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Dey M, Skipar P, Bartnik E, Piątkowski J, Sulejczak D, Czarnecka AM. MicroRNA signatures in osteosarcoma: diagnostic insights and therapeutic prospects. Mol Cell Biochem 2025; 480:2065-2075. [PMID: 39419925 PMCID: PMC11961547 DOI: 10.1007/s11010-024-05135-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 10/04/2024] [Indexed: 10/19/2024]
Abstract
Osteosarcoma (OSa) is the most prevalent primary malignant bone tumor in children and adolescents, characterized by complex genetic and epigenetic alterations. Traditional treatments face significant challenges due to high rates of drug resistance and lack of targeted therapies. Recent advances in microRNA (miRNA) research have opened new avenues for understanding and treating osteosarcoma. This review explores the many critical functions of miRNAs in osteosarcoma, particularly their potential for clinical use. The review highlights two key areas where miRNAs could be beneficial. Firstly, miRNAs can act as biomarkers for diagnosing osteosarcoma and predicting patient prognosis. Secondly, specific miRNAs can regulate cellular processes like proliferation, cell death, migration, and even resistance to chemotherapy drugs in osteosarcoma. This ability to target multiple pathways within cancer cells makes miRNA-based therapies highly promising. Additionally, though the interaction between miRNAs and circular RNAs (circRNAs) falls outside the scope of the paper, it has also been discussed briefly. While miRNA-based therapies offer exciting possibilities for targeting multiple pathways in osteosarcoma, challenges remain. Efficient delivery, potential off-target effects, tumor complexity, and rigorous testing are hurdles to overcome before these therapies can reach patients. Despite these challenges, continued research and collaboration among scientists, clinicians, and regulatory bodies hold the promise of overcoming them. This collaborative effort can pave the way for the development of safe and effective miRNA-based treatments for osteosarcoma.
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Affiliation(s)
- Mritunjoy Dey
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Cancer Research Institute in Warsaw, 02-781, Warsaw, Poland.
| | - Palina Skipar
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Cancer Research Institute in Warsaw, 02-781, Warsaw, Poland
- Faculty of Medicine, Warsaw Medical University, 02-091, Warsaw, Poland
| | - Ewa Bartnik
- Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, 02-106, Warsaw, Poland
| | - Jakub Piątkowski
- Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, 02-106, Warsaw, Poland
| | - Dorota Sulejczak
- Department of Experimental Pharmacology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | - Anna M Czarnecka
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Cancer Research Institute in Warsaw, 02-781, Warsaw, Poland
- Department of Experimental Pharmacology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
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Robbins GM, Vue YY, Rahrmann EP, Moriarity BS. Osteosarcoma: A comprehensive review of model systems and experimental therapies. MEDICAL RESEARCH ARCHIVES 2024; 12:6000. [PMID: 39916749 PMCID: PMC11801376 DOI: 10.18103/mra.v12i11.6000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/09/2025]
Abstract
Osteosarcoma (OSA) is a highly malignant bone tumor for which more than 50% of patients have or will develop metastatic disease, resulting in an abysmal 5-year survival rate of <29%. Despite the advances in science and medicine, the etiology of OSA remains unclear. Similarly, the standard of care (surgery and chemotherapy) has changed little in the past 5 decades. This stagnation in treatment options is in part due to inadequate preclinical models for OSA; many of these models are oversimplified and do not account for the complexities of patient disease. Further, current treatments are harsh and invasive (e.g. high dose chemotherapy and potential limb removal) leading to a reduction in a patient's quality of life (e.g. hearing loss, infertility, neuropathy), highlighting a need for developing more effective treatment strategies. Many experimental therapies have been tested in the preclinical and preclinical setting, with varying degrees of success. In this review, we will focus on pediatric and adolescent OSA, highlighting current animal models and experimental therapies.
