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Ghosh PK, Ghosh A. Dysregulation of noncoding RNA in chordoma; implications in identifying potential targets for novel therapeutic approaches. Mol Biol Rep 2024; 51:125. [PMID: 38236360 DOI: 10.1007/s11033-023-09017-9] [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: 08/19/2023] [Accepted: 10/23/2023] [Indexed: 01/19/2024]
Abstract
Chordoma is a rare form of bone cancer develops in the spinal cord and skull. Instead of conventional (radio/chemotherapies) and targeted therapies, the disease is associated with high rate of recurrence and poor patient survival. Thus, for better disease management, the molecular pathogenesis of chordoma should be studied in detail to identify dysregulated biomolecules that can be targeted by novel therapeutics. Recent research showed frequent dysregulation of long noncoding RNA (lncRNA), microRNA (miRNA), and circular RNA (circRNA) in association with aggressive tumor phenotypes like cell proliferation, migration, invasion, and metastasis in a variety of cancers, including chordoma. Apart from diagnostic and prognostic importance, noncoding RNAs may serve as promising targets for novel therapeutics in cancer. In this review, we summarized a list of miRNAs, lncRNAs, and circRNA found to be dysregulated in chordoma from available data published in relevant databases (PubMed), as such an approach seems to be rare to date. The dysregulated noncoding RNAs were also associated with adverse tumor phenotypes to assess the impact on disease pathogenesis and, associated downstream molecular pathways were focused. Synthetic compounds and natural products that were reported to target the noncoding RNAs in other malignancies were also listed from published literature and proposed as potential therapeutic agents in chordoma. This review will provide information for further research on chordoma focusing on detailed characterization of dysregulated lncRNAs, miRNAs, and circRNA to understand the disease pathogenesis and, exploration of suitable natural and synthetic products targeting dysregulated non-coding RNAs to develop effective therapeutic measures.
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Affiliation(s)
- Pramit Kumar Ghosh
- Department of Life Sciences, Presidency University, Kolkata, West Bengal, India
| | - Amlan Ghosh
- Department of Life Sciences, Presidency University, Kolkata, West Bengal, India.
- Genetics of Non-communicable Diseases, Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, 700073, India.
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Tu K, Lee S, Roy S, Sawant A, Shukla H. Dysregulated Epigenetics of Chordoma: Prognostic Markers and Therapeutic Targets. Curr Cancer Drug Targets 2022; 22:678-690. [PMID: 35440334 DOI: 10.2174/1568009622666220419122716] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 02/08/2022] [Accepted: 02/10/2022] [Indexed: 11/22/2022]
Abstract
Chordoma is a rare, slow-growing sarcoma that is locally aggressive, and typically resistant to conventional chemo- and radiotherapies. Despite its low incidence, chordoma remains a clinical challenge because therapeutic options for chordoma are limited, and little is known about the molecular mechanisms involved in resistance to therapies. Furthermore, there are currently no established predictive or prognostic biomarkers to follow disease progression or treatment. Whole-genome sequencing of chordoma tissues has demonstrated a low-frequency mutation rate compared to other cancers. This has generated interest in the role of epigenetic events in chordoma pathogenesis. In this review, we discuss the current understanding of the epigenetic drivers of chordoma and their potential applications in prognosis and the development of new therapies.
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Affiliation(s)
- Kevin Tu
- Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland school of Medicine, Baltimore, MD, USA.,Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, College Park, MD, USA
| | - Sang Lee
- Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
| | - Sanjit Roy
- Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland school of Medicine, Baltimore, MD, USA
| | - Amit Sawant
- Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland school of Medicine, Baltimore, MD, USA
| | - Hem Shukla
- Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland school of Medicine, Baltimore, MD, USA
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Zhang K, Liu Z, Tang Y, Shao X, Hua X, Liu H, Yang H, Chen K. LncRNA NONHSAT114552 Sponges miR-320d to Promote Proliferation and Invasion of Chordoma Through Upregulating NRP1. Front Pharmacol 2021; 12:773918. [PMID: 34721048 PMCID: PMC8548433 DOI: 10.3389/fphar.2021.773918] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 09/30/2021] [Indexed: 12/02/2022] Open
Abstract
Chordoma is a relatively rare malignant bone tumor with high local recurrence. To date, the mechanism remains unclear. lncRNAs play a pivotal role in tumorigenesis by acting as competitive endogenous RNAs of microRNAs. However, the biological role of lncRNA is still unclear in chordoma. In this research, our aim is to investigate the roles and regulation mechanisms of lncRNA NONHSAT114552 in chordoma development. The expression level of NONHSAT114552 and miR-320d in chordoma tissues was determined by qRT-PCR. Meantime, the correlation between NONHSAT114552 and clinical prognosis was also studied. Bioinformatics analysis and luciferase reporter assays were used to verify the relationship between NONHSAT114552 and miR-320d, and between miR-320d and Neuropilin 1 (NRP1). In addition, effects of NONHSAT114552 on chordoma cells (U-CH1 and U-CH2) proliferation and invasion and its regulation on miR-320d were also evaluated. Furthermore, the influences of NONHSAT114552/miR-320d/NRP1 axis on chordoma tumorigenesis were investigated in vivo. NONHSAT114552 was overexpressed while miR-320d was down-regulated in chordoma tissue compared to fetal nucleus pulposus. Kaplan-Meier survival analysis showed that NONHSAT114552 overexpression was associated with patients’ poor prognosis. Knockdown of NONHSAT114552 significantly suppressed chordoma cell proliferation and invasion. In vitro studies confirmed that NONHSAT114552 acted as ceRNA to regulate NRP1 by directly sponging miR-320d, thus facilitating chordoma cell proliferation and invasion. In vivo study demonstrated that NONHSAT114552 moderated chordoma growth by sponging miR-320d to regulating NRP1. Our findings indicate that lncRNA NONHSAT114552 exhibits a critical role in the tumorigenesis and development of chordoma and it may become one potential prognostic marker and therapeutic target for this disease. .
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Affiliation(s)
- Kai Zhang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zixiang Liu
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yingchuang Tang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiaofeng Shao
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xi Hua
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Hao Liu
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Huilin Yang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Kangwu Chen
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
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Circ-HIPK2 Accelerates Cell Apoptosis and Autophagy in Myocardial Oxidative Injury by Sponging miR-485-5p and Targeting ATG101. J Cardiovasc Pharmacol 2021; 76:427-436. [PMID: 33027196 DOI: 10.1097/fjc.0000000000000879] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Myocardial injury has been deemed as a major cause of heart diseases including myocarditis and coronary heart disease, which have brought multiple mortalities globally. Long non-coding RNAs (lncRNAs) are widely recognized in diverse diseases. However, the role of circular RNA HIPK2 (circ-HIPK2) remains unclear in myocardial injury induced by H2O2. We attempted to investigate the probable role of circ-HIPK2 in myocardial injury induced by H2O2. This study discovered that the treatment of H2O2 inhibited cell proliferation but boosted cell apoptosis and autophagy. ATG101 was upregulated in primary mouse neonatal cardiomyocytes under H2O2 treatment. ATG101 knockdown promoted proliferation and limited apoptosis by attenuating autophagy in H2O2-injured mouse neonatal cardiomyocytes. Furthermore, miR-485-5p was validated to combine with ATG101 and circ-HIPK2, and circ-HIPK2 positively regulated ATG101 expression by sponging miR-485-5p. At last, silenced circ-HIPK2 mediated the promotion of cell proliferation, and repression of cell apoptosis was restored by ATG101 amplification. In a word, circ-HIPK2 facilitates autophagy to accelerate cell apoptosis and cell death in H2O2-caused myocardial oxidative injury through the miR-485-5p/ATG101 pathway, indicating a novel therapeutic target point for patients with myocardial injury.
