zhi Cheng Gu
- State Key Laboratory of Functions and Applications of Medicinal, Plants Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medical Science, Guizhou Medical University, Guiyang 550004, China
| | - Wan Li Yan
- State Key Laboratory of Functions and Applications of Medicinal, Plants Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medical Science, Guizhou Medical University, Guiyang 550004, China
| | - Ling Yun Yue
- Department of Chemistry, College of Sciences, Shanghai University, Shanghai 200444, China
| | - Ren Guang Zhu
- State Key Laboratory of Functions and Applications of Medicinal, Plants Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medical Science, Guizhou Medical University, Guiyang 550004, China
| | - Yong Long Zhao
- State Key Laboratory of Functions and Applications of Medicinal, Plants Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medical Science, Guizhou Medical University, Guiyang 550004, China
| | - Lei Chen
- State Key Laboratory of Functions and Applications of Medicinal, Plants Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medical Science, Guizhou Medical University, Guiyang 550004, China
| | - Qing Jie Zhao
- The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Bin He
- State Key Laboratory of Functions and Applications of Medicinal, Plants Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medical Science, Guizhou Medical University, Guiyang 550004, China
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miR-486-5p Restrains Extracellular Matrix Production and Oxidative Damage in Human Trabecular Meshwork Cells by Targeting TGF-β/SMAD2 Pathway. J Ophthalmol 2022; 2022:3584192. [PMID: 35251709 PMCID: PMC8890899 DOI: 10.1155/2022/3584192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 01/26/2022] [Indexed: 11/17/2022] Open
Abstract
Background Glaucoma is characterized by elevated intraocular pressure caused by aqueous outflow dysfunction. Trabecular meshwork plays a key role in controlling intraocular pressure by modulating aqueous outflow. This study investigated the protective effects of miR-486-5p in H2O2-stimulated human trabecular meshwork cells (TMCs). Methods TMCs were disposed with 300 μM H2O2 to establish oxidative damage models in vitro. miR-486-5p mimics and its controls were transfected into TMCs, and cell apoptosis and extracellular matrix production (ECM) genes were measured by flow cytometry, western blotting, and immunofluorescence staining. Activities of superoxide dismutase (SOD) and malondialdehyde (MDA) were also assayed. Online tools and luciferase reporter assays were used to uncover the relationship between miR-486-5p and the TGF-β/SMAD2 pathway. Results We found that H2O2-induced oxidative damage in TMCs and miR-486-5p was downregulated in H2O2-stimulated TMCs. Overexpression of miR-486-5p mitigated H2O2-induced oxidative damage by inhibiting apoptosis, reducing cleaved caspase-3/9 expression, reducing MDA levels, and increasing SOD levels as well as downregulating ECM genes. SMAD2 was demonstrated to be targeted by miR-486-5p, and miR-486-5p inhibited TGF-β/SMAD2 signaling in H2O2-stimulated TMCs. Additionally, SMAD2 was upregulated by H2O2, and SMAD2 upregulation abrogated the protective effects of miR-486-5p against H2O2-induced injury. Conclusion miR-486-5p restrains H2O2-induced oxidative damage in TMCs by targeting the TGF-β/SMAD2 pathway.
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Integrative analysis of DNA methylation and gene expression profiles to identify biomarkers of glioblastoma. Cancer Genet 2021; 258-259:135-150. [PMID: 34773808 DOI: 10.1016/j.cancergen.2021.10.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 09/21/2021] [Accepted: 10/31/2021] [Indexed: 12/26/2022]
Abstract
Glioblastoma multiforme (GBM) is the most common, most invasive, and malignant type of primary brain tumor with poor prognosis and poor survival rate. Using GSE22891 the expression and methylation status of same GBM patients was evaluated to identify key epigenetic genes in GBM. Using |log2FC| > 1 and FDR 〈 0.05 as the threshold, DEGs including 4910 downregulated and 2478 upregulated were screened and by |log2FC| 〉 0.2 and p-value < 0.05, 3223 DMCs were detected. By merging the results of DEGs and DMCs, 643 genes were selected for network analysis by WGCNA, and based on expression values three modules and by methylation values, one module was selected. Using STRING and Cytoscape databases, PPI network of genes of all modules were constructed separately. According to the PPI network, core genes were picked out. The expression status of core genes was evaluated using GSE77043, GSE42656, GSE30563, GSE22891, GSE15824, and GSE122498, and 50 genes were validated. The methylation status of 50 genes was explored using GSE50923, GSE22891, and GSE36245, and finally, 12 hub genes including ARHGEF7, RAB11FIP4, PPP1R16B, OLFM1, CLDN10, BCAT1, C1QB, C1QC, IFI16, NUP37, PARP9, and PCLAF were selected. Using GEPIA database, the expression and by cBioportal the survival plot and also scatterplot of methylation versus expression of 12 hub genes were extracted based on TCGA. To determine the diagnostic values of the hub genes, the receiver operating characteristic (ROC) curve and the area under the curve (AUC) were extracted based on GSE22891 and GSE122498. Finally, we evaluated the expression level of the genes in tissue of 83 GBM patients and also non-tumoral adjacent (as control) tissues.
