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Zoroddu S, Sias F, Bagella L. The Double Life of microRNAs in Bone Sarcomas: Oncogenic Drivers and Tumor Suppressors. Int J Mol Sci 2025; 26:4814. [PMID: 40429954 PMCID: PMC12112630 DOI: 10.3390/ijms26104814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2025] [Revised: 05/09/2025] [Accepted: 05/15/2025] [Indexed: 05/29/2025] Open
Abstract
Bone sarcomas, including Osteosarcoma, Ewing's sarcoma, and Chondrosarcoma, are rare yet aggressive tumors with high metastatic potential and poor survival outcomes. Despite advances in surgical and chemotherapeutic techniques, these malignancies remain difficult to treat. They often exhibit resistance to conventional therapies and are associated with a limited prognosis for patients. MicroRNAs (miRNAs) have emerged as pivotal regulators of cancer biology, orchestrating crucial processes such as cell proliferation, apoptosis, and metastasis. Their double life as oncogenes or tumor suppressors underscores their significance in the pathogenesis of bone sarcomas. This review examines the multifaceted roles of miRNAs in these malignancies. By elucidating the complex networks affected by miRNA dysregulation, we seek to identify novel avenues for miRNA-based interventions. It is the intention of this work to stimulate future research and clinical strategies that exploit the potential of miRNAs to transform the management and outcomes of bone sarcomas.
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Affiliation(s)
- Stefano Zoroddu
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/b, 07100 Sassari, Italy
| | - Fabio Sias
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/b, 07100 Sassari, Italy
| | - Luigi Bagella
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/b, 07100 Sassari, Italy
- Sbarro Institute for Cancer Research and Molecular Medicine, Centre for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
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Jia S, Chen Y, Zhuo C, Hu M, Zhang C, Cai H, Li X, Chen H, Yu X. Aptamer-modified melittin micelles efficiently inhibit osteosarcoma deterioration by inducing immunogenic cell death. Colloids Surf B Biointerfaces 2025; 249:114512. [PMID: 39842274 DOI: 10.1016/j.colsurfb.2025.114512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Revised: 12/31/2024] [Accepted: 01/12/2025] [Indexed: 01/24/2025]
Abstract
Osteosarcoma (OS) is the most common primary bone malignancy characterized by deposition of an immature osteoid matrix. OS treatment has proven challenging because of the high risk of metastatic progression and recurrence after chemotherapy. Melittin (MLT) is recognized as a potential antitumor candidate to overcome chemotherapy resistance and provoke superior immunostimulatory effects. However, the application of MLT to OS is hampered by severe toxic side effects and a lack of tumor-targeting ability. Herein, a self-assembled nanopolymer named LC09-MLT@F127 was developed by binding MLT with F127 micelles and then modifying an aptamer (LC09) for targeted drug delivery during OS treatment. LC09-MLT@F127 exhibited significant OS-targeting ability in vitro and in vivo owing to the aptamer LC09 decoration. Moreover, LC09-MLT@F127 significantly reduced the hemolytic toxicity of MLT while maintaining its tumor-killing ability. In an orthotopic transplantation model of OS, LC09-MLT@F127 induced immunogenic cell death and facilitated the maturation of dendritic cells (DCs), thereby resulting in the activation of tumor-specific immune responses and the inhibition of OS deterioration. Taken together, these finding suggest that LC09-MLT@F127 may be an encouraging MLT-based immunotherapy option for OS.
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Affiliation(s)
- Siyu Jia
- The First College of Clinical Medical Science, China Three Gorges University, Yichang, China; Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, China; Department of Spinal Surgery, Yichang Central People's Hospital, Yichang, China
| | - Yaohui Chen
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, China
| | - Can Zhuo
- The First College of Clinical Medical Science, China Three Gorges University, Yichang, China; Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, China; Department of Spinal Surgery, Yichang Central People's Hospital, Yichang, China
| | - Ming Hu
- State Key Laboratory of Digital Medical Engineering, School of Biomedical Engineering, Hainan University, China; Key Laboratory of Biomedical Engineering of Hainan Province, One Health Institute, Hainan University
| | - Chengwei Zhang
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, China
| | - Huili Cai
- The First College of Clinical Medical Science, China Three Gorges University, Yichang, China; Department of Hematology, Yichang Central People's Hospital, Yichang, China
| | - Xinzhi Li
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, China
| | - Haidan Chen
- The First College of Clinical Medical Science, China Three Gorges University, Yichang, China; Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, China; Department of Spinal Surgery, Yichang Central People's Hospital, Yichang, China.
| | - Xiang Yu
- State Key Laboratory of Digital Medical Engineering, School of Biomedical Engineering, Hainan University, China; Key Laboratory of Biomedical Engineering of Hainan Province, One Health Institute, Hainan University.
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Mao J, Li HM, Huang Z. Comprehensive analysis of the expression and prognosis for cyclin-dependent protein kinase family in osteosarcoma. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2024:1-24. [PMID: 39357043 DOI: 10.1080/15257770.2024.2410957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 09/21/2024] [Accepted: 09/23/2024] [Indexed: 10/04/2024]
Abstract
BACKGROUND AND OBJECTIVE Cyclin-dependent protein kinases (CDKs) have been suggested as prospective therapeutic targets because they control processes vital to the survival and growth of cancer cells. However, research on the varied CDK expression profiles and prognostic factors in osteosarcoma is still lacking. METHODS The osteosarcoma microRNA (GSE65071) and gene expression profiles were retrieved from the Gene Expression Omnibus (GEO) database (GSE42352). A substantial variation in prognosis was discovered in CDKs using the TARGET database. Cytoscape was used to construct the miRNAs-CDKs network, and functional and pathway enrichment analyses were completed. It was looked at how immune checkpoint genes, m6A-related genes, and CDKs interact. RESULTS In patients with osteosarcoma compared to normal samples, CDK1-5, CDK18, CDK16, and CDK17 gene expression levels were considerably greater, whereas CDK7-9, CDK11B, CDK16, and CDK20 gene expression levels were significantly lower. Patients with osteosarcoma who had low CDK3 and 18 gene levels or high CDK6, 9 gene levels were predicted to have a favorable prognosis and a long-life expectancy. Immune checkpoint genes, m6A-related gene expression, and CDKs expression all showed some connection. Finally, a network of crucial CDKs and miRNAs was constructed. CONCLUSION According to our research, CDK3, 6, 9, and 18 have been identified as possible therapeutic targets for osteosarcoma, and CDKs may have a role in controlling m6A mutations in tumor cells as well as immune checkpoint regulation.
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Affiliation(s)
- Jianshui Mao
- Department of Orthopedics, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang, P R China
| | - Hui-Min Li
- Department of Orthopedics, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang, P R China
| | - Zhidan Huang
- Department of Orthopedics, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang, P R China
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Meng D, Dong Y, Shang Q, Sun Z. Anti-tumor effect and hepatotoxicity mechanisms of psoralen. Front Pharmacol 2024; 15:1442700. [PMID: 39161897 PMCID: PMC11331265 DOI: 10.3389/fphar.2024.1442700] [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: 06/02/2024] [Accepted: 07/18/2024] [Indexed: 08/21/2024] Open
Abstract
In recent years, natural products have gradually become an important source for new drug development due to their advantages of multi-components, multi-targets, and good safety profiles. Psoralen, a furanocoumarin compound extracted from the traditional Chinese medicine psoralea corylifolia, is widely distributed among various plants. It has attracted widespread attention in the research community due to its pharmacological activities, including antitumor, anti-inflammatory, antioxidant, and neuroprotective effects. Studies have shown that psoralen has broad spectrum anti-tumor activities, offering resistance to malignant tumors such as breast cancer, liver cancer, glioma, and osteosarcoma, making it a natural, novel potential antitumor drug. Psoralen mainly exerts its antitumor effects by inhibiting tumor cell proliferation, inducing apoptosis, inhibiting tumor cell migration, and reversing multidrug resistance, presenting a wide application prospect in the field of antitumor therapy. With the deepening research on psoralea corylifolia, its safety has attracted attention, and reports on the hepatotoxicity of psoralen have gradually increased. Therefore, this article reviews recent studies on the mechanism of antitumor effects of psoralen and focuses on the molecular mechanisms of its hepatotoxicity, providing insights for the clinical development of low-toxicity, high-efficiency antitumor drugs and the safety of clinical medication.
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Affiliation(s)
- Dandan Meng
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Yanling Dong
- Department of Breast and Thyroid Surgery, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Qingxin Shang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Ziyuan Sun
- Department of Breast and Thyroid Surgery, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
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Chen L, He L, Liu B, Zhou Y, Lv L, Wang Z. Intelligent structure prediction and visualization analysis of non-coding RNA in osteosarcoma research. Front Oncol 2024; 14:1255061. [PMID: 38532928 PMCID: PMC10964489 DOI: 10.3389/fonc.2024.1255061] [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: 07/11/2023] [Accepted: 02/23/2024] [Indexed: 03/28/2024] Open
Abstract
Background Osteosarcoma (OS) is the most common bone malignant tumor in children and adolescents. Recent research indicates that non-coding RNAs (ncRNAs) have been associated with OS occurrence and development, with significant progress made in this field. However, there is no intelligent structure prediction and literature visualization analysis in this research field. From the perspective of intelligent knowledge structure construction and bibliometrics, this study will comprehensively review the role of countries, institutions, journals, authors, literature citation relationships and subject keywords in the field of ncRNAs in OS. Based on this analysis, we will systematically analyze the characteristics of the knowledge structure of ncRNAs in OS disease research and identify the current research hotspots and trends. Methods The Web of Science Core Collection (WoSCC) database was searched for articles on ncRNAs in OS between 2001 and 2023. This bibliometric analysis was performed using VOSviewers, CiteSpace, and Pajek. Results This study involved 15,631 authors from 2,631 institutions across 57 countries/regions, with a total of 3,642 papers published in 553 academic journals. China has the highest number of published papers in this research field. The main research institutions include Nanjing Medical University (n = 129, 3.54%), Shanghai Jiao Tong University (n = 128, 3.51%), Zhengzhou University (n = 110, 3.02%), and China Medical University (n = 109, 2.99%). Oncology Letters (n =139, 3.82%), European Review for Medical Pharmacological Sciences (120, 3.31%), and Molecular Medicine Reports (n = 95, 2.61%) are the most popular journals in this field, with Oncotarget being the most co-cited journal (Co-Citation = 4,268). Wei Wang, Wei Liu, and Zhenfeng Duan published the most papers, with Wang Y being the most co-cited author. "miRNA", "lncRNA" and "circRNA" are the main focuses of ncRNAs in OS studies. Key themes include "migration and invasion", "apoptosis and proliferation", "prognosis", "biomarkers" and "chemoresistance". Since 2020, hotspots and trends in ncRNA research in OS include "tumor microenvironment", "immune" and "exosome". Conclusion This study represents the first comprehensive bibliometric analysis of the knowledge structure and development of ncRNAs in OS. These findings highlight current research hotspots and frontier directions, offering valuable insights for future studies on the role of ncRNAs in OS.
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Affiliation(s)
- Longhao Chen
- The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
- The Third Clinical Medical College, Zhejiang University of Chinese Medicine, Hangzhou, Zhejiang, China
| | - Liuji He
- Faculty of Orthopedics and Traumatology, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Baijie Liu
- Faculty of Orthopedics and Traumatology, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Yinghua Zhou
- First Affiliated Hospital, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Lijiang Lv
- The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
- The Third Clinical Medical College, Zhejiang University of Chinese Medicine, Hangzhou, Zhejiang, China
| | - Zhiguang Wang
- First Affiliated Hospital, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
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Zhu Y, Liu Z, Cao L, Fan G, Ji R, Zhang L, Daji S, Zhu H, Wang Y, Zhou G. FRS2 regulated by miR-429 and miR-206 promotes angiogenesis in osteosarcoma. Gene 2024; 898:148118. [PMID: 38159618 DOI: 10.1016/j.gene.2023.148118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 12/20/2023] [Accepted: 12/27/2023] [Indexed: 01/03/2024]
Abstract
FRS2 has demonstrated oncogenic roles in various malignancies, including liposarcoma and giant cell tumor of bone. However, its role in osteosarcoma remains less understood, and the upstream regulatory molecules influencing FRS2 remain unclear. This study aims to explore the clinical implications and biological function of FRS2 in osteosarcoma, and the potential regulatory microRNAs (miRNAs) governing its expression. Our study indicated significant upregulation of FRS2 in osteosarcoma cells and tissues by Western blotting and immunohistochemical staining. Elevated FRS2 expression correlated positively with increased angiogenesis and poor prognosis, possibly serving as an independent prognostic indicator for osteosarcoma patients. Functional assays revealed that attenuating FRS2 in osteosarcoma cells could mitigate proliferation, migration, and angiogenesis of vascular endothelial cells. Further investigations revealed that miR-429 and miR-206 directly targeted FRS2, exerting a negative regulation on its expression. Furthermore, FRS2 played a role in repressing osteosarcoma advancement influenced by miR-429 or miR-206. In summary, FRS2, influenced by miR-429 and miR-206, emerges as a promising therapeutic candidate for antiangiogenic osteosarcoma treatments.