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Huang W, Yan YG, Wang WJ, Ouyang ZH, Li XL, Zhang TL, Wang XB, Wang B, Lv GH, Li J, Zou MX. Development and Validation of a 6-miRNA Prognostic Signature in Spinal Chordoma. Front Oncol 2020; 10:556902. [PMID: 33194623 PMCID: PMC7656123 DOI: 10.3389/fonc.2020.556902] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 09/29/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Published data have suggested a critical role for microRNA (miRNA) expression in chordoma progression. However, most of these studies focus on single miRNA and no multi-miRNA prognostic signature has been currently established for chordoma. In this study, we sought to develop and validate a 6-miRNA risk score (miRscore) model for survival prediction. METHODS Medline, Embase, and Google scholar searches (from inception to July 20, 2018) were conducted to identify candidate miRNAs with prognostic value as per predefined criteria. Quantitative RT-PCR was used to measure miRNA levels in 114 spinal chordoma (54 in the training and 60 in the validation cohort) and 20 control specimens. Subsequently, the miRscore was built based on miRNAs data. RESULTS Literature searches identified six prognostic miRNAs (miR-574-3p, miR-1237-3p, miR-140-3p, miR-1, miR-155, and miR-1290) with differential expression in tumor tissues. Bioinformatical analysis revealed an important regulatory role for miR-574-3p/EGFR signaling in chordoma and showed that the target genes of these prognostic miRNAs were mainly enriched in transcription regulation, protein binding and cancer-related pathways. In both cohorts, the miRscore was associated with surrounding muscle invasion by tumor and/or other aggressive features. The miRscore model well predicted local recurrence-free survival and overall survival, which remained after adjusting for other relevant covariates. Further time-dependent receiver operating characteristics analysis in the two cohorts found that the miRscore classifier had stronger prognostic power than known clinical predictors and improved the ability of Enneking staging to predict outcomes. Importantly, recursive-partitioning analysis of both samples combined separated patients into four prognostically distinct risk subgroups for recurrence and survival (both P < 0.001). CONCLUSIONS These data suggest the miRscore as a useful prognostic stratification tool in spinal chordoma and may represent an important step toward future personalized treatment of patients.
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Affiliation(s)
- Wei Huang
- Department of Spine Surgery, The First Affiliated Hospital, University of South China, Hengyang, China
- Health Management Center, The First Affiliated Hospital, University of South China, Hengyang, China
| | - Yi-Guo Yan
- Department of Spine Surgery, The First Affiliated Hospital, University of South China, Hengyang, China
| | - Wen-Jun Wang
- Department of Spine Surgery, The First Affiliated Hospital, University of South China, Hengyang, China
| | - Zhi-Hua Ouyang
- Department of Spine Surgery, The First Affiliated Hospital, University of South China, Hengyang, China
| | - Xue-Lin Li
- Department of Spine Surgery, The First Affiliated Hospital, University of South China, Hengyang, China
| | - Tao-Lan Zhang
- Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, United States
| | - Xiao-Bin Wang
- Department of Spine Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Bing Wang
- Department of Spine Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Guo-Hua Lv
- Department of Spine Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Jing Li
- Department of Spine Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ming-Xiang Zou
- Department of Spine Surgery, The First Affiliated Hospital, University of South China, Hengyang, China
- Department of Spine Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
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Yao J, Wu X. Upregulation Of miR-149-3p Suppresses Spinal Chordoma Malignancy By Targeting Smad3. Onco Targets Ther 2019; 12:9987-9997. [PMID: 31819495 PMCID: PMC6875263 DOI: 10.2147/ott.s222380] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 10/18/2019] [Indexed: 12/17/2022] Open
Abstract
Purpose Dysregulation of miRNAs plays an important role in the malignancy of different tumors including chordoma. Expression of miR-149-3p was earlier reported to be downregulated in chordoma tissue. However, its biological role remains to be unrevealed in chordoma, especially in spinal chordoma. Methods Expression of miR-149-3p and Smad3 was detected by RT-qPCR and Western blot. Chordoma malignancy was evaluated by cell proliferation, migration, invasion, and apoptosis using MTT assay, transwell assay, flow cytometry analyzing apoptosis rate, and Western blot-determined expression of Bcl-2, Bax, and cleaved caspase 3, respectively. The target binding between miR-149-3p and Smad3 was predicted by TargetScan Human website and confirmed by luciferase reporter assay and RNA immunoprecipitation. Xenograft tumors were generated, and expression of miR-149-3p and Smad3 was investigated in vivo. Results miR-149-3p was downregulated in spinal chordoma tissues and cells, and its overexpression promoted chordoma cell apoptosis and inhibited proliferation, migration, and invasion in U-CH1 and MUG-Chor1 cells. Unexpectedly, Smad3 was a downstream target of miR-149-3p and negatively correlated with miR-149-3p expression in chordoma tissues. Besides, Smad3 was upregulated in chordoma tissues and its silencing had a similar effect as miR-149-3p overexpression in U-CH1 and MUG-Chor1 cells. Moreover, Smad3 upregulation could partially reverse the tumor-suppressive effect of miR-149-3p in chordoma cells. In vivo, the tumorigenesis of U-CH1 and MUG-Chor1 cells was impaired by upregulated miR-149-3p through decreasing Smad3 expression. Conclusion miR-149-3p could serve as a tumor suppressor in spinal chordoma through targeting and downregulating Smad3.
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Affiliation(s)
- Jie Yao
- Department of Spine, The Orthopedic Hospital of Zhengzhou, Zhengzhou, Henan 450099, People's Republic of China
| | - Xuejian Wu
- Department of Orthopaedics, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, People's Republic of China
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Yang CH, Wang Y, Sims M, Cai C, Pfeffer LM. MicroRNA-1 suppresses glioblastoma in preclinical models by targeting fibronectin. Cancer Lett 2019; 465:59-67. [DOI: 10.1016/j.canlet.2019.08.021] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 08/19/2019] [Accepted: 08/30/2019] [Indexed: 12/18/2022]
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Tuysuz EC, Gulluoglu S, Yaltirik CK, Ozbey U, Kuskucu A, Çoban EA, Sahin F, Türe U, Bayrak OF. Distinctive role of dysregulated miRNAs in chordoma cancer stem-like cell maintenance. Exp Cell Res 2019; 380:9-19. [DOI: 10.1016/j.yexcr.2019.03.039] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 01/08/2019] [Accepted: 03/28/2019] [Indexed: 12/16/2022]
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Zhou J, Jiang Y, Zhang H, Chen L, Luo P, Li L, Zhao J, Lv F, Zou D, Zhang Y, Jing Z. Clinicopathological implications of TIM3 + tumor-infiltrating lymphocytes and the miR-455-5p/Galectin-9 axis in skull base chordoma patients. Cancer Immunol Immunother 2019; 68:1157-1169. [PMID: 31197461 PMCID: PMC11028388 DOI: 10.1007/s00262-019-02349-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 05/24/2019] [Indexed: 12/14/2022]
Abstract
Chordoma is difficult to eradicate due to high local recurrence rates. The immune microenvironment is closely associated with tumor prognosis; however, its role in skull base chordoma is unknown. The expression of Galectin-9 (Gal9) and tumor-infiltrating lymphocyte (TIL) markers was assessed by immunohistochemistry. Kaplan-Meier and multivariate Cox analyses were used to assessing local recurrence-free survival (LRFS) and overall survival (OS) of patients. MiR-455-5p was identified as a regulator of Gal9 expression. Immunopositivity for Gal9 was associated with tumor invasion (p = 0.019), Karnofsky performance status (KPS) score (p = 0.017), and total TIL count (p < 0.001); downregulation of miR-455-5p was correlated with tumor invasion (p = 0.017) and poor prognosis; and the T-cell immunoglobulin and mucin-domain 3 (TIM3)+ TIL count was associated with chordoma invasion (p = 0.010) and KPS score (p = 0.037). Furthermore, multivariate analysis indicated that only TIM3+ TIL density was an independent prognostic factor for LRFS (p = 0.010) and OS (p = 0.016). These results can be used to predict clinical outcome and provide a basis for immune therapy in skull base chordoma patients.
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Affiliation(s)
- Jinpeng Zhou
- Department of Neurosurgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, China
| | - Yang Jiang
- Department of Neurosurgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, China
- Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 100 Haining Road, Shanghai, 200080, China
| | - Haiying Zhang
- International Education College, Liaoning University of Traditional Chinese Medicine, No. 79, Chongshan East Road, Huanggu District, Shenyang, 110032, China
| | - Lian Chen
- Department of Neurosurgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, China
| | - Peng Luo
- Department of Neurosurgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, China
| | - Long Li
- Department of Neurosurgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, China
| | - Junshuang Zhao
- Department of Neurosurgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, China
| | - Fei Lv
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, China
| | - Dan Zou
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, China
| | - Ye Zhang
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, China.
| | - Zhitao Jing
- Department of Neurosurgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Heping District, Shenyang, 110001, China.
