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Saloni, Sachan M, Rahul, Verma RS, Patel GK. SOXs: Master architects of development and versatile emulators of oncogenesis. Biochim Biophys Acta Rev Cancer 2025; 1880:189295. [PMID: 40058508 DOI: 10.1016/j.bbcan.2025.189295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 02/26/2025] [Accepted: 03/03/2025] [Indexed: 03/22/2025]
Abstract
Transcription factors regulate a variety of events and maintain cellular homeostasis. Several transcription factors involved in embryonic development, has been shown to be closely associated with carcinogenesis when deregulated. Sry-like high mobility group box (SOX) proteins are potential transcription factors which are evolutionarily conserved. They regulate downstream genes to determine cell fate, via various signaling pathways and cellular processes essential for tissue and organ development. Dysregulation of SOXs has been reported to promote or suppress tumorigenesis by modulating cellular reprogramming, growth, proliferation, angiogenesis, metastasis, apoptosis, immune modulation, lineage plasticity, maintenance of the stem cell pool, therapy resistance and cancer relapse. This review provides a crucial understanding of the molecular mechanism by which SOXs play multifaceted roles in embryonic development and carcinogenesis. It also highlights their potential in advancing therapeutic strategies aimed at targeting SOXs and their downstream effectors in various malignancies.
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Affiliation(s)
- Saloni
- Cancer and Stem Cell Laboratory, Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj 211004, India
| | - Manisha Sachan
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj 211004, India
| | - Rahul
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India
| | - Rama Shanker Verma
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj 211004, India.
| | - Girijesh Kumar Patel
- Cancer and Stem Cell Laboratory, Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj 211004, India.
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Wang T, Jiang R, Tang X, Yao Y, Jiang P. SOX2 promotes the glycolysis process to accelerate cervical cancer progression by regulating the expression of HK2. Acta Histochem 2025; 127:152230. [PMID: 39823909 DOI: 10.1016/j.acthis.2025.152230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 12/13/2024] [Accepted: 01/11/2025] [Indexed: 01/20/2025]
Abstract
BACKGROUND Cervical cancer is a major health burden in females worldwide, available studies indicated that sex-determining region Y-box 2 (SOX2) is closely related to the malignant phenotypes of multiple cancers including cervical cancer. However, the underlying mechanisms were blurred. EXPERIMENTAL PROCEDURES A bioinformatics analysis was conducted to investigate the clinical correlation between SOX2 and cervical cancer. Transient transfection and lentivirus infection were utilized to achieve overexpression and knockdown of SOX2, respectively. The role of SOX2 in cervical cancer was confirmed by transwell and colony-forming assays. Immunoblot, dual-luciferase reporter, chromatin immunoprecipitation (ChIP), and biochemical experiments were employed. In addition, the xenograft models and immunohistochemistry (IHC) experiments were performed to validate the findings in vivo. RESULTS The expression of SOX2 was significantly positively associated with the cell migration, invasion, and colony-forming abilities of cervical cancer cells. The following immunoblots revealed that the SOX2-induced malignant phenotypes might be related to the glycolysis process, since overexpressing SOX2 significantly promoted the hexokinase 2 (HK2) and glucose transporter-1 (GLUT1) expression, and increased the content of glucose and lactic acid. The further dual-luciferase reporter and ChIP experiments confirmed a binding relationship between SOX2 and HK2 promoter. More importantly, overexpressing SOX2 promoted tumor growth concomitant with a hyper-expression of HK2 and GLUT1 in xenograft tumor tissues, yet the treatment of glycolysis inhibitor significantly reversed those outcomes. CONCLUSION SOX2 promotes the malignant progression of cervical cancer by facilitating glycolysis.
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Affiliation(s)
- Ting Wang
- Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China
| | - Ruoan Jiang
- Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China
| | - Xueling Tang
- Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China
| | - Yingsha Yao
- Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China
| | - Peiyue Jiang
- Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China.
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Pan Y, Yuan C, Zeng C, Sun C, Xia L, Wang G, Chen X, Zhang B, Liu J, Ding ZY. Cancer stem cells and niches: challenges in immunotherapy resistance. Mol Cancer 2025; 24:52. [PMID: 39994696 PMCID: PMC11852583 DOI: 10.1186/s12943-025-02265-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Accepted: 02/06/2025] [Indexed: 02/26/2025] Open
Abstract
Cancer stem cells (CSCs) are central to tumor progression, metastasis, immune evasion, and therapeutic resistance. Characterized by remarkable self-renewal and adaptability, CSCs can transition dynamically between stem-like and differentiated states in response to external stimuli, a process termed "CSC plasticity." This adaptability underpins their resilience to therapies, including immune checkpoint inhibitors and adoptive cell therapies (ACT). Beyond intrinsic properties, CSCs reside in a specialized microenvironment-the CSC niche-which provides immune-privileged protection, sustains their stemness, and fosters immune suppression. This review highlights the critical role of CSCs and their niche in driving immunotherapy resistance, emphasizing the need for integrative approaches to overcome these challenges.
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Affiliation(s)
- Yonglong Pan
- Hepatic Surgery Center, Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Cellular Signaling laboratory, Key laboratory of Molecular Biophysics of MOE, International Research Center for Sensory Biology and Technology of MOST, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Chaoyi Yuan
- Hepatic Surgery Center, Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Chenglong Zeng
- Hepatic Surgery Center, Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Chaoyang Sun
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center, Key Laboratory of the MOE, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Limin Xia
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Guihua Wang
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Tongji Hospital, GI Cancer Research Institute, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xiaoping Chen
- Hepatic Surgery Center, Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Ministry of Education, National Health Commission, Chinese Academy of Medical Sciences, Wuhan, 430030, China
| | - Bixiang Zhang
- Hepatic Surgery Center, Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Jianfeng Liu
- Cellular Signaling laboratory, Key laboratory of Molecular Biophysics of MOE, International Research Center for Sensory Biology and Technology of MOST, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
| | - Ze-Yang Ding
- Hepatic Surgery Center, Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Liu Y, Kang L, Luo J, Yang M, Wang D, Ye J, Yang X, Wan W, Wong J, Xiao J. Targeting AKT as a promising strategy for SOX2-positive, chemoresistant osteosarcoma. Bone Res 2025; 13:25. [PMID: 39994220 PMCID: PMC11850766 DOI: 10.1038/s41413-024-00395-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 11/06/2024] [Accepted: 12/01/2024] [Indexed: 02/26/2025] Open
Abstract
Osteosarcoma (OS) is the most prevalent type of primary malignant bone cancer and currently lacks effective targeted treatments. Increasing evidence indicates that SOX2 overexpression is a primary driver of OS. By screening a small-molecule kinase inhibitor library, we identified AKT as a kinase essential for robust SOX2 expression in OS cells. AKT was found to be frequently overexpressed in OS and positively correlated with SOX2 protein levels. We demonstrated that AKT has no effect on SOX2 transcription but promotes SOX2 protein stability. Mechanistically, AKT binds to and phosphorylates SOX2 at T116, preventing SOX2 ubiquitination and proteasome-dependent degradation by ubiquitin E3 ligases UBR5 and STUB1. Moreover, we found that AKT-SOX2 axis is a significant modulator of cancer stemness and chemoresistance and that the combination of AKT inhibitor MK2206 and cisplatin resulted in a synergistic and potent inhibition of OS tumor growth in the PDX model. In conclusion, we identified a critical role for AKT in promoting SOX2 overexpression, tumor stemness, and chemoresistance in OS, and provided evidence that targeting AKT combined with chemotherapy may hold promise for treating refractory OS. Working model showing that AKT stabilizes SOX2 by phosphorylating T116 site. Phosphorylation by AKT restraints the binding and ubiquitinoylation of SOX2 by the UBR5 and STUB1, thus promoting SOX2 stability and tumorigenic activity. Targeting AKT by MK2206 inhibits T116 phosphorylation and promotes SOX2 ubiquitination pathway, which impairs SOX2 tumorigenic activity. A combined treatment with chemo reagent and AKT inhibitor could achieve better therapeutic effect for SOX2-positive OS.
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Affiliation(s)
- Yujie Liu
- Department of Orthopedic Oncology and Spine Tumor Center, Changzheng Hospital, Navy Medical University, Shanghai, 200001, China
- Naval Medical Center of PLA, Naval Medical University, Shanghai, China
| | - Li Kang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Jing Luo
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Minglei Yang
- Department of Orthopedic Oncology and Spine Tumor Center, Changzheng Hospital, Navy Medical University, Shanghai, 200001, China
| | - Da Wang
- Department of Orthopedic Oncology and Spine Tumor Center, Changzheng Hospital, Navy Medical University, Shanghai, 200001, China
| | - Juelan Ye
- Department of Orthopedic Oncology and Spine Tumor Center, Changzheng Hospital, Navy Medical University, Shanghai, 200001, China
- Wuxi School of Medicine, Jiangnan University, Shanghai, China
| | - Xinghai Yang
- Department of Orthopedic Oncology and Spine Tumor Center, Changzheng Hospital, Navy Medical University, Shanghai, 200001, China
| | - Wei Wan
- Department of Orthopedic Oncology and Spine Tumor Center, Changzheng Hospital, Navy Medical University, Shanghai, 200001, China.
| | - Jiemin Wong
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
| | - Jianru Xiao
- Department of Orthopedic Oncology and Spine Tumor Center, Changzheng Hospital, Navy Medical University, Shanghai, 200001, China.
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Xu E, Huang Z, Zhu K, Hu J, Ma X, Wang Y, Zhu J, Zhang C. Thrombospondin 1 Promotes Cytoskeleton Remodeling, Dedifferentiation, and Pulmonary Metastasis through ITGA1 and ITGA6 in Osteosarcoma. Int J Biol Sci 2025; 21:2083-2100. [PMID: 40083708 PMCID: PMC11900803 DOI: 10.7150/ijbs.93678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Accepted: 02/06/2025] [Indexed: 03/16/2025] Open
Abstract
Dedifferentiation of osteosarcoma cells leads to poor prognosis. We plan to identify the key molecules that are involved in cell dedifferentiation and explore how they promote the pulmonary metastasis of osteosarcoma cells. We performed a sphere formation assay and confirmed that the spheroid cells could be redifferentiated into osteoblasts, adipocytes, and chondrocytes in specific medium, and the stem cell-like markers Stro-1 and CD117 were detected on the cell surface, which indicated that the spheroid cells were dedifferentiated cells. Thrombospondin 1 (THBS1) and ITGAs were identified as the key molecules in dedifferentiation through mRNA-seq and analysis, and osteosarcoma patients with higher THBS1 expression had a worse prognosis than those with lower THBS1 expression. THBS1 promotes the accumulation of ITGA1 and ITGA6 on the cell membrane in the early phase of dedifferentiation, thereby increasing the phosphorylation of FAK, RasGRF1, and MLC2 in the cytoplasm and promoting cytoskeleton remodeling. Our results suggest that THBS1 promotes cell dedifferentiation and pulmonary metastasis by promoting cytoskeletal remodeling and that ITGA1 and ITGA6 play important roles in mediating extracellular to intracellular signals; this mediating effect takes place mainly in the early phase of dedifferentiation.
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Affiliation(s)
- Enjie Xu
- Department of Orthopedic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, PR China
- Institute of Bone Tumor Affiliated to Tongji University School of Medicine, Shanghai, 200072, PR China
| | - Zhen Huang
- Department of Orthopedic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, PR China
- Institute of Bone Tumor Affiliated to Tongji University School of Medicine, Shanghai, 200072, PR China
| | - Kunpeng Zhu
- Department of Orthopedic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, PR China
- Institute of Bone Tumor Affiliated to Tongji University School of Medicine, Shanghai, 200072, PR China
| | - Jianping Hu
- Department of Orthopedic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, PR China
- Institute of Bone Tumor Affiliated to Tongji University School of Medicine, Shanghai, 200072, PR China
| | - Xiaolong Ma
- Department of Orthopedic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, PR China
- Institute of Bone Tumor Affiliated to Tongji University School of Medicine, Shanghai, 200072, PR China
| | - Yongjie Wang
- Department of Orthopedic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, PR China
- Institute of Bone Tumor Affiliated to Tongji University School of Medicine, Shanghai, 200072, PR China
| | - Jiazhuang Zhu
- Department of Orthopedic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, PR China
- Institute of Bone Tumor Affiliated to Tongji University School of Medicine, Shanghai, 200072, PR China
| | - Chunlin Zhang
- Department of Orthopedic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, PR China
- Institute of Bone Tumor Affiliated to Tongji University School of Medicine, Shanghai, 200072, PR China
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Chen L, Zhao M, Liu L, Wang T, Gong X, Zhang J. ELAVL1 governs breast cancer malignancy by regulating cell stemness. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2025; 1872:119880. [PMID: 39603463 DOI: 10.1016/j.bbamcr.2024.119880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 11/13/2024] [Accepted: 11/22/2024] [Indexed: 11/29/2024]
Abstract
Despite advances in understanding breast cancer (BC) molecular subtypes, the mechanisms underlying its grade of malignancy remain unclear. Our study reveals that low expression of the RNA-binding protein ELAVL1 is linked to higher-grade malignancy and poorer prognosis in malignant BC subtypes. Notably, knockdown of ELAVL1 increased the expression of key stem cell markers (CD44, SOX2, OCT4, KLF4, and NANOG) and enhanced tumorsphere formation. These findings offer new insights into BC malignancy and suggest potential improvements in prognostic assessment and treatment strategies for better patient outcomes.
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Affiliation(s)
- Long Chen
- Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing, China
| | - Menglu Zhao
- Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing, China
| | - Linjing Liu
- Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing, China
| | - Tan Wang
- Laboratory of Nephropathy, Hangzhou Hospital of Traditional Chinese Medicine Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Xue Gong
- Nanjing Women and Children's Healthcare Institute, Women's Hospital of Nanjing Medical University, Nanjing Women and Children's Healthcare Hospital, Nanjing, China.
| | - Jun Zhang
- Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing, China.
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Curylova L, Staniczkova Zambo I, Neradil J, Kyr M, Jurackova N, Pavlova S, Polaskova K, Mudry P, Sterba J, Veselska R, Skoda J. Dysregulation of the p53 pathway provides a therapeutic target in aggressive pediatric sarcomas with stem-like traits. Cell Oncol (Dordr) 2024; 47:2317-2334. [PMID: 39630408 DOI: 10.1007/s13402-024-01020-x] [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] [Accepted: 11/24/2024] [Indexed: 01/11/2025] Open
Abstract
PURPOSE Pediatric sarcomas are bone and soft tissue tumors that often exhibit high metastatic potential and refractory stem-like phenotypes, resulting in poor outcomes. Aggressive sarcomas frequently harbor a disrupted p53 pathway. However, whether pediatric sarcoma stemness is associated with abrogated p53 function and might be attenuated via p53 reactivation remains unclear. METHODS We utilized a unique panel of pediatric sarcoma models and tumor tissue cohorts to investigate the correlation between the expression of stemness-related transcription factors, p53 pathway dysregulations, tumorigenicity in vivo, and clinicopathological features. TP53 mutation status was assessed by next-generation sequencing. Major findings were validated via shRNA-mediated silencing and functional assays. The p53 pathway-targeting drugs were used to explore the effects and selectivity of p53 reactivation against sarcoma cells with stem-like traits. RESULTS We found that highly tumorigenic stem-like sarcoma cells exhibit dysregulated p53, making them vulnerable to drugs that restore wild-type p53 activity. Immunohistochemistry of mouse xenografts and human tumor tissues revealed that p53 dysregulations, together with enhanced expression of the stemness-related transcription factors SOX2 or KLF4, are crucial features in pediatric osteosarcoma, rhabdomyosarcoma, and Ewing's sarcoma development. p53 dysregulation appears to be an important step for sarcoma cells to acquire a fully stem-like phenotype, and p53-positive pediatric sarcomas exhibit a high frequency of early metastasis. Importantly, reactivating p53 signaling via MDM2/MDMX inhibition selectively induces apoptosis in aggressive, stem-like Ewing's sarcoma cells while sparing healthy fibroblasts. CONCLUSIONS Our results indicate that restoring canonical p53 activity provides a promising strategy for developing improved therapies for pediatric sarcomas with unfavorable stem-like traits.