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Liu LJ, Liao JM, Zhu F. Proliferating cell nuclear antigen clamp associated factor, a potential proto-oncogene with increased expression in malignant gastrointestinal tumors. World J Gastrointest Oncol 2021; 13:1425-1439. [PMID: 34721775 PMCID: PMC8529917 DOI: 10.4251/wjgo.v13.i10.1425] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 06/11/2021] [Accepted: 07/23/2021] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal (GI) cancers, including malignancies in the gastrointestinal tract and accessory organs of digestion, represent the leading cause of death worldwide due to the poor prognosis of most GI cancers. An investigation into the potential molecular targets of prediction, diagnosis, prognosis, and therapy in GI cancers is urgently required. Proliferating cell nuclear antigen (PCNA) clamp associated factor (PCLAF), which plays an essential role in cell proliferation, apoptosis, and cell cycle regulation by binding to PCNA, is a potential molecular target of GI cancers as it contributes to a series of malignant properties, including tumorigenesis, epithelial-mesenchymal transition, migration, and invasion. Furthermore, PCLAF is an underlying plasma prediction target in colorectal cancer and liver cancer. In addition to GI cancers, PCLAF is also involved in other types of cancers and autoimmune diseases. Several pivotal pathways, including the Rb/E2F pathway, NF-κB pathway, and p53-p21 cascade, are implicated in PCLAF-mediated diseases. PCLAF also contributes to some diseases through dysregulation of the p53 pathway, WNT signal pathway, MEK/ERK pathway, and PI3K/AKT/mTOR signal cascade. This review mainly describes in detail the role of PCLAF in physiological status and GI cancers. The signaling pathways involved in PCLAF are also summarized. Suppression of the interaction of PCLAF/PCNA or the expression of PCLAF might be potential biological therapeutic strategies for GI cancers.
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Affiliation(s)
- Li-Juan Liu
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy & Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Jian-Ming Liao
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy & Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurosurgery, Renmin Hospital, Wuhan University, Wuhan 430060, Hubei Province, China
| | - Fan Zhu
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy & Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
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Yang L, Hu Z, Jin Y, Huang N, Xu S. MiR-4497 mediates oxidative stress and inflammatory injury in keratinocytes induced by ultraviolet B radiation through regulating NF-κB expression. Ital J Dermatol Venerol 2020; 157:84-91. [PMID: 33314897 DOI: 10.23736/s2784-8671.20.06825-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND To investigate the role and underlying mechanism of miR-4497 in oxidative stress and inflammatory injury in keratinocytes induced by ultraviolet B (UVB) radiation. METHODS An injury model of keratinocytes induced by UVB radiation was constructed. RT-qPCR, MTT assay and flow cytometry were adopted to detect miR-4497 expression in HaCaT cells, cell proliferation, and cell apoptosis, respectively. The levels of cytokines TNF-α, IL-18, IL-6 and IL-1β in cell culture supernatant were tested by ELISA. ROS levels in the cells were labeled by DCFH-DA fluorescent probe, and then quantitative fluorescence analysis was performed by flow cytometry. SOD activity in the cells was measured by xanthine oxidase assay kit. Western blot was used to determine NF-κB expression in cytoplasm and nucleus, and p-IκBα expression in the cells. RESULTS UVB radiation significantly increased miR-4497 expression in HaCaT cells, inhibited cell proliferation, and promoted cell apoptosis. Meanwhile, UVB radiation caused the promotion of secretion of cytokines TNF-α, IL-18, IL-6 and IL-1β. The production of reactive oxygen species (ROS) was promoted by UVB radiation, while SOD activity was inhibited. Nuclear transfer of NF-κB signal was also induced by UVB radiation. In addition, downregulation of miR-4497 expression significantly inhibited the effects of UVB radiation on cell proliferation, apoptosis, cytokine secretion, redox level and NF-κB signal in HaCaT cells, while overexpression of miR-4497 further enhanced these effects of UVB radiation on HaCaT cells. CONCLUSIONS UVB may promote the expression of inflammatory and oxidative stress signals in keratinocytes by upregulating miR-4497 expression, thus mediating cell injury.