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Liu J, Huang Y, Cheng Q, Wang J, Zuo J, Liang Y, Yuan G. miR-1-3p suppresses the epithelial-mesenchymal transition property in renal cell cancer by downregulating Fibronectin 1. Cancer Manag Res 2019; 11:5573-5587. [PMID: 31417307 PMCID: PMC6594013 DOI: 10.2147/cmar.s200707] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Accepted: 05/14/2019] [Indexed: 12/23/2022] Open
Abstract
Purpose Renal cell cancer (RCC) is one of the primary causes of malignancy deaths all over the world. The most important cause of RCC-related mortality is metastasis. Epithelial-mesenchymal transition (EMT) plays an important role in metastasis of malignant tumors including RCC. miR-1-3p is confirmed to be decreased in many types of cancer. Nevertheless, the function of miR-1-3p in RCC metastasis and EMT process was still unclear. Materials and methods In this study, information from clinical investigation, in vitro study, and in vivo study discovered miR-1-3p expression character and its status in RCC. The character of miR-1-3p in invasive and metastatic properties in vitro and in vivo was also inspected in RCC cells and xenograft tumor model, and expression levels of EMT markers were evaluated in RCC cells and tissues. Results miR-1-3p was proved to be decreased in RCC cell lines and tissues compared with normal renal cells and tissues. miR-1-3p expression level in RCC tissues was closely related with capsulation, lymph node metastasis, and vascular invasion. miR-1-3p was found to be able to block the EMT process in A498 and CAKI-1 RCC cells and tumors. Luciferase reporter assay and expression level rescue assays were employed to reveal that miR-1-3p inhibited the invasion and migration property of RCC cells by directly targeting Fibronectin 1. Upregulation of Fibronectin 1 partially reversed the suppressive effect of miR-1-3p on EMT process. Conclusion In brief, this study has verified that miR-1-3p blocked the EMT process of RCC cells by reducing Fibronectin 1 expression. miR-1-3p/Fibronectin 1 axis may be considered as a new target for drug development of RCC.
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Affiliation(s)
- Jianghui Liu
- Department of Emergency and Internal Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, People's Republic of China
| | - Yingxiong Huang
- Department of Emergency and Internal Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, People's Republic of China
| | - Quanyong Cheng
- Department of Emergency and Internal Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, People's Republic of China
| | - Jifei Wang
- Department of Emergency and Internal Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, People's Republic of China
| | - Jidong Zuo
- Department of Emergency and Internal Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, People's Republic of China
| | - Ying Liang
- Department of Nephrology, The Eighth People's Hospital of Guangzhou, Guangdong 510060, People's Republic of China
| | - Gang Yuan
- Department of Emergency and Internal Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, People's Republic of China
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Fujii R, Osaka E, Sato K, Tokuhashi Y. MiR-1 Suppresses Proliferation of Osteosarcoma Cells by Up-regulating p21 via PAX3. Cancer Genomics Proteomics 2019; 16:71-79. [PMID: 30587501 DOI: 10.21873/cgp.20113] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 10/18/2018] [Accepted: 10/19/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND/AIM miRNA-1(miR-1) is down-regulated in various cancer cells including osteosarcoma cells. This study was conducted to analyze the function of miR-1 in osteosarcoma cells. MATERIALS AND METHODS miR-1 expression in osteosarcoma cells was evaluated by qRT-PCR. Cell proliferation was evaluated after transfecting miR-1 by WST8 assay and FACS analysis, both in vitro and in vivo. RESULTS Overexpression of miR-1 suppressed cell proliferation and induced cell-cycle arrest in the G0-G1 phase by increasing p21 levels via a p53-independent pathway. Overexpression of miR-1 down-regulated PAX3, a potential p21-regulating gene. Moreover, knockdown of PAX3 suppressed cell proliferation by increasing p21 levels, and induced arrest at the G0/G1 phase. Administration of miR-1 showed an in vivo antitumor effect. CONCLUSION Overexpression of miR-1 suppressed cell proliferation and induced arrest in the G0/G1 phase by increasing p21 levels via a p53-independent pathway through PAX3 suppression. These results indicate that miR-1 could be a therapeutic target for osteosarcoma.
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Affiliation(s)
- Ryota Fujii
- Department of Orthopaedic Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Eiji Osaka
- Department of Orthopaedic Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Kentaro Sato
- Department of Orthopaedic Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Yasuaki Tokuhashi
- Department of Orthopaedic Surgery, Nihon University School of Medicine, Tokyo, Japan
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12
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Wang B, Zhang K, Chen H, Lu J, Wu G, Yang H, Chen K. miR-1290 inhibits chordoma cell proliferation and invasion by targeting Robo1. Transl Cancer Res 2019; 8:542-551. [PMID: 35116786 PMCID: PMC8797437 DOI: 10.21037/tcr.2019.03.13] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Accepted: 02/28/2019] [Indexed: 11/06/2022]
Abstract
BACKGROUND Chordoma is a low-grade aggressive bone tumor with a high local recurrence. MicroRNAs (miRNAs) have been reported to play crucial roles in the development of chordoma. Our previous study has shown miR-1290 is associated with muscle invasion and the prognosis of chordoma. However, the underlying mechanism of miR-1290 in chordoma remains unclear. In this study, we aimed to explore the function of miR-1290 in the biological behaviors of chordoma. METHODS Sixteen sacral chordoma samples and 10 fetal nucleus pulposus specimens were collected for the detection of miR-1290 and Robo1 at the First Affiliated Hospital of Soochow University. Bioinformatic analysis and a luciferase reporter assay was used to verify the interaction between miR-1290 and the target gene robo1 in chordoma. Effects of miR-1290 expression on chordoma cell proliferation and invasion were explored by clone formation and Transwell assay in vitro. The underlying mechanisms of miR-1290 and Robo1 in chordoma cell proliferation and invasion were also explored in the U-CH1 cell line. RESULTS In vitro functional analysis, including clone formation, and Transwell assays indicated overexpression of miR-1290 significantly suppressed chordoma cell proliferation and invasion. Bioinformatic analysis revealed Robo1 as a potential target of miR-1290, and luciferase reporter assays demonstrated the association between miR-1290 and the Robo1 gene in U-CH1 cells. Robo1 was further confirmed to be up-regulated in chordoma tissues by immunohistochemistry (IHC), which is negatively correlated with miR-1290 expression in chordoma tissue. Additionally, we found down-regulation of miR-1290 could induce the expression of Robo1 in chordoma cells, while the elevation of miR-1290 expression could inhibit Robo1 expression in chordoma cells. CONCLUSIONS miR-1290 inhibits chordoma cell proliferation and invasion by negatively regulating the Robo1 gene.
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Affiliation(s)
- Bin Wang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215000, China.,Department of Orthopaedic Surgery, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, China
| | - Kai Zhang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215000, China
| | - Hao Chen
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215000, China
| | - Jian Lu
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215000, China
| | - Guizhong Wu
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215000, China
| | - Huilin Yang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215000, China
| | - Kangwu Chen
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215000, China
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Gao S, Zhao Z, Wu R, Wu L, Tian X, Zhang Z. MiR-1 inhibits prostate cancer PC3 cells proliferation through the Akt/mTOR signaling pathway by binding to c-Met. Biomed Pharmacother 2019; 109:1406-1410. [DOI: 10.1016/j.biopha.2018.10.098] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Revised: 10/11/2018] [Accepted: 10/18/2018] [Indexed: 12/14/2022] Open
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14
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Yang S, Li H, Chen L. MicroRNA-140 attenuates myocardial ischemia-reperfusion injury through suppressing mitochondria-mediated apoptosis by targeting YES1. J Cell Biochem 2018; 120:3813-3821. [PMID: 30259997 DOI: 10.1002/jcb.27663] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 08/21/2018] [Indexed: 12/21/2022]
Abstract
Myocardial ischemia-reperfusion (I/R) injury is thought to have its detrimental role in coronary heart disease (CHD), which is considered as the foremost cause of death all over the world. However, molecular mechanism in the progression of myocardial I/R injury is still unclear. The goal of this study was to investigate the expression and function of microRNA-140 (miR-140) in the process of myocardial I/R injury. The miR-140 expression level was analyzed in the myocardium with I/R injury and control myocardium using quantitative real-time polymerase chain reaction. Then the relation between the level of miR-140 and YES proto-oncogene 1 (YES1) was also investigated via luciferase reporter assay. Assessment of myocardial infarct size measurement of serum myocardial enzymes and electron microscopy analysis were used for analyzing the effect of miR-140 on myocardial I/R injury. We also used Western blot analysis to examine the expression levels of the mitochondrial fission-related proteins, Drp1 and Fis1. miR-140 is downregulated, and YES1 is upregulated after myocardial I/R injury. Overexpression of miR-140 could reduce the increase related to myocardial I/R injury in infarct size and myocardial enzymes, and it also could inhibit the expression of proteins related to mitochondrial morphology and myocardial I/R-induced mitochondrial apoptosis by targeting YES1. Taken together, these findings may provide a novel insight into the molecular mechanism of miR-140 and YES1 in the progression of myocardial I/R injury. MiR-140 might become a promising therapeutic target for treating myocardial I/R injury.