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Affiliation(s)
- Gabrielle M Robbins
- Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
- Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA
- College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55455, USA
| | - Young Y Vue
- Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
- Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA
| | - Eric P Rahrmann
- The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
| | - Branden S Moriarity
- Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
- Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA
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Hu S, Ye J, Wang K, Xiong Y, Nie X. Inhibition of miR-9 Combined With Cisplatin Targeting APE1 Against Angiogenesis in Osteosarcoma. J Craniofac Surg 2024; 35:2189-2193. [PMID: 38771203 DOI: 10.1097/scs.0000000000010325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 04/13/2024] [Indexed: 05/22/2024] Open
Abstract
Osteosarcoma (OS) is a highly malignant tumor, and chemotherapy resistance suggests poor prognosis in OS patients. In this study, the authors discovered that miR-9 has a pro-angiogenic role in OS. The anti-angiogenic effects of cisplatin were greatly increased when miR-9 was suppressed in OS. In addition, the authors demonstrated that miR-9 plays a pro-angiogenic role by targeting apoptosis-inducing factor 1 (APE1) in OS. Importantly, our in vivo experiments showed that inhibition of miR-9 combined with cisplatin could suppress xenograft tumor growth by targeting APE1 and decreasing angiogenesis in OS. In summary, our results suggest that miR-9 plays a role as a tumor promoter, and inhibiting miR-9 and APE1 is a new strategy for inhibiting OS angiogenesis and chemotherapy resistance.
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Affiliation(s)
- Sunqiang Hu
- Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou
| | - Jiaqi Ye
- Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou
| | - Keyu Wang
- Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou
| | - Yan Xiong
- Department of Orthopaedics, Daping Hospital, Army Medical University, Chongqing, China
| | - Xin Nie
- Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou
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Mohamed AH, Patel AA, Abdulmonem WA, Muzammil K, Shafie A, Ashour AA, Mirdad TMAM, Mallick AK, Alsaiari AA, Almalki AA. The role of miR-765 in human cancers. Int Immunopharmacol 2024; 139:112779. [PMID: 39068750 DOI: 10.1016/j.intimp.2024.112779] [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: 05/10/2024] [Revised: 06/18/2024] [Accepted: 07/23/2024] [Indexed: 07/30/2024]
Abstract
MicroRNAs, a collection of short noncoding RNAs, are promising biomarkers for identifying cancer in its early stages and tracking the effectiveness of treatment. This is due to their critical role in regulating gene expression and other vital biological functions via cell-level epigenetic mechanisms. This review brings together data on the molecular and clinical effects of miR-765 on different types of cancer. Significant variation in miR-765 levels has been observed in a variety of cancer types, suggesting that it could have an oncogene or tumor suppressor role. A number of pathways, including PLP2/Notch, VEGFA/Akt1, PDX1, KLK4, RUNX2, DPF3, EMP3, APE1, ERK/EMT axis, and others, are impacted by the inclusion of miR-765 in their analysis. MiR-765 is an essential biomarker that shows promise as a diagnostic tool for various types of cancer. The latest research has identified them as reliable predictive markers for detecting tumor development at an early stage. Based on our study, miR-765 shows promising potential as a biomarker for prognosis in multiple types of cancer. Specifically, we suggest that miR-765 could be an early detection marker for tumor development, progression, and metastasis.
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Affiliation(s)
- Asma'a H Mohamed
- Biomedical Engineering Department, College of Engineering and Technologies, Al-Mustaqbal University, Babil 51001, Hilla, Iraq.