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Affiliation(s)
- Lucie Curylova
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, 625 00, Czech Republic
- International Clinical Research Center, St. Anne's University Hospital, Brno, 656 91, Czech Republic
| | - Iva Staniczkova Zambo
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, 625 00, Czech Republic
- International Clinical Research Center, St. Anne's University Hospital, Brno, 656 91, Czech Republic
- 1st Department of Pathology, St. Anne's University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Jakub Neradil
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, 625 00, Czech Republic
- International Clinical Research Center, St. Anne's University Hospital, Brno, 656 91, Czech Republic
| | - Michal Kyr
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, 625 00, Czech Republic
- Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, 613 00, Czech Republic
| | - Nicola Jurackova
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, 625 00, Czech Republic
- 1st Department of Pathology, St. Anne's University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Sarka Pavlova
- Central European Institute of Technology (CEITEC), Masaryk University, Brno, 625 00, Czech Republic
- Department of Internal Medicine, Hematology and Oncology, and Institute of Medical Genetics and Genomics, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, 625 00, Czech Republic
| | - Kristyna Polaskova
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, 625 00, Czech Republic
- Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, 613 00, Czech Republic
| | - Peter Mudry
- Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, 613 00, Czech Republic
| | - Jaroslav Sterba
- Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, 613 00, Czech Republic
| | - Renata Veselska
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, 625 00, Czech Republic
- International Clinical Research Center, St. Anne's University Hospital, Brno, 656 91, Czech Republic
| | - Jan Skoda
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, 625 00, Czech Republic.
- International Clinical Research Center, St. Anne's University Hospital, Brno, 656 91, Czech Republic.
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Xu E, Huang Z, Zhu K, Hu J, Ma X, Wang Y, Zhu J, Zhang C. PDGFRB promotes dedifferentiation and pulmonary metastasis through rearrangement of cytoskeleton under hypoxic microenvironment in osteosarcoma. Cell Signal 2024; 125:111501. [PMID: 39505287 DOI: 10.1016/j.cellsig.2024.111501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 10/15/2024] [Accepted: 10/30/2024] [Indexed: 11/08/2024]
Abstract
BACKGROUND Osteosarcoma (OS) cells commonly suffer from hypoxia and dedifferentiation, resulting in poor prognosis. We plan to identify the role of hypoxia on dedifferentiation and the associated cellular signaling. METHODS We performed sphere formation assays and determined spheroid cells as dedifferentiated cells by detecting stem cell-like markers. RNAi assay was used to explore the relationship between hypoxia inducible factor 1 subunit alpha (HIF1A) and platelet derived growth factor receptor beta (PDGFRB). We obtained PDGFRB knockdown and overexpression cells through lentiviral infection experiments and detected the expression of PDGFRB, p-PDGFRB, focal adhesion kinase (FAK), p-FAK, phosphorylated myosin light chain 2 (p-MLC2), and ras homolog family member A (RhoA) in each group. The effects of PDGFRB on cytoskeleton rearrangement and cell adhesion were explored by immunocytochemistry. Wound-healing experiments, transwell assays, and animal trials were employed to investigate the effect of PDGFRB on OS cell metastasis both in vitro and in vivo. RESULTS Dedifferentiated OS cells were found to exhibit high expression of HIF1A and PDGFRB, and HIF1A upregulated PDGFRB, subsequently activated RhoA, and increased the phosphorylation of MLC2. PDGFRB also enhanced the phosphorylation of FAK. The OS cell morphology and vinculin distribution were altered by PDGFRB. PDGFRB promoted cell dedifferentiation and had a significant impact on the migration and invasion abilities of OS cells in vitro. In addition, PDGFRB increased pulmonary metastasis of OS cells in vivo. CONCLUSION Our results demonstrated that HIF1A up-regulated PDGFRB under hypoxic conditions, and PDGFRB regulated the actin cytoskeleton, a process likely linked to the activation of RhoA and the phosphorylation of, thereby promoting OS dedifferentiation and pulmonary metastasis.
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Affiliation(s)
- Enjie Xu
- Department of Orthopedic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, PR China; Institute of Bone Tumor Affiliated to Tongji University School of Medicine, Shanghai 200072, PR China
| | - Zhen Huang
- Department of Orthopedic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, PR China; Institute of Bone Tumor Affiliated to Tongji University School of Medicine, Shanghai 200072, PR China
| | - Kunpeng Zhu
- Department of Orthopedic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, PR China; Institute of Bone Tumor Affiliated to Tongji University School of Medicine, Shanghai 200072, PR China
| | - Jianping Hu
- Department of Orthopedic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, PR China; Institute of Bone Tumor Affiliated to Tongji University School of Medicine, Shanghai 200072, PR China
| | - Xiaolong Ma
- Department of Orthopedic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, PR China; Institute of Bone Tumor Affiliated to Tongji University School of Medicine, Shanghai 200072, PR China
| | - Yongjie Wang
- Department of Orthopedic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, PR China; Institute of Bone Tumor Affiliated to Tongji University School of Medicine, Shanghai 200072, PR China
| | - Jiazhuang Zhu
- Department of Orthopedic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, PR China; Institute of Bone Tumor Affiliated to Tongji University School of Medicine, Shanghai 200072, PR China
| | - Chunlin Zhang
- Department of Orthopedic Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, PR China; Institute of Bone Tumor Affiliated to Tongji University School of Medicine, Shanghai 200072, PR China.
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Wang Y, Hu Q, Cao Y, Yao L, Liu H, Wen Y, Bao Y, Zhang S, Lv C, Zhao GS. FOSL1 promotes stem cell‑like characteristics and anoikis resistance to facilitate tumorigenesis and metastasis in osteosarcoma by targeting SOX2. Int J Mol Med 2024; 54:94. [PMID: 39219279 PMCID: PMC11374145 DOI: 10.3892/ijmm.2024.5418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 08/12/2024] [Indexed: 09/04/2024] Open
Abstract
Metastasis is the leading cause of cancer‑related death in osteosarcoma (OS). OS stem cells (OSCs) and anoikis resistance are considered to be essential for tumor metastasis formation. However, the underlying mechanisms involved in the maintenance of a stem‑cell phenotype and anoikis resistance in OS are mostly unknown. Fos‑like antigen 1 (FOSL1) is important in maintaining a stem‑like phenotype in various cancers; however, its role in OSCs and anoikis resistance remains unclear. In the present study, the dynamic expression patterns of FOSL1 were investigated during the acquisition of cancer stem‑like properties using RNA sequencing, PCR, western blotting and immunofluorescence. Flow cytometry, tumor‑sphere formation, clone formation assays, anoikis assays, western blotting and in vivo xenograft and metastasis models were used to further investigate the responses of the stem‑cell phenotype and anoikis resistance to FOSL1 overexpression or silencing in OS cell lines. The underlying molecular mechanisms were evaluated, focusing on whether SOX2 is crucially involved in FOSL1‑mediated stemness and anoikis in OS. FOSL1 expression was observed to be upregulated in OSCs and promoted tumor‑sphere formation, clone formation and tumorigenesis in OS cells. FOSL1 expression correlated positively with the expression of stemness‑related factors (SOX2, NANOG, CD117 and Stro1). Moreover, FOSL1 facilitated OS cell anoikis resistance and promoted metastases by regulating the expression of apoptosis related proteins BCL2 and BAX. Mechanistically, FOSL1 upregulated SOX2 expression by interacting with the SOX2 promoter and activating its transcription. The results also showed that SOX2 is critical for FOSL1‑mediated stem‑like properties and anoikis resistance. The current findings indicated that FOSL1 is an important regulator that promotes a stem cell‑like phenotype and anoikis resistance to facilitate tumorigenesis and metastasis in OS by regulating the transcription of SOX2. Thus, FOSL1 might represent an attractive target for therapeutic interventions in OS.
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Affiliation(s)
- Yang Wang
- Department of Emergency Medicine Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610064, P.R. China
| | - Qin Hu
- Department of Emergency Medicine Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610064, P.R. China
| | - Ya Cao
- Department of Pathology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, P.R. China
| | - Li Yao
- Department of Emergency Medicine Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610064, P.R. China
| | - Haoran Liu
- Department of Emergency Medicine Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610064, P.R. China
| | - Yafeng Wen
- Department of Spine Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Yixi Bao
- Department of Clinical Laboratory, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Shun Zhang
- Department of Emergency Medicine Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610064, P.R. China
| | - Chuanzhu Lv
- Department of Emergency Medicine Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610064, P.R. China
| | - Guo-Sheng Zhao
- Department of Spine Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
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10
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Niharika, Ureka L, Roy A, Patra SK. Dissecting SOX2 expression and function reveals an association with multiple signaling pathways during embryonic development and in cancer progression. Biochim Biophys Acta Rev Cancer 2024; 1879:189136. [PMID: 38880162 DOI: 10.1016/j.bbcan.2024.189136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/03/2024] [Accepted: 06/10/2024] [Indexed: 06/18/2024]
Abstract
SRY (Sex Determining Region) box 2 (SOX2) is an essential transcription factor that plays crucial roles in activating genes involved in pre- and post-embryonic development, adult tissue homeostasis, and lineage specifications. SOX2 maintains the self-renewal property of stem cells and is involved in the generation of induced pluripotency stem cells. SOX2 protein contains a particular high-mobility group domain that enables SOX2 to achieve the capacity to participate in a broad variety of functions. The information about the involvement of SOX2 with gene regulatory elements, signaling networks, and microRNA is gradually emerging, and the higher expression of SOX2 is functionally relevant to various cancer types. SOX2 facilitates the oncogenic phenotype via cellular proliferation and enhancement of invasive tumor properties. Evidence are accumulating in favor of three dimensional (higher order) folding of chromatin and epigenetic control of the SOX2 gene by chromatin modifications, which implies that the expression level of SOX2 can be modulated by epigenetic regulatory mechanisms, specifically, via DNA methylation and histone H3 modification. In view of this, and to focus further insights into the roles SOX2 plays in physiological functions, involvement of SOX2 during development, precisely, the advances of our knowledge in pre- and post-embryonic development, and interactions of SOX2 in this scenario with various signaling pathways in tumor development and cancer progression, its potential as a therapeutic target against many cancers are summarized and discussed in this article.
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Affiliation(s)
- Niharika
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Lina Ureka
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Ankan Roy
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Samir Kumar Patra
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India.
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11
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Colaco JC, Suresh B, Kaushal K, Singh V, Ramakrishna S. The Role of Deubiquitinating Enzymes in Primary Bone Cancer. Mol Biotechnol 2024:10.1007/s12033-024-01254-y. [PMID: 39177860 DOI: 10.1007/s12033-024-01254-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 07/01/2024] [Indexed: 08/24/2024]
Abstract
Bone is a living, intricate, and dynamic tissue providing locomotion and protection of the body. It also performs hematopoiesis and mineral homeostasis. Osteosarcoma (OS), Ewing sarcoma (ES), and chondrosarcoma (CS) are primary bone cancers. OS and ES mostly develop in younger individuals, and CS generally develops in adults. Ubiquitination regulates numerous cellular processes. The deubiquitinating enzymes (DUBs) detach the ubiquitin molecules from the ubiquitin labeled substrate, altering ubiquitinated protein functions and regulating protein stability via various signaling pathways. Protein homeostasis and bone remodeling are both crucially influenced by the UPS. Recently, there have been several reports on DUBs involved in bone homeostasis and various bone disorders through the regulation of osteoblasts and osteoclasts via NF-κB, Wnt/β-catenin, TRAF6, TGFβ, ERK1/2, and PI3K/Akt pathways. However, DUBs regulating function in bone homeostasis is still in its infancy. Here, we summarized several recent identifications on DUBs, with a focus on their role in bone cancer progression. Therefore, the study attempts to summarize association with the expression level of DUBs as key factors driving bone cancers and also provide new insights on DUBs as key pharmacologic targets for bone cancer therapeutics.
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Affiliation(s)
- Jencia Carminha Colaco
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, 04763, South Korea
| | - Bharathi Suresh
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, 04763, South Korea
| | - Kamini Kaushal
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, 04763, South Korea
| | - Vijai Singh
- Department of Biosciences, School of Science, Indrashil University, Rajpur, Mehsana, Gujarat, 382715, India.
| | - Suresh Ramakrishna
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, 04763, South Korea.
- College of Medicine, Hanyang University, Seoul, 04763, South Korea.
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12
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Li MY, Yang XL, Chung CC, Lai YJ, Tsai JC, Kuo YL, Yu JY, Wang TW. TRIP6 promotes neural stem cell maintenance through YAP-mediated Sonic Hedgehog activation. FASEB J 2024; 38:e23501. [PMID: 38411462 DOI: 10.1096/fj.202301805rrr] [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: 09/13/2023] [Revised: 01/24/2024] [Accepted: 02/06/2024] [Indexed: 02/28/2024]
Abstract
In the adult mammalian brain, new neurons are continuously generated from neural stem cells (NSCs) in the subventricular zone (SVZ)-olfactory bulb (OB) pathway. YAP, a transcriptional co-activator of the Hippo pathway, promotes cell proliferation and inhibits differentiation in embryonic neural progenitors. However, the role of YAP in postnatal NSCs remains unclear. Here, we showed that YAP was present in NSCs of the postnatal mouse SVZ. Forced expression of Yap promoted NSC maintenance and inhibited differentiation, whereas depletion of Yap by RNA interference or conditional knockout led to the decline of NSC maintenance, premature neuronal differentiation, and collapse of neurogenesis. For the molecular mechanism, thyroid hormone receptor-interacting protein 6 (TRIP6) recruited protein phosphatase PP1A to dephosphorylate LATS1/2, therefore inducing YAP nuclear localization and activation. Moreover, TRIP6 promoted NSC maintenance, cell proliferation, and inhibited differentiation through YAP. In addition, YAP regulated the expression of the Sonic Hedgehog (SHH) pathway effector Gli2 and Gli1/2 mediated the effect of YAP on NSC maintenance. Together, our findings demonstrate a novel TRIP6-YAP-SHH axis, which is critical for regulating postnatal neurogenesis in the SVZ-OB pathway.