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Affiliation(s)
- Shuguo Yang
- Department of Cardiology, Linyi Central Hospital, Linyi, Shandong, China
| | - Haide Li
- Department of Cardiology, Linyi Central Hospital, Linyi, Shandong, China
| | - Lianghua Chen
- Department of Cardiology, Shandong Provincial Hospital, Jinan, Shandong, China
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15
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Li X, Seebacher NA, Hornicek FJ, Xiao T, Duan Z. Application of liquid biopsy in bone and soft tissue sarcomas: Present and future. Cancer Lett 2018; 439:66-77. [PMID: 30223067 DOI: 10.1016/j.canlet.2018.09.012] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2018] [Revised: 08/13/2018] [Accepted: 09/06/2018] [Indexed: 02/06/2023]
Abstract
Bone and soft tissue sarcomas account for approximately 1% of adult solid malignancies and 20% of pediatric solid malignancies. Sarcomas are divided into more than 50 subtypes. Each subtype is highly heterogeneous and characterized by significant morphological and phenotypic variability. Currently, sarcoma characterization is based on tissue biopsies. However, primary and invasive tissue biopsies may not accurately reflect the current disease condition following treatment as is may cause marked changes to the tumor cells. Liquid biopsy offers an alternative minimally invasive approach to provide dynamic tumor information, allowing for the application of precision medicine in the treatment of sarcomas. Recently, there have been numerous blood-based tumor components identified by liquid biopsy in sarcomas, including circulating tumor cells, circulating cell-free nucleic acids, tumor-derived exosomes and metabolites in circulation. Here, we summarize the current evolving technologies and then elaborate on emerging novel concepts that may further propel the field of liquid biopsy in sarcomas. We address the applications in the context of our current knowledge about liquid biopsy in sarcomas and highlight the potential of translating these recent advances into the clinic for more effective management strategies for sarcoma patients.
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Affiliation(s)
- Xiaoyang Li
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, PR China; Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, David Geffen School of Medicine at University of Los Angeles, Los Angeles, CA, 90095, USA.
| | - Nicole A Seebacher
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, David Geffen School of Medicine at University of Los Angeles, Los Angeles, CA, 90095, USA.
| | - Francis J Hornicek
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, David Geffen School of Medicine at University of Los Angeles, Los Angeles, CA, 90095, USA.
| | - Tao Xiao
- Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, PR China.
| | - Zhenfeng Duan
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, David Geffen School of Medicine at University of Los Angeles, Los Angeles, CA, 90095, USA.
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16
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Lang WJ, Chen FY. The reciprocal link between EVI1 and miRNAs in human malignancies. Gene 2018; 672:56-63. [DOI: 10.1016/j.gene.2018.06.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2017] [Revised: 03/05/2018] [Accepted: 06/03/2018] [Indexed: 12/26/2022]
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17
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Zhang H, Yang K, Ren T, Huang Y, Tang X, Guo W. miR-16-5p inhibits chordoma cell proliferation, invasion and metastasis by targeting Smad3. Cell Death Dis 2018; 9:680. [PMID: 29880900 PMCID: PMC5992191 DOI: 10.1038/s41419-018-0738-z] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 05/18/2018] [Accepted: 05/22/2018] [Indexed: 12/17/2022]
Abstract
Aberrantly expressed miRNAs play a crucial role in the development of multiple cancer types, including chordoma. However, the detailed molecular mechanisms are unclear and need to be elucidated. In this study, miRNAs were screened by miRNA array analysis and then confirmed by real-time PCR analysis. We found that miR-16-5p was significantly downregulated in chordoma, and overexpression of miR-16-5p suppressed chordoma cell proliferation, invasion and migration in vitro and in vivo and correlated with the upregulated expression of E-cadherin and downregulated expression of N-cadherin and vimentin. Furthermore, Smad3 was identified as a target of miR-16-5p, and Smad3 was highly expressed in chordoma tissues. Further research showed that knockdown of Smad3 had an effect similar to that of overexpression of miR-16-5p in chordoma cells. Our findings demonstrate that miR-16-5p plays a tumor suppressor role in chordoma progression by targeting Smad3, which could provide a promising prognostic and therapeutic strategy for chordoma treatment.
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Affiliation(s)
- Hongliang Zhang
- Musculoskeletal Tumor Center, Peking University People's Hospital, No. 11 Xizhimen South Street, Beijing, 100044, People's Republic of China.,Beijing Key Laboratory of Musculoskeletal Tumor, No. 11 Xizhimen South Street, Beijing, 100044, People's Republic of China
| | - Kang Yang
- Musculoskeletal Tumor Center, Peking University People's Hospital, No. 11 Xizhimen South Street, Beijing, 100044, People's Republic of China.,Beijing Key Laboratory of Musculoskeletal Tumor, No. 11 Xizhimen South Street, Beijing, 100044, People's Republic of China
| | - Tingting Ren
- Musculoskeletal Tumor Center, Peking University People's Hospital, No. 11 Xizhimen South Street, Beijing, 100044, People's Republic of China.,Beijing Key Laboratory of Musculoskeletal Tumor, No. 11 Xizhimen South Street, Beijing, 100044, People's Republic of China
| | - Yi Huang
- Musculoskeletal Tumor Center, Peking University People's Hospital, No. 11 Xizhimen South Street, Beijing, 100044, People's Republic of China.,Beijing Key Laboratory of Musculoskeletal Tumor, No. 11 Xizhimen South Street, Beijing, 100044, People's Republic of China
| | - Xiaodong Tang
- Musculoskeletal Tumor Center, Peking University People's Hospital, No. 11 Xizhimen South Street, Beijing, 100044, People's Republic of China. .,Beijing Key Laboratory of Musculoskeletal Tumor, No. 11 Xizhimen South Street, Beijing, 100044, People's Republic of China.
| | - Wei Guo
- Musculoskeletal Tumor Center, Peking University People's Hospital, No. 11 Xizhimen South Street, Beijing, 100044, People's Republic of China. .,Beijing Key Laboratory of Musculoskeletal Tumor, No. 11 Xizhimen South Street, Beijing, 100044, People's Republic of China.
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18
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Abstract
RATIONALE Chordomas are malignant neoplasms derived from incomplete regression of notochordal tissue along the craniococcygeal axis.It is rare for Chordoma arising from the lumbar spine and the traditional long-term prognosis is typically poor. PATIENT CONCERNS The persistent pain in the left side of the waist about 2 years. DIAGNOSES Chordoma. INTERVENTIONS The patient was treated with surgical resection of the total tumor, followed by the spinal internal fixation of L1 to L2 with pedicle screws. OUTCOMES After 5 month follow-up,we find the recurrence in the original lesion.At the 15 month follow-up,the patient was dead after a lot of times revisit by various doctor. LESSONS So It is suggest that the diagnosis should be carried out accurately at the early stage, the lesions and source of lesions should be cut away as broadly as possible, also the radiation and chemotherapy should be carried out after the operation as necessary.
