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1
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Braungart S, Daff C. Expect the unexpected: neuroblastoma in a patient with the VACTERL association. BMJ Case Rep 2025; 18:e265123. [PMID: 40199601 DOI: 10.1136/bcr-2025-265123] [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] [Indexed: 04/10/2025] Open
Abstract
The VACTERL association is characterised by a variable combination of vertebral defects, anorectal malformation, cardiac defects, tracheo-oesophageal fistula, renal anomalies and limb abnormalities. Malignant tumours are not usually detected in these patients.We present the case of an infant diagnosed with the VACTERL association at birth due to an anorectal malformation, cardiac and vertebral anomalies. Further imaging was obtained to investigate potential spinal cord anomalies. This scan detected an incidental left adrenal mass. Diagnostic work-up including biopsy confirmed the adrenal mass as an intermediate risk left adrenal neuroblastoma with encasement of the left renal vessels and superior mesenteric artery.To our knowledge, this is the first case of an infant patient with the VACTERL association and simultaneous diagnosis of a neuroblastoma. This case demonstrates how careful expert review of specialist imaging can incidentally reveal unexpected findings which require a significant alteration of a patient's treatment pathway.
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Affiliation(s)
- Sarah Braungart
- Paediatric Surgery, Royal Hospital for Children Glasgow, NHS Greater Glasgow and Clyde, Glasgow, UK
| | - Caitlin Daff
- Paediatric Surgery, Royal Hospital for Children Glasgow, NHS Greater Glasgow and Clyde, Glasgow, UK
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2
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AlKhazal A, Chohan S, Ross DJ, Kim J, Brown EG. Emerging clinical and research approaches in targeted therapies for high-risk neuroblastoma. Front Oncol 2025; 15:1553511. [PMID: 40104501 PMCID: PMC11913827 DOI: 10.3389/fonc.2025.1553511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 02/06/2025] [Indexed: 03/20/2025] Open
Abstract
Neuroblastoma is a pediatric cancer that originates from neural crest cells and is the most common extracranial solid tumor in children under five years of age. While low-risk neuroblastoma often regresses spontaneously, high-risk neuroblastoma poses a significant clinical challenge. Recent advances in understanding neuroblastoma's molecular mechanisms have led to the development of targeted therapies that aim to selectively inhibit specific pathways involved in tumor growth and progression, improving patient outcomes while minimizing side effects. This review provides a comprehensive review of neuroblastoma biology and emerging therapeutic strategies. Key topics include (a) immunotherapies and immunotargets, (b) non-coding RNAs (long non-coding RNA, microRNA, and circular RNA), (c) molecular biomarkers and pathways, and (d) limitations and future directions.
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Affiliation(s)
- Albatool AlKhazal
- Department of Surgery, School of Medicine, University of California, Davis, Davis, CA, United States
| | - Samiha Chohan
- Department of Surgery, School of Medicine, University of California, Davis, Davis, CA, United States
- Department of Biological Sciences, California State University, Sacramento, Sacramento, CA, United States
| | - Destani J Ross
- Department of Surgery, School of Medicine, University of California, Davis, Davis, CA, United States
| | - Jinhwan Kim
- Department of Surgery, School of Medicine, University of California, Davis, Davis, CA, United States
- Department of Biomedical Engineering, University of California, Davis, Davis, CA, United States
| | - Erin G Brown
- Department of Surgery, School of Medicine, University of California, Davis, Davis, CA, United States
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3
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Wireko AA, Ben-Jaafar A, Kong JSH, Mannan KM, Sanker V, Rosenke SL, Boye ANA, Nkrumah-Boateng PA, Poornaselvan J, Shah MH, Abdul-Rahman T, Atallah O. Sonic hedgehog signalling pathway in CNS tumours: its role and therapeutic implications. Mol Brain 2024; 17:83. [PMID: 39568072 PMCID: PMC11580395 DOI: 10.1186/s13041-024-01155-w] [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: 08/13/2024] [Accepted: 11/04/2024] [Indexed: 11/22/2024] Open
Abstract
CNS tumours encompass a diverse group of neoplasms with significant morbidity and mortality. The SHH signalling pathway plays a critical role in the pathogenesis of several CNS tumours, including gliomas, medulloblastomas and others. By influencing cellular proliferation, differentiation and migration in CNS tumours, the SHH pathway has emerged as a promising target for therapeutic intervention. Current strategies such as vismodegib and sonidegib have shown efficacy in targeting SHH pathway activation. However, challenges such as resistance mechanisms and paradoxical effects observed in clinical settings underscore the complexity of effectively targeting this pathway. Advances in gene editing technologies, particularly CRISPR/Cas9, have provided valuable tools for studying SHH pathway biology, validating therapeutic targets and exploring novel treatment modalities. These innovations have paved the way for a better understanding of pathway dynamics and the development of more precise therapeutic interventions. In addition, the identification and validation of biomarkers of SHH pathway activation are critical to guide clinical decision making and improve patient outcomes. Molecular profiling and biomarker discovery efforts are critical steps towards personalised medicine approaches in the treatment of SHH pathway-associated CNS tumours. While significant progress has been made in understanding the role of the SHH pathway in CNS tumorigenesis, ongoing research is essential to overcome current therapeutic challenges and refine treatment strategies. The integration of molecular insights with advanced technologies and clinical expertise holds great promise for developing more effective and personalised therapies for patients with SHH pathway-driven CNS tumours.