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Affiliation(s)
| | | | | | | | - Su Xu
- Department of Dermatology
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Chen Y, Jin Y, Ying H, Zhang P, Chen M, Hu X. Synergistic effect of PAF inhibition and X-ray irradiation in non-small cell lung cancer cells. Strahlenther Onkol 2020; 197:343-352. [PMID: 33231712 DOI: 10.1007/s00066-020-01708-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Accepted: 10/23/2020] [Indexed: 12/30/2022]
Abstract
PURPOSE Proliferating cell nuclear antigen-associated factor (PAF) is involved in cancer cell growth and associated with cell death induced by ultraviolet (UV) radiation. However, the contribution of PAF to radiotherapy sensitivity in non-small cell lung cancer (NSCLC) is unknown. The aim of this study was to investigate the relationship between PAF expression and radiotherapy response in NSCLC. METHODS Associations between PAF expression and patient survival outcomes were evaluated using publicly available online gene expression datasets. RNA interference was performed to knockdown PAF expression in the NSCLC cells. The effects of PAF knockdown on cell proliferation, migration, apoptosis, DNA damage, and activation of MEK/ERK and Wnt/β-catenin signaling pathways following X‑ray irradiation were evaluated in vitro. RESULTS PAF was found to be overexpressed in lung cancer tissues compared with normal samples, and elevated PAF expression was significantly correlated with inferior patient survival. In vitro, knockdown of PAF inhibited cell proliferation, cell apoptosis, and migration induced by X‑ray irradiation. Moreover, X‑ray-induced intracellular DNA strand damage was more obvious following PAF knockdown. Additionally, PAF knockdown inhibited activation of the MEK/ERK and Wnt/β-catenin signaling pathways in X‑ray-irradiated A549 cells. CONCLUSION These data demonstrate that reduced expression of PAF enhances radiosensitivity in NSCLC cells. Mechanistically, inhibition of the MEK/ERK and Wnt/β-catenin signaling pathways caused by PAF interference may lead to impaired cell function and enhance sensitivity to X‑rays. Targeting PAF may therefore serve as a potential therapeutic strategy to increase the efficiency of radiotherapy in NSCLC patients, ultimately improving patient survival.
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Affiliation(s)
- Yamei Chen
- Zhejiang Key Laboratory of Radiation Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, 310022, Hangzhou, Zhejiang, China
| | - Ying Jin
- Zhejiang Key Laboratory of Radiation Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, 310022, Hangzhou, Zhejiang, China.,Department of Medical Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, 310022, Hangzhou, Zhejiang, China
| | - Hangjie Ying
- Zhejiang Key Laboratory of Radiation Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, 310022, Hangzhou, Zhejiang, China
| | - Peng Zhang
- Zhejiang Key Laboratory of Radiation Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, 310022, Hangzhou, Zhejiang, China
| | - Ming Chen
- Zhejiang Key Laboratory of Radiation Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, 310022, Hangzhou, Zhejiang, China. .,Department of Radiation Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, 310022, Hangzhou, Zhejiang, China.
| | - Xiao Hu
- Zhejiang Key Laboratory of Radiation Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, 310022, Hangzhou, Zhejiang, China. .,Department of Radiation Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, 310022, Hangzhou, Zhejiang, China.