| | - Ayyub Ali Patel
- Department of Clinical Biochemistry, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Waleed Al Abdulmonem
- Department of Pathology, College of Medicine, Qassim University, Buraidah, Saudi Arabia
| | - Khursheed Muzammil
- Department of Public Health, College of Applied Medical Sciences, Khamis Mushait Campus, King Khalid University, Abha 62561, Saudi Arabia
| | - Alaa Shafie
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O.Box 11099, Taif 21944, Saudi Arabia
| | - Amal Adnan Ashour
- Department of Oral & Maxillofacial Surgery and Diagnostic Sciences, Faculty of Dentistry. Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | | | - Ayaz Khurram Mallick
- Department of Clinical Biochemistry, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Ahad Amer Alsaiari
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O.Box 11099, Taif 21944, Saudi Arabia
| | - Abdulraheem Ali Almalki
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O.Box 11099, Taif 21944, Saudi Arabia
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Moghbeli M. MicroRNAs as the pivotal regulators of cisplatin resistance in osteosarcoma. Pathol Res Pract 2023; 249:154743. [PMID: 37549518 DOI: 10.1016/j.prp.2023.154743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 08/03/2023] [Indexed: 08/09/2023]
Abstract
Osteosarcoma (OS) is an aggressive bone tumor that originates from mesenchymal cells. It is considered as the eighth most frequent childhood cancer that mainly affects the tibia and femur among the teenagers and young adults. OS can be usually diagnosed by a combination of MRI and surgical biopsy. The intra-arterial cisplatin (CDDP) and Adriamycin is one of the methods of choices for the OS treatment. CDDP induces tumor cell death by disturbing the DNA replication. Although, CDDP has a critical role in improving the clinical complication in OS patients, a high ratio of CDDP resistance is observed among these patients. Prolonged CDDP administrations have also serious side effects in normal tissues and organs. Therefore, the molecular mechanisms of CDDP resistance should be clarified to define the novel therapeutic modalities in OS. Multidrug resistance (MDR) can be caused by various cellular and molecular processes such as drug efflux, detoxification, and signaling pathways. MicroRNAs (miRNAs) are the key regulators of CDDP response by the post transcriptional regulation of target genes involved in MDR. In the present review we have discussed all of the miRNAs associated with CDDP response in OS cells. It was observed that the majority of reported miRNAs increased CDDP sensitivity in OS cells through the regulation of signaling pathways, apoptosis, transporters, and autophagy. This review highlights the miRNAs as reliable non-invasive markers for the prediction of CDDP response in OS patients.
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Affiliation(s)
- Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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MicroRNAs and osteosarcoma: Potential targets for inhibiting metastasis and increasing chemosensitivity. Biochem Pharmacol 2022; 201:115094. [PMID: 35588853 DOI: 10.1016/j.bcp.2022.115094] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 05/10/2022] [Accepted: 05/11/2022] [Indexed: 12/12/2022]
Abstract
Osteosarcoma (OS) is the third most common cancer in young adults after lymphoma and brain cancer. Metastasis, like other cellular events, is dependent on signaling pathways; a series of changes in some proteins and signaling pathways pave the way for OS cells to invade and migrate. Ezrin, TGF-β, Notch, RUNX2, matrix metalloproteinases (MMPs), Wnt/β-catenin, and phosphoinositide 3-kinase (PI3K)/AKT are among the most important of these proteins and signaling pathways. Despite the improvements in treating OS, the overall survival of patients suffering from the metastatic disease has not experienced any significant change after surgical treatments and chemotherapy and 5-years overall survival in patients with metastatic OS is about 20%. Studies have shown that overexpression or inhibition of some microRNAs (miRNAs) has significant effects in limiting the invasion and migration of OS cells. The results of these studies highlight the potential of the clinical application of some miRNA mimics and miRNA inhibitors (antagomiRs) to inhibit OS metastasis in the future. In addition, some studies have shown that miRNAs are associated with the most important drug resistance mechanisms in OS, and some miRNAs are highly effective targets to increase chemosensitivity. The results of these studies suggest that miRNA mimics and antagomiRs may be helpful to increase the efficacy of conventional chemotherapy drugs in the treatment of metastatic OS. In this article, we discussed the role of various signaling pathways and the involved miRNAs in the metastasis of OS, attempting to provide a comprehensive review of the literature on OS metastasis and chemosensitivity.