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Affiliation(s)
| | - Adam Ben-Jaafar
- School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland
| | - Jonathan Sing Huk Kong
- School of Medicine, College of Medical & Veterinary Life Sciences, University of Glasgow, Glasgow, UK
| | - Krishitha Meenu Mannan
- School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, Belfast, UK
| | - Vivek Sanker
- Department of Neurosurgery, Stanford University, Stanford, CA, USA
| | | | | | | | | | - Muhammad Hamza Shah
- School of Medicine, Dentistry & Biomedical Sciences, Queen's University Belfast, Belfast, UK
| | | | - Oday Atallah
- Department of Neurosurgery, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany
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4
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Anoushirvani AA, Jafarian Yazdi A, Amirabadi S, Asouri SA, Shafabakhsh R, Sheida A, Hosseini Khabr MS, Jafari A, Tamehri Zadeh SS, Hamblin MR, Kalantari L, Talaei Zavareh SA, Mirzaei H. Role of non-coding RNAs in neuroblastoma. Cancer Gene Ther 2023; 30:1190-1208. [PMID: 37217790 DOI: 10.1038/s41417-023-00623-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 03/25/2023] [Accepted: 05/04/2023] [Indexed: 05/24/2023]
Abstract
Neuroblastoma is known as the most prevalent extracranial malignancy in childhood with a neural crest origin. It has been widely accepted that non-coding RNAs (ncRNAs) play important roles in many types of cancer, including glioma and gastrointestinal cancers. They may regulate the cancer gene network. According to recent sequencing and profiling studies, ncRNAs genes are deregulated in human cancers via deletion, amplification, abnormal epigenetic, or transcriptional regulation. Disturbances in the expression of ncRNAs may act either as oncogenes or as anti-tumor suppressor genes, and can lead to the induction of cancer hallmarks. ncRNAs can be secreted from tumor cells inside exosomes, where they can be transferred to other cells to affect their function. However, these topics still need more study to clarify their exact roles, so the present review addresses different roles and functions of ncRNAs in neuroblastoma.
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Affiliation(s)
- Ali Arash Anoushirvani
- Department of Internal Medicine, Firoozgar Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Sanaz Amirabadi
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Sahar Ahmadi Asouri
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University, Kashan, Iran
| | - Rana Shafabakhsh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University, Kashan, Iran
| | - Amirhossein Sheida
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Maryam Sadat Hosseini Khabr
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Ameneh Jafari
- ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, P.O. BOX: 15179/64311, Tehran, Iran
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, South Africa
| | - Leila Kalantari
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran.
| | | | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University, Kashan, Iran.
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5
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Jing J, Wu Z, Wang J, Luo G, Lin H, Fan Y, Zhou C. Hedgehog signaling in tissue homeostasis, cancers, and targeted therapies. Signal Transduct Target Ther 2023; 8:315. [PMID: 37596267 PMCID: PMC10439210 DOI: 10.1038/s41392-023-01559-5] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 07/05/2023] [Indexed: 08/20/2023] Open
Abstract
The past decade has seen significant advances in our understanding of Hedgehog (HH) signaling pathway in various biological events. HH signaling pathway exerts its biological effects through a complex signaling cascade involved with primary cilium. HH signaling pathway has important functions in embryonic development and tissue homeostasis. It plays a central role in the regulation of the proliferation and differentiation of adult stem cells. Importantly, it has become increasingly clear that HH signaling pathway is associated with increased cancer prevalence, malignant progression, poor prognosis and even increased mortality. Understanding the integrative nature of HH signaling pathway has opened up the potential for new therapeutic targets for cancer. A variety of drugs have been developed, including small molecule inhibitors, natural compounds, and long non-coding RNA (LncRNA), some of which are approved for clinical use. This review outlines recent discoveries of HH signaling in tissue homeostasis and cancer and discusses how these advances are paving the way for the development of new biologically based therapies for cancer. Furthermore, we address status quo and limitations of targeted therapies of HH signaling pathway. Insights from this review will help readers understand the function of HH signaling in homeostasis and cancer, as well as opportunities and challenges of therapeutic targets for cancer.
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Affiliation(s)
- Junjun Jing
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Zhuoxuan Wu
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
- Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Jiahe Wang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
- Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Guowen Luo
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
- Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Hengyi Lin
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
- Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Yi Fan
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
- Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
| | - Chenchen Zhou
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
- Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
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6
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Zou Z, Wang H, Zhang B, Zhang Z, Chen R, Yang L. Inhibition of Gli1 suppressed hyperglycemia-induced meibomian gland dysfunction by promoting pparγ expression. Biomed Pharmacother 2022; 151:113109. [PMID: 35594713 DOI: 10.1016/j.biopha.2022.113109] [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: 02/24/2022] [Revised: 05/01/2022] [Accepted: 05/10/2022] [Indexed: 11/19/2022] Open
Abstract
Diabetes is one of the risk factors for meibomian gland dysfunction (MGD); however, the underlying molecular mechanism remains unknown. The current study aims to examine the effects of glioma-associated oncogene homolog 1 (Gli1), a transcription factor of the sonic hedgehog (Shh) pathway, in the modulation of diabetic-related MGD. Here, using RNA sequencing and qRT-PCR, we examined the mRNA changes of Shh pathway involving genes. mRNA sequencing analysis showed that the Shh pathway involving genes Shh and Gli1 were markedly upregulated in diabetic MG, and qRT-PCR detection of Shh pathway-associated genes found that Gli1 expression increased most significantly. Contrary to the elevation of Gli1 level, the expression of pparγ was downregulated in diabetic MG and in high glucose treated organotypic cultured mouse MG. GANT61, an inhibitor of Gli1, effectively inhibited the reduction of pparγ expression and lipid accumulation induced by high glucose, which was suppressed by pparγ inhibitor T0070907. We further demonstrated that advanced glycation end products (AGEs) treatment also promoted the expression of Gli1 and pparγ in organotypic cultured mouse MG. AGEs inhibitor Aminoguanidine suppressed high glucose caused Gli1 upregulation in organotypic cultured mouse MG. These results suggest that suppression of Gli1 may be a potentially useful therapeutic option for diabetic-related MGD.
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Affiliation(s)
- Zongzheng Zou
- School of Medicine and Life Sciences, Shandong First Medical University, Jinan, China
| | - Huifeng Wang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Bin Zhang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Zhenzhen Zhang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Rong Chen
- School of Medicine and Life Sciences, Shandong First Medical University, Jinan, China
| | - Lingling Yang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China.