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Zhao H, Chen M, Wang J, Cao G, Chen W, Xu J. PCNA-associated factor KIAA0101 transcriptionally induced by ELK1 controls cell proliferation and apoptosis in nasopharyngeal carcinoma: an integrated bioinformatics and experimental study. Aging (Albany NY) 2020; 12:5992-6017. [PMID: 32275642 PMCID: PMC7185143 DOI: 10.18632/aging.102991] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 03/09/2020] [Indexed: 12/16/2022]
Abstract
KIAA0101, previously identified as PCNA-associated factor, is overexpressed among almost majority of human cancers and has emerged as an important regulator of cancer progression; however, its function in human nasopharyngeal carcinoma (NPC) remain unknown. Integrated bioinformatics approaches were employed to determine the KIAA0101 expressions in the NPC samples. Lentiviral vectors carrying KIAA0101 shRNA were constructed and stable transfected cells were validated by qRT-PCR and western blot. Cellular functions were then evaluated by MTT, colony formation, Brdu staining, and flow cytometry. Mechanistic studies were systematically investigated by UCSC Genome Browser, GEO, UALCAN, QIAGEN, PROMO and JASPAR, ChIP, and the cBioPortal, et al. The results showed that KIAA0101 ranked top overexpressed gene lists in GSE6631 dataset. KIAA0101 was highly expressed in NPC tissues and cell lines. Furthermore, knockdown of KIAA0101 significantly inhibited cell proliferation and DNA replication, promoted apoptosis and cell cycle arrest in vitro. Meanwhile, the mechanistic study revealed that MAP kinase phosphorylation-dependent activation of ELK1 may enhance neighbor gene expressions of KIAA0101 and TRIP4 by binding both promotor regions in the NPC cells. Taken together, our findings indicate that overexpression of KIAA0101 activated by MAP kinase phosphorylation-dependent activation of ELK1 may play an important role in NPC progression.
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Affiliation(s)
- Hu Zhao
- Fujian Provincial Key Laboratory of Transplant Biology, Department of Urology, 900 Hospital of the Joint Logistics Team, Xiamen University, Fuzhou 350025, Fujian, P.R. China.,Office of Science Education, 900 Hospital of the Joint Logistics Team, Xiamen University, Fuzhou 350025, Fujian, P.R. China
| | - Miaosheng Chen
- Pathology Department, Longyan First Hospital Affiliated to Fujian Medical University, Longyan 364000, Fujian, P.R. China
| | - Jie Wang
- Fujian Provincial Key Laboratory of Transplant Biology, Department of Urology, 900 Hospital of the Joint Logistics Team, Xiamen University, Fuzhou 350025, Fujian, P.R. China
| | - Gang Cao
- Department of Oral and Maxillofacial Surgery, Medical School of Nanjing University, Nanjing 210002, Jiangsu, P.R. China
| | - Wei Chen
- Department of Oral and Maxillofacial Surgery, Medical School of Nanjing University, Nanjing 210002, Jiangsu, P.R. China
| | - Jinke Xu
- Department of Oral and Maxillofacial Surgery, Medical School of Nanjing University, Nanjing 210002, Jiangsu, P.R. China
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Zhao J, Han M, Zhou L, Liang P, Wang Y, Feng S, Lu H, Yuan X, Han K, Chen X, Liu S, Cheng J. TAF and TDF attenuate liver fibrosis through NS5ATP9, TGFβ1/Smad3, and NF-κB/NLRP3 inflammasome signaling pathways. Hepatol Int 2019; 14:145-160. [PMID: 31758498 DOI: 10.1007/s12072-019-09997-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 10/23/2019] [Indexed: 01/04/2023]
Abstract
BACKGROUND This study aimed to investigate the roles and mechanisms of tenofovir alafenamide fumarate (TAF)/tenofovir disoproxil fumarate (TDF) in treating liver fibrosis. METHODS The effects of TAF/TDF on carbon tetrachloride (CCl4)-induced liver fibrosis in C57BL/6 wild-type or nonstructural protein 5A transactivated protein 9 (NS5ATP9) knockout mice were studied. The differentiation, activation, and proliferation of LX-2 cells after TAF/TDF treatment were tested in vitro. The expression of NS5ATP9 and activities of transforming growth factor-β1 (TGFβ1)/Sekelsky mothers against decapentaplegic homolog 3 (Smad3) and NF-κB/NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome signaling pathways were detected in TAF/TDF-treated mice and LX-2 cells. The genes related to extracellular matrix accumulation were detected in vivo and in vitro after NS5ATP9 silencing or knockout. RESULTS TAF/TDF significantly inhibited CCl4-induced liver fibrosis in mice, and regulated the differentiation, activation, and proliferation of hepatic stellate cells (HSCs). Furthermore, TAF/TDF suppressed the activities of TGFβ1/Smad3 and NF-κB/NLRP3 inflammasome signaling pathways in vivo and in vitro. NS5ATP9 inhibited liver fibrosis through TGFβ1/Smad3 and NF-κB signaling pathways. TAF/TDF upregulated the expression of NS5ATP9 in vivo and in vitro. Finally, TAF/TDF could only show marginal therapeutic effects when NS5ATP9 was silenced and knocked out in vivo and in vitro. CONCLUSIONS TAF/TDF prevented progression and promoted reversion of liver fibrosis through assembling TGFβ1/Smad3 and NF-κB/NLRP3 inflammasome signaling pathways via upregulating the expression of NS5ATP9. TAF/TDF also regulated the differentiation, activation, and proliferation of HSCs. The findings provided strong evidence for the role of TAF/TDF as a new promising therapeutic strategy in liver fibrosis.