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Affiliation(s)
- Yan Zhu
- Jinling Hospital, Department of Orthopaedics, Nanjing University, Nanjing 210002, China; Jinling Hospital, Department of Orthopaedics, Nanjing Medical University, Nanjing 210002, China
| | - Ziying Liu
- Jinling Hospital, Department of Orthopaedics, Nanjing University, Nanjing 210002, China
| | - Lili Cao
- Jinling Hospital, Department of Orthopaedics, Nanjing University, Nanjing 210002, China
| | - Gentao Fan
- Jinling Hospital, Department of Orthopaedics, Nanjing University, Nanjing 210002, China
| | - Ronghao Ji
- Jiangsu Cancer Hospital, Department of Pathology, Nanjing 210002, China
| | - Liming Zhang
- Jinling Hospital, Department of Orthopaedics, Nanjing University, Nanjing 210002, China
| | - Suolang Daji
- Jinling Hospital, Department of Orthopaedics, Nanjing University, Nanjing 210002, China
| | - Hao Zhu
- Jinling Hospital, Department of Orthopaedics, Nanjing University, Nanjing 210002, China
| | - Yicun Wang
- Jinling Hospital, Department of Orthopaedics, Nanjing University, Nanjing 210002, China; Jinling Hospital, Department of Orthopaedics, Nanjing Medical University, Nanjing 210002, China.
| | - Guangxin Zhou
- Jinling Hospital, Department of Orthopaedics, Nanjing University, Nanjing 210002, China; Wuxi Xishan NJU Institue of Applied Biotechnology, Wuxi 214101, China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China.
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Raoufinia R, Afrasiabi P, Dehghanpour A, Memarpour S, Hosseinian SHS, Saburi E, Naghipoor K, Rezaei S, Haghmoradi M, Keyhanvar N, Rostami M, Fakoor F, Kazemi MI, Moghbeli M, Rahimi HR. The Landscape of microRNAs in Bone Tumor: A Comprehensive Review in Recent Studies. Microrna 2024; 13:175-201. [PMID: 39005129 DOI: 10.2174/0122115366298799240625115843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 04/11/2024] [Accepted: 05/23/2024] [Indexed: 07/16/2024]
Abstract
Cancer, the second greatest cause of mortality worldwide, frequently causes bone metastases in patients with advanced-stage carcinomas such as prostate, breast, and lung cancer. The existence of these metastases contributes to the occurrence of skeletal-related events (SREs), which are defined by excessive pain, pathological fractures, hypercalcemia, and spinal cord compression. These injurious incidents leave uncomfortably in each of the cancer patient's life quality. Primary bone cancers, including osteosarcoma (OS), chondrosarcoma (CS), and Ewing's sarcoma (ES), have unclear origins. MicroRNA (miRNA) expression patterns have been changed in primary bone cancers such as OS, CS, and ES, indicating a role in tumor development, invasion, metastasis, and treatment response. These miRNAs are persistent in circulation and exhibit distinct patterns in many forms of bone tumors, making them potential biomarkers for early detection and treatment of such diseases. Given their crucial regulatory functions in various biological processes and conditions, including cancer, this study aims to look at miRNAs' activities and possible contributions to bone malignancies, focusing on OS, CS, and ES. In conclusion, miRNAs are valuable tools for diagnosing, monitoring, and predicting OS, CS, and ES outcomes. Further research is required to fully comprehend the intricate involvement of miRNAs in these bone cancers and to develop effective miRNA-based treatments.
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Affiliation(s)
- Ramin Raoufinia
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Parisa Afrasiabi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amir Dehghanpour
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sara Memarpour
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Ehsan Saburi
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Karim Naghipoor
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Samaneh Rezaei
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meisam Haghmoradi
- Orthopedic Research Center, Shahid Kamyab Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Neda Keyhanvar
- Department of Biochemistry & Biophysics, University of California San Francisco, San Francisco, CA, 94107, USA
| | - Mehdi Rostami
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farhad Fakoor
- Department of Paramedical Sciences, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammadali Izadpanah Kazemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Meysam Moghbeli
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid Reza Rahimi
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Hu J, Yang X, Ren J, Zhong S, Fan Q, Li W. Identification and verification of characteristic differentially expressed ferroptosis-related genes in osteosarcoma using bioinformatics analysis. Toxicol Mech Methods 2023; 33:781-795. [PMID: 37488941 DOI: 10.1080/15376516.2023.2240879] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 07/17/2023] [Accepted: 07/20/2023] [Indexed: 07/26/2023]
Abstract
BACKGROUND This study identified and verified the characteristic differentially expressed ferroptosis-related genes (CDEFRGs) in osteosarcoma (OS). METHODS We extracted ferroptosis-related genes (FRGs), identified differentially expressed FRGs (DEFRGs) in OS, and conducted correlation analysis between DEFRGs. Next, we conducted GO and KEGG analyses to explore the biological functions and pathways of DEFRGs. Furthermore, we used LASSO and SVM-RFE algorithms to screen CDEFRGs, and evaluated its accuracy in diagnosing OS through ROC curves. Then, we demonstrated the molecular function and pathway enrichment of CDEFRGs through GSEA analysis. In addition, we evaluated the differences in immune cell infiltration between OS and NC groups, as well as the correlation between CDEFRGs expressions and immune cell infiltrations. Finally, the expression of CDEFRGs was verified through qRT-PCR, western blotting, and immunohistochemistry experiments. RESULTS We identified 51 DEFRGs and the expression relationship between them. GO and KEGG analysis revealed their key functions and important pathways. Based on four CDEFRGs (PEX3, CPEB1, NOX1, and ALOX5), we built the OS diagnostic model, and verified its accuracy. GSEA analysis further revealed the important functions and pathways of CDEFRGs. In addition, there were differences in immune cell infiltration between OS group and NC group, and CDEFRGs showed significant correlation with certain infiltrating immune cells. Finally, we validated the differential expression levels of four CDEFRGs through external experiments. CONCLUSIONS This study has shed light on the molecular pathological mechanism of OS and has offered novel perspectives for the early diagnosis and immune-targeted therapy of OS patients.
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Affiliation(s)
- Jianhua Hu
- Department of Orthopedic Surgery, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, P. R. China
- Faculty of Medical Science, Kunming University of Science and Technology, Kunming, P. R. China
| | - Xi Yang
- Department of Orthopedic Surgery, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, P. R. China
- Yunnan Key Laboratory of Digital Orthopaedics, Kunming, P. R. China
| | - Jing Ren
- Department of Spinal Surgery, Qujing No. 1 Hospital, Affiliated Qujing Hospital of Kunming Medical University, Qujing, P. R. China
| | - Shixiao Zhong
- Faculty of Medical Science, Kunming University of Science and Technology, Kunming, P. R. China
- Yunnan Key Laboratory of Digital Orthopaedics, Kunming, P. R. China
| | - Qianbo Fan
- Faculty of Medical Science, Kunming University of Science and Technology, Kunming, P. R. China
- Yunnan Key Laboratory of Digital Orthopaedics, Kunming, P. R. China
| | - Weichao Li
- Department of Orthopedic Surgery, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, P. R. China
- Faculty of Medical Science, Kunming University of Science and Technology, Kunming, P. R. China
- Yunnan Key Laboratory of Digital Orthopaedics, Kunming, P. R. China
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Freeman FE, Dosta P, Shanley LC, Ramirez Tamez N, Riojas Javelly CJ, Mahon OR, Kelly DJ, Artzi N. Localized Nanoparticle-Mediated Delivery of miR-29b Normalizes the Dysregulation of Bone Homeostasis Caused by Osteosarcoma whilst Simultaneously Inhibiting Tumor Growth. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2023; 35:e2207877. [PMID: 36994935 DOI: 10.1002/adma.202207877] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 03/06/2023] [Indexed: 06/09/2023]
Abstract
Patients diagnosed with osteosarcoma undergo extensive surgical intervention and chemotherapy resulting in dismal prognosis and compromised quality of life owing to poor bone regeneration, which is further compromised with chemotherapy delivery. This study aims to investigate if localized delivery of miR-29b-which is shown to promote bone formation by inducing osteoblast differentiation and also to suppress prostate and cervical tumor growth-can suppress osteosarcoma tumors whilst simultaneously normalizing the dysregulation of bone homeostasis caused by osteosarcoma. Thus, the therapeutic potential of microRNA (miR)-29b is studied to promote bone remodeling in an orthotopic model of osteosarcoma (rather than in bone defect models using healthy mice), and in the context of chemotherapy, that is clinically relevant. A formulation of miR-29b:nanoparticles are developed that are delivered via a hyaluronic-based hydrogel to enable local and sustained release of the therapy and to study the potential of attenuating tumor growth whilst normalizing bone homeostasis. It is found that when miR-29b is delivered along with systemic chemotherapy, compared to chemotherapy alone, the therapy provided a significant decrease in tumor burden, an increase in mouse survival, and a significant decrease in osteolysis thereby normalizing the dysregulation of bone lysis activity caused by the tumor.
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Affiliation(s)
- Fiona E Freeman
- Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, D02 PN40, Ireland
- Department of Mechanical, Manufacturing, and Biomedical Engineering, School of Engineering, Trinity College Dublin, Dublin, D02 PN40, Ireland
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
- Department of Medicine, Division of Engineering in Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
- Advanced Materials and Bioengineering Research Centre (AMBER), Royal College of Surgeons in Ireland and Trinity College Dublin, Dublin, D02 YN77, Ireland
- School of Mechanical and Materials Engineering, Engineering and Materials Science Centre, University College Dublin, Dublin, D04 V1W8, Ireland
- Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, D04 V1W8, Ireland
| | - Pere Dosta
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
- Department of Medicine, Division of Engineering in Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA
| | - Lianne C Shanley
- Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, D02 PN40, Ireland
- Advanced Materials and Bioengineering Research Centre (AMBER), Royal College of Surgeons in Ireland and Trinity College Dublin, Dublin, D02 YN77, Ireland
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, D02 PN40, Ireland
| | - Natalia Ramirez Tamez
- Department of Medicine, Division of Engineering in Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Cristobal J Riojas Javelly
- Department of Medicine, Division of Engineering in Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Olwyn R Mahon
- Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, D02 PN40, Ireland
- School of Medicine, University of Limerick, Limerick, V94 T9PX, Ireland
| | - Daniel J Kelly
- Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, D02 PN40, Ireland
- Department of Mechanical, Manufacturing, and Biomedical Engineering, School of Engineering, Trinity College Dublin, Dublin, D02 PN40, Ireland
- Advanced Materials and Bioengineering Research Centre (AMBER), Royal College of Surgeons in Ireland and Trinity College Dublin, Dublin, D02 YN77, Ireland
- Department of Anatomy, Royal College of Surgeons in Ireland, Dublin, D02 YN77, Ireland
| | - Natalie Artzi
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
- Department of Medicine, Division of Engineering in Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA
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10
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Chadda KR, Blakey EE, Coleman N, Murray MJ. The clinical utility of dysregulated microRNA expression in paediatric solid tumours. Eur J Cancer 2022; 176:133-154. [PMID: 36215946 DOI: 10.1016/j.ejca.2022.09.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 09/10/2022] [Indexed: 12/15/2022]
Abstract
MicroRNAs (miRNAs) are short, non-protein-coding genes that regulate the expression of numerous protein-coding genes. Their expression is dysregulated in cancer, where they may function as oncogenes or tumour suppressor genes. As miRNAs are highly resistant to degradation, they are ideal biomarker candidates to improve the diagnosis and clinical management of cancer, including prognostication. Furthermore, miRNAs dysregulated in malignancy represent potential therapeutic targets. The use of miRNAs for these purposes is a particularly attractive option to explore for paediatric malignancies, where the mutational burden is typically low, in contrast to cancers affecting adult patients. As childhood cancers are rare, it has taken time to accumulate the necessary body of evidence showing the potential for miRNAs to improve clinical management across this group of tumours. Here, we review the current literature regarding the potential clinical utility of miRNAs in paediatric solid tumours, which is now both timely and justified. Exploring such avenues is warranted to improve the management and outcomes of children affected by cancer.
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Affiliation(s)
- Karan R Chadda
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK
| | - Ellen E Blakey
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK
| | - Nicholas Coleman
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK; Department of Paediatric Histopathology, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ, UK.
| | - Matthew J Murray
- Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK; Department of Paediatric Haematology and Oncology, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ, UK.
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11
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Xu HR, Chen JJ, Shen JM, Ding WH, Chen J. TYRO protein tyrosine kinase-binding protein predicts favorable overall survival in osteosarcoma and correlates with antitumor immunity. Medicine (Baltimore) 2022; 101:e30878. [PMID: 36181123 PMCID: PMC9524921 DOI: 10.1097/md.0000000000030878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
To explore the prognostic significance and underlying mechanism of TYRO protein tyrosine kinase-binding protein (TYROBP) in osteosarcoma. Firstly, the expression of TYROBP was analyzed using the t test. The Kaplan-Meier plotter analysis and a receiver operating characteristic curve were performed to evaluate the influence of TYROBP on overall survival (OS). Further, Cox regression analysis was conducted to predict the independent prognostic factors for OS of osteosarcoma patients, and a nomogram was constructed. Then, the relationship between TYROBP and clinicopathological characteristics was determined using statistical methods. Enrichment analyses were conducted to evaluate the biological functions of TYROBP. Finally, the ESTIMATE algorithm was used to assess the association of TYROBP with immune cell infiltration. TYROBP was significantly increased in osteosarcoma (all P < .001). However, the high expression of TYROBP was related to better OS in osteosarcoma patients. Cox regression analysis showed that TYROBP was an independent prognostic factor for predicting OS (P = .005), especially in patients of the male sex, age <18 years, metastasis, and tumor site leg/foot (all P < .05). Besides, TYROBP mRNA expression was significantly associated with the tumor site (P < .01) but had no remarkable relationship with age, gender, and metastasis status (all P > .05). Functional annotation and gene set enrichment analysis (GSEA) revealed that TYROBP was mainly involved in immune-related pathways. Importantly, TYROBP positively correlated with immune scores (P < .001, R = .87). TYROBP served as an independent prognostic biomarker for OS in osteosarcoma. High TYROBP expression might prolong the survival of osteosarcoma patients mainly through promoting antitumor immunity.