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Affiliation(s)
- Ming-Yang Li
- Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
| | - Xiu-Li Yang
- Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
| | - Chia-Chi Chung
- Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
| | - Yun-Ju Lai
- Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
| | - Jui-Cheng Tsai
- Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
| | - Ya-Lin Kuo
- Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
| | - Jenn-Yah Yu
- Department of Life Sciences, Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Tsu-Wei Wang
- Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
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13
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Roy S, Dukic T, Keepers Z, Bhandary B, Lamichhane N, Molitoris J, Ko YH, Banerjee A, Shukla HD. SOX2 and OCT4 mediate radiation and drug resistance in pancreatic tumor organoids. Cell Death Discov 2024; 10:106. [PMID: 38429272 PMCID: PMC10907757 DOI: 10.1038/s41420-024-01871-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 02/09/2024] [Accepted: 02/14/2024] [Indexed: 03/03/2024] Open
Abstract
Pancreatic cancer has a five-year survival rate of only 10%, mostly due to late diagnosis and limited treatment options. In patients with unresectable disease, either FOLFIRINOX, a combination of 5-fluorouracil (5-FU), oxaliplatin and irinotecan, or gemcitabine plus nab-paclitaxel combined with radiation are frontline standard regimens. However, chemo-radiation therapy has shown limited success because patients develop resistance to chemotherapy and/or radiation. In this study, we evaluated the role of pancreatic cancer stem cells (CSC) using OCT4 and SOX2, CSC markers in mouse pancreatic tumor organoids. We treated pancreatic tumor organoids with 4 or 8 Gy of radiation, 10 μM of 5-FU (5-Fluorouracil), and 100 μM 3-Bromopyruvate (3BP), a promising anti-cancer drug, as a single treatment modalities, and in combination with RT. Our results showed significant upregulation of, OCT4, and SOX2 expression in pancreatic tumor organoids treated with 4 and 8 Gy of radiation, and downregulation following 5-FU treatment. The expression of CSC markers with increasing treatment dose exhibited elevated upregulation levels to radiation and downregulation to 5-FU chemotherapy drug. Conversely, when tumor organoids were treated with a combination of 5-FU and radiation, there was a significant inhibition in SOX2 and OCT4 expression, indicating CSC self-renewal inhibition. Noticeably, we also observed that human pancreatic tumor tissues exhibited heterogeneous and aberrant OCT4 and SOX2 expression as compared to normal pancreas, indicating their potential role in pancreatic cancer growth and therapy resistance. In addition, the combination of 5-FU and radiation treatment exhibited significant inhibition of the β-catenin pathway in pancreatic tumor organoids, resulting in sensitization to treatment and organoid death. In conclusion, our study emphasizes the crucial role of CSCs in therapeutic resistance in PC treatment. We recommend using tumor organoids as a model system to explore the impact of CSCs in PC and identify new therapeutic targets.
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Affiliation(s)
- Sanjit Roy
- Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Tijana Dukic
- Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Zachery Keepers
- Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Binny Bhandary
- Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Narottam Lamichhane
- Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Jason Molitoris
- Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Young H Ko
- Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Aditi Banerjee
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Hem D Shukla
- Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA.
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14
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Chang TY, Lan KC, Wu CH, Sheu ML, Yang RS, Liu SH. Nε-(1-Carboxymethyl)-L-lysine/RAGE Signaling Drives Metastasis and Cancer Stemness through ERK/NFκB axis in Osteosarcoma. Int J Biol Sci 2024; 20:880-896. [PMID: 38250151 PMCID: PMC10797696 DOI: 10.7150/ijbs.90817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 12/29/2023] [Indexed: 01/23/2024] Open
Abstract
Osteosarcoma is an extremely aggressive bone cancer with poor prognosis. Nε-(1-Carboxymethyl)-L-lysine (CML), an advanced glycation end product (AGE), can link to cancer progression, tumorigenesis and metastasis, although the underlying mechanism remains unclear. The role of CML in osteosarcoma progression is still unclear. We hypothesized that CML could promote migration, invasion, and stemness in osteosarcoma cells. CML and its receptor (RAGE; receptor for AGE) were higher expressed at advanced stages in human osteosarcoma tissues. In mouse models, which streptozotocin was administered to induce CML accumulation in the body, the subcutaneous tumor growth was not affected, but the tumor metastasis using tail vein injection model was enhanced. In cell models (MG63 and U2OS cells), CML enhanced tumor sphere formation and acquisition of cancer stem cell characteristics, induced migration and invasion abilities, as well as triggered the epithelial-mesenchymal transition process, which were associated with RAGE expression and activation of downstream signaling pathways, especially the ERK/NFκB pathway. RAGE inhibition elicited CML-induced cell migration, invasion, and stemness through RAGE-mediated ERK/NFκB pathway. These results revealed a crucial role for CML in driving stemness and metastasis in osteosarcoma. These findings uncover a potential CML/RAGE connection and mechanism to osteosarcoma progression and set the stage for further investigation.
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Affiliation(s)
- Ting-Yu Chang
- Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Kuo-Cheng Lan
- Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chia-Hung Wu
- Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Meei-Ling Sheu
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Rong-Sen Yang
- Department of Orthopedics, National Taiwan University Hospital, Taipei, Taiwan
| | - Shing-Hwa Liu
- Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Department of Pediatrics, College of Medicine, National Taiwan University & Hospital, Taipei, Taiwan
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15
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Yadav D, Sharma PK, Mishra PS, Malviya R. The Potential of Stem Cells in Treating Breast Cancer. Curr Stem Cell Res Ther 2024; 19:324-333. [PMID: 37132308 DOI: 10.2174/1574888x18666230428094056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 11/26/2022] [Accepted: 12/29/2022] [Indexed: 05/04/2023]
Abstract
There has been a lot of interest in stem cell therapy as a means of curing disease in recent years. Despite extensive usage of stem cell therapy in the treatment of a wide range of medical diseases, it has been hypothesized that it plays a key part in the progression of cancer. Breast cancer is still the most frequent malignancy in women globally. However, the latest treatments, such as stem cell targeted therapy, are considered to be more effective in preventing recurrence, metastasis, and chemoresistance of breast cancer than older methods like chemotherapy and radiation. This review discusses the characteristics of stem cells and how stem cells may be used to treat breast cancer.
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Affiliation(s)
- Deepika Yadav
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Pramod Kumar Sharma
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Prem Shankar Mishra
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Rishabha Malviya
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
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16
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Zhang S, Yang R, Ouyang Y, Shen Y, Hu L, Xu C. Cancer stem cells: a target for overcoming therapeutic resistance and relapse. Cancer Biol Med 2023; 20:j.issn.2095-3941.2023.0333. [PMID: 38164743 PMCID: PMC10845928 DOI: 10.20892/j.issn.2095-3941.2023.0333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 11/20/2023] [Indexed: 01/03/2024] Open
Abstract
Cancer stem cells (CSCs) are a small subset of cells in cancers that are thought to initiate tumorous transformation and promote metastasis, recurrence, and resistance to treatment. Growing evidence has revealed the existence of CSCs in various types of cancers and suggested that CSCs differentiate into diverse lineage cells that contribute to tumor progression. We may be able to overcome the limitations of cancer treatment with a comprehensive understanding of the biological features and mechanisms underlying therapeutic resistance in CSCs. This review provides an overview of the properties, biomarkers, and mechanisms of resistance shown by CSCs. Recent findings on metabolic features, especially fatty acid metabolism and ferroptosis in CSCs, are highlighted, along with promising targeting strategies. Targeting CSCs is a potential treatment plan to conquer cancer and prevent resistance and relapse in cancer treatment.
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Affiliation(s)
- Shuo Zhang
- Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610042, China
| | - Rui Yang
- Department of Ultrasound in Medicine, Chengdu Wenjiang District People’s Hospital, Chengdu 611130, China
| | - Yujie Ouyang
- Acupuncture and Massage College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yang Shen
- Department of Oncology & Cancer Institute, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- School of Pharmacy, Macau University of Science and Technology, Macau SAR 999078, China
| | - Lanlin Hu
- Department of Oncology & Cancer Institute, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Yu-Yue Pathology Scientific Research Center, Chongqing 400039, China
- Jinfeng Laboratory, Chongqing 401329, China
| | - Chuan Xu
- Department of Oncology & Cancer Institute, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Yu-Yue Pathology Scientific Research Center, Chongqing 400039, China
- Jinfeng Laboratory, Chongqing 401329, China
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17
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Sun R, Lee EJ, Lee S, Kim G, Kim J. KPT6566 induces apoptotic cell death and suppresses the tumorigenicity of testicular germ cell tumors. Front Cell Dev Biol 2023; 11:1220179. [PMID: 38020885 PMCID: PMC10652286 DOI: 10.3389/fcell.2023.1220179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 10/19/2023] [Indexed: 12/01/2023] Open
Abstract
Testicular germ cell tumors (TGCTs) frequently affect adolescent and young adult males. Although TGCT is more responsive to cisplatin-based chemotherapy than other solid tumors, some patients are nonresponders, and following treatment, many patients continue to experience acute and long-term cytotoxic effects from cisplatin-based chemotherapy. Consequently, it is imperative to develop new therapeutic modalities for treatment-resistant TGCTs. Peptidyl-prolyl isomerase (Pin1) regulates the activity and stability of many cancer-associated target proteins. Prior findings suggest that Pin1 contributes to the pathogenesis of multiple human cancers. However, the specific function of Pin1 in TGCTs has not yet been elucidated. TGCT cell proliferation and viability were examined using cell cycle analysis and apoptosis assays following treatment with KPT6566, a potent, selective Pin1 inhibitor that covalently binds to the catalytic domain of Pin1. A xenograft mouse model was used to assess the effect of KPT6566 on tumor growth in vivo. KPT6566 effectively suppressed cell proliferation, colony formation, and ATP production in P19 and NCCIT cells. Further, KPT6566 induced apoptotic cell death by generating cellular reactive oxygen species and downregulating the embryonic transcription factors Oct-4 and Sox2. Finally, KPT6566 treatment significantly reduced tumor volume and mass in P19 cell xenografts. The Pin1 inhibitor KPT6566 has significant antiproliferative and antitumor effects in TGCT cells. These findings suggest that Pin1 inhibitors could be considered as a potential therapeutic approach for TGCTs.
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Affiliation(s)
| | | | | | | | - Jungho Kim
- Laboratory of Molecular and Cellular Biology, Department of Life Science, Sogang University, Seoul, Republic of Korea
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18
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Chen Y, Zhang K, Zhang R, Wang Z, Yang L, Zhao T, Zhang S, Lin Y, Zhao H, Liu Y, Wei Y, Zhou Y, Zhang J, Ye X, Zhao J, Li X, Que J, Shi S, Liu K. Targeting the SOX2/CDP protein complex with a peptide suppresses the malignant progression of esophageal squamous cell carcinoma. Cell Death Discov 2023; 9:399. [PMID: 37891174 PMCID: PMC10611744 DOI: 10.1038/s41420-023-01693-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 09/28/2023] [Accepted: 10/16/2023] [Indexed: 10/29/2023] Open
Abstract
Emerging evidence indicates that SOX2 is an oncogene for esophageal squamous cell carcinoma (ESCC). However, direct targeting of SOX2 is not feasible given that this transcription factor plays important roles in the maintenance of tissues such as the brain. Here, we identified CDP (Homeobox protein cut-like 1 or CASP) as a unique SOX2 binding partner enriched in ESCC with Duolink proximity ligation assay, bimolecular fluorescence complementation (BiFc) and immunoprecipitation. We then screened a peptide aptamer library using BiFc and immunoprecipitation and identified several peptide aptamers, including P58, that blocked the CDP/SOX2 interaction, leading to the inhibition of ESCC progress in vitro and in vivo. Upon administration, synthetic peptide P58, containing the YGRKKRRQRRR cell-penetrating peptide and the fluorophore TAMRA, also blocked the growth and metastasis of ESCC in both mice and zebrafish. Therefore, targeting the SOX2 binding partner CDP with peptide P58 offers an alternative avenue to treat ESCC with increased SOX2 levels.
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Affiliation(s)
- Yunyun Chen
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, P. R. China
- School of Medicine, Xiamen University, Xiamen, Fujian, 361102, P. R. China
| | - Kun Zhang
- Department of General Surgery, Fuzhou First General Hospital affiliated with Fujian Medical University, Fuzhou, Fujian, 350009, P. R. China
| | - Rui Zhang
- Department of Laboratory Medicine, The Second Hospital of Fuzhou, Fuzhou, Fujian, 350007, P. R. China
| | - Zhuo Wang
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, P. R. China
- School of Medicine, Xiamen University, Xiamen, Fujian, 361102, P. R. China
| | - Liang Yang
- Westlake University, Hangzhou, Zhejiang, 310024, P. R. China
| | - Tingting Zhao
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, P. R. China
- School of Medicine, Xiamen University, Xiamen, Fujian, 361102, P. R. China
| | - Shihui Zhang
- Centre for Translational Stem Cell Biology, School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, 999077, P. R. China
| | - Yong Lin
- Science and Technology Service Center, Fujian Health College, Fuzhou, Fujian, 350101, P. R. China
| | - Hongzhou Zhao
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, P. R. China
- School of Medicine, Xiamen University, Xiamen, Fujian, 361102, P. R. China
| | - Yongpan Liu
- School of Life Science, Xiamen University, Xiamen, Fujian, 361102, P. R. China
| | - Yuxuan Wei
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, P. R. China
- School of Medicine, Xiamen University, Xiamen, Fujian, 361102, P. R. China
| | - Yijian Zhou
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, P. R. China
- School of Medicine, Xiamen University, Xiamen, Fujian, 361102, P. R. China
| | - Jiaying Zhang
- School of Life Science, Xiamen University, Xiamen, Fujian, 361102, P. R. China
| | - Xianzong Ye
- Department of Pathology, 900 Hospital of the Joint Logistics Team (Dongfang Hospital, Xiamen University), Fuzhou, Fujian, 350025, P. R. China
| | - Jing Zhao
- School of Medicine, Xiamen University, Xiamen, Fujian, 361102, P. R. China
| | - Xinxin Li
- School of Medicine, Xiamen University, Xiamen, Fujian, 361102, P. R. China
| | - Jianwen Que
- Department of Medicine, Columbia University Medical Center, New York, NY, 10032, USA
| | - Songlin Shi
- School of Medicine, Xiamen University, Xiamen, Fujian, 361102, P. R. China.
| | - Kuancan Liu
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, P. R. China.
- School of Medicine, Xiamen University, Xiamen, Fujian, 361102, P. R. China.
- School of Life Science, Nanchang Normal University, Nanchang, Jiangxi, 330032, P. R. China.