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7
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Villasante A, Godier-Furnemont A, Hernandez-Barranco A, Coq JL, Boskovic J, Peinado H, Mora J, Samitier J, Vunjak-Novakovic G. Horizontal transfer of the stemness-related markers EZH2 and GLI1 by neuroblastoma-derived extracellular vesicles in stromal cells. Transl Res 2021; 237:82-97. [PMID: 34217898 PMCID: PMC9204390 DOI: 10.1016/j.trsl.2021.06.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 06/24/2021] [Accepted: 06/27/2021] [Indexed: 01/05/2023]
Abstract
Neuroblastoma (NB) is the most common extracranial pediatric solid cancer originating from undifferentiated neural crest cells. NB cells express EZH2 and GLI1 genes that are known to maintain the undifferentiated phenotype of cancer stem cells (CSC) in NB. Recent studies suggest that tumor-derived extracellular vesicles (EVs) can regulate the transformation of surrounding cells into CSC by transferring tumor-specific molecules they contain. However, the horizontal transfer of EVs molecules in NB remains largely unknown. We report the analysis of NB-derived EVs in bioengineered models of NB that are based on a collagen 1/hyaluronic acid scaffold designed to mimic the native tumor niche. Using these models, we observed an enrichment of GLI1 and EZH2 mRNAs in NB-derived EVs. As a consequence of the uptake of NB-derived EVs, the host cells increased the expression levels of GLI1 and EZH2. These results suggest the alteration of the expression profile of stromal cells through an EV-based mechanism, and point the GLI1 and EZH2 mRNAs in the EV cargo as diagnostic biomarkers in NB.
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Affiliation(s)
- Aranzazu Villasante
- Department of Biomedical Engineering, Columbia University, New York, New York,USA; Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain; Department of Electronics and Biomedical Engineering, University of Barcelona, Barcelona, Spain.
| | | | - Alberto Hernandez-Barranco
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Johanne Le Coq
- Electron Microscopy Unit, Structural Biology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Jasminka Boskovic
- Electron Microscopy Unit, Structural Biology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Hector Peinado
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Jaume Mora
- Oncology Department, Pediatric Cancer Center Barcelona, Hospital Sant Joan de Deu, Barcelona, Spain
| | - Josep Samitier
- Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain; Department of Electronics and Biomedical Engineering, University of Barcelona, Barcelona, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Madrid, Spain
| | - Gordana Vunjak-Novakovic
- Department of Biomedical Engineering, Columbia University, New York, New York,USA; Department of Medicine, Columbia University, New York, New York, USA.
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Li Y, Feng C, Chen Y, Huang K, Li C, Xiong X, Li P, Zhou D, Peng X, Weng W, Deng X, Wu Y, Fang J. Improved Outcomes with Induction Chemotherapy Combined with Arsenic Trioxide in Stage 4 Neuroblastoma: A Case Series. Technol Cancer Res Treat 2021; 20:15330338211041454. [PMID: 34569870 PMCID: PMC8485563 DOI: 10.1177/15330338211041454] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Objective: The apoptotic and cytotoxic effects of arsenic trioxide (ATO) makes it a potentially suitable agent for the treatment of patients with neuroblastoma with poor prognosis; therefore, we try to evaluate the effectiveness and safety of ATO combined with reinduction/induction chemotherapy in children with recurrent/refractory or newly diagnosed stage 4 neuroblastoma. Methods: Retrospective analysis was performed on seven pediatric patients with recurrent /refractory or newly diagnosed stage 4 neuroblastoma treated with traditional reinduction/induction chemotherapy combined with ATO. Results: A total of 7 patients were treated synchronously with ATO and chemotherapy for up to nine courses; all patients received conventional chemotherapy plus a 0.16 mg/kg/day dose of intravenous ATO during reinduction/induction chemotherapy. Treatment was effective in five patients and ineffective in the other two patients. The overall response rate was 71.43% (5 of 7). The side effects of the ATO combination were minor, whereby only treatment in one patient was terminated at the sixth course due to a prolonged QT interval (0.51 s), which returned to normal after symptomatic treatment. Conclusions: ATO can be safely and effectively combined with chemotherapy drugs as a potential alternative means of treatment for high-risk stage 4 neuroblastoma, and we have observed that ATO can restore the sensitivity of chemotherapy in some patients who were resistant to previous chemotherapy. Further investigations and clinical data are required to confirm these observations.