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Affiliation(s)
- Hai-Ru Xu
- Department of Orthopaedic, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jun-Jie Chen
- Department of Orthopaedic, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jin-Ming Shen
- Department of Orthopaedic, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Wei-Hang Ding
- Department of Orthopaedic, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jie Chen
- Department of Orthopaedic, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
- *Correspondence: Jie Chen, Department of Orthopaedic, The First Affiliated Hospital of Zhejiang Chinese Medical University, No. 54 Youdian Road, Shangcheng District, Hangzhou 310002, Zhejiang, China (e-mail: )
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12
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The Role of miR-29 Family in TGF-β Driven Fibrosis in Glaucomatous Optic Neuropathy. Int J Mol Sci 2022; 23:ijms231810216. [PMID: 36142127 PMCID: PMC9499597 DOI: 10.3390/ijms231810216] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 08/30/2022] [Accepted: 09/02/2022] [Indexed: 11/17/2022] Open
Abstract
Primary open angle glaucoma (POAG), a chronic optic neuropathy, remains the leading cause of irreversible blindness worldwide. It is driven in part by the pro-fibrotic cytokine transforming growth factor beta (TGF-β) and leads to extracellular matrix remodelling at the lamina cribrosa of the optic nerve head. Despite an array of medical and surgical treatments targeting the only known modifiable risk factor, raised intraocular pressure, many patients still progress and develop significant visual field loss and eventual blindness. The search for alternative treatment strategies targeting the underlying fibrotic transformation in the optic nerve head and trabecular meshwork in glaucoma is ongoing. MicroRNAs are small non-coding RNAs known to regulate post-transcriptional gene expression. Extensive research has been undertaken to uncover the complex role of miRNAs in gene expression and miRNA dysregulation in fibrotic disease. MiR-29 is a family of miRNAs which are strongly anti-fibrotic in their effects on the TGF-β signalling pathway and the regulation of extracellular matrix production and deposition. In this review, we discuss the anti-fibrotic effects of miR-29 and the role of miR-29 in ocular pathology and in the development of glaucomatous optic neuropathy. A better understanding of the role of miR-29 in POAG may aid in developing diagnostic and therapeutic strategies in glaucoma.
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13
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Li J, Li P, Su H, Feng H, Bai Z, Xi Y. Expression and Significance of Cyclin-Dependent Protein Kinase 6 in Diffuse Large B-Cell Lymphoma. Int J Gen Med 2022; 15:7265-7276. [PMID: 36133914 PMCID: PMC9483138 DOI: 10.2147/ijgm.s380496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 08/22/2022] [Indexed: 11/23/2022] Open
Abstract
Objective To study the relationship between cyclin-dependent protein kinase 6 (CDK6) expression in diffuse large B-cell lymphoma (DLBCL) and the clinical biological behavior and prognosis. Methods Data mining was performed using the Oncomine and The Cancer Genome Atlas (TCGA) databases to analyze the expression level of CDK6 in DLBCL. CDK6 alterations in DLBCL and related functional networks were analyzed with c-BioPortal and the Gene Set Enrichment Analysis was performed by using DAVID and FunRich software. In addition, screening for differential gene expression of CDK6 was done and enriched by using LinkedOmics. Finally, formalin-fixed and paraffin-embedded (FFPE) tissue samples from 102 patients with DLBCL were collected from the Department of Pathology, Shanxi Cancer Hospital (Taiyuan, Shanxi, China) from January 2015 through December 2020. All cases had complete clinical course records. Thirty cases of lymph node reactive hyperplasia tissues were used as controls. The expression of CDK6 in DLBCL tissues was detected by qRT‑PCR and immunohistochemistry. Results Bioinformatics analysis: The data showed that mRNA expression level and DNA copy number variations (CNVs) of CDK6 were significantly higher in DLBCL as compared to normal tissue (P ˂ 0.05). Based on C-BioPortal analysis, we speculated that amplification was the most common copy of CDK6 CNV in DLBCL. Through Gene Ontology (GO) analysis of these genes, it was found that the proteins were mainly located in the nucleus and cytoplasm. The biological interaction network of CDK6 alterations were found to participate primarily in the G1-S phase of the process. Analysis of LinkedOmics mRNA sequencing data showed that three genes were positively correlated with CDK6 expression: PSMD1, C2orf29 and ASB1. Through experimental verification, we found that CDK6 was overexpressed in DLBCL, and the expression of CDK6 mRNA and protein in DLBCL were positively correlated with Ann Arbor staging and IPI score (P<0.05), and negatively correlated with overall survival (P<0.001). Conclusion Data mining results and experiments revealed and confirmed multi-level evidence for the importance of CDK6 in DLBCL; hence, CDK6 may be a potential marker in DLBCL. Thus, our study will perhaps lay the foundation for further research on the role of CDK6 in the genesis and development of DLBCL.
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Affiliation(s)
- Jing Li
- Department of Pathology, Cancer Hospital Affiliated to Shanxi Medical University, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, Shanxi, 030013, People’s Republic of China
| | - Peng Li
- Department of Breast Surgery, Cancer Hospital Affiliated to Shanxi Medical University, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, Shanxi, 030013, People’s Republic of China
| | - Hong Su
- Department of Pathology, Cancer Hospital Affiliated to Shanxi Medical University, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, Shanxi, 030013, People’s Republic of China
| | - Haonan Feng
- Department of Pathology, Chengdu Second People’s Hospital, Chengdu, Sichuan, 610000, People’s Republic of China
| | - Zhongyuan Bai
- Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, 030001, People’s Republic of China
| | - Yanfeng Xi
- Department of Pathology, Cancer Hospital Affiliated to Shanxi Medical University, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, Shanxi, 030013, People’s Republic of China
- Correspondence: Yanfeng Xi, Department of Pathology, Cancer Hospital Affiliated to Shanxi Medical University, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, 3 Workers’ New Village Street, Xing Hua Ling, Taiyuan, Shanxi, 030013, People’s Republic of China, Email
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14
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Motahari Rad H, Mowla SJ, Ramazanali F, Rezazadeh Valojerdi M. Characterization of altered microRNAs related to different phenotypes of polycystic ovarian syndrome (PCOS) in serum, follicular fluid, and cumulus cells. Taiwan J Obstet Gynecol 2022; 61:768-779. [PMID: 36088043 DOI: 10.1016/j.tjog.2022.05.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/16/2022] [Indexed: 10/14/2022] Open
Abstract
OBJECTIVE Polycystic ovarian syndrome (PCOS) is a metabolic syndrome in which steroidogenesis, folliculogenesis, and cellular adhesion play crucial roles in its prognosis. These pathways are controlled and regulated by some small non-coding RNAs called microRNAs (miRs). Several miRs have differential expression in PCOS compared to healthy women, and their dysregulation suggests important roles of miRs in PCOS pathophysiology. However, the role of miRs is still unclear, especially in various phenotypes of PCOS. MATERIALS AND METHODS This study was conducted to evaluate the diagnostic potential of miR-212-3p, miR-490-5p, miR-647, and miR-4643 in different subtypes of PCOS. Accordingly, nineteen PCOS patients with different subtypes based on Rotterdam criteria (A: 8, B: not detected in this study, C: 5, and D: 6 patients) and six control age and BMI matched women under ICSI treatment were selected. The relative expression of miRs was then measured in blood serum before hormonal treatment (S1) and before ovum pickup (S2), follicular fluid (FF), and cumulus cells (CC) in all subjects. Also, the expression of miRs predicted target genes (AMH, AR, CYP11A1, CYP17A1, CYP19A1, GDF9, and HSD17B12) were done in the CC of understudy groups. RESULTS In general, the results indicated that PCOS significantly increased the expression of miR-212-3p, miR-490-5p, and miR-4643 in FF and CCs compared to control. Although these miRs tend to increase in serum 1 of the PCOS patients, the differences were insignificant. However, there was a significant reduction in the expression of miR-647 in FF and CCs between PCOS vs. control. In addition, the miRs had significantly different expressions in various phenotypes of PCOS. For example, high levels of miR-647 in S2 and low levels of miR-490 in FF and miR-212 in CC can differentiate phenotype A from the other. Also, upregulation of miR-212 in FF and miR-4643 in S1 and low levels of this miR in FF can specifically differentiate subtype A from D. On the other hand, high levels of miR-4643 in FF and miR-490 in CC and lower titter of miR-647 can distinguish subtype C from the other. On the other hand, high levels of AMH, AR, CYP11, CYP17, and HSD17 in the hyperandrogenic PCOS and upregulation of CYP19A1 in the hypoandrogenic group can validate the role of selected miRs in the prognosis of PCOS. CONCLUSION Characterization of altered microRNAs in serum, FF, and CCs and their targets in CC showed that the miRs might play critical roles in steroidogenesis and folliculogenesis. These miRs may be used for molecular classification of PCOS subtypes and as biomarkers for PCOS diagnosis.
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Affiliation(s)
- Hanieh Motahari Rad
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Seyed Javad Mowla
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Fariba Ramazanali
- Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Mojtaba Rezazadeh Valojerdi
- Department of Anatomy, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran; Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.
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15
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Nguyen TTP, Suman KH, Nguyen TB, Nguyen HT, Do DN. The Role of miR-29s in Human Cancers—An Update. Biomedicines 2022; 10:biomedicines10092121. [PMID: 36140219 PMCID: PMC9495592 DOI: 10.3390/biomedicines10092121] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 08/22/2022] [Accepted: 08/24/2022] [Indexed: 11/25/2022] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that directly bind to the 3’ untranslated region (3’-UTR) of the target mRNAs to inhibit their expression. The miRNA-29s (miR-29s) are suggested to be either tumor suppressors or oncogenic miRNAs that are strongly dysregulated in various types of cancer. Their dysregulation alters the expression of their target genes, thereby exerting influence on different cellular pathways including cell proliferation, apoptosis, migration, and invasion, thereby contributing to carcinogenesis. In the present review, we aimed to provide an overview of the current knowledge on the miR-29s biological network and its functions in cancer, as well as its current and potential applications as a diagnostic and prognostic biomarker and/or a therapeutic target in major types of human cancer.
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Affiliation(s)
- Thuy T. P. Nguyen
- Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Kamrul Hassan Suman
- Department of Fisheries, Ministry of Fisheries and Livestock, Dhaka 1205, Bangladesh
| | - Thong Ba Nguyen
- Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96813, USA
| | - Ha Thi Nguyen
- Institute of Research and Development, Duy Tan University, Danang 550000, Vietnam
- Center for Molecular Biology, College of Medicine and Pharmacy, Duy Tan University, Danang 550000, Vietnam
- Correspondence: (H.T.N.); (D.N.D.)
| | - Duy Ngoc Do
- Department of Animal Science and Aquaculture, Dalhousie University, Truro, NS B2N 5E3, Canada
- Correspondence: (H.T.N.); (D.N.D.)
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16
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Cheng X, Chen Q, Sun P. Natural phytochemicals that affect autophagy in the treatment of oral diseases and infections: A review. Front Pharmacol 2022; 13:970596. [PMID: 36091810 PMCID: PMC9461701 DOI: 10.3389/fphar.2022.970596] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 08/03/2022] [Indexed: 01/01/2023] Open
Abstract
Autophagy is a critical factor in eukaryotic evolution. Cells provide nutrition and energy during autophagy by destroying non-essential components, thereby allowing intracellular material conversion and managing temporary survival stress. Autophagy is linked to a variety of oral disorders, including the type and extent of oral malignancies. Furthermore, autophagy is important in lymphocyte formation, innate immunity, and the regulation of acquired immune responses. It is also required for immunological responses in the oral cavity. Knowledge of autophagy has aided in the identification and treatment of common oral disorders, most notably cancers. The involvement of autophagy in the oral immune system may offer a new understanding of the immune mechanism and provide a novel approach to eliminating harmful bacteria in the body. This review focuses on autophagy creation, innate and acquired immunological responses to autophagy, and the status of autophagy in microbial infection research. Recent developments in the regulatory mechanisms of autophagy and therapeutic applications in oral illnesses, particularly oral cancers, are also discussed. Finally, the relationship between various natural substances that may be used as medications and autophagy is investigated.