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19
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Liu N, Kang Y, Qu N, Kong C, Han Y. Clinical perspectives and outcomes of the giant breast phyllodes tumor and sarcoma: a real-world retrospective study. BMC Cancer 2023; 23:801. [PMID: 37635229 PMCID: PMC10463853 DOI: 10.1186/s12885-023-11279-2] [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: 06/07/2023] [Accepted: 08/08/2023] [Indexed: 08/29/2023] Open
Abstract
BACKGROUND Giant breast malignant phyllodes tumor or sarcoma (GBPS) are rare entities with diameter larger than 10 cm and variously histological pleomorphisms. This disease poses a significant threat to the quality of life of individuals, and its prognosis remains unclear. This study aimed to explore the differential diagnosis, treatment, and prognosis of GBPS in a real-world retrospective cohort. METHODS We collected GBPS (diameter > 10 cm, n = 10) and BPS (diameter ≤ 10 cm, n = 126) from patients diagnosed with sarcoma or malignant phyllodes tumor between 2008 and 2022. We analyzed clinical characteristics, histological status, treatment, and local recurrence using the Fisher's exact test between GBPS (diameter > 10 cm) and BPS (diameter ≤ 10 cm) cohort. We described overall survival (OS) and disease-free survival (DFS) using Kaplan-Meier curves and identified risk factors for local recurrence using logistic regression. The tumor size, age at diagnosis, and differential immunohistochemistry markers of breast sarcoma or phyllodes tumor to determine the prognosis of GBPS. RESULTS In our retrospective analysis of breast malignancies, we identified 10 cases of GBPS and 126 cases of BPS, corresponding to a GBPS prevalence of 0.17% (10/6000). The median age was 38.5 years (inter-quartile range, IQR: 28.25-48.5 years). During the follow-up of period (median: 80.5 months, IQR: 36.75-122 months), the local recurrence (LR) rate was 40% and 20.6%, respectively. Clinical characteristics of young age (HR:2.799, 95%CI -00.09276-0.017, p < 0.05) and cytological characteristics of marked stromal atypia (HR:0.88, 95% CI 0.39-1.40, p < 0.05) were risk factors for the poor prognosis of GBPS by COX regression model analysis. The Kaplan-Meier curves of GBPS 5-year disease-free survival (DFS) and overall survival (OS) were 31.5 months and 40 months, respectively, and were not associated with adjuvant radiation or chemotherapy. CONCLUSION We recommend mastectomy with a clear surgical margin as the preferred treatment for GBPS. Age and stromal atypia are significantly associated with recurrence. Adjuvant radiation therapy is advised; however, there was no improvement in overall survival. There is no consensus on the effectiveness of adjuvant chemotherapy and genetic methods, highlighting the need for further research into this aggressive tumor. We recommend a multidisciplinary approach involving a dedicated team for the management of GBPS.
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Affiliation(s)
- Naiquan Liu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Ye Kang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Ningxin Qu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Chenhui Kong
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Ye Han
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
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20
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Manogaran P, Anandan A, Vijaya Padma V. Isoliensinine augments the therapeutic potential of paclitaxel in multidrug-resistant colon cancer stem cells and induced mitochondria-mediated cell death. J Biochem Mol Toxicol 2023; 37:e23395. [PMID: 37424111 DOI: 10.1002/jbt.23395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 04/03/2023] [Accepted: 05/26/2023] [Indexed: 07/11/2023]
Abstract
Previously we have reported the isoliensinine (ISO) potentates the therapeutic potential of cisplatin in cisplatin resistant colorectal cancer stem cells. The present study evaluates the chemo-sensitizing potential of the combinatorial regimen of ISO and Paclitaxcel (PTX) on multidrug-resistant (MDR)-HCT-15 cells to reduce the dose requirement of both ISO and PTX. The results of the present study suggest that treatment with the combinatorial regimen of ISO and PTX enhanced the cytotoxic effect with resultant increase in apoptosis in MDR-HCT-15 cells as evident from the altered cellular morphology, G2/M cell cycle arrest, propidium iodide uptake, Annexin V, increased intracellular Ca2+ accumulation, decreased mitochondrial membrane potential, diminished ATP production, PARP-1 cleavage, altered expression of ERK1/2, and apoptotic proteins. Treatment with combinatorial regimen of ISO and PTX also modulated the expression of the transcription factors SOX2, OCT4 which determine the stemness of cancer cells. Thus, results of the present study suggest that ISO and PTX combination regimen induces apoptosis in MDR-HCT-15 in a synergistic manner.
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Affiliation(s)
- Prasath Manogaran
- Department of Biotechnology, Bharathiar University, Coimbatore, India
| | - Aparna Anandan
- Department of Biotechnology, Bharathiar University, Coimbatore, India
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21
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Urlić I, Jovičić MŠ, Ostojić K, Ivković A. Cellular and Genetic Background of Osteosarcoma. Curr Issues Mol Biol 2023; 45:4344-4358. [PMID: 37232745 DOI: 10.3390/cimb45050276] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 04/28/2023] [Accepted: 05/06/2023] [Indexed: 05/27/2023] Open
Abstract
Osteosarcoma describes a tumor of mesenchymal origin with an annual incidence rate of four to five people per million. Even though chemotherapy treatment has shown success in non-metastatic osteosarcoma, metastatic disease still has a low survival rate of 20%. A targeted therapy approach is limited due to high heterogeneity of tumors, and different underlying mutations. In this review, we will summarize new advances obtained by new technologies, such as next generation sequencing and single-cell sequencing. These new techniques have enabled better assessment of cell populations within osteosarcoma, as well as an understanding of the molecular pathogenesis. We also discuss the presence and properties of osteosarcoma stem cells-the cell population within the tumor that is responsible for metastasis, recurrence, and drug resistance.
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Affiliation(s)
- Inga Urlić
- Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
| | - Marijana Šimić Jovičić
- Department of Paediatric Orthopaedics, Children's Hospital Zagreb, 10000 Zagreb, Croatia
| | - Karla Ostojić
- Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
| | - Alan Ivković
- Department of Orthopaedics and Traumatology, University Hospital Sveti Duh, 10000 Zagreb, Croatia
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Professional Study in Physiotherapy, University of Applied Health Sciences, 10000 Zagreb, Croatia
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22
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Chico MA, Mesas C, Doello K, Quiñonero F, Perazzoli G, Ortiz R, Prados J, Melguizo C. Cancer Stem Cells in Sarcomas: In Vitro Isolation and Role as Prognostic Markers: A Systematic Review. Cancers (Basel) 2023; 15:cancers15092449. [PMID: 37173919 PMCID: PMC10177331 DOI: 10.3390/cancers15092449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 04/19/2023] [Accepted: 04/22/2023] [Indexed: 05/15/2023] Open
Abstract
Sarcomas are a diverse group of neoplasms with an incidence rate of 15% of childhood cancers. They exhibit a high tendency to develop early metastases and are often resistant to available treatments, resulting in poor prognosis and survival. In this context, cancer stem cells (CSCs) have been implicated in recurrence, metastasis, and drug resistance, making the search for diagnostic and prognostic biomarkers of the disease crucial. The objective of this systematic review was to analyze the expression of CSC biomarkers both after isolation from in vitro cell lines and from the complete cell population of patient tumor samples. A total of 228 publications from January 2011 to June 2021 was retrieved from different databases, of which 35 articles were included for analysis. The studies demonstrated significant heterogeneity in both the markers detected and the CSC isolation techniques used. ALDH was identified as a common marker in various types of sarcomas. In conclusion, the identification of CSC markers in sarcomas may facilitate the development of personalized medicine and improve treatment outcomes.
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Affiliation(s)
- Maria Angeles Chico
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain
- Instituto Biosanitario de Granada (ibs. GRANADA), 18014 Granada, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
| | - Cristina Mesas
- Instituto Biosanitario de Granada (ibs. GRANADA), 18014 Granada, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
| | - Kevin Doello
- Instituto Biosanitario de Granada (ibs. GRANADA), 18014 Granada, Spain
- Medical Oncology Service, Hospital Universitario Virgen de las Nieves, 18014 Granada, Spain
| | - Francisco Quiñonero
- Instituto Biosanitario de Granada (ibs. GRANADA), 18014 Granada, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Medical Oncology Service, Hospital Universitario Virgen de las Nieves, 18014 Granada, Spain
| | - Gloria Perazzoli
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain
- Instituto Biosanitario de Granada (ibs. GRANADA), 18014 Granada, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Department of Medicine, Faculty of Health Sciences, University of Almería, 04120 Granada, Spain
| | - Raul Ortiz
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain
- Instituto Biosanitario de Granada (ibs. GRANADA), 18014 Granada, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
| | - Jose Prados
- Instituto Biosanitario de Granada (ibs. GRANADA), 18014 Granada, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Medical Oncology Service, Hospital Universitario Virgen de las Nieves, 18014 Granada, Spain
| | - Consolacion Melguizo
- Instituto Biosanitario de Granada (ibs. GRANADA), 18014 Granada, Spain
- Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
- Medical Oncology Service, Hospital Universitario Virgen de las Nieves, 18014 Granada, Spain
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23
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Pershina AG, Nevskaya KV, Morozov KR, Litviakov NV. Methods for assessing the effect of microRNA on stemness genes. BULLETIN OF SIBERIAN MEDICINE 2023. [DOI: 10.20538/1682-0363-2022-4-170-182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
According to the latest concepts, for micrometastasis to develop into macrometastasis, differentiated cancer cells must revert to a dedifferentiated state. Activation of stemness genes plays a key role in this transition. Suppression of stemness gene expression using microRNAs can become the basis for the development of effective anti-metastatic drugs. This article provides an overview of the existing methods for assessing the effect of microRNAs on stemness genes and cancer cell dedifferentiation.
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Affiliation(s)
| | | | | | - N. V. Litviakov
- Siberian State Medical University;
Cancer Research Institute, Tomsk National Research Medical Center (NRMC), Russian Academy of Sciences
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24
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SOX2 Modulates the Nuclear Organization and Transcriptional Activity of the Glucocorticoid Receptor. J Mol Biol 2022; 434:167869. [PMID: 36309135 DOI: 10.1016/j.jmb.2022.167869] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 10/07/2022] [Accepted: 10/19/2022] [Indexed: 11/07/2022]
Abstract
Steroid receptors (SRs) are ligand-dependent transcription factors (TFs) relevant to key cellular processes in both physiology and pathology, including some types of cancer. SOX2 is a master TF of pluripotency and self-renewal of embryonic stem cells, and its dysregulation is also associated with various types of human cancers. A potential crosstalk between these TFs could be relevant in malignant cells yet, to the best of our knowledge, no formal study has been performed thus far. Here we show, by quantitative live-cell imaging microscopy, that ectopic expression of SOX2 disrupts the formation of hormone-dependent intranuclear condensates of many steroid receptors (SRs), including those formed by the glucocorticoid receptor (GR). SOX2 also reduces GR's binding to specific DNA targets and modulates its transcriptional activity. SOX2-driven effects on GR condensates do not require the intrinsically disordered N-terminal domain of the receptor and, surprisingly, neither relies on GR/SOX2 interactions. SOX2 also alters the intranuclear dynamics and compartmentalization of the SR coactivator NCoA-2 and impairs GR/NCoA-2 interactions. These results suggest an indirect mechanism underlying SOX2-driven effects on SRs involving this coactivator. Together, these results highlight that the transcriptional program elicited by GR relies on its nuclear organization and is intimately linked to the distribution of other GR partners, such as the NCoA-2 coactivator. Abnormal expression of SOX2, commonly observed in many tumors, may alter the biological action of GR and, probably, other SRs as well. Understanding this crosstalk may help to improve steroid hormone-based therapies in cancers with elevated SOX2 expression.
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25
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Kiso-Farnè K, Yaoi T, Fujimoto T, Itoh K. Low Doses of Bisphenol A Disrupt Neuronal Differentiation of Human Neuronal Stem/Progenitor Cells. Acta Histochem Cytochem 2022; 55:193-202. [PMID: 36688137 PMCID: PMC9840471 DOI: 10.1267/ahc.22-00090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 11/15/2022] [Indexed: 12/23/2022] Open
Abstract
Bisphenol A (BPA) is an endocrine disrupting chemical. Human epidemiological studies have suggested that adverse neurobehavioral outcomes are induced by fetal exposure to BPA. The remarkable differences in the corticogenesis between human and agyrencephalic mammals are an increase in the intermediate progenitor cells (IPCs) and a following increase in the subplate thickness. It is uncertain whether low doses of BPA (low-BPA) affect human early corticogenesis when basal progenitor cells (BPs) produce IPCs resulting in amplified neurogenesis. In this study, human-derived neuronal stem/progenitor cells were exposed to low-BPA or the vehicle only, and the resultant cell type-specific molecular changes and morphology were analyzed. We focused on stem cells immunoreactive for SOX2, BPs for NHLH1, and immature neurons for DCX. SOX2-positive cells significantly decreased at day in vitro (DIV) 4 and 7, whereas NHLH1-positive cells tended to be higher, while DCX-positive cells significantly increased at DIV7 when exposed to 100 nM of BPA compared with the vehicle. Morphologically DCX-positive cells showed a decrease in unipolar cells and an increase in multipolar cells when exposed to 100 nM of BPA compared with the vehicle. These results provide insights into the in vivo effect of low-BPA on neuronal differentiation in the human fetal corticogenesis.
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Affiliation(s)
- Kaori Kiso-Farnè
- Department of Pathology and Applied Neurobiology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Takeshi Yaoi
- Department of Pathology and Applied Neurobiology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Takahiro Fujimoto
- Department of Pathology and Applied Neurobiology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Kyoko Itoh
- Department of Pathology and Applied Neurobiology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
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26
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Jin ML, Yang L, Jeong KW. SETD1A-SOX2 axis is involved in tamoxifen resistance in estrogen receptor α-positive breast cancer cells. Theranostics 2022; 12:5761-5775. [PMID: 35966598 PMCID: PMC9373809 DOI: 10.7150/thno.72599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 07/02/2022] [Indexed: 12/03/2022] Open
Abstract
Rationale: Approximately 30-40% of estrogen receptor (ER)-positive breast cancer (BC) cases recur after tamoxifen therapy. Thus, additional studies on the mechanisms underlying tamoxifen resistance and more specific prognostic biomarkers are required. In this study, we investigated the role of the SET domain containing 1A (SETD1A), a histone H3-lysine 4 (H3K4) methyltransferase, in the development of tamoxifen resistance in BC. Methods: The relationship between tamoxifen resistance and SETD1A protein level was investigated using resistant cell lines derived from the parent BC cells. Biochemical and molecular assays, such as RNA-sequencing, reverse transcription-quantitative polymerase chain reaction, chromatin-immunoprecipitation, and protein-binding assays, were used to identify the SETD1A target gene in tamoxifen-resistant BC cells. Additionally, the role of SETD1A in cancer stem cells (CSCs) was investigated using CSCs isolated from tamoxifen-resistant BC cells. Comprehensive transcriptome analysis and immunofluorescence staining using clinical datasets and tissue microarray were performed to determine the correlation between the expression of the SETD1A-SRY-box transcription factor 2 (SOX2) pair and recurrence in tamoxifen-treated patients with BC. Results: SETD1A was expressed at higher levels in tamoxifen-resistant BC cells than in primary BC cells. Notably, SETD1A-depleted tamoxifen-resistant MCF-7 cells showed restored sensitivity to tamoxifen, whereas SETD1A overexpression in MCF-7 cells resulted in decreased sensitivity. SETD1A is recruited to the SOX2 gene via its interaction with SOX2, thereby enhancing the expression of SOX2 genes in tamoxifen-resistant BC cells. The growth of tamoxifen-resistant cells and CSCs was effectively suppressed by SETD1A knockdown. In addition, high levels of SETD1A and SOX2 were significantly correlated with a low survival rate in patients with ER-positive tamoxifen-resistant BC. Conclusion: Our findings provide the first evidence of the critical role of the SETD1A-SOX2 axis in tamoxifen-resistant BC cells, implying that SETD1A may serve as a molecular target and prognostic indicator of a therapeutic response in patients with tamoxifen-resistant BC.