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Affiliation(s)
- Yang Li
- 56713Sun Yet-Sen Memorial Hospital, Sun Yet-Sen University, Guangzhou, China
| | - Chuchu Feng
- 56713Sun Yet-Sen Memorial Hospital, Sun Yet-Sen University, Guangzhou, China
| | - Yantao Chen
- 56713Sun Yet-Sen Memorial Hospital, Sun Yet-Sen University, Guangzhou, China
| | - Ke Huang
- 56713Sun Yet-Sen Memorial Hospital, Sun Yet-Sen University, Guangzhou, China
| | - Chunmou Li
- 56713Sun Yet-Sen Memorial Hospital, Sun Yet-Sen University, Guangzhou, China
| | - Xilin Xiong
- 56713Sun Yet-Sen Memorial Hospital, Sun Yet-Sen University, Guangzhou, China
| | - Peng Li
- 302944South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Dunhua Zhou
- 56713Sun Yet-Sen Memorial Hospital, Sun Yet-Sen University, Guangzhou, China
| | - Xiaomin Peng
- 56713Sun Yet-Sen Memorial Hospital, Sun Yet-Sen University, Guangzhou, China
| | - Wenjun Weng
- 56713Sun Yet-Sen Memorial Hospital, Sun Yet-Sen University, Guangzhou, China
| | - Xiaogeng Deng
- 56713Sun Yet-Sen Memorial Hospital, Sun Yet-Sen University, Guangzhou, China
| | - Yaohao Wu
- 56713Sun Yet-Sen Memorial Hospital, Sun Yet-Sen University, Guangzhou, China
| | - Jianpei Fang
- 56713Sun Yet-Sen Memorial Hospital, Sun Yet-Sen University, Guangzhou, China
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Li C, Peng X, Feng C, Xiong X, Li J, Liao N, Yang Z, Liu A, Wu P, Liang X, He Y, Tian X, Lin Y, Wang S, Li Y. Excellent Early Outcomes of Combined Chemotherapy With Arsenic Trioxide for Stage 4/M Neuroblastoma in Children: A Multicenter Nonrandomized Controlled Trial. Oncol Res 2021; 28:791-800. [PMID: 33858561 PMCID: PMC8420893 DOI: 10.3727/096504021x16184815905096] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
This nonrandomized, multicenter cohort, open-label clinical trial evaluated the efficacy and safety of combined chemotherapy with arsenic trioxide (ATO) in children with stage 4/M neuroblastoma (NB). We enrolled patients who were newly diagnosed with NB and assessed as stage 4/M and received either traditional chemotherapy or ATO combined with chemotherapy according to their own wishes. Twenty-two patients were enrolled in the trial group (ATO combined with chemotherapy), and 13 patients were enrolled in the control group (traditional chemotherapy). Objective response rate (ORR) at 4 weeks after completing induction chemotherapy was defined as the main outcome, and adverse events were monitored and graded in the meantime. Data cutoff date was December 31, 2019. Finally, we found that patients who received ATO combined with chemotherapy had a significantly higher response rate than those who were treated with traditional chemotherapy (ORR: 86.36% vs. 46.16%, p=0.020). Reversible cardiotoxicity was just observed in three patients who were treated with ATO, and no other differential adverse events were observed between the two groups. ATO combined with chemotherapy can significantly improve end-induction response in high-risk NB, and our novel regimen is well tolerated in pediatric patients. These results highlight the superiority of chemotherapy with ATO, which creates new opportunity for prolonging survival. In addition, this treatment protocol minimizes therapeutic costs compared with anti-GD2 therapy, MIBG, and proton therapy and can decrease the burden to families and society. However, we also need to evaluate more cases to consolidate our conclusion.
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Affiliation(s)
- Chunmou Li
- *Pediatric Hematology/Oncology, Sun Yet-Sen Memorial Hospital, Sun Yet-Sen University, Guangzhou, P.R. China
| | - Xiaomin Peng
- *Pediatric Hematology/Oncology, Sun Yet-Sen Memorial Hospital, Sun Yet-Sen University, Guangzhou, P.R. China
| | - Chuchu Feng
- *Pediatric Hematology/Oncology, Sun Yet-Sen Memorial Hospital, Sun Yet-Sen University, Guangzhou, P.R. China
| | - Xilin Xiong
- *Pediatric Hematology/Oncology, Sun Yet-Sen Memorial Hospital, Sun Yet-Sen University, Guangzhou, P.R. China
| | - Jianxin Li
- †Department of Hematology and Oncology, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, P.R. China
| | - Ning Liao
- ‡Department of Pediatrics, The First Affiliated Hospital of GuangXi Medical University, Nanning, P.R. China
| | - Zhen Yang
- §Department of Hematology, Kunming Children’s Hospital, Kunming, P.R. China
| | - Aiguo Liu
- ¶Department of Pediatric Hematology & Oncology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, P.R. China
| | - Pingping Wu
- *Pediatric Hematology/Oncology, Sun Yet-Sen Memorial Hospital, Sun Yet-Sen University, Guangzhou, P.R. China
| | - Xuehong Liang
- †Department of Hematology and Oncology, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, P.R. China
| | - Yunyan He
- ‡Department of Pediatrics, The First Affiliated Hospital of GuangXi Medical University, Nanning, P.R. China
| | - Xin Tian
- §Department of Hematology, Kunming Children’s Hospital, Kunming, P.R. China
| | - Yunbi Lin
- §Department of Hematology, Kunming Children’s Hospital, Kunming, P.R. China
| | - Songmi Wang
- ¶Department of Pediatric Hematology & Oncology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, P.R. China
| | - Yang Li
- *Pediatric Hematology/Oncology, Sun Yet-Sen Memorial Hospital, Sun Yet-Sen University, Guangzhou, P.R. China
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10
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Farina AR, Cappabianca LA, Zelli V, Sebastiano M, Mackay AR. Mechanisms involved in selecting and maintaining neuroblastoma cancer stem cell populations, and perspectives for therapeutic targeting. World J Stem Cells 2021; 13:685-736. [PMID: 34367474 PMCID: PMC8316860 DOI: 10.4252/wjsc.v13.i7.685] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/09/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Pediatric neuroblastomas (NBs) are heterogeneous, aggressive, therapy-resistant embryonal tumours that originate from cells of neural crest (NC) origin and in particular neuroblasts committed to the sympathoadrenal progenitor cell lineage. Therapeutic resistance, post-therapeutic relapse and subsequent metastatic NB progression are driven primarily by cancer stem cell (CSC)-like subpopulations, which through their self-renewing capacity, intermittent and slow cell cycles, drug-resistant and reversibly adaptive plastic phenotypes, represent the most important obstacle to improving therapeutic outcomes in unfavourable NBs. In this review, dedicated to NB CSCs and the prospects for their therapeutic eradication, we initiate with brief descriptions of the unique transient vertebrate embryonic NC structure and salient molecular protagonists involved NC induction, specification, epithelial to mesenchymal transition and migratory behaviour, in order to familiarise the reader with the embryonic cellular and molecular origins and background to NB. We follow this by introducing NB and the potential NC-derived stem/progenitor cell origins of NBs, before providing a comprehensive review of the salient molecules, signalling pathways, mechanisms, tumour microenvironmental and therapeutic conditions involved in promoting, selecting and maintaining NB CSC subpopulations, and that underpin their therapy-resistant, self-renewing metastatic behaviour. Finally, we review potential therapeutic strategies and future prospects for targeting and eradication of these bastions of NB therapeutic resistance, post-therapeutic relapse and metastatic progression.
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Affiliation(s)
- Antonietta Rosella Farina
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Lucia Annamaria Cappabianca
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Veronica Zelli
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Michela Sebastiano
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Andrew Reay Mackay
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy.