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Affiliation(s)
| | | | - Ping Sun
- *Correspondence: Ping Sun, ; Qianming Chen,
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17
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Tan JD, Zhou MF, Yang S, Lin JP. Long noncoding RNA HCP5 promotes osteosarcoma cell proliferation, invasion, and migration via the miR-29b-3p-LOXL2 axis. Kaohsiung J Med Sci 2022; 38:960-970. [PMID: 35899856 DOI: 10.1002/kjm2.12577] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 06/20/2022] [Accepted: 06/23/2022] [Indexed: 11/11/2022] Open
Abstract
Osteosarcoma (OS) is the second most common primary malignant bone tumors in adolescents that causes cancer-related deaths. Previous studies have confirmed the promoting role of lncRNA HCP5 in the development of OS, but the specific mechanism is still not well understood. MiRNA levels were measured via RT-qPCR and protein expression was detected via western blotting. Cell proliferation was analyzed by CCK-8 assays and colony formations assay were conducted to measure colony formation ability. Dual-luciferase reporter assay was performed to detect the targeting relationship between HCP5 and miR-29b-3p, and between miR-29b-3p and LOXL2. Wound healing assays and Transwell assays were conducted to verify the migration and invasion abilities of OS cells. Correlations between the levels of HCP5 and miR-29b-3p, and between miR-29b-3p and LOXL2 were determined by Pearson correlation coefficient analysis. MiR-29b-3p expression was decreased and HCP5 and LOXL2 levels were increased in OS tissues and cell lines. MiR-29b-3p could directly act on LOXL2 and knockdown of LOXL2 restrained the proliferation, migration, and invasion of OS cells. Moreover, transfection with sh-HCP5-1 and sh-HCP5-2 suppressed the malignant biological behavior of OS cells. HCP5 directly targeted miR-29b-3p, and promoted OS proliferation, migration, and invasion via the miR-29b-3p/LOXL2 axis. The lncRNA HCP5 may upregulate LOXL2 expression by targeting miR-29b-3p, thereby promoting OS proliferation, migration, and invasion.
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Affiliation(s)
- Jin-Dian Tan
- Department of Orthopaedic Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, Hainan Province, China
| | - Mei-Feng Zhou
- Department of Oncology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, Hainan Province, China
| | - Song Yang
- Department of Orthopaedic Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, Hainan Province, China
| | - Jian-Ping Lin
- Department of Orthopaedic Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, Hainan Province, China
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18
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Liu J, Shang G. The Roles of Noncoding RNAs in the Development of Osteosarcoma Stem Cells and Potential Therapeutic Targets. Front Cell Dev Biol 2022; 10:773038. [PMID: 35252166 PMCID: PMC8888953 DOI: 10.3389/fcell.2022.773038] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 01/31/2022] [Indexed: 12/11/2022] Open
Abstract
Osteosarcoma (OS) is the common bone tumor in children and adolescents. Because of chemotherapy resistance, the OS patients have a poor prognosis. The one reason of chemotherapeutic resistance is the development of cancer stem cells (CSCs). CSCs represent a small portion of tumor cells with the capacity of self-renewal and multipotency, which are associated with tumor initiation, metastasis, recurrence and drug resistance. Recently, noncoding RNAs (ncRNAs) have been reported to critically regulate CSCs. Therefore, in this review article, we described the role of ncRNAs, especially miRNAs, lncRNAs and circRNAs, in regulating CSCs development and potential mechanisms. Specifically, we discussed the role of multiple miRNAs in targeting CSCs, including miR-26a, miR-29b, miR-34a, miR-133a, miR-143, miR-335, miR-382, miR-499a, miR-1247, and let-7days. Moreover, we highlighted the functions of lncRNAs in regulating CSCs in OS, such as B4GALT1-AS1, DANCR, DLX6-AS1, FER1L4, HIF2PUT, LINK-A, MALAT1, SOX2-OT, and THOR. Due to the critical roles of ncRNAs in regulation of OS CSCs, targeting ncRNAs might be a novel strategy for eliminating CSCs for OS therapy.
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Affiliation(s)
- Jinxin Liu
- Department of Orthopedic Surgery, Shengjing Hospital, China Medical University, Shenyang, China
| | - Guanning Shang
- Department of Orthopedic Surgery, Shengjing Hospital, China Medical University, Shenyang, China
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19
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Liu Y, Tang W, Ren L, Liu T, Yang M, Wei Y, Chen Y, Ji M, Chen G, Chang W, Xu J. Activation of miR-500a-3p/CDK6 axis suppresses aerobic glycolysis and colorectal cancer progression. J Transl Med 2022; 20:106. [PMID: 35241106 PMCID: PMC8896266 DOI: 10.1186/s12967-022-03308-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 02/14/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the lethal cancers with a high mortality rate worldwide and understanding the mechanisms behind its progression is critical for improving patients' prognosis and developing therapeutics. MiR-500a-3p has been demonstrated to be involved in the progression of several human cancers but its role in CRC remains unclear. The aim of this study is to uncover the expression pattern and mechanisms of action of miR-500a-3p during the CRC progression. METHODS The expression of miR-500a-3p and Cyclin-dependent kinases 6 (CDK6) in 134 CRC tissues were tested by quantitative PCR (qPCR) and immunohistochemistry staining (IHC), respectively. The effect of miR-500a-3p on cell proliferation was explored in vitro and in vivo. The glycolysis of CRC cells was determined by Mass Spectrometry and Seahorse XF 96 Extracellular Flux Analyzer. A dual-luciferase reporter assay was performed to validate the relationship between miR-500a-3p and CDK6. RESULTS miR-500a-3p was abnormally downregulated in CRC tissues and cell lines and was negatively associated with a worse prognosis. miR-500a-3p mimics impeded CRC cell proliferation in vitro and in vivo. miR-500a-3p inhibited glucose consumption, lactate and ATP production, and down-regulated the expression of hexokinase2 (HK2). In silico prediction combined with western blot and luciferase assay confirmed that CDK6 is a direct target of miR-500a-3p. Overexpression of CDK6 phenotypically rescued the inhibitory effect of miR-500a-3p on the proliferation and glycolysis of CRC cells. CONCLUSIONS Our study revealed a potential tumor-suppressive role of miR-500a-3p in CRC, specifically targeting CDK6 and inhibiting cancer cell proliferation and aerobic glycolysis, which may provide new insights into novel prognostic biomarkers and therapeutic targets for CRC.
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Affiliation(s)
- Yu Liu
- Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wentao Tang
- Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, China
| | - Li Ren
- Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, China
| | - Tianyu Liu
- Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Meng Yang
- National Clinical Research Center for Cancer, Tianjin Cancer Institute, Tianjin, China
| | - Ye Wei
- Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, China
| | - Yijiao Chen
- Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Meiling Ji
- Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.,Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, China
| | - Guosong Chen
- The State Key Laboratory of Molecular Engineering of Polymers and Department of Macromolecular Science, Shanghai, China
| | - Wenju Chang
- Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China. .,Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. .,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, China.
| | - Jianmin Xu
- Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China. .,Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. .,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, China.
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20
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Horita M, Hsu SN, Raper A, Farquharson C, Stephen LA. miR-29b inhibits TGF-β1-induced cell proliferation in articular chondrocytes. Biochem Biophys Rep 2022; 29:101216. [PMID: 35128082 PMCID: PMC8800026 DOI: 10.1016/j.bbrep.2022.101216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/12/2022] [Accepted: 01/20/2022] [Indexed: 10/25/2022] Open
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21
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Gao SS, Zhang GX, Zhang WT. MicroRNAs as prognostic biomarkers for survival outcome in osteosarcoma: A meta-analysis. World J Meta-Anal 2021; 9:568-584. [DOI: 10.13105/wjma.v9.i6.568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 10/08/2021] [Accepted: 12/24/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Osteosarcoma was considered to be one of the most prevalent malignant bone tumors in adolescents.
AIM To explore the prognostic significance of microRNA (miRNA) in osteosarcoma.
METHODS The literature was selected by searching online in PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, and Wanfang Database until July 1, 2021. The pooled hazard ratio (HR) with corresponding 95% confidence interval (CI) for the outcomes of overall survival (OS), disease-free survival (DFS), progression-free survival (PFS) and recurrence-free survival were calculated. Subgroup analyses were carried out to identify potential sources of heterogeneity. Publication bias was assessed by Egger’s bias indicator test.
RESULTS A total of 60 studies from 54 articles with 5824 osteosarcoma patients were included for this meta-analysis. The pooled HR for OS, DFS, PFS were 2.92 (95%CI: 2.43-3.41, P = 0.000), 3.70 (95%CI: 2.80-4.61, P = 0.000), and 3.57 (95%CI: 1.60-5.54, P = 0.000), respectively. The high miR-21 expression levels were related to poor OS in osteosarcoma (HR = 2.86, 95%CI: 1.20-4.53, P = 0.001). Subgroup analysis demonstrated that a high expression level of miRNA correlated with worse OS (HR: 3.56, 95%CI: 2.59-4.54, P = 0.000). In addition, miRNA from tissue (HR: 3.20, 95%CI: 2.16-4.23, P = 0.000) may be a stronger prognostic biomarker in comparison with that from serum and plasma.
CONCLUSION miRNA (especially miR-21) could be served as a potential prognostic biomarker for osteosarcoma. A high expression level of miRNA in tumor tissue correlated with worse OS of osteosarcoma.
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Affiliation(s)
- Shuai-Shuai Gao
- International Doctoral School, University of Seville, Seville 41004, Spain
- Department of Traumatology and Orthopedic Surgery, Xi'an Daxing Hospital, Xi'an 710016, Shaanxi Province, China
| | - Guo-Xun Zhang
- International Doctoral School, University of Seville, Seville 41004, Spain
| | - Wen-Ting Zhang
- International Doctoral School, University of Seville, Seville 41004, Spain
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Cao Q, Li Y, Li Y, Li L. miR-151-5p alleviates corneal allograft rejection by activating PI3K/AKT signaling pathway and balancing Th17/Treg after corneal transplantation via targeting IL-2Rɑ. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1410. [PMID: 34733962 PMCID: PMC8506781 DOI: 10.21037/atm-21-2054] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 08/26/2021] [Indexed: 12/29/2022]
Abstract
Background Worldwide, corneal transplantation (CT) is the most common type of tissue replacement and the increased rate of corneal graft rejection (CGR) after CT is a critical problem. Corneal endothelium cells (CECs) are often targets of the immune response mediated by graft-attacking effector T cells. However, the molecular mechanism underlying CGR remains poorly understood. Methods The differentially expressed microRNAs (miRNAs) and mRNA of graft-fail corneas were measured by transcriptome sequencing (RNA-Seq). real-time quantitative polymerase chain reaction was used to measure gene expression levels. Western blot and immunofluorescence staining were used to measure protein expression levels. Kaplan-Meier survival curves were constructed to assess corneal graft survival. Hematoxylin and eosin staining was used for histopathological examination. CCK-8 and ELISA staining were used to detect cell viability and inflammatory cytokines levels, respectively. Flow cytometry was used to detect cell apoptosis and the population of Treg and Th17. Transwell migration and wound-healing assays were used to measure cell migration. Results We identified 453 miRNAs and 4,279 mRNAs aberrant expression in the corneas showing CGR. The differentially expressed miR-151-5p and its potential target gene [interleukin 2 receptor subunit alpha (IL-2Rɑ)] were selected from the RNA-Seq microarrays. The levels of miR-151-5p and IL-2Rɑ were respectively downregulated and upregulated in the CGR. The luciferase activity assay suggested that IL-2Rɑ is a target of miR-151-5p in 293 T cells. In addition, the miR-151-5p inhibitor, si-IL-2Rɑ, and oe-IL-2Rɑ transfection tests in CECs further confirmed that miR-151-5p downregulation and IL-2Rɑ overexpression promoted apoptosis of CECs and inhibited CEC migration, tight junction-related protein ZO-1 and Claudin-5 expression, and PI3K/AKT signaling pathway activity; however, downregulation of IL-2Rɑ abolished the inhibitor effect of miR-151-5p. Similarly, upregulation of miR-151-5p alleviated CGR via activation of the PI3K/AKT signaling pathway and balancing of Th17/Treg, and upregulation of IL-2Rɑ abolished the alleviating effect of miR-151-5p. Conclusions Upregulation of miR-151-5p alleviated CGR by activating the PI3K/AKT signaling pathway and balancing Th17/Treg via targeting of IL-2Rɑ, which contributes to improving the results of CT.
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Affiliation(s)
- Qian Cao
- Department of Ophthalmology, The Affiliated Calmette Hospital of Kunming Medical University, Kunming, China
| | - Yunchuan Li
- Department of Ophthalmology, The Affiliated Calmette Hospital of Kunming Medical University, Kunming, China
| | - Yong Li
- Department of Ophthalmology, The Affiliated Calmette Hospital of Kunming Medical University, Kunming, China
| | - Lan Li
- Department of Ophthalmology, The Affiliated Calmette Hospital of Kunming Medical University, Kunming, China
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MiR-29b-1-5p regulates the proliferation and differentiation of chicken primary myoblasts and analysis of its effective targets. Poult Sci 2021; 101:101557. [PMID: 34852967 PMCID: PMC8639469 DOI: 10.1016/j.psj.2021.101557] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/05/2021] [Accepted: 10/14/2021] [Indexed: 12/19/2022] Open
Abstract
Several recent studies investigated the role of the miR-29 family in muscle development. However, only a few studies focused on chicken skeletal muscle. In the present study, cell cycle, 5-ethynyl-2'-deoxyuridine (EdU), cell counting kit-8 (CCK-8), and other assays indicated that miR-29b-1-5p can inhibit the proliferation of chicken primary myoblasts (CPMs); the western blot assay and immunofluorescence detection of MYHC demonstrated that miR-29b-1-5p can promote the differentiation of myoblasts. The functional enrichment analysis revealed that the target genes of miR-29b-1-5p may be involved in muscle tissue development, muscle organ development, and striated muscle tissue development, which are biological processes related to muscle development. The correlation analysis showed that these 6 genes, that is, ankyrin repeat domain 9 (ANKRD9), lactate dehydrogenase A (LDHA), transcription factor 12 (TCF12), FAT atypical cadherin 1 (FAT1), lin-9 homolog (LIN9), and integrin beta 3 binding protein (ITGB3BP), can be used as effective candidate target genes of miR-29b-1-5p. Moreover, miR-29b-1-5p inhibits the expression of ANKRD9 by directly binding the 3'UTR of ANKRD9. Overall, these data indicate that miR-29b-1-5p inhibits the proliferation of primary chicken myoblasts, stimulates their differentiation, and is involved in the process of muscle development and that its effective target gene is ANKRD9. This study identified the molecular mechanism of miR-29b-1-5p in chicken muscle development.