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Affiliation(s)
- Ming Li Jin
- Gachon Research Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon, 21936, Republic of Korea
| | - Liu Yang
- Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases Co-Constructed by Henan Province & Education Ministry of P.R. China, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Kwang Won Jeong
- Gachon Research Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon, 21936, Republic of Korea
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27
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Regan JL, Schumacher D, Staudte S, Steffen A, Lesche R, Toedling J, Jourdan T, Haybaeck J, Golob-Schwarzl N, Mumberg D, Henderson D, Győrffy B, Regenbrecht CR, Keilholz U, Schäfer R, Lange M. Identification of a neural development gene expression signature in colon cancer stem cells reveals a role for EGR2 in tumorigenesis. iScience 2022; 25:104498. [PMID: 35720265 PMCID: PMC9204726 DOI: 10.1016/j.isci.2022.104498] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 02/28/2022] [Accepted: 05/26/2022] [Indexed: 11/12/2022] Open
Abstract
Recent evidence demonstrates that colon cancer stem cells (CSCs) can generate neurons that synapse with tumor innervating fibers required for tumorigenesis and disease progression. Greater understanding of the mechanisms that regulate CSC driven tumor neurogenesis may therefore lead to more effective treatments. RNA-sequencing analyses of ALDHPositive CSCs from colon cancer patient-derived organoids (PDOs) and xenografts (PDXs) showed CSCs to be enriched for neural development genes. Functional analyses of genes differentially expressed in CSCs from PDO and PDX models demonstrated the neural crest stem cell (NCSC) regulator EGR2 to be required for tumor growth and to control expression of homebox superfamily embryonic master transcriptional regulator HOX genes and the neural stem cell and master cell fate regulator SOX2. These data support CSCs as the source of tumor neurogenesis and suggest that targeting EGR2 may provide a therapeutic differentiation strategy to eliminate CSCs and block nervous system driven disease progression.
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Affiliation(s)
- Joseph L. Regan
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Dirk Schumacher
- Laboratory of Molecular Tumor Pathology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany
- German Cancer Consortium (DKTK), DKFZ, 69120 Heidelberg, Germany
| | - Stephanie Staudte
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
- German Cancer Consortium (DKTK), DKFZ, 69120 Heidelberg, Germany
- Department of Radiation Oncology and Radiotherapy, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Andreas Steffen
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
| | - Ralf Lesche
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
- Nuvisan ICB GmbH, 13353 Berlin, Germany
| | - Joern Toedling
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
- Nuvisan ICB GmbH, 13353 Berlin, Germany
| | - Thibaud Jourdan
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
| | - Johannes Haybaeck
- Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Diagnostic and Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, 8036 Graz, Austria
| | - Nicole Golob-Schwarzl
- Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Department of Dermatology and Venereology, Medical University of Graz, 8036 Graz, Austria
| | - Dominik Mumberg
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
| | - David Henderson
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
- Bayer AG, Business Development and Licensing and Open Innovation, Pharmaceuticals, 13342 Berlin, Germany
| | - Balázs Győrffy
- Department of Bioinformatics, Semmelweis University, 1094 Budapest, Hungary
- TTK Cancer Biomarker Research Group, Institute of Enzymology, 1117 Budapest, Hungary
| | - Christian R.A. Regenbrecht
- Laboratory of Molecular Tumor Pathology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany
- CELLphenomics GmbH, 13125 Berlin, Germany
- Institute of Pathology, University Medical Center Göttingen, 37075 Göttingen, Germany
| | - Ulrich Keilholz
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Reinhold Schäfer
- Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
- Laboratory of Molecular Tumor Pathology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany
- German Cancer Consortium (DKTK), DKFZ, 69120 Heidelberg, Germany
| | - Martin Lange
- Bayer AG, Research and Development, Pharmaceuticals, 13342 Berlin, Germany
- Nuvisan ICB GmbH, 13353 Berlin, Germany
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28
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Oncofetal proteins and cancer stem cells. Essays Biochem 2022; 66:423-433. [PMID: 35670043 DOI: 10.1042/ebc20220025] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/17/2022] [Accepted: 05/20/2022] [Indexed: 12/12/2022]
Abstract
Abstract
Cancer stem cells (CSCs) are considered as a small population of cells with stem-like properties within the tumor bulk, and are largely responsible for tumor recurrence, metastasis, and therapy resistance. CSCs share critical features with embryonic stem cells (ESCs). The pluripotent transcription factors (TFs) and developmental signaling pathways of ESCs are invariably hijacked by CSCs termed ‘oncofetal drivers’ in many cancers, which are rarely detectable in adult tissues. The unique expression pattern makes oncofetal proteins ideal therapeutic targets in cancer treatment. Therefore, elucidation of oncofetal drivers in cancers is critical for the development of effective CSCs-directed therapy. In this review, we summarize the common pluripotent TFs such as OCT4, SOX2, NANOG, KLF4, MYC, SALL4, and FOXM1, as well as the development signaling including Wnt/β-catenin, Hedgehog (Hh), Hippo, Notch, and TGF-β pathways of ESCs and CSCs. We also describe the newly identified oncofetal proteins that drive the self-renewal, plasticity, and therapy-resistance of CSCs. Finally, we explore how the clinical implementation of targeting oncofetal drivers, including small-molecule inhibitors, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) can facilitate the development of CSCs-directed therapy.
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29
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Pouremamali F, Vahedian V, Hassani N, Mirzaei S, Pouremamali A, Kazemzadeh H, Faridvand Y, Jafari-gharabaghlou D, Nouri M, Maroufi NF. The role of SOX family in cancer stem cell maintenance: With a focus on SOX2. Pathol Res Pract 2022; 231:153783. [DOI: 10.1016/j.prp.2022.153783] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/17/2022] [Accepted: 01/25/2022] [Indexed: 02/06/2023]
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Keyimu R, Tuerdi M, Zhao Z. MSX2 represses tumor stem cell phenotypes within oral squamous cell carcinomas via SOX2 degradation. Exp Biol Med (Maywood) 2021; 246:2660-2670. [PMID: 34435915 PMCID: PMC8669173 DOI: 10.1177/15353702211041029] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 08/02/2021] [Indexed: 02/05/2023] Open
Abstract
Oral squamous cell carcinoma (OSCC) is the sixth malignancy in the world with high incidence. The MSX2 (muscle segment homeobox 2)-Sry-related high-mobility box 2 (SOX2) signaling pathway plays a significant role in maintaining cancer stem cells, which are the origin of malignancy, leading to unfavorable outcomes in several carcinomas. This study aims to elucidate the mechanisms through which the MSX2-SOX2 pathway controls the cancer stem cell-like characterization in OSCC. The results showed that MSX2 was remarkably downregulated in OSCC and that the MSX2 expression level was related to unfavorable outcomes in patients with OSCC. Meanwhile, the MSX2 expression level was lower in the CD44+/CD24- population than in the other populations of OSCC cells. The OSCC2 cells exhibited decreased percentage of CD44+/CD24- cells, owing to MSX2 overexpression but increased owing to MSX2 knockdown. Moreover, a negative correlation was observed between MSX2 expression and is SOX2 transcriptional levels in different populations within the OSCC cell lines. Regarding the loss and gain of function, cancer stem cell phenotypes such as tumor globular formation, CD44+ subpopulation cells, and stem cell-associated gene expression were enhanced by MSX2 knockdown in OSCC CD44+/CD24- cells but decreased by MSX2 overexpression in other OSCC populations. However, these events were counteracted by the co-knockdown or SOX2 overexpression. Cells with MSX2 overexpression or knockdown formed smaller or bigger cancers in vivo, thereby showing a lower or a higher tumor incidence, respectively. Thus, our results confirm that MSX2 has a tumor suppression effect on the cancer stem cell phenotypes of OSCC and indicate that the MSX2-SOX2 signaling pathway could be a useful target for OSCC treatment.
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Affiliation(s)
- Reziwan Keyimu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Sichuan 610041, China
| | - Maimaitituxun Tuerdi
- Department of Oral and Maxillofacial Trauma and Orthognathic Surgery, The First Affiliated Hospital (Stomatological Hospital) of Xinjiang Medical University, Urumqi 830000, China
| | - Zhihe Zhao
- National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Chengdu 610041, China
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Xu A, Qian C, Lin J, Yu W, Jin J, Liu B, Tao H. Cell Differentiation Trajectory-Associated Molecular Classification of Osteosarcoma. Genes (Basel) 2021; 12:genes12111685. [PMID: 34828292 PMCID: PMC8625454 DOI: 10.3390/genes12111685] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/19/2021] [Accepted: 10/21/2021] [Indexed: 01/01/2023] Open
Abstract
This study aims to investigate the differentiation trajectory of osteosarcoma cells and to construct molecular subtypes with their respective characteristics and generate a multi-gene signature for predicting prognosis. Integrated single-cell RNA-sequencing (scRNA-seq) data, bulk RNA-seq data and microarray data from osteosarcoma samples were used for analysis. Via scRNA-seq data, time-related as well as differentiation-related genes were recognized as osteosarcoma tumor stem cell-related genes (OSCGs). In Gene Expression Omnibus (GEO) cohort, osteosarcoma patients were classified into two subtypes based on prognostic OSCGs and it was found that molecular typing successfully predicted overall survival, tumor microenvironment and immune infiltration status. Further, available drugs for influencing osteosarcoma via prognostic OSCGs were revealed. A 3-OSCG-based prognostic risk score signature was generated and by combining other clinic-pathological independent prognostic factor, stage at diagnosis, a nomogram was established to predict individual survival probability. In external independent TARGET cohort, the molecular types, the 3-gene signature as well as nomogram were validated. In conclusion, osteosarcoma cell differentiation occupies a crucial position in many facets, such as tumor prognosis and microenvironment, suggesting promising therapeutic targets for this disease.
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Affiliation(s)
- Ankai Xu
- Department of Orthopedics Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88, Jiefang Road, Hangzhou 310009, China; (A.X.); (C.Q.); (J.L.); (W.Y.); (J.J.); (B.L.)
- Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China
| | - Chao Qian
- Department of Orthopedics Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88, Jiefang Road, Hangzhou 310009, China; (A.X.); (C.Q.); (J.L.); (W.Y.); (J.J.); (B.L.)
- Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China
| | - Jinti Lin
- Department of Orthopedics Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88, Jiefang Road, Hangzhou 310009, China; (A.X.); (C.Q.); (J.L.); (W.Y.); (J.J.); (B.L.)
- Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China
| | - Wei Yu
- Department of Orthopedics Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88, Jiefang Road, Hangzhou 310009, China; (A.X.); (C.Q.); (J.L.); (W.Y.); (J.J.); (B.L.)
- Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China
| | - Jiakang Jin
- Department of Orthopedics Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88, Jiefang Road, Hangzhou 310009, China; (A.X.); (C.Q.); (J.L.); (W.Y.); (J.J.); (B.L.)
- Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China
| | - Bing Liu
- Department of Orthopedics Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88, Jiefang Road, Hangzhou 310009, China; (A.X.); (C.Q.); (J.L.); (W.Y.); (J.J.); (B.L.)
- Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China
| | - Huimin Tao
- Department of Orthopedics Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88, Jiefang Road, Hangzhou 310009, China; (A.X.); (C.Q.); (J.L.); (W.Y.); (J.J.); (B.L.)
- Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China
- Correspondence:
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Stemness-Suppressive Effect of Bibenzyl from Dendrobium ellipsophyllum in Human Lung Cancer Stem-Like Cells. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:5516655. [PMID: 34349823 PMCID: PMC8328707 DOI: 10.1155/2021/5516655] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 07/15/2021] [Indexed: 12/17/2022]
Abstract
Cancer stem-like cells (CSCs) are key mediators driving tumor initiation, metastasis, therapeutic failure, and subsequent cancer relapse. Thus, targeting CSCs has recently emerged as a potential strategy to improve chemotherapy. In this study, the anticancer activity and stemness-regulating capacity of 4,5,4'-trihydroxy-3,3'-dimethoxybibenzyl (TDB), a bibenzyl extracted from Dendrobium ellipsophyllum, are revealed in CSCs of various human lung cancer cells. Culture with TDB (5-10 μM) strongly abolished tumor-initiating cells in lung cancer H460, H23, and A549 cells in both anchorage-dependent and anchorage-independent colony formation assays. Through the 3D single-spheroid formation model, attenuation of self-renewal capacity was observed in CSC-enriched populations treated with 1-10 μM TDB for 7 days. Flow cytometry analysis confirmed the attenuation of %cell overexpressing CD133, a CSC biomarker, in TDB-treated lung cancer spheroids. TDB at 5-10 μM remarkably suppressed regulatory signals of p-Akt/Akt, p-GSK3β/GSK3β, and β-catenin corresponding to the downregulated mRNA level of stemness transcription factors including Nanog, Oct4, and Sox2. Moreover, the antiapoptosis Bcl-2 and Mcl-1 proteins, which are downstream molecules of Akt signaling, were evidently decreased in CSC-enriched spheroids after culture with TDB (1-10 μM) for 24 h. Interestingly, the diminution of Akt expression by specific siAkt effectively reversed suppressive activity of TDB targeting on the CSC phenotype in human lung cancer cells. These findings provide promising evidence of the inhibitory effect of TDB against lung CSCs via suppression of Akt/GSK3β/β-catenin cascade and related proteins, which would facilitate the development of this bibenzyl natural compound as a novel CSC-targeted therapeutic approach for lung cancer treatment.
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The Effect of Fluid Flow Shear Stress and Substrate Stiffness on Yes-Associated Protein (YAP) Activity and Osteogenesis in Murine Osteosarcoma Cells. Cancers (Basel) 2021; 13:cancers13133128. [PMID: 34201496 PMCID: PMC8268052 DOI: 10.3390/cancers13133128] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/08/2021] [Accepted: 06/18/2021] [Indexed: 01/06/2023] Open
Abstract
Osteosarcoma (OS) is an aggressive bone cancer originating in the mesenchymal lineage. Prognosis for metastatic disease is poor, with a mortality rate of approximately 40%; OS is an aggressive disease for which new treatments are needed. All bone cells are sensitive to their mechanical/physical surroundings and changes in these surroundings can affect their behavior. However, it is not well understood how OS cells specifically respond to fluid movement, or substrate stiffness-two stimuli of relevance in the tumor microenvironment. We used cells from spontaneous OS tumors in a mouse engineered to have a bone-specific knockout of pRb-1 and p53 in the osteoblast lineage. We silenced Sox2 (which regulates YAP) and tested the effect of fluid flow shear stress (FFSS) and substrate stiffness on YAP expression/activity-which was significantly reduced by loss of Sox2, but that effect was reversed by FFSS but not by substrate stiffness. Osteogenic gene expression was also reduced in the absence of Sox2 but again this was reversed by FFSS and remained largely unaffected by substrate stiffness. Thus we described the effect of two distinct stimuli on the mechanosensory and osteogenic profiles of OS cells. Taken together, these data suggest that modulation of fluid movement through, or stiffness levels within, OS tumors could represent a novel consideration in the development of new treatments to prevent their progression.