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11
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Li X, Li Y, Li S, Li H, Yang C, Lin J. The role of Shh signalling pathway in central nervous system development and related diseases. Cell Biochem Funct 2020; 39:180-189. [PMID: 32840890 DOI: 10.1002/cbf.3582] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/07/2020] [Accepted: 08/01/2020] [Indexed: 12/15/2022]
Abstract
Sonic hedgehog (Shh) plays important roles in developmental of vertebrate animal central nervous system (CNS), and Gli is its downstream signal molecule. Shh signalling is essential for pattern formation, cell-fate specification, axon guidance, proliferation, survival and differentiation of neurons in CNS development. The abnormal signalling pathway of Shh leads to the occurrence of many nervous system diseases. The mechanism of Shh signalling is complex and remains incompletely understood. Nevertheless, studies have revealed that Shh signalling pathway is classified into canonical and non-canonical pathways. Here we review the role of the Shh signalling pathway and its impact in CNS development and related diseases. Specifically, we discuss the role of Shh in the spinal cord and brain development, cell differentiation and proliferation in CNS and related diseases such as brain tumour, Parkinson's diseases, epilepsy, autism, depression and traumatic brain injury. We also highlight future directions of research that could help to clarify the mechanisms and consequences of Shh signalling in the process of CNS development and related diseases. SIGNIFICANCE OF THE STUDY: This review summarized the role of Shh signalling pathway in CNS development and related diseases such as brain tumour, Parkinson's diseases, epilepsy, autism, depression and traumatic brain injury. It also presented the author's opinions on the future research direction of Shh signalling pathway.
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Affiliation(s)
- Xiaoying Li
- Stem Cells & Biotherapy Engineering Research Center of Henan, College of Life Science and Technology, Xinxiang Medical University, Xinxiang, China
| | - Yunxiao Li
- Stem Cells & Biotherapy Engineering Research Center of Henan, College of Life Science and Technology, Xinxiang Medical University, Xinxiang, China
| | - Shuanqing Li
- Stem Cells & Biotherapy Engineering Research Center of Henan, College of Life Science and Technology, Xinxiang Medical University, Xinxiang, China
| | - Han Li
- Stem Cells & Biotherapy Engineering Research Center of Henan, College of Life Science and Technology, Xinxiang Medical University, Xinxiang, China.,Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Ciqing Yang
- Stem Cells & Biotherapy Engineering Research Center of Henan, College of Life Science and Technology, Xinxiang Medical University, Xinxiang, China.,Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Juntang Lin
- Stem Cells & Biotherapy Engineering Research Center of Henan, College of Life Science and Technology, Xinxiang Medical University, Xinxiang, China.,Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
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12
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Yang J, Yu L, Yan J, Xiao Y, Li W, Xiao J, Lei J, Xiang D, Zhang S, Yu X. Circular RNA DGKB Promotes the Progression of Neuroblastoma by Targeting miR-873/GLI1 Axis. Front Oncol 2020; 10:1104. [PMID: 32793474 PMCID: PMC7390925 DOI: 10.3389/fonc.2020.01104] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 06/02/2020] [Indexed: 12/18/2022] Open
Abstract
Accumulated evidences suggested that circular RNAs (circRNA) played critical roles in tumorigenesis and progression. To our knowledge, no study reported the function of circular RNA DGKB (circDGKB, circRNA ID: hsa_circ_0133622) on progression of neuroblastoma (NB). Here, we showed that circDGKB was upregulated in NB tissues compared to the normal dorsal root ganglia. Moreover, the expression level of circDGKB was negatively correlated with the survival rate of NB patients. Mechanically, overexpression of circDGKB promoted the proliferation, migration, invasion, and tumorigenesis of NB cells and reduced cell apoptosis, and vice versa. In addition, qRT-PCR and/or Western blot results showed that circDGKB overexpression inhibited the expression level of miR-873 and enhanced GLI1 expression. Moreover, miR-873 functioned an opposite role to circDGKB and significantly weakened circDGKB role in promoting NB progression. Furthermore, GLI1 upregulation also rescued the miR-873 role in inhibiting NB progression. In conclusion, our work proved that circDGKB promoted NB progression via targeting miR-873/GLI1 axis in vitro and in vivo. Our study provided a new target for NB treatment and indicated that circDGKB could act as a novel diagnostic marker for NB.
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Affiliation(s)
- Jiale Yang
- Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Leitao Yu
- Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jinlong Yan
- Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yu Xiao
- Department of General Surgery, Jiangxi Provincial Children's Hospital, Nanchang, China
| | - Weiming Li
- Department of General Surgery, Jiangxi Provincial Children's Hospital, Nanchang, China
| | - Juhua Xiao
- Department of Ultrasound, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, China
| | - Jun Lei
- Department of General Surgery, Jiangxi Provincial Children's Hospital, Nanchang, China
| | - Deng Xiang
- Department of General Surgery, Jiangxi Provincial Children's Hospital, Nanchang, China
| | - Shouhua Zhang
- Department of General Surgery, Jiangxi Provincial Children's Hospital, Nanchang, China
| | - Xin Yu
- Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China
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13
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Szemes M, Greenhough A, Malik K. Wnt Signaling Is a Major Determinant of Neuroblastoma Cell Lineages. Front Mol Neurosci 2019; 12:90. [PMID: 31040767 PMCID: PMC6476918 DOI: 10.3389/fnmol.2019.00090] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 03/21/2019] [Indexed: 01/09/2023] Open
Abstract
The neural crest (NC), which has been referred to as the fourth germ layer, comprises a multipotent cell population which will specify diverse cells and tissues, including craniofacial cartilage and bones, melanocytes, the adrenal medulla and the peripheral nervous system. These cell fates are known to be determined by gene regulatory networks (GRNs) acting at various stages of NC development, such as induction, specification, and migration. Although transcription factor hierarchies and some of their interplay with morphogenetic signaling pathways have been characterized, the full complexity of activities required for regulated development remains uncharted. Deregulation of these pathways may contribute to tumorigenesis, as in the case of neuroblastoma, a frequently lethal embryonic cancer thought to arise from the sympathoadrenal lineage of the NC. In this “Hypothesis and Theory” article, we utilize the next generation sequencing data from neuroblastoma cells and tumors to evaluate the possible influences of Wnt signaling on NC GRNs and on neuroblastoma cell lineages. We propose that Wnt signaling is a major determinant of regulatory networks that underlie mesenchymal/neural crest cell (NCC)-like cell identities through PRRX1 and YAP/TAZ transcription factors. Furthermore, Wnt may also co-operate with Hedgehog signaling in driving proneural differentiation programmes along the adrenergic (ADRN) lineage. Elucidation of Signaling Regulatory Networks can augment and complement GRNs in characterizing cell identities, which may in turn contribute to the design of improved therapeutics tailored to primary and relapsing neuroblastoma.