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19
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He Y, Chen X, Yu Y, Li J, Hu Q, Xue C, Chen J, Shen S, Luo Y, Ren F, Li C, Bao J, Yan J, Qian G, Ren Z, Sun R, Cui G. LDHA is a direct target of miR-30d-5p and contributes to aggressive progression of gallbladder carcinoma. Mol Carcinog 2018; 57:772-783. [PMID: 29569755 DOI: 10.1002/mc.22799] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 03/06/2018] [Indexed: 01/03/2023]
Abstract
Gallbladder cancer (GBC) is the most general biliary tract malignancy, with poor prognosis due to rapid tumor progression and lack of specific symptoms. Lactate dehydrogenase-A (LDHA) can promote Warburg effect to produce lactate and Adenosine Triphosphate (ATP) in aerobic condition, which contributes to oncogenesis metastasis and drug resistance in various cancers. However, the expression and functional role of LDHA in GBC are largely unknown. We determined that LDHA was over-expressed in GBC tumor tissues compared with normal tissues, which was also an independent prognostic factor for the overall survival of GBC patients by tissue microarrays analysis. In addition, RNAi-mediated LDHA silencing could suppress the GBC cell proliferation, invasion, colony formation and glycolysis while promoting cell apoptosis in vitro. Similar results were observed in GBC cells treated with LDHA specific inhibitor FX11. Moreover, we confirmed that knockdown of LDHA could inhibit tumor growth in vivo. Additionally, we found that the 3'-untranslated region (3'-UTR) of LDHA mRNA was the direct target of microRNA-30d-5p (miR-30d-5p), which was low expressed in GBC tissues and associated with poor prognosis of GBC patients. Our findings disclose a novel role for miR-30d-5p/LDHA axis contribute to aggressive progression by reprogramming the metabolic process in GBC cells, and suggest a potential application of miR-30d-5p/LDHA axis in prognosis prediction and GBC treatment.
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Affiliation(s)
- Yuting He
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaolong Chen
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yan Yu
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Juan Li
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qiuyue Hu
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chen Xue
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jianan Chen
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shen Shen
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yonggang Luo
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Fang Ren
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chao Li
- Department of Bone and Soft Tissue, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Jie Bao
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jingya Yan
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guowu Qian
- Department of General Surgery, The Affiliated Nanyang Central Hospital of Zhengzhou University, Nanyang, China
| | - Zhigang Ren
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ranran Sun
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guangying Cui
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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20
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Sun R, Shen J, Gao Y, Zhou Y, Yu Z, Hornicek F, Kan Q, Duan Z. Overexpression of EZH2 is associated with the poor prognosis in osteosarcoma and function analysis indicates a therapeutic potential. Oncotarget 2018; 7:38333-38346. [PMID: 27223261 PMCID: PMC5122393 DOI: 10.18632/oncotarget.9518] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 05/08/2016] [Indexed: 12/24/2022] Open
Abstract
Osteosarcoma is a primary malignant bone tumor that has a poor prognosis due to local recurrence, metastasis, and chemotherapy resistance. Therefore, there is an urgent need to develop novel potential therapeutic targets for osteosarcoma. Enhancer of zeste homologue 2 (EZH2) is a member of the polycomb group of proteins, which has important functions in epigenetic silencing and cell cycle regulation. Overexpression of EZH2 has been found in several malignancies, however, its expression and the role of EZH2 in osteosarcoma is largely unknown. In this study, we examined EZH2 expression by immunohistochemistry in a large series of osteosarcoma tissues in association with tumor characteristics and patient outcomes. EZH2 expression was also analyzed in a microarray dataset of osteosarcoma. Results showed that higher expression of EZH2 was significantly associated with more aggressive tumor behavior and poor patient outcomes of osteosarcoma. We subsequently investigated the functional and therapeutic relevance of EZH2 as a target in osteosarcoma. Immunohistochemical analysis indicated that EZH2 expression was significantly associated with more aggressive tumor behavior and poorer patient outcomes of osteosarcoma. EZH2 silencing by siRNA inhibited osteosarcoma cell growth, proliferation, migration, and invasion. Moreover, suppression of EZH2 attenuated cancer stem cell functions. Similar results were observed in osteosarcoma cells treated with EZH2 specific inhibitor 3-deazaneplanocin A (DZNep), which exhausted cellular levels of EZH2. These results suggest that EZH2 is critical for the growth and metastasis of osteosarcoma, and an epigenetic therapy that pharmacologically targets EZH2 via specific inhibitors may constitute a novel approach to the treatment of osteosarcoma.
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Affiliation(s)
- Ranran Sun
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China.,Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Jacson Shen
- Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Yan Gao
- Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Yubing Zhou
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China
| | - Zujiang Yu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China
| | - Francis Hornicek
- Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Quancheng Kan
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China
| | - Zhenfeng Duan
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China.,Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, MA, 02114, USA
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21
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Wang Y, Chen K, Chen H, Zhang K, Lu J, Mao H, Yang H. Low expression of miRNA-1290 associated with local invasion and recurrence in sacral chordoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2017; 10:10934-10940. [PMID: 31966437 PMCID: PMC6965869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Accepted: 10/24/2017] [Indexed: 06/10/2023]
Abstract
Chordoma is a rare, locally aggressive neoplasm of bone, usually with poor prognosis. The treatment for chordoma has been unsatisfactory for decades. MiRNAs were recently introduced into this field and provided new insights to the pathogenesis and pathophysiology of chordoma. However, molecular basis of chordoma remains ambiguous up to now. This research aims to discover novel miRNA molecules as potential biomarkers and therapeutic targets. We measured the expression of miRNA-1290 in chordoma tissues and fetal nucleus pulposus tissues by quantitative real-time PCR. Further, we analyzed its association with the clinical features as well as the prognosis of patients. The expression of miRNA-1290 in chordoma samples was significantly lower than fetal nucleus pulposus samples (P=0.026). Low expression of miRNA-1290 contributed to tumor invasion into surrounding muscle (P=0.013), while no obvious significance was identified between miRNA-1290 expression and patients' age, gender, tumor location and size (P>0.05). Log-rank test showed that low-level miRNA-1290 expression had a prominent impact on the patients' RFS (P=0.004). Conclusively, miRNA-1290 might be a valuable prognostic biomarker and efficient therapeutic target for sacral chordoma.
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Affiliation(s)
- Yucheng Wang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University Suzhou, Jiangsu, P. R. China
| | - Kangwu Chen
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University Suzhou, Jiangsu, P. R. China
| | - Hao Chen
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University Suzhou, Jiangsu, P. R. China
| | - Kai Zhang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University Suzhou, Jiangsu, P. R. China
| | - Jian Lu
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University Suzhou, Jiangsu, P. R. China
| | - Haiqing Mao
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University Suzhou, Jiangsu, P. R. China
| | - Huilin Yang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Soochow University Suzhou, Jiangsu, P. R. China
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22
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Genetic aberrations and molecular biology of skull base chordoma and chondrosarcoma. Brain Tumor Pathol 2017; 34:78-90. [PMID: 28432450 DOI: 10.1007/s10014-017-0283-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Accepted: 03/27/2017] [Indexed: 12/20/2022]
Abstract
Chordomas and chondrosarcomas are two major malignant bone neoplasms located at the skull base. These tumors are rarely metastatic, but can be locally invasive and resistant to conventional chemotherapies and radiotherapies. Accordingly, therapeutic approaches for the treatment of these tumors can be difficult. Additionally, their location at the skull base makes them problematic. Although accurate diagnosis of these tumors is important because of their distinct prognoses, distinguishing between these tumor types is difficult due to overlapping radiological and histopathological findings. However, recent accumulation of molecular and genetic studies, including extracranial location analysis, has provided us clues for accurate diagnosis. In this report, we review the genetic aberrations and molecular biology of these two tumor types. Among the abundant genetic features of these tumors, brachyury immunohistochemistry and direct sequencing of IDH1/2 are simple and useful techniques that can be used to distinguish between these tumors. Although it is still unclear why these tumors, which have such distinct genetic backgrounds, show similar histopathological findings, comparison of their genetic backgrounds could provide essential information.