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Affiliation(s)
- Jing Zhao
- Peking University Ditan Teaching Hospital, Beijing, 100015, China
- Institiute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China
| | - Ming Han
- Institiute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China
| | - Li Zhou
- Institiute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China
- Department of Infectious Disease, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Pu Liang
- Institiute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China
| | - Yun Wang
- Peking University Ditan Teaching Hospital, Beijing, 100015, China
- Institiute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China
| | - Shenghu Feng
- Institiute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China
- Department of Infectious Diseases and Clinical Microbiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China
| | - Hongping Lu
- Institiute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China
| | - Xiaoxue Yuan
- Institiute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China
| | - Kai Han
- Institiute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China
| | - Xiaofan Chen
- Institiute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing, 100034, China
| | - Shunai Liu
- Institiute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China
| | - Jun Cheng
- Peking University Ditan Teaching Hospital, Beijing, 100015, China.
- Institiute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China.
- Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University & Capital Medical University, Beijing, 100191, China.
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Assessment of miR-182, miR-183, miR-184, and miR-221 Expressions in Primary Pterygium and Comparison With the Normal Conjunctiva. Eye Contact Lens 2019; 45:208-211. [PMID: 30688676 DOI: 10.1097/icl.0000000000000573] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES The aim of this study was to investigate the expression levels of miR-126-3p, miR-182-5p, miR-183-5p, miR-184, miR-221-3p, and miR-205-5p in primary pterygium tissue and compare these levels with those in healthy conjunctiva tissue. METHODS Twenty-four patients who were diagnosed with grade 3 primary pterygium and scheduled for surgery between January 2014 and January 2016 and had no systemic disease or other ocular pathology were included in the study. The control group comprised nasal interpalpebral conjunctival tissue specimens from 24 age- and sex-matched patients with no history of systemic disease or ocular pathology other than cataract. Expression levels of miR-126-3p, miR-182-5p, miR-183-5p, miR-184, miR-221-3p, and miR-205-5p were determined and compared between the pterygium and conjunctiva specimens. RESULTS Expression levels of miR-182-5p, miR-183-5p, and miR-184 were significantly higher in pterygium tissue compared with normal conjunctival specimens (P<0.0001, P=0.01, and P=0.01, respectively), whereas expression of miR-221-3p was significantly lower (P=0.02). Expression levels of miR-126-3p and miR-205-5p did not differ significantly between the 2 groups (P>0.05). CONCLUSIONS Expression levels of miR-182-5p, miR-183-5p, and miR-184 are increased, whereas expression of miR-221-3p is decreased in primary pterygium tissue, and these miRNAs may play a role in the pathogenesis of pterygium.