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Affiliation(s)
- Marianna Szemes
- Cancer Epigenetics Laboratory, School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
| | - Alexander Greenhough
- Cancer Epigenetics Laboratory, School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
| | - Karim Malik
- Cancer Epigenetics Laboratory, School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
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14
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Réda J, Vachtenheim J, Vlčková K, Horák P, Vachtenheim J, Ondrušová L. Widespread Expression of Hedgehog Pathway Components in a Large Panel of Human Tumor Cells and Inhibition of Tumor Growth by GANT61: Implications for Cancer Therapy. Int J Mol Sci 2018; 19:ijms19092682. [PMID: 30201866 PMCID: PMC6163708 DOI: 10.3390/ijms19092682] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Revised: 08/29/2018] [Accepted: 09/06/2018] [Indexed: 12/15/2022] Open
Abstract
The sonic Hedgehog/GLI signaling pathway (HH) is critical for maintaining tissue polarity in development and contributes to tumor stemness. Transcription factors GLI1–3 are the downstream effectors of HH and activate oncogenic targets. To explore the completeness of the expression of HH components in tumor cells, we performed a screen for all HH proteins in a wide spectrum of 56 tumor cell lines of various origin using Western blot analysis. Generally, all HH proteins were expressed. Important factors GLI1 and GLI2 were always expressed, only exceptionally one of them was lowered, suggesting the functionality of HH in all tumors tested. We determined the effect of a GLI inhibitor GANT61 on proliferation in 16 chosen cell lines. More than half of tumor cells were sensitive to GANT61 to various extents. GANT61 killed the sensitive cells through apoptosis. The inhibition of reporter activity containing 12xGLI consensus sites by GANT61 and cyclopamine roughly correlated with cell proliferation influenced by GANT61. Our results recognize the sensitivity of tumor cell types to GANT61 in cell culture and support a critical role for GLI factors in tumor progression through restraining apoptosis. The use of GANT61 in combined targeted therapy of sensitive tumors, such as melanomas, seems to be immensely helpful.
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Affiliation(s)
- Jiri Réda
- Department of Transcription and Cell Signaling, Institute of Medical Biochemistry and Laboratory Diagnostics, Charles University Prague, 12108 Prague, Czech Republic.
| | - Jiri Vachtenheim
- Department of Transcription and Cell Signaling, Institute of Medical Biochemistry and Laboratory Diagnostics, Charles University Prague, 12108 Prague, Czech Republic.
| | - Kateřina Vlčková
- Department of Transcription and Cell Signaling, Institute of Medical Biochemistry and Laboratory Diagnostics, Charles University Prague, 12108 Prague, Czech Republic.
| | - Pavel Horák
- Department of Transcription and Cell Signaling, Institute of Medical Biochemistry and Laboratory Diagnostics, Charles University Prague, 12108 Prague, Czech Republic.
| | - Jiri Vachtenheim
- Third Department of Surgery, First Faculty of Medicine, Charles University Prague and University Hospital Motol, 15006 Prague, Czech Republic.
| | - Lubica Ondrušová
- Department of Transcription and Cell Signaling, Institute of Medical Biochemistry and Laboratory Diagnostics, Charles University Prague, 12108 Prague, Czech Republic.
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15
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Zeng X, Ju D. Hedgehog Signaling Pathway and Autophagy in Cancer. Int J Mol Sci 2018; 19:E2279. [PMID: 30081498 PMCID: PMC6121518 DOI: 10.3390/ijms19082279] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 07/29/2018] [Accepted: 07/31/2018] [Indexed: 12/19/2022] Open
Abstract
Hedgehog (Hh) pathway controls complex developmental processes in vertebrates. Abnormal activation of Hh pathway is responsible for tumorigenesis and maintenance of multiple cancers, and thus addressing this represents promising therapeutic opportunities. In recent years, two Hh inhibitors have been approved for basal cell carcinoma (BCC) treatment and show extraordinary clinical outcomes. Meanwhile, a series of novel agents are being developed for the treatment of several cancers, including lung cancer, leukemia, and pancreatic cancer. Unfortunately, Hh inhibition fails to show satisfactory benefits in these cancer types compared with the success stories in BCC, highlighting the need for better understanding of Hh signaling in cancer. Autophagy, a conserved biological process for cellular component elimination, plays critical roles in the initiation, progression, and drug resistance of cancer, and therefore, implied potential to be targeted. Recent evidence demonstrated that Hh signaling interplays with autophagy in multiple cancers. Importantly, modulating this crosstalk exhibited noteworthy capability to sensitize primary and drug-resistant cancer cells to Hh inhibitors, representing an emerging opportunity to reboot the efficacy of Hh inhibition in those insensitive tumors, and to tackle drug resistance challenges. This review will highlight recent advances of Hh pathway and autophagy in cancers, and focus on their crosstalk and the implied therapeutic opportunities.
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Affiliation(s)
- Xian Zeng
- Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery MOE, School of Pharmacy, Fudan University, Shanghai 201203, China.
- Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore 117543, Singapore.
| | - Dianwen Ju
- Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery MOE, School of Pharmacy, Fudan University, Shanghai 201203, China.