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Yang YK, Chan CM, Zhang Q, Xu HR, Niu XH. Computer Navigation-aided Resection of Sacral Chordomas. Chin Med J (Engl) 2017; 129:162-8. [PMID: 26830986 PMCID: PMC4799542 DOI: 10.4103/0366-6999.173465] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND Resection of sacral chordomas is challenging. The anatomy is complex, and there are often no bony landmarks to guide the resection. Achieving adequate surgical margins is, therefore, difficult, and the recurrence rate is high. Use of computer navigation may allow optimal preoperative planning and improve precision in tumor resection. The purpose of this study was to evaluate the safety and feasibility of computer navigation-aided resection of sacral chordomas. METHODS Between 2007 and 2013, a total of 26 patients with sacral chordoma underwent computer navigation-aided surgery were included and followed for a minimum of 18 months. There were 21 primary cases and 5 recurrent cases, with a mean age of 55.8 years old (range: 35-84 years old). Tumors were located above the level of the S3 neural foramen in 23 patients and below the level of the S3 neural foramen in 3 patients. Three-dimensional images were reconstructed with a computed tomography-based navigation system combined with the magnetic resonance images using the navigation software. Tumors were resected via a posterior approach assisted by the computer navigation. Mean follow-up was 38.6 months (range: 18-84 months). RESULTS Mean operative time was 307 min. Mean intraoperative blood loss was 3065 ml. For computer navigation, the mean registration deviation during surgery was 1.7 mm. There were 18 wide resections, 4 marginal resections, and 4 intralesional resections. All patients were alive at the final follow-up, with 2 (7.7%) exhibiting tumor recurrence. The other 24 patients were tumor-free. The mean Musculoskeletal Tumor Society Score was 27.3 (range: 19-30). CONCLUSIONS Computer-assisted navigation can be safely applied to the resection of the sacral chordomas, allowing execution of preoperative plans, and achieving good oncological outcomes. Nevertheless, this needs to be accomplished by surgeons with adequate experience and skill.
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Affiliation(s)
| | | | | | | | - Xiao-Hui Niu
- Department of Orthopedic Oncology Surgery, Beijing Ji Shui Tan Hospital, Peking University, Beijing 100035, China
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24
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Abstract
Chordomas are rare primary bone tumors arising from embryonic remnants of the notochord. They are slow-growing, locally aggressive, and destructive and typically involve the axial skeleton. Genetic studies have identified several mutations implicated in the pathogenesis of these tumors. Treatment poses a challenge given their insidious progression, degree of local invasion at presentation, and high recurrence rate. They tend to respond poorly to conventional chemotherapy and radiation. This makes radical resection the mainstay of their treatment. Recent advances in targeted chemotherapy and focused particle beam radiation, however, have improved the management and prognosis of these tumors.
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Affiliation(s)
- Carl Youssef
- Department of Neurosurgery, University of Texas Southwestern Medical Center, Dallas, Texas, 75390, USA
| | - Salah G Aoun
- Department of Neurosurgery, University of Texas Southwestern Medical Center, Dallas, Texas, 75390, USA
| | - Jessica R Moreno
- Department of Neurosurgery, University of Texas Southwestern Medical Center, Dallas, Texas, 75390, USA
| | - Carlos A Bagley
- Department of Neurosurgery, University of Texas Southwestern Medical Center, Dallas, Texas, 75390, USA
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25
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Yang Y, Niu X, Li Y, Liu W, Xu H. Recurrence and survival factors analysis of 171 cases of sacral chordoma in a single institute. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2016; 26:1910-1916. [DOI: 10.1007/s00586-016-4906-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2016] [Revised: 11/01/2016] [Accepted: 11/30/2016] [Indexed: 01/01/2023]
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26
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Han C, Shen JK, Hornicek FJ, Kan Q, Duan Z. Regulation of microRNA-1 (miR-1) expression in human cancer. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2016; 1860:227-232. [PMID: 27923712 DOI: 10.1016/j.bbagrm.2016.12.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Revised: 11/30/2016] [Accepted: 12/02/2016] [Indexed: 02/07/2023]
Abstract
MicroRNAs (miRs) have been found to play important roles in tumorigenesis, apoptosis, metastasis, and drug resistance in cancer. Among a number of miRs, miR-1 was shown to be predominantly downregulated in almost all examined human cancers. As a tumor suppressor miR involved in post-transcriptional regulation of crucial tumor associated gene expression, miR-1 represents a promising target for anticancer therapy. Re-expression of miR-1 can suppress cancer cell proliferation, promote apoptosis, and reverse drug resistance in cancers both in vitro and in vivo. Recently, the regulatory mechanisms of miR-1 expression have been studied in various cancers in different model systems. In this review, we summarize the mechanisms of miR-1 expression through epigenetic, transcriptional, and post-transcriptional regulation. These regulatory mechanisms of miR-1 expression could help us to understand the functions of altered miR-1 expression and provide valuable insights for further investigations into miR-1 based cancer therapy.
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Affiliation(s)
- Chao Han
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China; Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Jacson K Shen
- Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Francis J Hornicek
- Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Quancheng Kan
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China.
| | - Zhenfeng Duan
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China; Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, MA, USA.
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27
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Liu HT, Gao P. The roles of microRNAs related with progression and metastasis in human cancers. Tumour Biol 2016; 37:15383–15397. [PMID: 27714675 DOI: 10.1007/s13277-016-5436-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 09/23/2016] [Indexed: 02/06/2023] Open
Abstract
Metastasis is an important factor in predicting the prognosis of the patients with cancers and contributes to high cancer-related mortality. Recent studies indicated that microRNAs (miRNAs) played a functional role in the initiation and progression of human malignancies. MicroRNAs are small non-coding RNAs of about 22 nucleotides in length that can induce messenger RNA (mRNA) degradation or repress mRNA translation by binding to the 3' untranslated region (3'-UTR) of their target genes. Overwhelming reports indicated that miRNAs could regulate cancer invasion and metastasis via epithelial-to-mesenchymal transition (EMT)-related and/or non-EMT-related mechanisms. In this review, we concentrate on the underlying mechanisms of miRNAs in regulating cancer progression and metastasis.
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Affiliation(s)
- Hai-Ting Liu
- Department of Pathology, Qilu Hospital, Shandong University, Jinan, People's Republic of China
- Department of Pathology, School of Basic Medicine, Shandong University, Jinan, People's Republic of China
| | - Peng Gao
- Department of Pathology, Qilu Hospital, Shandong University, Jinan, People's Republic of China.
- Department of Pathology, School of Basic Medicine, Shandong University, Jinan, People's Republic of China.
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Wei W, Zhang Q, Wang Z, Yan B, Feng Y, Li P. miR-219-5p inhibits proliferation and clonogenicity in chordoma cells and is associated with tumor recurrence. Oncol Lett 2016; 12:4568-4576. [PMID: 28105164 PMCID: PMC5228431 DOI: 10.3892/ol.2016.5222] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Accepted: 09/16/2016] [Indexed: 01/01/2023] Open
Abstract
Chordoma is a rare malignant bone tumor that is usually localized to the skull base, vertebral column and sacrum. The transcription factor brachyury, which is encoded by the T gene, has a critical role in the development and progression of chordoma, although the mechanisms underlying brachyury regulation remain unclear. The aim of the current study was to identify and characterize microRNAs (miRs) that regulate brachyury expression in chordoma. MicroRNAs that target brachyury were predicted using miRanda and TargetScan. Using reverse transcription-quantitative polymerase chain reaction, miR-219-5p was shown to be significantly downregulated in chordoma tissues and the U-CH2 chordoma cell lines. A dual-luciferase reporter assay was used to validate the inhibitory effect of miR-219-5p on brachyury mRNA expression. The expression level of brachyury was downregulated in U-CH2 cells following transfection with miR-219-5p mimics and upregulated following transfection with the miR-219-5p inhibitor. The effects of miR-219-5p on the proliferation and clonogenicity of chordoma cells were assessed using cell counting kit-8, EdU and clone formation assays. These in vitro results indicated that miR-219-5p may have an important role in regulating the cell proliferation and clonogenicity of human chordoma cells, potentially by targeting brachyury. Furthermore, the associations between the expression levels of miR-219-5p and various clinicopathological factors were analyzed, and miR-219-5p expression was shown to correlate with tumor extent and recurrence. These results suggested that miR-219-5p functions as a tumor suppressor in chordoma and, therefore, that miR-219-50 may be a potential target for therapeutic intervention.