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Zhang X, Zhu H, Qu X, Yu Z, Zhang J. Suppressing LncRNA HOXA-AS3 by CRISPR-dCas9 inhibits pancreatic cancer development. J Cancer 2021; 12:6439-6444. [PMID: 34659534 PMCID: PMC8489150 DOI: 10.7150/jca.62631] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 08/18/2021] [Indexed: 12/24/2022] Open
Abstract
The lncRNA HOXA-AS3 has been reported as a potential oncogene in tumors. Nevertheless, the molecular mechanism of HOXA-AS3 in pancreatic cancer (PC) progression remains unknown. We performed quantitative real-time (qRT) PCR assay to detect the expression levels of HOXA-AS3, miR-29c in PC specimens. Then, we transfected sgRNA-HOXA-AS3, miR-29c mimics, miR-29c inhibitors, or vector-CDK6 plasmids into PC cell lines to regulate the expression levels of HOXA-AS3, miR-29c or CDK6. Luciferase reporter assay was performed to identify the correlations among miR-29c, HOXA-AS3 and 3' UTR of CDK6.The ability of cell proliferation was assessed by cell counting and subcutaneous tumor growth assay. HOXA-AS3 level was upregulated in PC, and its knockdown suppressed PC cells proliferation, whereas miR-29c antagonized the regulatory effect of HOXA-AS3 knockdown by directly binding to HOXA-AS3.Moreover, CDK6 was a target of miR-29c and miR-29c exerted anti-proliferation effects through inhibiting CDK6. HOXA-AS3 could accelerate the growth of PC cells partially by regulating the miR-29c/CDK6 axis, which could be used as a potential therapeutic target in CRISPR-mediated PC treatment.
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Affiliation(s)
- Xiaoli Zhang
- The First Affiliated Hospital, Department of Pathology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Hongbo Zhu
- The First Affiliated Hospital, Department of Pathology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Xiaoguang Qu
- The First Affiliated Hospital, Department of Pathology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Ziying Yu
- The First Affiliated Hospital, Department of Pathology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Jing Zhang
- The First Affiliated Hospital, Department of Pathology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
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Li C, Qin Y, Ouyang T, Yao M, Zhang A, Luo P, Pan X. miR-122-5p Mediates Fluoride-Induced Osteoblast Activation by Targeting CDK4. Biol Trace Elem Res 2021; 199:1215-1227. [PMID: 32572801 DOI: 10.1007/s12011-020-02239-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 06/08/2020] [Indexed: 02/07/2023]
Abstract
Chronic intake of fluoride, existing in the environment, may cause endemic fluorosis, which is characterized by the occurrence of skeletal and dental fluorosis. However, the pathogenesis of fluorosis has not yet been elucidated. Abnormal osteoblast proliferation and activation have a pivotal role in bone turnover disorders which are linked to skeletal fluorosis. MicroRNAs are involved in fundamental cellular processes, including cell proliferation. Based on our previous study, population study and in vitro experiments were designed to understand the effect of miR-122-5p on osteoblast activation in skeletal fluorosis through targeting cyclin-dependent kinase 4 (CDK4). In human populations with coal-burning type fluoride exposure, the results showed that miR-122-5p was downregulated but CDK4 expression was upregulated and miR-122-5p was negatively correlated with CDK4 expression. Furthermore, in human osteoblasts treated with sodium fluoride, we demonstrated that miR-122-5p mediated osteoblast activation of skeletal fluorosis via upregulation of the CDK4 protein. In support of this, dual-luciferase reporter assay showed that miR-122-5p modulated CDK4 protein levels by targeting its 3'-untranslated region. These findings show, for the first time, that miR-122-5p may be involved in the cause and development of skeletal fluorosis by targeting CDK4.
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Affiliation(s)
- Chen Li
- School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, 550025, China
| | - Yu Qin
- Guizhou Orthopedics Hospital, Guiyang, 550007, China
| | - Ting Ouyang
- School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, 550025, China
| | - Maolin Yao
- School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, 550025, China
| | - Aihua Zhang
- School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, 550025, China
| | - Peng Luo
- School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, 550025, China
| | - Xueli Pan
- School of Public Health, the key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, 550025, China.
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Stem cell-derived exosomes repair ischemic muscle injury by inhibiting the tumor suppressor Rb1-mediated NLRP3 inflammasome pathway. Signal Transduct Target Ther 2021; 6:121. [PMID: 33727530 PMCID: PMC7966359 DOI: 10.1038/s41392-021-00520-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 01/18/2021] [Accepted: 01/20/2021] [Indexed: 02/03/2023] Open
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CEA, CA 15-3, and miRNA expression as potential biomarkers in canine mammary tumors. Chromosome Res 2021; 29:175-188. [PMID: 33638118 DOI: 10.1007/s10577-021-09652-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 01/26/2021] [Accepted: 02/02/2021] [Indexed: 10/22/2022]
Abstract
The most often detected tumor in intact bitches is mammary tumors and represents a significant clinical problem throughout the world. Mammary neoplasms in canine have heterogeneous morphology, so the choice of the most appropriate biomarker is the biggest challenge in CMT detection. We performed a retrospective analysis and evaluated the canine cancer antigens and miRNA expression profiles as potential biomarkers. Sixty dogs based on histological examination divided into three groups, viz., dogs with a benign mammary tumor, malignant mammary tumor, and control/healthy. The CA 15-3 was found more sensitive than CEA but detection of both will increase sensitivity. miR-21 expression differed significantly in all three groups. miR-29b expression differed significantly between the control and benign group and control and malignant group. The miR-21 overexpression and miR-29b downregulation with CMT are associated with clinical stage and can be used as non-invasive diagnostic and prognostic biomarkers. Hence, evaluation of CA 15-3 along with CEA would be a non-invasive technique for detecting canine mammary tumors. Evaluation of deregulated circulating miR-21 could be a valuable prognostic marker for early detection of mammary tumors in canines while miR-29b can add sensitivity in the detection of the canine mammary tumors if evaluated with miR-21.
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Yang GJ, Wang W, Lei PM, Leung CH, Ma DL. A 7-methoxybicoumarin derivative selectively inhibits BRD4 BD2 for anti-melanoma therapy. Int J Biol Macromol 2020; 164:3204-3220. [DOI: 10.1016/j.ijbiomac.2020.08.194] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 08/18/2020] [Accepted: 08/24/2020] [Indexed: 01/07/2023]
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Chen S, Yang M, Chang S. LncRNA CCAL Promotes Angiogenesis Through Regulating the MiR-29b/ANGPTL4 Axis in Osteosarcoma. Cancer Manag Res 2020; 12:10521-10530. [PMID: 33122950 PMCID: PMC7591080 DOI: 10.2147/cmar.s272230] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 09/14/2020] [Indexed: 12/29/2022] Open
Abstract
Purpose The objective of this study was to detect the expression of the long noncoding RNA (lncRNA) colorectal cancer-associated lncRNA (CCAL) in osteosarcoma tissues and to investigate its role in angiogenesis and the potential molecular mechanisms associated with this effect in osteosarcoma. Materials and Methods CCAL expression in 40 osteosarcoma tissues and 40 noncancerous tissues was measured by qRT-PCR (quantitative real-time polymerase chain reaction). Tube formation assays were performed to explore the role of CCAL in angiogenesis in osteosarcoma. In addition, the regulatory interaction between CCAL, miR-29b, and ANGPTL4 was investigated via luciferase reporter assay and bioinformatics predictive analysis. Results Compared with noncancerous tissues, the expression of CCAL was markedly upregulated in osteosarcoma tissues. Higher CCAL expression levels were closely related to shorter overall survival in patients with osteosarcoma. Additionally, functional analysis indicated that CCAL could facilitate tumour angiogenesis in vitro and in vivo in osteosarcoma. Mechanistically, CCAL upregulated ANGPTL4 expression in osteosarcoma cells, and ANGPTL4 mediated angiogenic induction by CCAL in osteosarcoma. Moreover, CCAL directly targeted miR-29b in osteosarcoma. More importantly, we demonstrated that CCAL upregulated the expression of ANGPTL4 by sponging miR-29b, which promoted angiogenesis in osteosarcoma. Conclusion Our results show that CCAL promotes angiogenesis by regulating the miR-29b/ANGPTL4 axis in osteosarcoma.
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Affiliation(s)
- Shiyi Chen
- Department of Orthopaedic Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, People's Republic of China
| | - Mingjia Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Southeast University, Nanjing, Jiangsu Province 210096, People's Republic of China
| | - Shimin Chang
- Department of Orthopaedic Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, People's Republic of China
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Chen H, Yu C, Shen L, Wu Y, Wu D, Wang Z, Song G, Chen L, Hong Y. NFIB functions as an oncogene in estrogen receptor-positive breast cancer and is regulated by miR-205-5p. Pathol Res Pract 2020; 216:153236. [PMID: 33038688 DOI: 10.1016/j.prp.2020.153236] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 09/27/2020] [Accepted: 09/29/2020] [Indexed: 12/15/2022]
Abstract
Nuclear factor I/B(NFIB) is a prominent transcription factor that plays a critical role in cancer progression. In this study, we found that the protein level of NFIB was significantly upregulated in estrogen receptor (ER) positive breast cancer tissues compared to matched adjacent noncancerous tissues while the NFIB mRNA expression level was not obviously dysregulated. Similarly, ER-positive breast cancer cell line, MCF7 express a high protein level of NFIB, while the mRNA level is not significantly upregulated. The function assays indicated that NFIB promoted MCF-7 cell cycle progression, cell proliferation and suppressed apoptosis in vitro. Furthermore, we explored the molecular mechanisms of NFIB as a target gene of miR-205-5p. Finally, we found that miR-205-5p was significantly downregulated in ER -positive breast cancer, and had the opposite eff ;ects on breast cancer cells compared with NFIB. Taken together, this study highlighted the molecular mechanisms of NFIB as an oncogene in ER-positive breast cancer, which was negatively regulated by miR-205-5p in breast cancer.
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Affiliation(s)
- Hanxiao Chen
- College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Chong Yu
- Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
| | - Lu Shen
- College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Yanqian Wu
- College of Laboratory Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, 310053, China
| | - Deqi Wu
- Department of Gastrointestinal Thyroid and Breast, Shulan (Hangzhou) Hospital, Hangzhou, Zhejiang, 310000, China
| | - Zhen Wang
- Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
| | - Guangzhong Song
- College of Laboratory Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, 310053, China
| | - Linjie Chen
- College of Laboratory Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, 310053, China
| | - Yeting Hong
- College of Laboratory Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, 310053, China.
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Sun D, Zhu D. Circular RNA hsa_circ_0001649 suppresses the growth of osteosarcoma cells via sponging multiple miRNAs. Cell Cycle 2020; 19:2631-2643. [PMID: 32954926 DOI: 10.1080/15384101.2020.1814026] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Osteosarcoma (OS) is a serious bone malignancy commonly occurred in childhood and adolescence. Circular RNA (circRNA) is a novel endogenous RNA that may be considered as a new biomarker for diseases' diagnosis or prognosis. This study explored the roles and mechanism of circ_0001649 in OS. The qRT-PCR was performed to test circ_0001649 expression in OS tissues and cells. Luciferase was used to confirm the binding of circ_0001649 with miR-338-5p, miR-647 and miR-942. OS cells were stably transfected with pEX-circ_0001649 or miRNAs mimic, CCK-8 kit, colony formation, apoptosis and western blot analysis were used to detect the roles of circ_0001649. Circ_0001649 was low-expressed in OS tissues and cell lines. Circ_0001649 overexpression suppressed U2OS and HOS cell viability and survival fraction, and induced apoptosis presented as the increasing levels of Apaf-1, cleaved-caspase-3 and cleaved-caspase-9. Further, circ_0001649 worked as a sponge to absorb miR-338-5p, miR-647 and miR-942 to suppress cell proliferation, induce apoptosis and inhibit STAT pathway. Circ_0001649 suppressed OS cell proliferation and STAT pathway and induced apoptosis through sponging miR-338-5p, miR-647 and miR-942.