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16
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Wang J, Huang S, Tian R, Chen J, Gao H, Xie C, Shan Y, Zhang Z, Gu S, Xu M. The protective autophagy activated by GANT-61 in MYCN amplified neuroblastoma cells is mediated by PERK. Oncotarget 2018; 9:14413-14427. [PMID: 29581853 PMCID: PMC5865679 DOI: 10.18632/oncotarget.24214] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Accepted: 11/16/2017] [Indexed: 12/11/2022] Open
Abstract
The proto-oncogene MYC can trigger the unfolded protein response (UPR). The double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK), one of three primary branches of the UPR, is a key regulator of autophagy, promoting tumorigenesis. Upon activation of PERK, there is an increase in phosphorylation of the eukaryotic initiation factor-2 alpha (eIF2α), which in turn, activates the transcription factor-4 (ATF4), responsible for an increased expression of LC3, a common autophagy marker. PERK is repressed upon GLI1 and GLI2 induction. GANT-61 is an inhibitor of GLI1 and GLI2, known to reduce autophagy in MYCN non-amplified, but not in MYCN amplified neuroblastoma (NB) cells. In our study, we tested the effect of the joint administration of a PERK inhibitor (GSK2606414) and the GLI inhibitor GANT-61 to MYCN amplified and MYCN non-amplified NB cells. Our results suggest that inhibition of PERK impairs GANT-61 induced autophagy in NB cells with MYCN amplification, but had no effect on the MYCN non-amplified NB cells. In summary, PERK seems to be a good therapeutic target for NB. Inhibition of PERK reduces autophagy in MYCN amplified NB cells, thus amplifying the efficacy of the GLI inhibitor GANT-61 in reducing proliferation of this type of cancer cells.
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Affiliation(s)
- Jing Wang
- Department of Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
| | - Siqi Huang
- Department of Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
| | - Ruicheng Tian
- Department of Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
| | - Jing Chen
- Department of Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
| | - Hongxiang Gao
- Department of Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
| | - Chenjie Xie
- Department of Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
| | - Yuhua Shan
- Department of Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
| | - Zhen Zhang
- Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
- Shanghai Pediatric Congenital Heart Disease Institute, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
| | - Song Gu
- Department of Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
| | - Min Xu
- Department of Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China
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17
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NOX4-driven ROS formation regulates proliferation and apoptosis of gastric cancer cells through the GLI1 pathway. Cell Signal 2018; 46:52-63. [PMID: 29496628 DOI: 10.1016/j.cellsig.2018.02.007] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2017] [Revised: 02/13/2018] [Accepted: 02/15/2018] [Indexed: 12/21/2022]
Abstract
NADPH Oxidase 4 (NOX4), a member of the NOX family, has emerged as a significant source of reactive oxygen species, playing an important role in tumor cell proliferation, apoptosis, and other physiological processes. However, the potential function of NOX4 in gastric cancer (GC) cell proliferation is yet unknown. The aim of this study was to illustrate whether NOX4 plays a role in regulating gastric cancer cell growth. First, the clinical information from 90 patients was utilized to explore the clinical value of NOX4 as a predictive tool for tumor size and prognosis. Results showed that NOX4 expression was correlated with tumor size and prognosis. In vitro assays confirmed that knockdown of NOX4 expression blocked cell proliferation and the expression of Cyclin D1, BAX, and so on. Interestingly, NOX4 promoted cell proliferation via activation of the GLI1 pathway. GLI1, a well-known transcription factor in the Hedgehog signaling pathway, was overexpressed to test whether NOX4 activates downstream signaling via GLI1. Overexpression of GLI1 reversed the inhibition of proliferation induced by NOX4 knockdown. In addition, overexpression of NOX4 increased GLI1 expression, and depletion of GLI1 expression decreased the effects induced by NOX4 overexpression. Further, ROS generated by NOX4 was required for GLI1 expression, as shown by use of the ROS inhibitor, diphenylene iodonium (DPI). In summary, the findings indicate that NOX4 plays an important role in gastric cancer cell growth and apoptosis through the generation of ROS and subsequent activation of GLI1 signaling. Hence, the targeting of NOX4 may be an attractive therapeutic strategy for blocking gastric cancer cell proliferation.
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18
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De Wilde B, Beckers A, Lindner S, Kristina A, De Preter K, Depuydt P, Mestdagh P, Sante T, Lefever S, Hertwig F, Peng Z, Shi LM, Lee S, Vandermarliere E, Martens L, Menten B, Schramm A, Fischer M, Schulte J, Vandesompele J, Speleman F. The mutational landscape of MYCN, Lin28b and ALKF1174L driven murine neuroblastoma mimics human disease. Oncotarget 2017; 9:8334-8349. [PMID: 29492199 PMCID: PMC5823580 DOI: 10.18632/oncotarget.23614] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 10/28/2017] [Indexed: 12/27/2022] Open
Abstract
Genetically engineered mouse models have proven to be essential tools for unraveling fundamental aspects of cancer biology and for testing novel therapeutic strategies. To optimally serve these goals, it is essential that the mouse model faithfully recapitulates the human disease. Recently, novel mouse models for neuroblastoma have been developed. Here, we report on the further genomic characterization through exome sequencing and DNA copy number analysis of four of the currently available murine neuroblastoma model systems (ALK, Th-MYCN, Dbh-MYCN and Lin28b). The murine tumors revealed a low number of genomic alterations – in keeping with human neuroblastoma - and a positive correlation of the number of genetic lesions with the time to onset of tumor formation was observed. Gene copy number alterations are the hallmark of both murine and human disease and frequently affect syntenic genomic regions. Despite low mutational load, the genes mutated in murine disease were found to be enriched for genes mutated in human disease. Taken together, our study further supports the validity of the tested mouse models for mechanistic and preclinical studies of human neuroblastoma.