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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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Wang J, Wang L, Zhang C. miR-765 Acts as a Tumor Promoter and Indicates Poor Prognosis in Non-Small Cell Lung Cancer. Onco Targets Ther 2021; 14:4335-4343. [PMID: 34376998 PMCID: PMC8349552 DOI: 10.2147/ott.s284212] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 12/11/2020] [Indexed: 12/18/2022] Open
Abstract
PURPOSE Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related death worldwide with poor prognosis. Accumulating evidence indicates that miR-765 is an important regulator in the progression and prognosis of various cancers. In this study, the function in the progression and prognosis of NSCLC was investigated. PATIENTS AND METHODS The expression of miR-765 in NSCLC was analyzed by qRT-PCR. The effect of miR-765 on cell proliferation, migration, and invasion of NSCLC was evaluated by CCK8 and Transwell assay. Kaplan-Meier analysis and Cox regression analysis were employed to assess the prognostic value of miR-765. RESULTS The results demonstrated the significant upregulation of miR-765 in NSCLC tissues and cell lines relative to normal tissues and cells. High miR-765 expression was significantly correlated with the TNM stage of patients. Patients with high miR-765 expression showed a poorer prognosis than that of patients with low miR-765 expression. Cox analysis indicated that miR-765 could be considered as an independent prognostic factor for NSCLC. Additionally, the upregulation of miR-765 was revealed to promote NSCLC cell proliferation, migration, and invasion by targeting BMP6. CONCLUSION The overexpression of miR-765 in NSCLC was associated with TNM stage and poor prognosis of patients. miR-765 served as a tumor promoter of NSCLC by regulating BMP6. These findings provide a potential biomarker and therapeutic target for the prognosis and treatment of NSCLC.
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Affiliation(s)
- Jiying Wang
- Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of China
| | - Li Wang
- Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of China
| | - Congjun Zhang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People’s Republic of China
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Tang Z, Lu Y, Chen Y, Zhang J, Chen Z, Wang Q. Research Progress of MicroRNA in Chemotherapy Resistance of Osteosarcoma. Technol Cancer Res Treat 2021; 20:15330338211034262. [PMID: 34323141 PMCID: PMC8326994 DOI: 10.1177/15330338211034262] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Osteosarcoma (OS) is a malignant tumor prevalent in adolescents; however, a
clinically effective treatment for this malignancy is lacking. The lack of
effective treatment methods and factors, such as recurrence and drug resistance,
further dampen the prospect of clinically treating OS. In recent years, small
molecule microRNAs (miRNAs) with a length of approximately 20-24 nucleotides
have gradually attracted the attention of the medical community. Studies have
found that miRNAs can regulate the cell cycle, apoptosis, cell proliferation,
and cell proliferation. The metabolic response of cancer cells, invasion and
metastasis of cancer cells, and angiogenesis play an important role in the
process of tumorigenesis. miRNAs regulate gene expression by regulating mRNA
expression after transcription. A large amount of data from many studies
indicate that they have diagnostic and prognostic biomarker effects in OS and
are involved in regulating the metabolism of cancer cells and resistance or
sensitivity to chemotherapy drugs. Chemotherapy resistance is one of the most
critical problems in clinically treating OS. A large number of basic studies and
systematic summaries are required to provide a theoretical basis for elucidating
the mechanism and drug development of chemotherapeutic agents. Therefore, this
article discusses the role of miRNAs in OS resistance. Herein, the related
research progress of the studies is reviewed to provide more useful information
for the development of effective therapy.