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Affiliation(s)
- Deping Sun
- Department of Orthopedic Trauma, Yantai Affiliated Hospital of Binzhou Medical University , Yantai 264000, Shandong, China
| | - Dongsheng Zhu
- Department of Orthopedic Trauma, Yantai Affiliated Hospital of Binzhou Medical University , Yantai 264000, Shandong, China
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Zhang L, Zhao G, Ji S, Yuan Q, Zhou H. Downregulated Long Non-Coding RNA MSC-AS1 Inhibits Osteosarcoma Progression and Increases Sensitivity to Cisplatin by Binding to MicroRNA-142. Med Sci Monit 2020; 26:e921594. [PMID: 32155139 PMCID: PMC7081928 DOI: 10.12659/msm.921594] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background Osteosarcoma (OS) is the most prevalent malignant primary bone tumor, resulting from severe transformation of primitive mesenchymal cells, which induces osteogenesis. Long non-coding RNA (lncRNA) MSC-AS1 triggers osteogenic differentiation by sponging microRNA (miR)-140-5p. The present study assessed the mechanism of lncRNA MSC-AS1 in OS biological features and sensitivity to cisplatin (DDP) by binding to miR-142. Material/Methods Firstly, lncRNA MSC-AS1 expression in OS tissues and cells was analyzed. OS cells were transfected with silenced MSC-AS1 to determine its role in OS biological behaviors, and we also assessed the effect of MSC-AS1 on OS sensitivity to DDP. Then, website prediction and dual-luciferase reporter gene assay were utilized for verification of the binding site between MSC-AS1 and miR-142. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis were performed to determine the effect of MSC-AS1 on expression of miR-142, cyclin-dependent kinase 6 (CDK6), and the PI3K/AKT signaling pathway. Xenograft transplantation was also applied to confirm the in vitro experiments. Results Overexpressed MSC-AS1 was associated with poor prognosis of OS patients. OS cell proliferation, invasion, and migration were reduced after silencing MSC-AS1, while cell apoptosis was enhanced. Moreover, silencing MSC-AS1 made OS cells more sensitive to DDP. Interestingly, MSC-AS1 knockdown induced miR-142 expression and reduced CDK6 levels, thereby decreasing the protein expression of p-PI3K/t-PI3K and p-AKT/t-AKT. Silencing MSC-AS1 repressed OS progression in vivo. Conclusions Our study demonstrated that silencing MSC-AS1 inhibited OS biological behaviors by enhancing miR-142 to decrease CDK6 and inactivating the PI3K/AKT axis. Our results may provide new insights for OS treatment.
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Affiliation(s)
- Longqiang Zhang
- Department of Orthopedics, Yidu Central Hospital of Weifang, Weifang, Shandong, China (mainland)
| | - Guangzong Zhao
- Department of Orthopedics, Yidu Central Hospital of Weifang, Weifang, Shandong, China (mainland)
| | - Shaolin Ji
- Department of Orthopedics, Yidu Central Hospital of Weifang, Weifang, Shandong, China (mainland)
| | - Qihua Yuan
- Department of Orthopedics, Yidu Central Hospital of Weifang, Weifang, Shandong, China (mainland)
| | - Haiyan Zhou
- Health Management Center, Weifang People's Hospital, Weifang, Shandong, China (mainland)
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Yang W, Qi YB, Si M, Hou Y, Nie L. A comprehensive analysis for associations between multiple microRNAs and prognosis of osteosarcoma patients. PeerJ 2020; 8:e8389. [PMID: 31998559 PMCID: PMC6977468 DOI: 10.7717/peerj.8389] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 12/13/2019] [Indexed: 12/25/2022] Open
Abstract
Background Osteosarcoma (OS) is the most common malignant primary bone tumor occurring in children and young adults, which occupies the second important cause of tumor-associated deaths among children and young adults. Recent studies have demonstrated that many microRNAs (miRNAs) have abnormal expression in OS, and can function as prognostic factors of OS patients. However, no previous studies have comprehensively analyzed the relationship between multiple miRNAs and prognosis of OS patients. Methods A total of 63 OS patients were retrospectively enrolled. The clinical characteristics were collected, and the expression levels of miRNA-21, miRNA-30c, miRNA-34a, miRNA-101, miRNA-133a, miRNA-214, miRNA-218, miRNA-433 and miRNA-539 in tumor tissues were measured through quantitative real-time polymerasechain reaction. Kaplan–Meier analysis was used to perform univariate survival analysis, and Cox regression model was used to perform multivariate survival analysis which included the variables with P < 0.1 in univariate survival analysis. Results The cumulative survival for 1, 2 and 5 years was 90.48%, 68.25% and 38.10%, respectively, and mean survival time was (45.39 ± 3.60) months (95% CI [38.34–52.45]). Kaplan–Meier analysis demonstrated that TNM stage, metastasis or recurrence, miRNA-21, miRNA-214, miRNA-34a, miRNA-133a and miRNA-539 were correlated with cum survival, but gender, age, tumor diameter, differentiation, miRNA-30c, miRNA-433, miRNA-101 and miRNA-218 were not. Multivariate survival analysis demonstrated that miRNA-21 (hazard ratio (HR): 3.457, 95% CI [2.165–11.518]), miRNA (HR: 3.138, 95% CI [2.014–10.259]), miRNA-34a (HR: 0.452, 95% CI [0.202–0.915]), miRNA-133a (HR: 0.307, 95% CI [0.113–0.874]) and miRNA-539 (HR: 0.358, 95% CI [0.155–0.896]) were independent prognostic markers of OS patients after adjusting for TNM stage (HR: 2.893, 95% CI [1.496–8.125]), metastasis or recurrence (HR: 3.628, 95% CI [2.217–12.316]) and miRNA-30c (HR: 0.689, 95% CI [0.445–1.828]). Conclusions High expression of miRNA-21 and miRNA-214 and low expression of miRNA-34a, miRNA-133a and miRNA-539 were associated with poor prognosis of OS patients after adjusting for TNM stage, metastasis or recurrence and miRNA-30c.
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Affiliation(s)
- Wen Yang
- Department of Orthopaedics, Qilu Hospital of Shandong University, Jinan, Shandong Province, China.,Department of Spinal Surgery, Heze Municipal Hospital, Heze, Shandong Province, China
| | - Yu-Bin Qi
- Department of Orthopaedics, Shandong Provincial Qianfoshan Hospital, Jinan, Shandong Province, China
| | - Meng Si
- Department of Orthopaedics, Qilu Hospital of Shandong University, Jinan, Shandong Province, China
| | - Yong Hou
- Department of Orthopaedics, Qilu Hospital of Shandong University, Jinan, Shandong Province, China
| | - Lin Nie
- Department of Orthopaedics, Qilu Hospital of Shandong University, Jinan, Shandong Province, China
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Viera GM, Salomao KB, de Sousa GR, Baroni M, Delsin LEA, Pezuk JA, Brassesco MS. miRNA signatures in childhood sarcomas and their clinical implications. Clin Transl Oncol 2019; 21:1583-1623. [PMID: 30949930 DOI: 10.1007/s12094-019-02104-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 03/27/2019] [Indexed: 02/06/2023]
Abstract
Progresses in multimodal treatments have significantly improved the outcomes for childhood cancer. Nonetheless, for about one-third of patients with Ewing sarcoma, rhabdomyosarcoma, or osteosarcoma steady remission has remained intangible. Thus, new biomarkers to improve early diagnosis and the development of precision-targeted medicine remain imperative. Over the last decade, remarkable progress has been made in the basic understanding of miRNAs function and in interpreting the contribution of their dysregulation to cancer development and progression. On this basis, this review focuses on what has been learned about the pivotal roles of miRNAs in the regulation of key genes implicated in childhood sarcomas.
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Affiliation(s)
- G M Viera
- Ribeirao Preto School of Medicine, University of Sao Paulo, Ribeirao Preto, Brasil
| | - K B Salomao
- Ribeirao Preto School of Medicine, University of Sao Paulo, Ribeirao Preto, Brasil
| | - G R de Sousa
- Ribeirao Preto School of Medicine, University of Sao Paulo, Ribeirao Preto, Brasil
| | - M Baroni
- Ribeirao Preto School of Medicine, University of Sao Paulo, Ribeirao Preto, Brasil
| | - L E A Delsin
- Ribeirao Preto School of Medicine, University of Sao Paulo, Ribeirao Preto, Brasil
| | - J A Pezuk
- Anhanguera University of Sao Paulo, UNIAN/SP, Sao Paulo, Brasil
| | - M S Brassesco
- Faculty of Philosophy, Sciences and Letters at Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brasil.
- Departamento de Biologia, FFCLRP-USP, Av. Bandeirantes, 3900, Bairro Monte Alegre, Ribeirao Preto, SP, CEP 14040-901, Brazil.
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Zhong F, Huang T, Leng J. Serum miR-29b as a novel biomarker for glioblastoma diagnosis and prognosis. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2019; 12:4106-4112. [PMID: 31933806 PMCID: PMC6949802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Accepted: 09/27/2019] [Indexed: 06/10/2023]
Abstract
Altered expression of serum microRNAs (miRNA) has been reported to correlate with carcinogenesis and progression of glioblastoma (GBM). This study assessed the potential diagnostic and prognostic value of serum miR-29b for GBM. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to detect the expression levels of serum miR-29b in 107 patients with GBM patients, 40 patients with anaplastic astrocytoma (AA) and 80 healthy volunteers. The results showed that serum miR-29b levels were much lower in patients with GBM than in those with AA or healthy controls. Receiver operating characteristic (ROC) curve analysis revealed that serum exosomal miR-29b could effectively distinguish GBM patients from AA patients or normal controls. In addition, serum exosomal miR-29b level was significantly increased after treatment. Low serum exosomal miR-29b expression was strongly associated with aggressive clinical findings and shorter survival. Moreover, the Cox regression analysis demonstrated that serum exosomal miR-29b was an independent prognostic indicator. Collectively, serum exosomal miR-29b might be a promising biomarker for predicting prognosis of GBM.
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Affiliation(s)
- Fengying Zhong
- Department of Neurosurgery, Jiangxi Provincial People’s HospitalNanchang City, Jiangxi Province, P. R. China
| | - Ting Huang
- Department of Neurology, Jiangxi Provincial Children’s HospitalNanchang City, Jiangxi Province, P. R. China
| | - Jingxing Leng
- Department of Neurosurgery, Jiangxi Provincial People’s HospitalNanchang City, Jiangxi Province, P. R. China
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WIN55,212-2-Induced Expression of Mir-29b1 Favours the Suppression of Osteosarcoma Cell Migration in a SPARC-Independent Manner. Int J Mol Sci 2019; 20:ijms20205235. [PMID: 31652569 PMCID: PMC6834304 DOI: 10.3390/ijms20205235] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 10/09/2019] [Accepted: 10/18/2019] [Indexed: 12/23/2022] Open
Abstract
WIN55,212-2 (WIN) is a synthetic agonist of cannabinoid receptors that displays promising antitumour properties. The aim of this study is to demonstrate that WIN is able to block the migratory ability of osteosarcoma cells and characterize the mechanisms involved. Using wound healing assay and zymography, we showed that WIN affects cell migration and reduces the activity of the metalloproteases MMP2 and MMP9. This effect seemed to be independent of secreted protein acidic and rich in cysteine (SPARC), a matricellular protein involved in tissue remodeling and extracellular matrix deposition. SPARC release was indeed prevented by WIN, and SPARC silencing by RNA interference did not influence the effect of the cannabinoid on cell migration. WIN also increased the release of extracellular vesicles and dramatically upregulated miR-29b1, a key miRNA that modulates cell proliferation and migration. Interestingly, reduced cell migration was observed in stably miR-29b1-transfected cells, similarly to WIN-treated cells. Finally, we show the absence of SPARC in the extracellular vesicles released by osteosarcoma cells and no changes in SPARC level in miR-29b1 overexpressing cells. Overall, these findings suggest that WIN markedly affects cell migration, dependently on miR-29b1 and independently of SPARC, and can thus be considered as a potential innovative therapeutic agent in the treatment of osteosarcoma.
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Purvis IJ, Avilala J, Guda MR, Venkataraman S, Vibhakar R, Tsung AJ, Velpula KK, Asuthkar S. Role of MYC-miR-29-B7-H3 in Medulloblastoma Growth and Angiogenesis. J Clin Med 2019; 8:jcm8081158. [PMID: 31382461 PMCID: PMC6723910 DOI: 10.3390/jcm8081158] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 07/23/2019] [Accepted: 07/30/2019] [Indexed: 12/14/2022] Open
Abstract
Medulloblastoma (MB) is the most common embryonal neuroepithelial tumor, with poor patient outcomes and secondary complications. In this study, we investigated the role of the B7 family of immune checkpoint homolog 3 (B7-H3) expression in MB angiogenesis. B7-H3, a co-inhibitory immune checkpoint, is highly expressed and is associated with lower overall survival in MYC+ MB's. Evidence for a direct transcriptional role of MYC on the B7-H3 gene promoter was confirmed by MYC inhibition and anti-MYC antibody ChIP analysis. Interestingly, MYC inhibition not only downregulated the B7-H3 protein expression, but also rescued miR-29 expression, thus indicating a triangular regulatory relationship between MYC, miR-29, and B7-H3 in Group 3 MB cells. From RNA seq and IPAD assay, we observed a negative feedback loop between miR-29 and MYC that may control B7-H3 expression levels in MB cells. Our studies show that B7-H3 expression levels play a crucial role in promoting MB angiogenesis which can be inhibited by miR-29 overexpression via miR-29-mediated B7-H3 downregulation. The tumor suppressor role of miR-29 is mediated by the activation of JAK/STAT1 signaling that further plays a role in MYC-B7-H3 downregulation in MB. This study highlights B7-H3 as a viable target in MB angiogenesis, and that the expression of miR-29 can inhibit B7-H3 and sensitize MB cells to treatment with MYC-inhibiting drugs.