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Wu Y, Jin Y, Yamamoto N, Takeuchi A, Miwa S, Tsuchiya H, Yang Z. MSX2 inhibits the growth and migration of osteosarcoma cells by repressing SOX2. Am J Transl Res 2021; 13:5851-5865. [PMID: 34306330 PMCID: PMC8290658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 04/19/2021] [Indexed: 06/13/2023]
Abstract
SRY (sex determining region Y)-box 2 (SOX2) plays a key role in the maintenance of stemness and resistance to drugs, whereas tumor necrosis factor (TNF)-α is essential for maintaining cancer cell proliferation and metastasis. Accumulation of muscle segment homeobox 2 (MSX2) leads to downregulation of SOX2 expression. Here, we explored the MSX2-SOX2-TNF-α signaling axis and its function in the tumor phenotypes of osteosarcoma cells. Colony formation assay, cell counting kit (CCK)-8 assay, and Flow cytometry were used to examine cell growth, viability, and death, respectively. Wound healing and Transwell invasive assay were employed to examine cell migratory and invasive activities, respectively. Western blotting and RT-qPCR were used to determine the protein and mRNA expressions of MSX2, SOX2, TNF-α, Bax, and matrix metalloproteinase-2 (MMP-2). Osteosarcoma clinical samples and cells showed lower levels of MSX2 than normal healthy control samples. Overexpression of MSX2 led to a reduced activity of SOX2 and TNF-α, whereas MSX2 depletion did not contribute to upregulated SOX2 levels. A gain-of-function experiment showed that osteosarcoma cell viability and growth were reduced, cell death was increased, and migration and invasion were inhibited in the MSX2 overexpression group compared with those in the non-transfected group. Furthermore, co-overexpression of MSX2 and SOX2 counteracted the inhibitory effects of MSX2 on the abovementioned tumor phenotypes of osteosarcoma cells. An in vivo tumor growth assay showed that MSX2 overexpression slowed the growth rate of osteosarcoma xenograft tumors. Thus, MSX2 loss plays a crucial role in the osteosarcoma phenotype by elevating SOX2 and TNF-α levels.
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Affiliation(s)
- Yue Wu
- Department of Orthopedics, Beijing United Family HealthcareBeijing, China
| | - Yi Jin
- Joint Surgery Department of Orthopedics, Changsha Central Hospital Affiliated to South China UniversityChangsha, China
| | - Norio Yamamoto
- Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa UniversityKanazawa, Japan
| | - Akihiko Takeuchi
- Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa UniversityKanazawa, Japan
| | - Shinji Miwa
- Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa UniversityKanazawa, Japan
| | - Hiroyuki Tsuchiya
- Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa UniversityKanazawa, Japan
| | - Zhijun Yang
- Department of Trauma Orthopedics, The First Affiliated Hospital of South China UniversityHengyang 421001, Hunan, China
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adipoSIGHT in Therapeutic Response: Consequences in Osteosarcoma Treatment. Bioengineering (Basel) 2021; 8:bioengineering8060083. [PMID: 34200614 PMCID: PMC8229256 DOI: 10.3390/bioengineering8060083] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 06/01/2021] [Accepted: 06/03/2021] [Indexed: 12/02/2022] Open
Abstract
Chemotherapeutic resistance is a major problem in effective cancer treatment. Cancer cells engage various cells or mechanisms to resist anti-cancer therapeutics, which results in metastasis and the recurrence of disease. Considering the cellular heterogeneity of cancer stroma, the involvement of stem cells is reported to affect the proliferation and metastasis of osteosarcoma. Hence, the duo (osteosarcoma: Saos 2 and human adipose-derived stem cells: ASCs) is co-cultured in present study to investigate the therapeutic response using a nonadherent, concave surface. Staining with a cell tracker allows real-time microscopic monitoring of the cell arrangement within the sphere. Cell–cell interaction is investigated by means of E-cadherin expression. Comparatively high expression of E-cadherin and compact organization is observed in heterotypic tumorspheres (Saos 2–ASCs) compared to homotypic ones (ASCs), limiting the infiltration of chemotherapeutic compound doxorubicin into the heterotypic tumorsphere, which in turn protects cells from the toxic effect of the chemotherapeutic. In addition, genes known to be associated with drug resistance, such as SOX2, OCT4, and CD44 are overexpressed in heterotypic tumorspheres post-chemotherapy, indicating that the duo collectively repels the effect of doxorubicin. The interaction between ASCs and Saos 2 in the present study points toward the growing oncological risk of using ASC-based regenerative therapy in cancer patients and warrants further investigation.
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Drug Resistance in Osteosarcoma: Emerging Biomarkers, Therapeutic Targets and Treatment Strategies. Cancers (Basel) 2021; 13:cancers13122878. [PMID: 34207685 PMCID: PMC8228414 DOI: 10.3390/cancers13122878] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 06/05/2021] [Indexed: 01/02/2023] Open
Abstract
Simple Summary Despite the adoption of aggressive, multimodal treatment schedules, the cure rate of high-grade osteosarcoma (HGOS) has not significantly improved in the last 30 years. The most relevant problem preventing improvement in HGOS prognosis is drug resistance. Therefore, validated novel biomarkers that help to identify those patients who could benefit from innovative treatment options and the development of drugs enabling personalized therapeutic protocols are necessary. The aim of this review was to give an overview on the most relevant emerging drug resistance-related biomarkers, therapeutic targets and new agents or novel candidate treatment strategies, which have been highlighted and suggested for HGOS to improve the success rate of clinical trials. Abstract High-grade osteosarcoma (HGOS), the most common primary malignant tumor of bone, is a highly aggressive neoplasm with a cure rate of approximately 40–50% in unselected patient populations. The major clinical problems opposing the cure of HGOS are the presence of inherent or acquired drug resistance and the development of metastasis. Since the drugs used in first-line chemotherapy protocols for HGOS and clinical outcome have not significantly evolved in the past three decades, there is an urgent need for new therapeutic biomarkers and targeted treatment strategies, which may increase the currently available spectrum of cure modalities. Unresponsive or chemoresistant (refractory) HGOS patients usually encounter a dismal prognosis, mostly because therapeutic options and drugs effective for rescue treatments are scarce. Tailored treatments for different subgroups of HGOS patients stratified according to drug resistance-related biomarkers thus appear as an option that may improve this situation. This review explores drug resistance-related biomarkers, therapeutic targets and new candidate treatment strategies, which have emerged in HGOS. In addition to consolidated biomarkers, specific attention has been paid to the role of non-coding RNAs, tumor-derived extracellular vesicles, and cancer stem cells as contributors to drug resistance in HGOS, in order to highlight new candidate markers and therapeutic targets. The possible use of new non-conventional drugs to overcome the main mechanisms of drug resistance in HGOS are finally discussed.
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Yu Y, Tao M, Xu L, Cao L, Le B, An N, Dong J, Xu Y, Yang B, Li W, Liu B, Wu Q, Lu Y, Xie Z, Lian X. Systematic screening reveals synergistic interactions that overcome MAPK inhibitor resistance in cancer cells. Cancer Biol Med 2021; 19:j.issn.2095-3941.2020.0560. [PMID: 34106558 PMCID: PMC8832956 DOI: 10.20892/j.issn.2095-3941.2020.0560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 01/13/2021] [Indexed: 11/11/2022] Open
Abstract
OBJECTIVE Effective adjuvant therapeutic strategies are urgently needed to overcome MAPK inhibitor (MAPKi) resistance, which is one of the most common forms of resistance that has emerged in many types of cancers. Here, we aimed to systematically identify the genetic interactions underlying MAPKi resistance, and to further investigate the mechanisms that produce the genetic interactions that generate synergistic MAPKi resistance. METHODS We conducted a comprehensive pair-wise sgRNA-based high-throughput screening assay to identify synergistic interactions that sensitized cancer cells to MAPKi, and validated 3 genetic combinations through competitive growth, cell viability, and spheroid formation assays. We next conducted Kaplan-Meier survival analysis based on The Cancer Genome Atlas database and conducted immunohistochemistry to determine the clinical relevance of these synergistic combinations. We also investigated the MAPKi resistance mechanisms of these validated synergistic combinations by using co-immunoprecipitation, Western blot, qRT-PCR, and immunofluorescence assays. RESULTS We constructed a systematic interaction network of MAPKi resistance and identified 3 novel synergistic combinations that effectively targeted MAPKi resistance (ITGB3 + IGF1R, ITGB3 + JNK, and HDGF + LGR5). We next analyzed their clinical relevance and the mechanisms by which they sensitized cancer cells to MAPKi exposure. Specifically, we discovered a novel protein complex, HDGF-LGR5, that adaptively responded to MAPKi to enhance cancer cell stemness, which was up- or downregulated by the inhibitors of ITGB3 + JNK or ITGB3 + IGF1R. CONCLUSIONS Pair-wise sgRNA library screening provided systematic insights into elucidating MAPKi resistance in cancer cells. ITGB3- + IGF1R-targeting drugs (cilengitide + linsitinib) could be used as an effective therapy for suppressing the adaptive formation of the HDGF-LGR5 protein complex, which enhanced cancer stemness during MAPKi stress.
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Affiliation(s)
- Yu Yu
- Department of Cell Biology, Basic Medical College, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Minzhen Tao
- MOE Key Laboratory of Bioinformatics and Bioinformatics Division, Center for Synthetic and System Biology, Department of Automation, Beijing National Research Center for Information Science and Technology, Tsinghua University, Beijing 100084, China
| | - Libin Xu
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Lei Cao
- Department of Thoracic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Baoyu Le
- Beijing Syngentech Co., Ltd, Beijing 102206, China
| | - Na An
- Beijing Syngentech Co., Ltd, Beijing 102206, China
| | - Jilin Dong
- Beijing Syngentech Co., Ltd, Beijing 102206, China
| | - Yajie Xu
- Beijing Syngentech Co., Ltd, Beijing 102206, China
| | - Baoxing Yang
- Beijing Syngentech Co., Ltd, Beijing 102206, China
| | - Wei Li
- Beijing Syngentech Co., Ltd, Beijing 102206, China
| | - Bing Liu
- Beijing Syngentech Co., Ltd, Beijing 102206, China
| | - Qiong Wu
- School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Yinying Lu
- The Comprehensive Liver Cancer Center, The 5th Medical Center of PLA General Hospital, Beijing 100039, China
| | - Zhen Xie
- MOE Key Laboratory of Bioinformatics and Bioinformatics Division, Center for Synthetic and System Biology, Department of Automation, Beijing National Research Center for Information Science and Technology, Tsinghua University, Beijing 100084, China
| | - Xiaohua Lian
- Department of Cell Biology, Basic Medical College, Army Medical University (Third Military Medical University), Chongqing 400038, China
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Kim JW, Chung JY, Ylaya K, Park Y, Jun SY, Hong SM, Hewitt SM. Prognostic implication of SOX2 expression in small intestinal adenocarcinoma. Virchows Arch 2021; 478:1049-1060. [PMID: 33103210 PMCID: PMC9815101 DOI: 10.1007/s00428-020-02946-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 09/23/2020] [Accepted: 10/05/2020] [Indexed: 01/11/2023]
Abstract
The presence of KRAS mutation enhances the stem cell features of colorectal carcinoma cells containing mutant adenomatous polyposis coli (APC). However, their potential role in small intestinal adenocarcinoma remains elusive. Here, we aimed to investigate the clinical significance of cancer stem cell markers expression in the context of small intestinal adenocarcinoma with the KRAS genotype. SOX2, NANOG, and OCT4 expression were assessed by immunohistochemistry and digital image analysis, and their potential association with KRAS was further examined in 185 Korean patients with small intestinal adenocarcinomas, which were collected from 22 institutions in South Korea. Positive expression of SOX2, NANOG, and OCT4 was detected in 65 (35.1%), 94 (50.8%), and 82 (44.3%) of patients, respectively. Patients with high SOX2 (SOX2+) expression displayed worse overall survival compared to those with low SOX2 (SOX2-) expression (P < 0.001). Patients with SOX2+/mutant KRAS (KRASMT) (11.1 months) had significantly shorter overall survival than those with SOX2-/KRASWT (53.6 months) (P < 0.001). In multivariate analysis, SOX2+, distal location, high pT and pN categories, microsatellite stable, and absence of predisposing diseases were independent prognostic factors for worse overall survival. These results suggest that SOX2 expression has the potential to predict clinical outcomes in patients with small intestinal adenocarcinomas.
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Affiliation(s)
- Jeong Won Kim
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA,Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07441, Republic of Korea
| | - Joon-Yong Chung
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Kris Ylaya
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Yoonho Park
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Sun-Young Jun
- Department of Pathology, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 21431, Republic of Korea
| | - Seung-Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05550, Republic of Korea
| | - Stephen M. Hewitt
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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SOX2 promotes chemoresistance, cancer stem cells properties, and epithelial-mesenchymal transition by β-catenin and Beclin1/autophagy signaling in colorectal cancer. Cell Death Dis 2021; 12:449. [PMID: 33953166 PMCID: PMC8100126 DOI: 10.1038/s41419-021-03733-5] [Citation(s) in RCA: 111] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 04/19/2021] [Accepted: 04/19/2021] [Indexed: 12/21/2022]
Abstract
Sex-determining region Y-box2 (SOX2), a master regulator of embryonic and induced pluripotent stem cells, drives cancer stem cells (CSCs) properties, fuels tumor initiation, and contributes to tumor aggressiveness. Our previous study has demonstrated the oncogenic role of SOX2 in colorectal cancer (CRC). In this study, we sought to elucidate the underlying mechanisms. Cell function experiments were performed to detect chemoresistance, proliferation, stemness, migration, and invasion in vitro. Chromatin immunoprecipitation, co-immunoprecipitation, luciferase reporter assay, and immunofluorescence were performed to explore the regulation of ABCC2, β-catenin, and Beclin1 by SOX2. The carcinogenic role of SOX2-β-catenin/Beclin1-ABCC2 axis in vivo was analyzed by CRC tissues and xenograft models. Here, we reported that SOX2 sustained chemoresistance by transcriptional activation of ABCC2 expression. Suppressing either β-catenin or autophagy signaling curbed SOX2-driven chemoresistance, stemness, and epithelial-mesenchymal transition (EMT). Mechanistically, SOX2 combined with β-catenin and increased its nuclear expression and transcriptional activity. Transcriptional activation of Beclin1 expression by SOX2 consequently activating autophagy and inducing malignant phenotype. Furthermore, overexpression of β-catenin or Beclin1 facilitated ABCC2 expression. The clinical analyses showed that high expression of ABCC2 and Beclin1 were positively correlated with SOX2 and were associated with poor prognosis in CRC patients. Finally, xenograft models revealed that inhibition of SOX2 expression and autophagy restrained tumor growth and chemoresistance in vivo. Conclusively, we demonstrated a novel mechanism by which the SOX2-β-catenin/Beclin1/autophagy signaling axis regulates chemoresistance, stemness, and EMT in CRC. Our findings provide novel insights into CRC carcinogenesis and may help develop potential therapeutic candidates for CRC.