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Affiliation(s)
- Zhaopeng Tang
- Department of Orthopaedics, 586778Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou, Gansu, China
| | - Yubao Lu
- The Second Clinical Medical College, 12426Lanzhou University, Lanzhou, Gansu, China.,Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yutong Chen
- The Second Clinical Medical College, 12426Lanzhou University, Lanzhou, Gansu, China
| | - Jiarui Zhang
- The First Clinical Medical College, 12426Lanzhou University, Lanzhou, Gansu, China
| | - Zhijun Chen
- The First Clinical Medical College, 12426Lanzhou University, Lanzhou, Gansu, China
| | - Qianfeng Wang
- Department of Gastroenterology, Gansu Provincial People's Hospital, Lanzhou, Gansu, China
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Circular RNA circPVT1 Contributes to Doxorubicin (DXR) Resistance of Osteosarcoma Cells by Regulating TRIAP1 via miR-137. BIOMED RESEARCH INTERNATIONAL 2021; 2021:7463867. [PMID: 33981772 PMCID: PMC8088374 DOI: 10.1155/2021/7463867] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 08/25/2020] [Accepted: 04/13/2021] [Indexed: 12/21/2022]
Abstract
Background Chemoresistance is a major obstacle to the treatment of osteosarcoma patients. Circular RNA (circRNA) circPVT1 has been reported to be related to the doxorubicin (DXR) resistance in osteosarcoma. This study is designed to explore the role and mechanism of circPVT1 in the DXR resistance of osteosarcoma. Methods circPVT1, microRNA-137 (miR-137), and TP53-regulated inhibitor of apoptosis 1 (TRIAP1) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). The protein levels of ATP-binding cassette, subfamily C, member 1 (ABCC1), multidrug resistance-associated protein 1 (MRP-1), cleaved- (c-) caspase-3, B-cell lymphoma-2 (Bcl-2), and TRIAP1 were examined by a western blot assay. Cell viability, proliferation, and apoptosis were detected by cell counting kit-8 (CCK-8), colony formation, and flow cytometry assays, severally. The binding relationship between miR-137 and circPVT1 or TRIAP1 was predicted by starbase 3.0 and then verified by dual-luciferase reporter and RNA Immunoprecipitation (RIP) assays. The biological role of circPVT1 in osteosarcoma tumor growth and drug resistance was examined by the xenograft tumor model in vivo. Results. circPVT1 and TRIAP1 were highly expressed, and miR-137 was decreased in DXR-resistant osteosarcoma tissues and cells. Moreover, circPVT1 knockdown could boost DXR sensitivity by inhibiting DXR-caused proliferation and DXR-induced apoptosis in DXR-resistant osteosarcoma cells in vitro. The mechanical analysis discovered that circPVT1 acted as a sponge of miR-137 to regulate TRIAP1 expression. circPVT1 silencing increased the drug sensitivity of osteosarcoma in vivo. Conclusion. circPVT1 boosted DXR resistance of osteosarcoma cells partly by regulating the miR-137/TRIAP1 axis, hinting a promising therapeutic target for the osteosarcoma treatment.
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Sadoughi F, Maleki Dana P, Asemi Z, Yousefi B. DNA damage response and repair in osteosarcoma: Defects, regulation and therapeutic implications. DNA Repair (Amst) 2021; 102:103105. [PMID: 33836418 DOI: 10.1016/j.dnarep.2021.103105] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 03/20/2021] [Indexed: 01/03/2023]
Abstract
Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents which has the survival rate of 20% in its advanced stages. Osteosarcomas are mostly resistance to our common treatments. DNA damage response (DDR) is a specialized multistep process containing abundant proteins which are necessary for the survival of any cell and organism. DDR machinery detects a diversity of DNA lesions and inhibits the cell cycle progression if these lesions are not repairable. DDR is involved in aging, age-related diseases, and cancer. In recent years, DDR inhibitors have gained the attention of researches due to their potentials in offering novel therapeutic targets and improving the response of many cancers to either chemo- or radio-therapy. In this regard, we tried to gather a great body of evidence about the role of DDR ingredients in osteosarcoma's initiation/progression, prognosis, and treatment.