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Affiliation(s)
- Wei Wei
- Department of Otolaryngology, Head and Neck Surgery, Skull Base Surgery Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. China
| | - Qiuhang Zhang
- Department of Otolaryngology, Head and Neck Surgery, Skull Base Surgery Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. China
| | - Zhenlin Wang
- Department of Otolaryngology, Head and Neck Surgery, Skull Base Surgery Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. China
| | - Bo Yan
- Department of Otolaryngology, Head and Neck Surgery, Skull Base Surgery Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. China
| | - Yanjun Feng
- Department of Otolaryngology, Head and Neck Surgery, Skull Base Surgery Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. China
| | - Pu Li
- Department of Otolaryngology, Head and Neck Surgery, Skull Base Surgery Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. China
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Expression of programmed cell death ligand 1 (PD-L1) and prevalence of tumor-infiltrating lymphocytes (TILs) in chordoma. Oncotarget 2016; 6:11139-49. [PMID: 25871477 PMCID: PMC4484445 DOI: 10.18632/oncotarget.3576] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 02/21/2015] [Indexed: 12/31/2022] Open
Abstract
Chordomas are primary malignant tumors of the notochord that are resistant to conventional chemotherapy. Expression of programmed cell death ligand 1 (PD-L1), prevalence of tumor-infiltrating lymphocytes (TILs), and their clinical relevance in chordoma remain unknown. We evaluated PD-L1 expression in three chordoma cell lines and nine chordoma tissue samples by western blot. Immunohistochemical staining was performed on a chordoma tissue microarray (TMA) that contained 78 tissue specimens. We also correlated the expression of PD-L1 and TILs with clinical outcomes. PD-L1 protein expression was demonstrated to be induced by IFN-γ in both UCH1 and UCH2 cell lines. Across nine human chordoma tissue samples, PD-L1 protein was differentially expressed. 94.9% of chordoma samples showed positive PD-L1 expression in the TMA. The expression score of PD-L1 for metastatic chordoma tumors was significant higher as compared with non-metastatic chordoma tumors. Expression of PD-L1 protein significantly correlates with the presence of elevated TILs, which correlates with metastasis. In summary, our study showed high levels of PD-L1 are expressed in chordoma, which is correlated with the prevalence of TILs. The current study suggests targeting PD-L1 may be a novel immunotherapeutic strategy for chordoma clinical trials.
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Abstract
Chordoma is an extremely rare cancer, with an incidence of about one case per million persons per year in the USA and Europe (about 300 and 450 cases per year, respectively). The estimated median overall survival of patients with chordoma is approximately 6–7 years, yielding a rough estimate of chordoma prevalence at about 2000 in the USA and 3000 in Europe. Primary tumor develops along the axial spine between the clivus and sacrum and develops from the residual embryonic notochord. Brachyury (T), a transcription factor required for normal embryonic development, is expressed in the notochord and overexpressed in almost all cases of chordoma. The primary treatment for chordoma is surgical excision with wide local margins, when possible. Radiotherapy also plays a significant role in the adjuvant setting and when surgery is not possible. Unfortunately, in the advanced and/or metastatic setting, where the role of surgery and/or radiation is less clear, treatment options are very limited. To date, there have been no randomized, controlled trials in chordoma that have resulted in defined agents of clinical benefit for systemic treatment. This review briefly describes the natural history and initial treatment of chordoma and focuses on treatment options for advanced disease and potential avenues of research that may lead to improved treatment options in the future.
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Affiliation(s)
- Christopher R Heery
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 USA
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31
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Wu Z, Li X, Cai X, Huang C, Zheng M. miR-497 inhibits epithelial mesenchymal transition in breast carcinoma by targeting Slug. Tumour Biol 2015; 37:7939-50. [PMID: 26700673 DOI: 10.1007/s13277-015-4665-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2015] [Accepted: 12/16/2015] [Indexed: 12/21/2022] Open
Abstract
Epithelial to mesenchymal transition (EMT) is a critical step in the growth and dissemination of malignant diseases, including breast cancer. It is known that microRNAs (miRNAs) play important roles in the regulation of tumor properties in cancers. However, whether miR-497 contributes to EMT in breast cancer cells remains unknown. Our study demonstrated that the expression of miR-497 was significantly decreased in human breast cancer cell lines and breast cancer specimens. In breast cancer cells, EMT was inhibited and promoted by the over-expression as well as depletion of miR-497, respectively. Dual-Luciferase ReporterAassay confirmed that Slug was a direct target of miR-497. The upregulation of miR-497 in breast cancer cells suppressed cell proliferation and induced apoptosis both in vitro and in vivo. Correlation analysis indicated that miR-497 was highly negatively correlated with Slug expression in breast cancer specimens. The knockdown of Slug expression in breast cancer cells significantly suppressed cell proliferation and promoted apoptosis. Our results suggested that the expression of miR-497 is significantly correlated with EMT in breast cancer cells by regulating Slug at the transcriptional as well as translational levels. Therefore, targeting miR-497 may provide a novel strategy for the treatment of breast cancer.
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Affiliation(s)
- Zhihao Wu
- Department of Breast Surgery, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, 109 Xueyuanxi Road, Wenzhou, 325000, Zhejiang, China
| | - Xiangli Li
- Department of Breast Surgery, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, 109 Xueyuanxi Road, Wenzhou, 325000, Zhejiang, China
| | - Xuehong Cai
- Department of General Surgery, The First People Hospital of Yueyang, 39 Dongmaolin Road, Yueyang, 414000, Hunan, China
| | - Chenggang Huang
- Department of General Surgery, The First People Hospital of Yueyang, 39 Dongmaolin Road, Yueyang, 414000, Hunan, China
| | - Min Zheng
- Department of Breast Surgery, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, 109 Xueyuanxi Road, Wenzhou, 325000, Zhejiang, China. .,Department of General Surgery, The First People Hospital of Yueyang, 39 Dongmaolin Road, Yueyang, 414000, Hunan, China.
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Abstract
PURPOSE OF REVIEW Clival chordomas are rare malignant tumors associated with a poor prognosis. In this article, we review the current literature to identify a variety of strategies that provide guidelines toward the optimal management for this aggressive tumor. RECENT FINDINGS Molecular disease, particularly, the development of characterized chordoma cell lines, has become one of the new cornerstones for the histological diagnosis of chordomas and for the development of effective chemotherapeutic agents against this tumor. Brachyury, a transcription factor in notochord development, seems to provide an excellent diagnostic marker for chordoma and may also prove to be a valuable target for chordoma therapy. Aggressive cytoreductive surgery aiming for gross total resection with maintenance of key neurovascular structures, followed by proton beam or hadron radiation, provides the best local recurrence and overall survival rates. SUMMARY Clival chordomas are locally aggressive tumors that are challenging to treat because of their unique biology, proximity to key neurovascular structures and poor prognosis. Currently, chordomas are optimally managed with aggressive surgery, whilst preserving key structures, and postoperative radiation in a multidisciplinary setting with an experienced team. The advancement of molecular techniques offers exciting future diagnostic and therapeutic options in the management of chordomas.
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MicroRNAs in the pathobiology of sarcomas. J Transl Med 2015; 95:987-94. [PMID: 26121318 DOI: 10.1038/labinvest.2015.81] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Revised: 04/17/2015] [Accepted: 05/02/2015] [Indexed: 12/19/2022] Open
Abstract
Sarcomas are a rare and heterogeneous group of tumors. The last decade has witnessed extensive efforts to understand the pathobiology of many aggressive sarcoma types. In parallel, we have also begun to unravel the complex gene regulation processes mediated by microRNAs (miRNAs) in sarcomas and other cancers, discovering that microRNAs have critical roles in the majority of both oncogenic and tumor suppressor signaling networks. Expression profiles and a greater understanding of the biologic roles of microRNAs and other noncoding RNAs have considerably expanded our current knowledge and provided key pathobiological insights into many sarcomas, and helped identify novel therapeutic targets. The limited number of sarcoma patients in each sarcoma type and their heterogeneity pose distinct challenges in translating this knowledge into the clinic. It will be critical to prioritize these novel targets and choose those that have a broad applicability. A small group of microRNAs have conserved roles across many types of sarcomas and other cancers. Therapies that target these key microRNA-gene signaling and regulatory networks, in combination with standard of care treatment, may be the pivotal component in significantly improving treatment outcomes in patients with sarcoma or other cancers.