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Jahangiri L, Ishola T, Pucci P, Trigg RM, Pereira J, Williams JA, Cavanagh ML, Gkoutos GV, Tsaprouni L, Turner SD. The Role of Autophagy and lncRNAs in the Maintenance of Cancer Stem Cells. Cancers (Basel) 2021; 13:cancers13061239. [PMID: 33799834 PMCID: PMC7998932 DOI: 10.3390/cancers13061239] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/06/2021] [Accepted: 03/08/2021] [Indexed: 12/18/2022] Open
Abstract
Simple Summary Cancer stem cells (CSCs) represent a distinct cancer subpopulation that can influence the tumour microenvironment, in addition to cancer progression and relapse. A multitude of factors including CSC properties, long noncoding RNAs (lncRNAs), and autophagy play pivotal roles in maintaining CSCs. We discuss the methods of detection of CSCs and how our knowledge of regulatory and cellular processes, and their interaction with the microenvironment, may lead to more effective targeting of these cells. Autophagy and lncRNAs can regulate several cellular functions, thereby promoting stemness factors and CSC properties, hence understanding this triangle and its associated signalling networks can lead to enhanced therapy response, while paving the way for the development of novel therapeutic approaches. Abstract Cancer stem cells (CSCs) possess properties such as self-renewal, resistance to apoptotic cues, quiescence, and DNA-damage repair capacity. Moreover, CSCs strongly influence the tumour microenvironment (TME) and may account for cancer progression, recurrence, and relapse. CSCs represent a distinct subpopulation in tumours and the detection, characterisation, and understanding of the regulatory landscape and cellular processes that govern their maintenance may pave the way to improving prognosis, selective targeted therapy, and therapy outcomes. In this review, we have discussed the characteristics of CSCs identified in various cancer types and the role of autophagy and long noncoding RNAs (lncRNAs) in maintaining the homeostasis of CSCs. Further, we have discussed methods to detect CSCs and strategies for treatment and relapse, taking into account the requirement to inhibit CSC growth and survival within the complex backdrop of cellular processes, microenvironmental interactions, and regulatory networks associated with cancer. Finally, we critique the computationally reinforced triangle of factors inclusive of CSC properties, the process of autophagy, and lncRNA and their associated networks with respect to hypoxia, epithelial-to-mesenchymal transition (EMT), and signalling pathways.
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Affiliation(s)
- Leila Jahangiri
- Department of Life Sciences, Birmingham City University, Birmingham B15 3TN, UK; (T.I.); (M.L.C.); (L.T.)
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK; (P.P.); (R.M.T.); (S.D.T.)
- Correspondence: (L.J.); (G.V.G.)
| | - Tala Ishola
- Department of Life Sciences, Birmingham City University, Birmingham B15 3TN, UK; (T.I.); (M.L.C.); (L.T.)
| | - Perla Pucci
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK; (P.P.); (R.M.T.); (S.D.T.)
| | - Ricky M. Trigg
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK; (P.P.); (R.M.T.); (S.D.T.)
- Department of Functional Genomics, GlaxoSmithKline, Stevenage SG1 2NY, UK
| | - Joao Pereira
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA;
| | - John A. Williams
- Institute of Translational Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK;
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2SY, UK
| | - Megan L. Cavanagh
- Department of Life Sciences, Birmingham City University, Birmingham B15 3TN, UK; (T.I.); (M.L.C.); (L.T.)
| | - Georgios V. Gkoutos
- Institute of Translational Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK;
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2SY, UK
- Mammalian Genetics Unit, Medical Research Council Harwell Institute, Oxfordshire OX110RD, UK
- MRC Health Data Research Midlands, University of Birmingham, Birmingham B15 2TT, UK
- NIHR Experimental Cancer Medicine Centre, Birmingham B15 2TT, UK
- NIHR Surgical Reconstruction and Microbiology Research Centre, Birmingham B15 2TT, UK
- NIHR Biomedical Research Centre, Birmingham B15 2TT, UK
- Correspondence: (L.J.); (G.V.G.)
| | - Loukia Tsaprouni
- Department of Life Sciences, Birmingham City University, Birmingham B15 3TN, UK; (T.I.); (M.L.C.); (L.T.)
| | - Suzanne D. Turner
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK; (P.P.); (R.M.T.); (S.D.T.)
- Central European Institute of Technology (CEITEC), Masaryk University, 625 00 Brno, Czech Republic
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41
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Jiao H, Fang F, Fang T, You Y, Feng M, Wang X, Yin Z, Zhao W. SOX13 regulates cancer stem-like properties and tumorigenicity in hepatocellular carcinoma cells. Am J Cancer Res 2021; 11:760-772. [PMID: 33791152 PMCID: PMC7994154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 12/16/2020] [Indexed: 06/12/2023] Open
Abstract
Sex-determining region Y (SRY)-related high mobility group (HMG) box (SOX) proteins are pivotal transcriptional factors that play essential roles in embryonic development, cell fate decisions and cancer development. The molecular mechanism of SOX13, a member of the SOX family, in hepatocellular carcinoma (HCC) remains largely unknown. In the current study, we found that HCC cells were able to form spheroids in serum-free suspension culture and that SOX13 expression was upregulated in spheroids enriched for cancer stem cells (CSCs). Inhibition of SOX13 in HCC-LM3 and MHCC-97H cells decreased the expression of stemness-related genes; attenuated spheroid formation, anchor-dependent and anchor-independent cell proliferation and tumorigenicity; and enhanced sensitivity to drug treatment. Furthermore, based on analysis of TCGA dataset, the results indicated that SOX13 expression was obviously upregulated and closely associated with poor prognosis in HCC patients. Moreover, SOX13 was correlated with TAZ and CD24 expression. These data strongly demonstrated that SOX13 is involved in maintaining cancer stem-like properties in HCC cells and plays a critical role in HCC development.
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Affiliation(s)
- Hui Jiao
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen Translational Medical Key Laboratory of Digestive Tumor, Zhongshan Hospital, Xiamen University Xiamen 361004, People's Republic of China
| | - Fei Fang
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen Translational Medical Key Laboratory of Digestive Tumor, Zhongshan Hospital, Xiamen University Xiamen 361004, People's Republic of China
| | - Ting Fang
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen Translational Medical Key Laboratory of Digestive Tumor, Zhongshan Hospital, Xiamen University Xiamen 361004, People's Republic of China
| | - Yuting You
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen Translational Medical Key Laboratory of Digestive Tumor, Zhongshan Hospital, Xiamen University Xiamen 361004, People's Republic of China
| | - Min Feng
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen Translational Medical Key Laboratory of Digestive Tumor, Zhongshan Hospital, Xiamen University Xiamen 361004, People's Republic of China
| | - Xiaomin Wang
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen Translational Medical Key Laboratory of Digestive Tumor, Zhongshan Hospital, Xiamen University Xiamen 361004, People's Republic of China
| | - Zhenyu Yin
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen Translational Medical Key Laboratory of Digestive Tumor, Zhongshan Hospital, Xiamen University Xiamen 361004, People's Republic of China
| | - Wenxiu Zhao
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen Translational Medical Key Laboratory of Digestive Tumor, Zhongshan Hospital, Xiamen University Xiamen 361004, People's Republic of China
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42
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Slemmons KK, Deel MD, Lin YT, Oristian KM, Kuprasertkul N, Genadry KC, Chen PH, Chi JTA, Linardic CM. A method to culture human alveolar rhabdomyosarcoma cell lines as rhabdospheres demonstrates an enrichment in stemness and Notch signaling. Biol Open 2021; 10:bio.050211. [PMID: 33372065 PMCID: PMC7888706 DOI: 10.1242/bio.050211] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The development of three-dimensional cell culture techniques has allowed cancer researchers to study the stemness properties of cancer cells in in vitro culture. However, a method to grow PAX3-FOXO1 fusion-positive rhabdomyosarcoma (FP-RMS), an aggressive soft tissue sarcoma of childhood, has to date not been reported, hampering efforts to identify the dysregulated signaling pathways that underlie FP-RMS stemness. Here, we first examine the expression of canonical stem cell markers in human RMS tumors and cell lines. We then describe a method to grow FP-RMS cell lines as rhabdospheres and demonstrate that these spheres are enriched in expression of canonical stemness factors as well as Notch signaling components. Specifically, FP-RMS rhabdospheres have increased expression of SOX2, POU5F1 (OCT4), and NANOG, and several receptors and transcriptional regulators in the Notch signaling pathway. FP-RMS rhabdospheres also exhibit functional stemness characteristics including multipotency, increased tumorigenicity in vivo, and chemoresistance. This method provides a novel practical tool to support research into FP-RMS stemness and chemoresistance signaling mechanisms. Summary: Here we report on a method to culture human PAX3-FOXO1 fusion-positive rhabdomyosarcoma cells in three dimensions, and use these rhabdospheres as a novel tool to study their stemness and chemoresistance signaling mechanisms.
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Affiliation(s)
- Katherine K Slemmons
- Departments of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina
| | - Michael D Deel
- Pediatrics, Duke University School of Medicine, Durham, North Carolina
| | - Yi-Tzu Lin
- Pediatrics, Duke University School of Medicine, Durham, North Carolina
| | - Kristianne M Oristian
- Departments of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.,Pediatrics, Duke University School of Medicine, Durham, North Carolina
| | | | - Katia C Genadry
- Pediatrics, Duke University School of Medicine, Durham, North Carolina
| | - Po-Han Chen
- Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina
| | - Jen-Tsan Ashley Chi
- Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina
| | - Corinne M Linardic
- Departments of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina .,Pediatrics, Duke University School of Medicine, Durham, North Carolina
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43
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Hirozane T, Masuda M, Sugano T, Sekita T, Goto N, Aoyama T, Sakagami T, Uno Y, Moriyama H, Sawa M, Asano N, Nakamura M, Matsumoto M, Nakayama R, Kondo T, Kawai A, Kobayashi E, Yamada T. Direct conversion of osteosarcoma to adipocytes by targeting TNIK. JCI Insight 2021; 6:137245. [PMID: 33400690 PMCID: PMC7934882 DOI: 10.1172/jci.insight.137245] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 12/23/2020] [Indexed: 02/06/2023] Open
Abstract
Osteosarcoma (OS) is an aggressive mesenchymal tumor for which no molecularly targeted therapies are available. We have previously identified TRAF2- and NCK-interacting protein kinase (TNIK) as an essential factor for the transactivation of Wnt signal target genes and shown that its inhibition leads to eradication of colorectal cancer stem cells. The involvement of Wnt signaling in the pathogenesis of OS has been implicated. The aim of the present study was to examine the potential of TNIK as a therapeutic target in OS. RNA interference or pharmacological inhibition of TNIK suppressed the proliferation of OS cells. Transcriptome analysis suggested that a small-molecule inhibitor of TNIK upregulated the expression of genes involved in OS cell metabolism and downregulated transcription factors essential for maintaining the stem cell phenotype. Metabolome analysis revealed that this TNIK inhibitor redirected the metabolic network from carbon flux toward lipid accumulation in OS cells. Using in vitro and in vivo OS models, we confirmed that TNIK inhibition abrogated the OS stem cell phenotype, simultaneously driving conversion of OS cells to adipocyte-like cells through induction of PPARγ. In relation to potential therapeutic targeting in clinical practice, TNIK was confirmed to be in an active state in OS cell lines and clinical specimens. From these findings, we conclude that TNIK is applicable as a potential target for treatment of OS, affecting cell fate determination.
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Affiliation(s)
- Toru Hirozane
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan.,Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Mari Masuda
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan
| | - Teppei Sugano
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan.,Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Tetsuya Sekita
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan.,Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Naoko Goto
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan
| | - Toru Aoyama
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan.,Keio University School of Medicine, Tokyo, Japan
| | - Takato Sakagami
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan.,Keio University School of Medicine, Tokyo, Japan
| | - Yuko Uno
- Carna Biosciences Inc., Kobe, Japan
| | | | | | - Naofumi Asano
- Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan.,Division of Rare Cancer Research, National Cancer Center Research Institute, Tokyo, Japan
| | - Masaya Nakamura
- Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Morio Matsumoto
- Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Robert Nakayama
- Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Tadashi Kondo
- Division of Rare Cancer Research, National Cancer Center Research Institute, Tokyo, Japan
| | - Akira Kawai
- Division of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Eisuke Kobayashi
- Division of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Tesshi Yamada
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan.,Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
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44
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Mamun MA, Mannoor K, Cao J, Qadri F, Song X. SOX2 in cancer stemness: tumor malignancy and therapeutic potentials. J Mol Cell Biol 2021; 12:85-98. [PMID: 30517668 PMCID: PMC7109607 DOI: 10.1093/jmcb/mjy080] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Revised: 11/18/2018] [Accepted: 12/04/2018] [Indexed: 12/12/2022] Open
Abstract
Cancer stem cells (CSCs), a minor subpopulation of tumor bulks with self-renewal and seeding capacity to generate new tumors, posit a significant challenge to develop effective and long-lasting anti-cancer therapies. The emergence of drug resistance appears upon failure of chemo-/radiation therapy to eradicate the CSCs, thereby leading to CSC-mediated clinical relapse. Accumulating evidence suggests that transcription factor SOX2, a master regulator of embryonic and induced pluripotent stem cells, drives cancer stemness, fuels tumor initiation, and contributes to tumor aggressiveness through major drug resistance mechanisms like epithelial-to-mesenchymal transition, ATP-binding cassette drug transporters, anti-apoptotic and/or pro-survival signaling, lineage plasticity, and evasion of immune surveillance. Gaining a better insight and comprehensive interrogation into the mechanistic basis of SOX2-mediated generation of CSCs and treatment failure might therefore lead to new therapeutic targets involving CSC-specific anti-cancer strategies.
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Affiliation(s)
- Mahfuz Al Mamun
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Kaiissar Mannoor
- Oncology Laboratory, Institute for Developing Science & Health Initiatives (ideSHi), Dhaka, Bangladesh
| | - Jun Cao
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Firdausi Qadri
- Oncology Laboratory, Institute for Developing Science & Health Initiatives (ideSHi), Dhaka, Bangladesh
| | - Xiaoyuan Song
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China.,CAS Key Laboratory of Brain Function and Disease, CAS Center for Excellence in Molecular Cell Science, School of Life Sciences, University of Science and Technology of China, Hefei, China
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45
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Stucky A, Gao L, Sun L, Li SC, Chen X, Park TH, Cai J, Kabeer MH, Zhang X, Sinha UK, Zhong JF. Evidence for AJUBA-catenin-CDH4-linked differentiation resistance of mesenchymal stem cells implies tumorigenesis and progression of head and neck squamous cell carcinoma: a single-cell transcriptome approach. BLOOD AND GENOMICS 2021; 5:29-39. [PMID: 34368804 PMCID: PMC8346230 DOI: 10.46701/bg.2021012021106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
An increasing number of reports indicate that mesenchymal stem cells (MSCs) play an essential role in promoting tumorigenesis and progression of head and neck squamous cell carcinoma (HNSCC). However, the molecular mechanisms underlying this process remain unclear. Using the MSC model system, this study analyzes the molecular pathway by which differentiation resistant MSCs promote HNSCC. MSCs were cultured in osteogenic differentiation media and harvested on days 12 and 19. Cells were stained for cell differentiation analysis using Alizarin Red. The osteogenesis-resistant MSCs (OR-MSCs) and MSC-differentiation-derived osteoblasts (D-OSTBs) were identified and subjected to the single-cell transcriptome analysis. Gene-specific analyses of these two sub-populations were performed for the patterns of differential expression. A total of 1 780 differentially expressed genes were determined to distinguish OR-MSCs significantly from D-OSTB. Notably, AJUBA, β-catenin, and CDH4 expression levels were upregulated considerably within the OR-MSCs compared to D-OSTBs. To confirm their clinical relevance, a survey of a clinical cohort revealed a high correlation among the expression levels of AJUBA, β-catenin and CDH4. The results shed new light that OR-MSCs participate in the development of HNSCC via a pathway mediated by AJUBA, β-catenin, CDH4, and CTNNB1, thereby implying that MSC-based therapy is a promising therapeutic approach in the management of HNSCC.