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Affiliation(s)
- Fatemeh Sadoughi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| | - Parisa Maleki Dana
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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12
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Mechanisms of Resistance to Conventional Therapies for Osteosarcoma. Cancers (Basel) 2021; 13:cancers13040683. [PMID: 33567616 PMCID: PMC7915189 DOI: 10.3390/cancers13040683] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/02/2021] [Accepted: 02/03/2021] [Indexed: 02/06/2023] Open
Abstract
Osteosarcoma (OS) is the most common primary bone tumor, mainly occurring in children and adolescents. Current standard therapy includes tumor resection associated with multidrug chemotherapy. However, patient survival has not evolved for the past decades. Since the 1970s, the 5-year survival rate is around 75% for patients with localized OS but dramatically drops to 20% for bad responders to chemotherapy or patients with metastases. Resistance is one of the biological processes at the origin of therapeutic failure. Therefore, it is necessary to better understand and decipher molecular mechanisms of resistance to conventional chemotherapy in order to develop new strategies and to adapt treatments for patients, thus improving the survival rate. This review will describe most of the molecular mechanisms involved in OS chemoresistance, such as a decrease in intracellular accumulation of drugs, inactivation of drugs, improved DNA repair, modulations of signaling pathways, resistance linked to autophagy, disruption in genes expression linked to the cell cycle, or even implication of the micro-environment. We will also give an overview of potential therapeutic strategies to circumvent resistance development.
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13
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Prudowsky ZD, Yustein JT. Recent Insights into Therapy Resistance in Osteosarcoma. Cancers (Basel) 2020; 13:E83. [PMID: 33396725 PMCID: PMC7795058 DOI: 10.3390/cancers13010083] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 12/25/2020] [Accepted: 12/28/2020] [Indexed: 12/22/2022] Open
Abstract
Osteosarcoma, the most common bone malignancy of childhood, has been a challenge to treat and cure. Standard chemotherapy regimens work well for many patients, but there remain minimal options for patients with progressive or resistant disease, as clinical trials over recent decades have failed to significantly improve survival. A better understanding of therapy resistance is necessary to improve current treatments and design new strategies for future treatment options. In this review, we discuss known mechanisms and recent scientific advancements regarding osteosarcoma and its patterns of resistance against chemotherapy, radiation, and other newly-introduced therapeutics.
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Affiliation(s)
- Zachary D. Prudowsky
- Texas Children’s Cancer and Hematology Centers and The Faris D. Virani Ewing Sarcoma Center, Houston, TX 77030, USA;
- Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jason T. Yustein
- Texas Children’s Cancer and Hematology Centers and The Faris D. Virani Ewing Sarcoma Center, Houston, TX 77030, USA;
- Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
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Lilienthal I, Herold N. Targeting Molecular Mechanisms Underlying Treatment Efficacy and Resistance in Osteosarcoma: A Review of Current and Future Strategies. Int J Mol Sci 2020; 21:ijms21186885. [PMID: 32961800 PMCID: PMC7555161 DOI: 10.3390/ijms21186885] [Citation(s) in RCA: 185] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/13/2020] [Accepted: 09/15/2020] [Indexed: 12/12/2022] Open
Abstract
Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Due to micrometastatic spread, radical surgery alone rarely results in cure. Introduction of combination chemotherapy in the 1970s, however, dramatically increased overall survival rates from 20% to approximately 70%. Unfortunately, large clinical trials aiming to intensify treatment in the past decades have failed to achieve higher cure rates. In this review, we revisit how the heterogenous nature of osteosarcoma as well as acquired and intrinsic resistance to chemotherapy can account for stagnation in therapy improvement. We summarise current osteosarcoma treatment strategies focusing on molecular determinants of treatment susceptibility and resistance. Understanding therapy susceptibility and resistance provides a basis for rational therapy betterment for both identifying patients that might be cured with less toxic interventions and targeting resistance mechanisms to sensitise resistant osteosarcoma to conventional therapies.
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Affiliation(s)
- Ingrid Lilienthal
- Division of Paediatric Oncology, Department of Women’s and Children’s Health, Karolinska Institutet, SE-171 76 Stockholm, Sweden
- Correspondence: (I.L.); (N.H.); Tel.: +46-(0)8-52483204 (I.L. & N.H.)
| | - Nikolas Herold
- Division of Paediatric Oncology, Department of Women’s and Children’s Health, Karolinska Institutet, SE-171 76 Stockholm, Sweden
- Paediatric Oncology, Astrid Lindgren’s Children Hospital, Karolinska University Hospital, SE-171 76 Stockholm, Sweden
- Correspondence: (I.L.); (N.H.); Tel.: +46-(0)8-52483204 (I.L. & N.H.)
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