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Affiliation(s)
- Ian J Purvis
- Departments of Cancer Biology and Pharmacology, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USA
| | - Janardhan Avilala
- Departments of Cancer Biology and Pharmacology, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USA
| | - Maheedhara R Guda
- Departments of Cancer Biology and Pharmacology, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USA
| | - Sujatha Venkataraman
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Rajeev Vibhakar
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Andrew J Tsung
- Departments of Cancer Biology and Pharmacology, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USA
- Departments of Neurosurgery, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USA
| | - Kiran K Velpula
- Departments of Cancer Biology and Pharmacology, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USA
- Departments of Neurosurgery, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USA
- Departments of Pediatrics, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USA
| | - Swapna Asuthkar
- Departments of Cancer Biology and Pharmacology, University of Illinois College of Medicine Peoria, Peoria, IL 61605, USA.
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Kong J, He X, Wang Y, Li J. Effect of microRNA-29b on proliferation, migration, and invasion of endometrial cancer cells. J Int Med Res 2019; 47:3803-3817. [PMID: 31187677 PMCID: PMC6726808 DOI: 10.1177/0300060519844403] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Objective Aberrant expression of microRNAs is a key regulator of tumorigenesis and progression in endometrial cancer. We assessed the effect of microRNA-29b (miR-29b) on proliferation, chemosensitivity, migration, and invasion of endometrial cancer cells. Methods The proliferation of endometrial cancer cells was examined by water-soluble tetrazolium (WST)-1 assay. The effects of miR-29b on migration and invasion were evaluated by transwell migration and Matrigel invasion assays. Western blotting was used to assess protein expression levels after altered expression of miR-29b. The effect of miR-29b on cisplatin-induced apoptosis was examined by Caspase-Glo 3/7 assay. Results miR-29b inhibited proliferation and decreased migration and invasion of endometrial cancer cells. It also enhanced the sensitivity of endometrial cancer cells to cisplatin and increased cisplatin-induced apoptosis by regulating expression of BAX and Bcl-2. Moreover, miR-29b changed the expression level of phosphatase and tensin homolog (PTEN) and p-AKT by directly binding to the 3′ untranslated region of PTEN. Conclusion miR-29b played important roles in proliferation and progression in endometrial cancer cells by direct regulation of PTEN. It might be used as a biomarker to predict chemotherapy response and prognosis in endometrial cancer.
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Affiliation(s)
- Jian Kong
- Department of Geriatrics, The First Hospital of Jilin University, Changchun City, Jilin Province, China
| | - Xiuting He
- Department of Geriatrics, The First Hospital of Jilin University, Changchun City, Jilin Province, China
| | - Yan Wang
- Department of Geriatrics, The First Hospital of Jilin University, Changchun City, Jilin Province, China
| | - Jie Li
- Department of Geriatrics, The First Hospital of Jilin University, Changchun City, Jilin Province, China
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Zhang T, Xue X, Peng H. Therapeutic Delivery of miR-29b Enhances Radiosensitivity in Cervical Cancer. Mol Ther 2019; 27:1183-1194. [PMID: 31029553 PMCID: PMC6554684 DOI: 10.1016/j.ymthe.2019.03.020] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 03/15/2019] [Accepted: 03/15/2019] [Indexed: 12/19/2022] Open
Abstract
Radioresistant cervical cancer is likely to give rise to local recurrence, distant metastatic relapse, and decreased survival rates. Recent studies revealed microRNA mediated regulation of tumor aggressiveness and metastasis; however, whether specific microRNAs regulate tumor radioresistance and can be exploited as radiosensitizing agents remains unclear. Here, we find that miR-29b could promote radiosensitivity in radioresistant subpopulations of cervical cancer cells. Notably, therapeutic delivery of miR-29b mimics via R11-SSPEI nanoparticle, whose specificity has been proved by our previous studies, can sensitize the tumor to radiation in a xenograft model. Mechanistically, we reveal a novel function of miR-29b in regulating intracellular reactive oxygen species signaling and explore a potential application for its use in combination with therapies known to increase oxidative stress such as radiation. Moreover, miR-29b inhibits DNA damage repair by targeting phosphate and tension homology deleted on chromsome ten (PTEN), and overexpression of PTEN could partially rescue miR-29b-mediated homologous recombination (HR)-DNA damage repair and increase radiosensitivity. These findings identify miR-29b as a radiosensitizing microRNA and reveal a new therapeutic strategy for radioresistant tumors.
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Affiliation(s)
- Tingting Zhang
- Department of Gynecology, The Second Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, China; Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, China
| | - Xiang Xue
- Department of Gynecology, The Second Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, China; Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, China.
| | - Huixia Peng
- Department of Gynecology, The Second Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, China
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40
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Sun Z, Chen C, Su Y, Wang W, Yang S, Zhou Q, Wang G, Li Z, Song J, Zhang Z, Yuan W, Liu J. Regulatory mechanisms and clinical perspectives of circRNA in digestive system neoplasms. J Cancer 2019; 10:2885-2891. [PMID: 31281465 PMCID: PMC6590048 DOI: 10.7150/jca.31167] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 04/14/2019] [Indexed: 12/16/2022] Open
Abstract
A new star, circular RNA (circRNA), is a class of noncoding RNA with a stable cyclic structure. Exonic circRNA mainly exists in the eukaryotic cytoplasm. Intronic circRNAs (ciRNA) and exonic circRNAs with introns (EIciRNA) are found in the nucleus. Recent evidences showed the functional diversity of circRNAs, which could be microRNA (miRNA) sponges, interact with protein or translate into small peptide. Due to the change of human eating habits, digestive cancer remains one of the most common cancers worldwide and it is prone to metastasis. Increasing studies have found a number of circRNAs using RNA sequencing technology and displayed double roles of circRNA in digestive cancer. In this review, we surveyed the biogenesis and regulation of circRNAs, discussed circRNA functions and clinical applications (especially circRNAs in exosome) in digestive cancers, which implied that circRNAs could be as potential biomarkers in diagnosis and treatment of digestive cancers in the future.
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Affiliation(s)
- Zhenqiang Sun
- Department of Anorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Chen Chen
- Department of Anorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yingfeng Su
- Department of gastrointestinal surgery, The people's hospital of Dezhou, Dezhou, Shandong 253014, China
| | - Weiwei Wang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.,Department of Pathology, School of Basic Medicine, Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Shuaixi Yang
- Department of Anorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Quanbo Zhou
- Department of Anorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Guixian Wang
- Department of Anorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Zhen Li
- Department of Anorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Junmin Song
- Department of Anorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Zhiyong Zhang
- Department of Anorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Weitang Yuan
- Department of Anorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Jinbo Liu
- Department of Anorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
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Zhang Z, Li P, Li T, Zhao C, Wang G. Velvet Antler compounds targeting major cell signaling pathways in osteosarcoma - a new insight into mediating the process of invasion and metastasis in OS. OPEN CHEM 2019. [DOI: 10.1515/chem-2019-0028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
AbstractVelvet antler is the only renewable bone tissue of mammalian animals, which consists of a variety of growth factors, amino acids and polypeptides. But the mechanism of high-speed proliferation without carcinogenesis is still mystifying. The previous study of this work found that the velvet antler peptides (VAP) could not only inhibit the proliferation and migration of osteosarcoma cell lines MG-63 and U2OS, but also induced U2OS apoptosis and inhibited MG-63 epithelial-mesenchymal transition (EMT) through TGF-β and Notch pathways. These results lead us to conclude that VAP has the potential ability to mediate osteosarcoma cells by regulating related signaling pathways and growth factors. Therefore, finding a new appropriate inhibitor for OS is a valuable research direction, which will give patients a better chance to receive proper therapy. From an applied perspective, this review summarized the effects of velvet antler, genes, growth factors and research progress of relative pathways and genes of osteosarcoma, which are poised to help link regenerative molecular biology and regenerative medicine in osteosarcoma pathogenesis.
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Affiliation(s)
- Zhengyao Zhang
- School of Life Science and Medicine, Dalian University of Technology, DaGong Road, PanjinLiaoning 124221, China
| | - Pengfei Li
- School of Life Science and Medicine, Dalian University of Technology, DaGong Road, PanjinLiaoning 124221, China
| | - Tie Li
- Acupuncture and Tuina Institute, Changchun University of Chinese Medicine, ChangchunJilin 130021, China
| | - Changwei Zhao
- Department of Orthopedics, Changchun University of Chinese Medicine, ChangchunJilin 130021, China
| | - Guoxiang Wang
- Cancer Center, The First Hospital of Jilin University, ChangchunJilin 130021, China
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Krimpenfort P, Snoek M, Lambooij JP, Song JY, van der Weide R, Bhaskaran R, Teunissen H, Adams DJ, de Wit E, Berns A. A natural WNT signaling variant potently synergizes with Cdkn2ab loss in skin carcinogenesis. Nat Commun 2019; 10:1425. [PMID: 30926782 PMCID: PMC6441055 DOI: 10.1038/s41467-019-09321-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Accepted: 02/13/2019] [Indexed: 12/15/2022] Open
Abstract
Cdkn2ab knockout mice, generated from 129P2 ES cells develop skin carcinomas. Here we show that the incidence of these carcinomas drops gradually in the course of backcrossing to the FVB/N background. Microsatellite analyses indicate that this cancer phenotype is linked to a 20 Mb region of 129P2 chromosome 15 harboring the Wnt7b gene, which is preferentially expressed from the 129P2 allele in skin carcinomas and derived cell lines. ChIPseq analysis shows enrichment of H3K27-Ac, a mark for active enhancers, in the 5' region of the Wnt7b 129P2 gene. The Wnt7b 129P2 allele appears sufficient to cause in vitro transformation of Cdkn2ab-deficient cell lines primarily through CDK6 activation. These results point to a critical role of the Cdkn2ab locus in keeping the oncogenic potential of physiological levels of WNT signaling in check and illustrate that GWAS-based searches for cancer predisposing allelic variants can be enhanced by including defined somatically acquired lesions as an additional input.
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Affiliation(s)
- Paul Krimpenfort
- Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
- Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Margriet Snoek
- Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Jan-Paul Lambooij
- Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
- Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Ji-Ying Song
- Department of Experimental Animal Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Robin van der Weide
- Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
- Division of Gene Regulation, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Rajith Bhaskaran
- Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
- Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Hans Teunissen
- Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
- Division of Gene Regulation, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - David J Adams
- Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge, CB10 1SA, UK
| | - Elzo de Wit
- Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
- Division of Gene Regulation, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Anton Berns
- Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
- Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
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Pourbagheri-Sigaroodi A, Bashash D, Safaroghli-Azar A, Farshi-Paraasghari M, Momeny M, Mansoor FN, Ghaffari SH. Contributory role of microRNAs in anti-cancer effects of small molecule inhibitor of telomerase (BIBR1532) on acute promyelocytic leukemia cell line. Eur J Pharmacol 2019; 846:49-62. [PMID: 30658112 DOI: 10.1016/j.ejphar.2019.01.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Revised: 01/01/2019] [Accepted: 01/14/2019] [Indexed: 12/29/2022]
Abstract
Telomerase-mediated immortalization and proliferation of tumor cells is a promising anti-cancer treatment strategy and development of potent telomerase inhibitors is believed to open new window of treatments in human malignancies. In the present study, we found that BIBR1532, a small molecule inhibitor of human telomerase, exerted cytotoxic effects on a panel of human cancer cells spanning from solid tumors to hematologic malignancies; however, as compared with solid tumors, leukemic cells were more sensitive to this inhibitor. This was independent of molecular status of p53 in the leukemic cells. The results of a miRNA PCR array revealed that BIBR1532-induced cytotoxic effects in NB4, the most sensitive cell line, was coupled with alteration in a substantial number of cancer-related miRNAs. Interestingly, most of these miRNAs were found to act as tumor suppressors with validated targets in cell cycle or nuclear factor (NF)-κB-mediated apoptosis. In accordance with a bioinformatics analysis, our experimental studies showed that BIBR1532-induced apoptosis is mediated, at least partly, by inhibition of NF-κB. Moreover, we found that the alteration in the expression of miRNAs was coupled with the alteration in the cell cycle progression. To sum up with, a straightforward interpretation of our results is that telomerase inhibition using BIBR1532 not only induced CDKN1A-mediated G1 arrest in NB4, but also resulted in a caspase-3-dependent apoptotic cell death mostly through suppression of NF-κB axis.