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Affiliation(s)
- Andres Stucky
- Department of Otolaryngology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Li Gao
- Department of Otolaryngology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Lan Sun
- Department of Otolaryngology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Shengwen Calvin Li
- Department of Otolaryngology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Neuro-Oncology and Stem Cell Research Laboratory, Center for Neuroscience Research, CHOC Children's Research Institute, Children's Hospital of Orange County (CHOC), Orange, CA 92868, USA
- Department of Neurology, University of California - Irvine School of Medicine, Orange, CA 92868, USA
| | - Xuelian Chen
- Department of Otolaryngology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Tiffany H. Park
- Department of Otolaryngology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Jin Cai
- Department of Otolaryngology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Mustafa H. Kabeer
- Division of Pediatric General and Thoracic Surgery, Children's Hospital of Orange County, Orange, CA 92868, USA
- Department of Surgery, University of California - Irvine School of Medicine, Orange, CA 92868, USA
| | - Xi Zhang
- Department of Otolaryngology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Uttam K. Sinha
- Department of Otolaryngology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Jiang F. Zhong
- Department of Otolaryngology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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46
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Scaffold-based 3D cellular models mimicking the heterogeneity of osteosarcoma stem cell niche. Sci Rep 2020; 10:22294. [PMID: 33339857 PMCID: PMC7749131 DOI: 10.1038/s41598-020-79448-y] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 12/08/2020] [Indexed: 12/13/2022] Open
Abstract
The failure of the osteosarcoma conventional therapies leads to the growing need for novel therapeutic strategies. The lack of specificity for the Cancer Stem Cells (CSCs) population has been recently identified as the main limitation in the current therapies. Moreover, the traditional two-dimensional (2D) in vitro models, employed in the drug testing and screening as well as in the study of cell and molecular biology, are affected by a poor in vitro-in vivo translation ability. To overcome these limitations, this work provides two tumour engineering approaches as new tools to address osteosarcoma and improve therapy outcomes. In detail, two different hydroxyapatite-based bone-mimicking scaffolds were used to recapitulate aspects of the in vivo tumour microenvironment, focusing on CSCs niche. The biological performance of human osteosarcoma cell lines (MG63 and SAOS-2) and enriched-CSCs were deeply analysed in these complex cell culture models. The results highlight the fundamental role of the tumour microenvironment proving the mimicry of osteosarcoma stem cell niche by the use of CSCs together with the biomimetic scaffolds, compared to conventional 2D culture systems. These advanced 3D cell culture in vitro tumour models could improve the predictivity of preclinical studies and strongly enhance the clinical translation.
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47
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Long Noncoding RNA DANCR Activates Wnt/β-Catenin Signaling through MiR-216a Inhibition in Non-Small Cell Lung Cancer. Biomolecules 2020; 10:biom10121646. [PMID: 33302540 PMCID: PMC7764320 DOI: 10.3390/biom10121646] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/06/2020] [Accepted: 12/06/2020] [Indexed: 12/12/2022] Open
Abstract
Long noncoding RNA differentiation antagonizing nonprotein coding RNA (lncRNA-DANCR) is associated with poor prognosis in multiple cancers, and promotes cancer stemness and invasion. However, the exact mechanisms by which DANCR promotes non-small cell lung cancer (NSCLC) remain elusive. In this study, we determined that DANCR knockdown (KD) impeded cell migration and reduced stem-like characteristics in two NSCLC cell lines, A549 and H1755. Wnt signaling was shown to promote NSCLC proliferation, stemness, and invasion; therefore, we hypothesized that DANCR may regulate these activities through induction of the Wnt/β-catenin pathway. DANCR KD reduced β-catenin signaling and protein expression, and decreased the expression of β-catenin gene targets c-Myc and Axin2. One of the well-defined functions of lncRNAs is their ability to bind and inhibit microRNAs. Through in silico analysis, we identified tumor suppressor miR-216a as a potential binding partner to DANCR, and confirmed this binding through coimmunoprecipitation and luciferase-reporter assays. Furthermore, we show that DANCR-induced β-catenin protein expression may be blocked with miR-216a overexpression. Our findings illustrate a role of DANCR in NSCLC migration and stemness, and suggest a novel DANCR/miR-216a signaling axis in the Wnt/β-catenin pathway.
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48
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Grünewald TGP, Alonso M, Avnet S, Banito A, Burdach S, Cidre‐Aranaz F, Di Pompo G, Distel M, Dorado‐Garcia H, Garcia‐Castro J, González‐González L, Grigoriadis AE, Kasan M, Koelsche C, Krumbholz M, Lecanda F, Lemma S, Longo DL, Madrigal‐Esquivel C, Morales‐Molina Á, Musa J, Ohmura S, Ory B, Pereira‐Silva M, Perut F, Rodriguez R, Seeling C, Al Shaaili N, Shaabani S, Shiavone K, Sinha S, Tomazou EM, Trautmann M, Vela M, Versleijen‐Jonkers YMH, Visgauss J, Zalacain M, Schober SJ, Lissat A, English WR, Baldini N, Heymann D. Sarcoma treatment in the era of molecular medicine. EMBO Mol Med 2020; 12:e11131. [PMID: 33047515 PMCID: PMC7645378 DOI: 10.15252/emmm.201911131] [Citation(s) in RCA: 170] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 07/20/2020] [Accepted: 07/24/2020] [Indexed: 12/14/2022] Open
Abstract
Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult-to-treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma.
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Affiliation(s)
- Thomas GP Grünewald
- Max‐Eder Research Group for Pediatric Sarcoma BiologyInstitute of PathologyFaculty of MedicineLMU MunichMunichGermany
- Division of Translational Pediatric Sarcoma ResearchGerman Cancer Research Center (DKFZ), Hopp Children's Cancer Center (KiTZ), German Cancer Consortium (DKTK)HeidelbergGermany
- Institute of PathologyHeidelberg University HospitalHeidelbergGermany
| | - Marta Alonso
- Program in Solid Tumors and BiomarkersFoundation for the Applied Medical ResearchUniversity of Navarra PamplonaPamplonaSpain
| | - Sofia Avnet
- Orthopedic Pathophysiology and Regenerative Medicine UnitIRCCS Istituto Ortopedico RizzoliBolognaItaly
| | - Ana Banito
- Pediatric Soft Tissue Sarcoma Research GroupGerman Cancer Research Center (DKFZ)HeidelbergGermany
| | - Stefan Burdach
- Department of Pediatrics and Children's Cancer Research Center (CCRC)Technische Universität MünchenMunichGermany
| | - Florencia Cidre‐Aranaz
- Max‐Eder Research Group for Pediatric Sarcoma BiologyInstitute of PathologyFaculty of MedicineLMU MunichMunichGermany
| | - Gemma Di Pompo
- Orthopedic Pathophysiology and Regenerative Medicine UnitIRCCS Istituto Ortopedico RizzoliBolognaItaly
| | | | | | | | | | | | - Merve Kasan
- Max‐Eder Research Group for Pediatric Sarcoma BiologyInstitute of PathologyFaculty of MedicineLMU MunichMunichGermany
| | | | | | - Fernando Lecanda
- Division of OncologyAdhesion and Metastasis LaboratoryCenter for Applied Medical ResearchUniversity of NavarraPamplonaSpain
| | - Silvia Lemma
- Orthopedic Pathophysiology and Regenerative Medicine UnitIRCCS Istituto Ortopedico RizzoliBolognaItaly
| | - Dario L Longo
- Institute of Biostructures and Bioimaging (IBB)Italian National Research Council (CNR)TurinItaly
| | | | | | - Julian Musa
- Max‐Eder Research Group for Pediatric Sarcoma BiologyInstitute of PathologyFaculty of MedicineLMU MunichMunichGermany
- Department of General, Visceral and Transplantation SurgeryUniversity of HeidelbergHeidelbergGermany
| | - Shunya Ohmura
- Max‐Eder Research Group for Pediatric Sarcoma BiologyInstitute of PathologyFaculty of MedicineLMU MunichMunichGermany
| | | | - Miguel Pereira‐Silva
- Department of Pharmaceutical TechnologyFaculty of PharmacyUniversity of CoimbraCoimbraPortugal
| | - Francesca Perut
- Orthopedic Pathophysiology and Regenerative Medicine UnitIRCCS Istituto Ortopedico RizzoliBolognaItaly
| | - Rene Rodriguez
- Instituto de Investigación Sanitaria del Principado de AsturiasOviedoSpain
- CIBER en oncología (CIBERONC)MadridSpain
| | | | - Nada Al Shaaili
- Department of Oncology and MetabolismUniversity of SheffieldSheffieldUK
| | - Shabnam Shaabani
- Department of Drug DesignUniversity of GroningenGroningenThe Netherlands
| | - Kristina Shiavone
- Department of Oncology and MetabolismUniversity of SheffieldSheffieldUK
| | - Snehadri Sinha
- Department of Oral and Maxillofacial DiseasesUniversity of HelsinkiHelsinkiFinland
| | | | - Marcel Trautmann
- Division of Translational PathologyGerhard‐Domagk‐Institute of PathologyMünster University HospitalMünsterGermany
| | - Maria Vela
- Hospital La Paz Institute for Health Research (IdiPAZ)MadridSpain
| | | | | | - Marta Zalacain
- Institute of Biostructures and Bioimaging (IBB)Italian National Research Council (CNR)TurinItaly
| | - Sebastian J Schober
- Department of Pediatrics and Children's Cancer Research Center (CCRC)Technische Universität MünchenMunichGermany
| | - Andrej Lissat
- University Children′s Hospital Zurich – Eleonoren FoundationKanton ZürichZürichSwitzerland
| | - William R English
- Department of Oncology and MetabolismUniversity of SheffieldSheffieldUK
| | - Nicola Baldini
- Orthopedic Pathophysiology and Regenerative Medicine UnitIRCCS Istituto Ortopedico RizzoliBolognaItaly
- Department of Biomedical and Neuromotor SciencesUniversity of BolognaBolognaItaly
| | - Dominique Heymann
- Department of Oncology and MetabolismUniversity of SheffieldSheffieldUK
- Université de NantesInstitut de Cancérologie de l'OuestTumor Heterogeneity and Precision MedicineSaint‐HerblainFrance
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49
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Chen J, Wang F, Lu Y, Yang S, Chen X, Huang Y, Lin X. CLC-3 and SOX2 regulate the cell cycle in DU145 cells. Oncol Lett 2020; 20:372. [PMID: 33154770 PMCID: PMC7608052 DOI: 10.3892/ol.2020.12235] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 07/23/2020] [Indexed: 12/28/2022] Open
Abstract
Sex determining region Y-box 2 (SOX2) is a transcription factor that serves a role in numerous different types of malignant cancer. Altered expression of chloride channel proteins has been described in a variety of malignancies. However, the association between SOX2 and chloride channel proteins is not yet fully understood. The present study investigated the association between SOX2 and chloride voltage-gated channel 3 (CLC-3) in prostate cancer. Flow cytometry demonstrated that the inactivation of CLC-3 or SOX2 arrested cell cycle progression in the G0/G1 phase. Furthermore, CLC-3 was observed to bind to SOX2, and vice versa, by co-immunoprecipitation. SOX2 appears to initiate and maintain prostate cancer tumorigenesis, in part, by modulating the cell cycle. These findings indicate the potential of SOX2 and CLC-3 as targets for the development of multi-targeted therapeutics.
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Affiliation(s)
- Jiahong Chen
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Fang Wang
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Yuli Lu
- Department of Epidemiology and Health Statistics, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Shangqi Yang
- Department of Epidemiology and Health Statistics, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Xueqin Chen
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Youwei Huang
- Department of Pathology and Pathophysiology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Xi Lin
- Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China.,Key Laboratory for Environmental Exposure and Health, Environment College, Jinan University, Guangzhou, Guangdong 510632, P.R. China
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Li J, Chen J, Hu Z, Xu W. MicroRNA-1236-3p inhibits human osteosarcoma growth. Oncol Lett 2020; 20:367. [PMID: 33133267 PMCID: PMC7590435 DOI: 10.3892/ol.2020.12229] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 09/18/2020] [Indexed: 12/16/2022] Open
Abstract
Osteosarcoma (OS) is a common bone tumor with high mortality worldwide. The long-term survival rate of patients with metastatic or recurrent disease is <20%. The present study explored the biological role of microRNA (miRNA/miR)-1236-3p in OS. miRNA and mRNA expression levels were measured via reverse transcription-quantitative PCR. Fluorescence in situ hybridization was performed to determine miR-1236-3p expression levels in clinical specimens. Protein expression was measured via western blotting. Immunohistochemical analysis was used to detect Wnt target gene expression in tumor tissues. The interaction between the Wnt3a 3′untranslated region and miR-1236-3p was assessed via dual-luciferase reporter assays. Cell cycle, Transwell, Cell Counting Kit-8 and wound healing assays were conducted to evaluate the function of the miR-1236-3p/Wnt3a axis. Human OS (HOS) cells stably transfected with vector or miR-1236-3p sponge were injected subcutaneously into nude mice to assess the role of miR-1236-3p in vivo. miR-1236-3p expression was downregulated in OS tissues compared with chondroma tissues, and miR-1236-3p overexpression inhibited OS cell migration and proliferation compared with the negative control group. Furthermore, in vivo xenograft assays displayed enhanced tumour growth rates in the miR-1236-3p sponge group compared with the vector control group. In the present study, the results indicated that miR-1236-3p inhibited OS progression and Wnt3a was identified as a target of miR-1236-3p.
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Affiliation(s)
- Jiarui Li
- Department of Urology Surgery, The First Affiliated Hospital of Nanchang University, Medical College of Nanchang University, Nanchang, Jiangxi 330000, P.R. China
| | - Junxin Chen
- Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University & Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, Zhejiang 310016, P.R. China
| | - Zhijun Hu
- Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University & Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, Zhejiang 310016, P.R. China
| | - Wenbin Xu
- Department of Orthopedic Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University & Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, Zhejiang 310016, P.R. China
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