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Yin R, Chen X. Regulatory effect of miR-144-3p on the function of human trabecular meshwork cells and fibronectin-1. Exp Ther Med 2019; 18:647-653. [PMID: 31258702 PMCID: PMC6566054 DOI: 10.3892/etm.2019.7584] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 04/23/2019] [Indexed: 12/23/2022] Open
Abstract
Role of microRNA (miR)-144-3p in regulating the function of human trabecular meshwork cells (HTMCs) and fibronectin-1 (FN-1) was investigated. HTM cell lines were divided into five groups, of which four groups established oxidative stress HTMC models and one served as a control group. The four model groups were transfected with miR-144-3p independent sequence, inhibitory sequence, over-expression sequence, and the blank group received no transfection. In addition, 40 primary open angle glaucoma patients treated in Xuzhou No. 1 People's Hospital were included in the observation group, and 40 healthy individuals were enrolled as a normal group. RT-qPCR was used for the detection of miR-144-3p expression in serum and cells of patients and healthy people in each group, western blot analysis for FN-1 expression in cells, CCK-8 kit for cell proliferation, and Transwell for cell invasion. The expression of serum miR-144-3p in the observation group was significantly lower than that in the normal group (P<0.05). The cell optical density value in the over-expression group was significantly higher than that in the other groups (P<0.05), and in the inhibition group was significantly lower than that in the other groups (P<0.05). The number of cell-penetration in the over-expression group was significantly higher than that in the other groups (P<0.05). The expression of FN-1 protein in the over-expression group was significantly lower than that in the other four groups (P<0.05), and the expression in the inhibition group was significantly higher than that in the other four groups (P<0.05). The over-expression of miR-144-3p promotes proliferation and invasion of HTMCs by inhibiting the expression of FN-1 in inoxidative stress HTMCs, and is a potential target for glaucoma treatment.
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Affiliation(s)
- Ruoxi Yin
- Postgraduate School, Xuzhou Medical University, Xuzhou Eye Hospital, Xuzhou, Jiangsu 221000, P.R. China
| | - Xiaoya Chen
- Department of Ophthalmology, Xuzhou No. 1 People's Hospital, Xuzhou Municipal Hospital Affiliated to Xuzhou Medical University, Xuzhou Eye Hospital, Xuzhou, Jiangsu 221000, P.R. China
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Azqueta A, Rundén-Pran E, Elje E, Nicolaissen B, Berg KH, Smeringaiova I, Jirsova K, Collins AR. The comet assay applied to cells of the eye. Mutagenesis 2018; 33:21-24. [PMID: 29077953 DOI: 10.1093/mutage/gex025] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 08/26/2017] [Indexed: 12/27/2022] Open
Abstract
The human eye is relatively unexplored as a source of cells for investigating DNA damage. There have been some clinical studies, using cells from surgically removed tissues, and altered DNA bases as well as strand breaks have been measured using the comet assay. Tissues examined include corneal epithelium and endothelium, lens capsule, iris and retinal pigment epithelium. For the purpose of biomonitoring for exposure to potential mutagens in the environment, the eye-relatively unprotected as it is compared with the skin-would be a valuable object for study; non-invasive techniques exist to collect lachrymal duct cells from tears, or cells from the ocular surface by impression cytology, and these methods should be further developed and validated.
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Affiliation(s)
- Amaya Azqueta
- Department of Nutrition, Food Science and Toxicology, Schools of Pharmacy and Sciences, University of Navarra, Irunlarrea, Pamplona, Spain.,IdiSNA, Navarra Institute for Health Research
| | - Elisa Rundén-Pran
- NILU (Norwegian Institute for Air Research), Instituttveien, Kjeller, Norway
| | - Elisabeth Elje
- NILU (Norwegian Institute for Air Research), Instituttveien, Kjeller, Norway
| | - Bjørn Nicolaissen
- Centre for Eye Research, Department of Ophthalmology, Oslo University Hospital, Ullevål and University of Oslo, Kirkeveien, Oslo, Norway
| | - Kristiane Haug Berg
- Centre for Eye Research, Department of Ophthalmology, Oslo University Hospital, Ullevål and University of Oslo, Kirkeveien, Oslo, Norway
| | - Ingrida Smeringaiova
- Laboratory of the Biology and Pathology of the Eye, Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Katerina Jirsova
- Laboratory of the Biology and Pathology of the Eye, Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Andrew R Collins
- Department of Nutrition, Institute for Basic Medical Sciences, University of Oslo, Sognsvannsveien, Oslo, Norway
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Overexpressed miR-183 promoted glioblastoma radioresistance via down-regulating LRIG1. Biomed Pharmacother 2018; 97:1554-1563. [DOI: 10.1016/j.biopha.2017.11.050] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 10/26/2017] [Accepted: 11/07/2017] [Indexed: 11/19/2022] Open
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