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Mitchelson KR, Qin WY. Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease. World J Biol Chem 2015; 6:162-208. [PMID: 26322174 PMCID: PMC4549760 DOI: 10.4331/wjbc.v6.i3.162] [Citation(s) in RCA: 121] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Revised: 03/13/2015] [Accepted: 05/28/2015] [Indexed: 02/05/2023] Open
Abstract
MicroRNAs are small non-coding RNAs that participate in different biological processes, providing subtle combinational regulation of cellular pathways, often by regulating components of signalling pathways. Aberrant expression of miRNAs is an important factor in the development and progression of disease. The canonical myomiRs (miR-1, -133 and -206) are central to the development and health of mammalian skeletal and cardiac muscles, but new findings show they have regulatory roles in the development of other mammalian non-muscle tissues, including nerve, brain structures, adipose and some specialised immunological cells. Moreover, the deregulation of myomiR expression is associated with a variety of different cancers, where typically they have tumor suppressor functions, although examples of an oncogenic role illustrate their diverse function in different cell environments. This review examines the involvement of the related myomiRs at the crossroads between cell development/tissue regeneration/tissue inflammation responses, and cancer development.
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Yu X, Li Z. Epigenetic deregulations in chordoma. Cell Prolif 2015; 48:497-502. [PMID: 26256106 DOI: 10.1111/cpr.12204] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Accepted: 06/22/2015] [Indexed: 12/13/2022] Open
Abstract
Chordoma is a rare type of malignant bone tumour arising from remnant notochord and prognosis of patients with it remains poor as its molecular and genetic mechanisms are not well understood. Increasing evidence has demonstrated that epigenetic mechanisms (DNA methylation, histone modification and nucleosome remodelling), play a crucial role in the pathogenesis of many diseases. Aberrant epigenetic patterns are present in patients with chordoma, indicating a potential role for epigenetic mechanisms inthis malignancy. Furthermore, epigenetic alterations may provide novel biomarkers for diagnosis and prognosis as well as therapeutic targets for treatment. In this review, we discuss relevant epigenetic findings associated with chordoma, and their potential application for diagnosis, prognosis and treatment.
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Affiliation(s)
- Xin Yu
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100042, China
| | - Zheng Li
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100042, China
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36
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Han C, Zhou Y, An Q, Li F, Li D, Zhang X, Yu Z, Zheng L, Duan Z, Kan Q. MicroRNA-1 (miR-1) inhibits gastric cancer cell proliferation and migration by targeting MET. Tumour Biol 2015; 36:6715-23. [PMID: 25874496 PMCID: PMC4644207 DOI: 10.1007/s13277-015-3358-6] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Accepted: 03/18/2015] [Indexed: 12/18/2022] Open
Abstract
MicroRNAs (miRs) are short endogenous non-coding RNAs that act as posttranscriptional regulatory factors of gene expression. Downregulation of miR-1 has been reported in gastric cancer; however, the mechanisms underlying its functions via target genes in gastric cancer remain largely unknown. The purpose of this study was to investigate the mechanism by which miR-1 inhibits gastric cancer cell proliferation and migration. The effects of miR-1 on gastric cancer cell proliferation and migration were determined by MTT and wound-healing assays. Cell protein expression of the miR-1 target gene MET was analyzed by Western blotting. Finally, MET expression was evaluated by immunohistochemistry in a stomach tumor tissue microarray (TMA). Ectopic expression of miR-1 inhibited proliferation and migration in both AGS and SGC-7901 gastric cancer cell lines. miR-1 directly targets the MET gene and downregulates its expression. MET siRNA also inhibited proliferation and migration in both cell lines. Immunohistochemistry revealed significantly higher MET expression levels in gastric cancer tissues compared with matched adjacent non-cancer tissues. These findings indicate that the miR-1/MET pathway is a potential therapeutic target due to its crucial role in gastric cancer cell proliferation and migration.
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Affiliation(s)
- Chao Han
- Department of Clinical Pharmacology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China
| | - Yubing Zhou
- Department of Clinical Pharmacology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China
| | - Qi An
- Department of Clinical Pharmacology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China
| | - Feng Li
- Department of Clinical Pharmacology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China
| | - Duolu Li
- Department of Clinical Pharmacology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China
| | - Xiaojian Zhang
- Department of Clinical Pharmacology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China
| | - Zujing Yu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Lili Zheng
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Zhenfeng Duan
- Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Quancheng Kan
- Department of Clinical Pharmacology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China.
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Feng Y, Sassi S, Shen JK, Yang X, Gao Y, Osaka E, Zhang J, Yang S, Yang C, Mankin HJ, Hornicek FJ, Duan Z. Targeting CDK11 in osteosarcoma cells using the CRISPR-Cas9 system. J Orthop Res 2015; 33:199-207. [PMID: 25348612 PMCID: PMC4304907 DOI: 10.1002/jor.22745] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2014] [Accepted: 09/02/2014] [Indexed: 02/04/2023]
Abstract
Osteosarcoma is the most common type primary malignant tumor of bone. Patients with regional osteosarcoma are routinely treated with surgery and chemotherapy. In addition, many patients with metastatic or recurrent osteosarcoma show poor prognosis with current chemotherapy agents. Therefore, it is important to improve the general condition and the overall survival rate of patients with osteosarcoma by identifying novel therapeutic strategies. Recent studies have revealed that CDK11 is essential in osteosarcoma cell growth and survival by inhibiting CDK11 mRNA expression with RNAi. Here, we apply the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 system, a robust and highly efficient novel genome editing tool, to determine the effect of targeting endogenous CDK11 gene at the DNA level in osteosarcoma cell lines. We show that CDK11 can be efficiently silenced by CRISPR-Cas9. Inhibition of CDK11 is associated with decreased cell proliferation and viability, and induces cell death in osteosarcoma cell lines KHOS and U-2OS. Furthermore, the migration and invasion activities are also markedly reduced by CDK11 knockout. These results demonstrate that CRISPR-Cas9 system is a useful tool for the modification of endogenous CDK11 gene expression, and CRISPR-Cas9 targeted CDK11 knockout may be a promising therapeutic regimen for the treatment of osteosarcoma.
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Affiliation(s)
- Yong Feng
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Jackson 1115, Boston, Massachusetts 02114,Department of Orthopaedic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jie Fang Avenue, Wuhan, China, 430022
| | - Slim Sassi
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
| | - Jacson K Shen
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Jackson 1115, Boston, Massachusetts 02114
| | - Xiaoqian Yang
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Jackson 1115, Boston, Massachusetts 02114
| | - Yan Gao
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Jackson 1115, Boston, Massachusetts 02114
| | - Eiji Osaka
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Jackson 1115, Boston, Massachusetts 02114
| | - Jianming Zhang
- Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School Boston, MA, 02114
| | - Shuhua Yang
- Department of Orthopaedic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jie Fang Avenue, Wuhan, China, 430022
| | - Cao Yang
- Department of Orthopaedic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jie Fang Avenue, Wuhan, China, 430022
| | - Henry J. Mankin
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Jackson 1115, Boston, Massachusetts 02114
| | - Francis J Hornicek
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Jackson 1115, Boston, Massachusetts 02114
| | - Zhenfeng Duan
- Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Jackson 1115, Boston, Massachusetts 02114
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Li J, Dong X, Wang Z, Wu J. MicroRNA-1 in Cardiac Diseases and Cancers. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2014; 18:359-63. [PMID: 25352753 PMCID: PMC4211117 DOI: 10.4196/kjpp.2014.18.5.359] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Revised: 06/17/2014] [Accepted: 08/09/2014] [Indexed: 11/15/2022]
Abstract
MicroRNAs (miRs) are endogenous ≈22-nt non-coding RNAs that participate in the regulation of gene expression at post-transcriptional level. MiR-1 is one of the muscle-specific miRs, aberrant expression of miR-1 plays important roles in many physiological and pathological processes. In this review, we focus on the recent studies about miR-1 in cardiac diseases and cancers. The findings indicate that miR-1 may be a novel, important biomarker, and a potential therapeutic target in cardiac diseases and cancers.
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Affiliation(s)
- Jianzhe Li
- Department of Pharmacy, Ruikang Hospital, Guangxi University of Chinese Medicine, Nanning, Guangxi 530011, China
| | - Xiaomin Dong
- Department of Osteology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China
| | - Zhongping Wang
- Department of Physiology and pathophysiology, school of Basic Medical Sciences, Jiujiang University, Jiujiang, Jiangxi 332000, China
| | - Jianhua Wu
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China
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