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Affiliation(s)
- Atieh Pourbagheri-Sigaroodi
- Department of Biotechnology, Faculty of Advanced Sciences and Technology, Pharmaceutical Sciences Branch, Islamic Azad University (IAUPS), Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Ava Safaroghli-Azar
- Student Research Committee, Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoumeh Farshi-Paraasghari
- Student Research Committee, Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Majid Momeny
- Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland
| | - Fahimeh Nemati Mansoor
- Department of Biotechnology, Faculty of Advanced Sciences and Technology, Pharmaceutical Sciences Branch, Islamic Azad University (IAUPS), Tehran, Iran
| | - Seyed H Ghaffari
- Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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Gallant-Behm CL, Piper J, Lynch JM, Seto AG, Hong SJ, Mustoe TA, Maari C, Pestano LA, Dalby CM, Jackson AL, Rubin P, Marshall WS. A MicroRNA-29 Mimic (Remlarsen) Represses Extracellular Matrix Expression and Fibroplasia in the Skin. J Invest Dermatol 2018; 139:1073-1081. [PMID: 30472058 DOI: 10.1016/j.jid.2018.11.007] [Citation(s) in RCA: 187] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 10/26/2018] [Accepted: 11/04/2018] [Indexed: 12/29/2022]
Abstract
MicroRNA-29 (miR-29) negatively regulates fibrosis and is downregulated in multiple fibrotic organs and tissues, including in the skin. miR-29 mimics prevent pulmonary fibrosis in mouse models but have not previously been tested in the skin. This study aimed to identify pharmacodynamic biomarkers of miR-29 in mouse skin, to translate those biomarkers across multiple species, and to assess the pharmacodynamic activity of a miR-29b mimic (remlarsen) in a clinical trial. miR-29 biomarkers were selected based on gene function and mRNA expression using quantitative reverse transcriptase polymerase chain reaction. Those biomarkers comprised multiple collagens and other miR-29 direct and indirect targets and were conserved across species; remlarsen regulated their expression in mouse, rat, and rabbit skin wounds and in human skin fibroblasts in culture, while a miR-29 inhibitor reciprocally regulated their expression. Biomarker expression translated to clinical proof-of-mechanism; in a double-blinded, placebo-randomized, within-subject controlled clinical trial of single and multiple ascending doses of remlarsen in normal healthy volunteers, remlarsen repressed collagen expression and the development of fibroplasia in incisional skin wounds. These results suggest that remlarsen may be an effective therapeutic to prevent formation of a fibrotic scar (hypertrophic scar or keloid) or to prevent cutaneous fibrosis, such as scleroderma.
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Affiliation(s)
| | - Joseph Piper
- miRagen Therapeutics, Inc, Boulder, Colorado, USA
| | | | - Anita G Seto
- miRagen Therapeutics, Inc, Boulder, Colorado, USA
| | - Seok Jong Hong
- Division of Surgery, Northwestern University, Chicago, Illinois, USA
| | - Thomas A Mustoe
- Division of Surgery, Northwestern University, Chicago, Illinois, USA
| | | | | | | | | | - Paul Rubin
- miRagen Therapeutics, Inc, Boulder, Colorado, USA
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Abuduaini R, Miao X, Xu J, Che L, Zhou W, Guo Z, Sun J. MicroRNA-194-3p inhibits the metastatic biological behaviors of spinal osteosarcoma cells by the repression of matrix metallopeptidase 9. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:5257-5264. [PMID: 31949606 PMCID: PMC6963041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/16/2018] [Accepted: 09/25/2018] [Indexed: 06/10/2023]
Abstract
Osteosarcoma is the most common primary malignant bone tumor, but only 3%-5% of cases occur in the spine. Spinal osteosarcoma presents a significant challenge, and most patients die in spite of aggressive surgery. MicroRNAs (miRNAs) are small noncoding RNAs that have a pivotal role in the post-transcriptional regulation of gene expression. The aim of this study was to investigate the role of miR-194-3p and to identify its potential mechanism in spinal osteosarcoma. Here, spinal osteosarcoma tissues showed down-regulated expression of miR-194-3p compared to adjacent non-tumorous tissues. The level of miR-194-3p was negatively correlated with metastasis in patients with spinal osteosarcoma. MiR-194-3p over-expression in spinal osteosarcoma cells significantly inhibited cell migration and invasion in vitro. Furthermore, mechanistic analyses showed that MMP-9 (matrix metallopeptidase 9) is a direct target of miR-194-3p, and the ectopic expression of miR-194-3p inhibits MMP-9 expression by directly binding to the 3'-untranslated region (3'-UTR) of the MMP-9 gene. In summary, our results demonstrate that miR-194-3p suppresses migration and invasion of spinal osteosarcoma cells by targeting MMP-9, indicating miR-194-3p may serve as a promising novel target for spinal osteosarcoma therapy.
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Affiliation(s)
- Rewuti Abuduaini
- Department of Orthopedic Trauma, People's Hospital of Xinjiang Uygur Autonomous Region Urumqi, People's Republic of China
| | - Xiaogang Miao
- Department of Orthopedic Trauma, People's Hospital of Xinjiang Uygur Autonomous Region Urumqi, People's Republic of China
| | - Jiangbo Xu
- Department of Orthopedic Trauma, People's Hospital of Xinjiang Uygur Autonomous Region Urumqi, People's Republic of China
| | - Lixin Che
- Department of Orthopedic Trauma, People's Hospital of Xinjiang Uygur Autonomous Region Urumqi, People's Republic of China
| | - Wenzheng Zhou
- Department of Orthopedic Trauma, People's Hospital of Xinjiang Uygur Autonomous Region Urumqi, People's Republic of China
| | - Zigang Guo
- Department of Orthopedic Trauma, People's Hospital of Xinjiang Uygur Autonomous Region Urumqi, People's Republic of China
| | - Jungang Sun
- Department of Orthopedic Trauma, People's Hospital of Xinjiang Uygur Autonomous Region Urumqi, People's Republic of China
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46
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Emerging roles of non-coding RNAs in the pathogenesis, diagnosis and prognosis of osteosarcoma. Invest New Drugs 2018; 36:1116-1132. [DOI: 10.1007/s10637-018-0624-7] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Accepted: 06/18/2018] [Indexed: 12/13/2022]
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47
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Zhao W, Shen G, Ren H, Liang D, Yu X, Zhang Z, Huang J, Qiu T, Tang J, Shang Q, Yu P, Wu Z, Jiang X. Therapeutic potential of microRNAs in osteoporosis function by regulating the biology of cells related to bone homeostasis. J Cell Physiol 2018; 233:9191-9208. [PMID: 30078225 DOI: 10.1002/jcp.26939] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 06/13/2018] [Indexed: 12/13/2022]
Abstract
MicroRNAs (miRNAs) are novel regulatory factors that play important roles in numerous cellular processes through the posttranscriptional regulation of gene expression. Recently, deregulation of the miRNA-mediated mechanism has emerged as an important pathological factor in osteoporosis. However, a detailed molecular mechanism between miRNAs and osteoporosis is still not available. In this review, the roles of miRNAs in the regulation of cells related to bone homeostasis as well as miRNAs that deregulate in human or animal are discussed. Moreover, the miRNAs that act as clusters in the biology of cells in the bone microenvironment and the difference of some important miRNAs for bone homeostasis between bone and other organs are mentioned. Overall, miRNAs that contribute to the pathogenesis of osteoporosis and their therapeutic potential are considered.
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Affiliation(s)
- Wenhua Zhao
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Gengyang Shen
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hui Ren
- Department of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - De Liang
- Department of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiang Yu
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhida Zhang
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jinjing Huang
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ting Qiu
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jingjing Tang
- Department of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qi Shang
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Peiyuan Yu
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zixian Wu
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaobing Jiang
- Department of Spinal Surgery, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,Laboratory Affiliated to National Key Discipline of Orthopaedic and Traumatology of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
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48
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TGF-β2 induces proliferation and inhibits apoptosis of human Tenon capsule fibroblast by miR-26 and its targeting of CTGF. Biomed Pharmacother 2018; 104:558-565. [DOI: 10.1016/j.biopha.2018.05.059] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 05/11/2018] [Accepted: 05/14/2018] [Indexed: 02/06/2023] Open
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49
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Xie L, Yao Z, Zhang Y, Li D, Hu F, Liao Y, Zhou L, Zhou Y, Huang Z, He Z, Han L, Yang Y, Yang Z. Deep RNA sequencing reveals the dynamic regulation of miRNA, lncRNAs, and mRNAs in osteosarcoma tumorigenesis and pulmonary metastasis. Cell Death Dis 2018; 9:772. [PMID: 29991755 PMCID: PMC6039476 DOI: 10.1038/s41419-018-0813-5] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 05/23/2018] [Accepted: 05/25/2018] [Indexed: 02/06/2023]
Abstract
Osteosarcoma (OS) is the most common pediatric malignant bone tumor, and occurrence of pulmonary metastasis generally causes a rapid and fatal outcome. Here we aimed to provide clues for exploring the mechanism of tumorigenesis and pulmonary metastasis for OS by comprehensive analysis of microRNA (miRNA), long non-coding RNA (lncRNA), and mRNA expression in primary OS and OS pulmonary metastasis. In this study, deep sequencing with samples from primary OS (n = 3), pulmonary metastatic OS (n = 3), and normal controls (n = 3) was conducted and differentially expressed miRNAs (DEmiRNAs), lncRNAs (DElncRNAs), and mRNAs (DEmRNAs) between primary OS and normal controls as well as pulmonary metastatic and primary OS were identified. A total of 65 DEmiRNAs, 233 DElncRNAs, and 1405 DEmRNAs were obtained between primary OS and normal controls; 48 DEmiRNAs, 50 DElncRNAs, and 307 DEmRNAs were obtained between pulmonary metastatic and primary OS. Then, the target DEmRNAs and DElncRNAs regulated by the same DEmiRNAs were searched and the OS tumorigenesis-related and OS pulmonary metastasis-related competing endogenous RNA (ceRNA) networks were constructed, respectively. Based on these ceRNA networks and Venn diagram analysis, we obtained 3 DEmiRNAs, 15 DElncRNAs, and 100 DEmRNAs, and eight target pairs including miR-223-5p/(CLSTN2, AC009951.1, LINC01705, AC090673.1), miR-378b/(ALX4, IGSF3, SULF1), and miR-323b-3p/TGFBR3 were involved in both tumorigenesis and pulmonary metastasis of OS. The TGF-β superfamily co-receptor TGFBR3, which is regulated by miR-323b-3p, acts as a tumor suppressor in OS tumorigenesis and acts as a tumor promoter in pulmonary metastatic OS via activation of the epithelial-mesenchymal transition (EMT) program.In conclusion, the OS transcriptome (miRNA, lncRNA, and mRNA) is dynamically regulated. These analyses might provide new clues to uncover the molecular mechanisms and signaling networks that contribute to OS progression, toward patient-tailored and novel-targeted treatments.
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MESH Headings
- Adolescent
- Adult
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinogenesis/genetics
- Carcinogenesis/metabolism
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Computational Biology
- Female
- Gene Expression Regulation, Neoplastic/genetics
- Gene Expression Regulation, Neoplastic/physiology
- High-Throughput Nucleotide Sequencing/methods
- Humans
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Male
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Osteosarcoma/genetics
- Osteosarcoma/metabolism
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Sequence Analysis, RNA/methods
- Young Adult
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Affiliation(s)
- Lin Xie
- Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China
- Department of Medical Oncology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China
| | - Zhihong Yao
- Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China
| | - Ya Zhang
- Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China
| | - Dongqi Li
- Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China
| | - Fengdi Hu
- Department of Medical Oncology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China
| | - Yedan Liao
- Department of Medical Oncology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China
| | - Ling Zhou
- Department of Medical Oncology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China
| | - Yonghong Zhou
- Department of Medical Oncology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China
| | - Zeyong Huang
- Medical School, Kunming University of Science and Technology, Kunming, 650504, Yunnan, China
| | - Zewei He
- Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China
| | - Lei Han
- Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China
| | - Yihao Yang
- Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China
| | - Zuozhang Yang
- Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China.
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50
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Xi L, Zhang Y, Kong S, Liang W. miR-34 inhibits growth and promotes apoptosis of osteosarcoma in nude mice through targetly regulating TGIF2 expression. Biosci Rep 2018; 38:BSR20180078. [PMID: 29895719 PMCID: PMC5997800 DOI: 10.1042/bsr20180078] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 04/12/2018] [Accepted: 04/16/2018] [Indexed: 01/21/2023] Open
Abstract
miR-34 was reported to be involved in multiple tumors occurrence and development. The aim of the present study was to explore the impact of miR-34 on osteosarcoma and related mechanisms. Tumor tissues and non-tumor tissues of 34 patients with osteosarcoma were collected. qRT-PCR detection revealed that miR-34 was significantly down-regulated in tumor tissues (P<0.05). hFOB 1.19 and MG-63 cells were cultured. qRT-PCR detection showed that miR-34 was also significantly down-regulated in MG-63 cells (P<0.05). After transfection by miR-34 mimics, MG-63 cells proliferation in nude mice was significantly impaired (P<0.05), and percentage of apoptosis as well as caspase-3 positive cells proportion of osteosarcoma tissue in nude mice was markly increased (P<0.05). Western blot and immunofluorescence results also demonstrated that TGIF2 relative expression and TGIF2 positive cells proportion were both dramatically decreased (P<0.05). By luciferase reporter assay, we found that TGIF2 was the target gene of miR-34. After transfected by TGIF2 overexpression vector or co-transfected by miR-34 mimics and TGIF2 overexpression vector, we observed that, compared with blank group, tumor volume was significantly increased and apoptotic cells as well as caspase-3 positive cells proportion was obviously decreased in TGIF2 group (P<0.05), while no significant difference was found in these indicators between blank group and TGIF2 + mimics group. We concluded that miR-34 inhibited growth and promoted apoptosis of osteosarcoma in nude mice through targetting regulated TGIF2 expression.
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Affiliation(s)
- Liang Xi
- Department of Orthopaedic Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China
| | - Yongfeng Zhang
- Department of Orthopaedic Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China
| | - Shengnan Kong
- Department of Medical Oncology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China
| | - Wei Liang
- Department of Orthopaedic Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China
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