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Affiliation(s)
- Bram De Wilde
- Center for Medical Genetics, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent, Ghent University, Ghent, Belgium
| | | | - Sven Lindner
- Department of Pediatric Oncology and Hematology, University Children's Hospital, Essen, Germany
| | - Althoff Kristina
- Department of Pediatric Oncology and Hematology, University Children's Hospital, Essen, Germany
| | - Katleen De Preter
- Center for Medical Genetics, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent, Ghent University, Ghent, Belgium
| | - Pauline Depuydt
- Center for Medical Genetics, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent, Ghent University, Ghent, Belgium
| | - Pieter Mestdagh
- Center for Medical Genetics, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent, Ghent University, Ghent, Belgium
| | - Tom Sante
- Center for Medical Genetics, Ghent University, Ghent, Belgium
| | - Steve Lefever
- Center for Medical Genetics, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent, Ghent University, Ghent, Belgium
| | - Falk Hertwig
- Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Zhiyu Peng
- BGI-Shenzhen, Bei Shan Industrial Zone, Yantian District, Shenzhen, Guangdong, China
| | - Le-Ming Shi
- Center for Pharmacogenomics and Fudan-Zhangjiang Center for Clinical Genomics, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Sangkyun Lee
- Department of Computer Science, Artificial Intelligence Group, TU Dortmund, Dortmund, Germany
| | - Elien Vandermarliere
- Medical Biotechnology Center, VIB, Ghent, Belgium.,Department of Biochemistry, Ghent University, Ghent, Belgium
| | - Lennart Martens
- Medical Biotechnology Center, VIB, Ghent, Belgium.,Department of Biochemistry, Ghent University, Ghent, Belgium
| | - Björn Menten
- Center for Medical Genetics, Ghent University, Ghent, Belgium
| | - Alexander Schramm
- Department of Pediatric Oncology and Hematology, University Children's Hospital, Essen, Germany
| | - Matthias Fischer
- Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Johannes Schulte
- Pediatric Oncology and Hematology, Charité University Medicine, Berlin, Germany
| | - Jo Vandesompele
- Center for Medical Genetics, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent, Ghent University, Ghent, Belgium
| | - Frank Speleman
- Center for Medical Genetics, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent, Ghent University, Ghent, Belgium
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19
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Whole exome sequencing identified sixty-five coding mutations in four neuroblastoma tumors. Sci Rep 2017; 7:17787. [PMID: 29259192 PMCID: PMC5736554 DOI: 10.1038/s41598-017-17162-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 11/20/2017] [Indexed: 12/30/2022] Open
Abstract
Neuroblastoma is a pediatric tumor characterized by histologic heterogeneity, and accounts for ~15% of childhood deaths from cancer. The five-year survival for patients with high-risk stage 4 disease has not improved in two decades. We used whole exome sequencing (WES) to identify mutations present in three independent high-risk stage 4 neuroblastoma tumors (COA/UAB-3, COA/UAB -6 and COA/UAB -8) and a stage 3 tumor (COA/UAB-14). Among the four tumors WES analysis identified forty-three mutations that had not been reported previously, one of which was present in two of the four tumors. WES analysis also corroborated twenty-two mutations that were reported previously. No single mutation occurred in all four tumors or in all stage 4 tumors. Three of the four tumors harbored genes with CADD scores ≥20, indicative of mutations associated with human pathologies. The average depth of coverage ranged from 39.68 to 90.27, with >99% sequences mapping to the genome. In summary, WES identified sixty-five coding mutations including forty-three mutations not reported previously in primary neuroblastoma tumors. The three stage 4 tumors contained mutations in genes encoding protein products that regulate immune function or cell adhesion and tumor cell metastasis.
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20
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Improved therapy for neuroblastoma using a combination approach: superior efficacy with vismodegib and topotecan. Oncotarget 2017; 7:15215-29. [PMID: 26934655 PMCID: PMC4924781 DOI: 10.18632/oncotarget.7714] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 01/30/2016] [Indexed: 12/11/2022] Open
Abstract
Aberrant activation/expression of pathways/molecules including NF-kB, mTOR, hedgehog and polo-like-kinase-1 (PLK1) are correlated with poor-prognosis neuroblastoma. Therefore, to identify a most efficacious treatment for neuroblastoma, we investigated the efficacy of NF-kB/mTOR dual-inhibitor 13-197, hedgehog inhibitor vismodegib and PLK1 inhibitor BI2536 alone or combined with topotecan against high-risk neuroblastoma. The in vitro efficacy of the inhibitors alone or combined with topotecan on cell growth/apoptosis and molecular mechanism(s) were investigated. Results showed that as single agents 13-197, BI2536 and vismodegib significantly decreased neuroblastoma cell growth and induced apoptosis by targeting associated pathways/molecules. In combination with topotecan, 13-197 did not show significant additive/synergistic effects against neuroblastoma. However, BI2536 or vismodegib further significantly decreased neuroblastoma cell growth/survival. These results clearly showed that vismodegib combination with topotecan was synergistic and more efficacious compared with BI2536 in combination. Together, in vitro data demonstrated that vismodegib was most efficacious in potentiating topotecan-induced antineuroblastoma effects. Therefore, we tested the combined efficacy of vismodegib and topotecan against neuroblastoma in vivo using NSG mice. This resulted in significantly (p<0.001) reduced tumor growth and increased survival of mice. Together, the combination of vismodegib and topotecan showed a significant enhanced antineuroblastoma efficacy by targeting associated pathways/molecules which warrants further preclinical evaluation for translation to the clinic.
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21
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Lee DH, Lee SY, Oh SC. Hedgehog signaling pathway as a potential target in the treatment of advanced gastric cancer. Tumour Biol 2017. [DOI: 10.1177/1010428317692266] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Affiliation(s)
- Dae-Hee Lee
- Division of Brain Korea 21 Program for Biomedicine Science, College of Medicine, Korea University, Seoul, Republic of Korea
- Division of Oncology and Hematology, Department of Internal Medicine, College of Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Suk-young Lee
- Division of Oncology and Hematology, Department of Internal Medicine, College of Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Sang Cheul Oh
- Division of Brain Korea 21 Program for Biomedicine Science, College of Medicine, Korea University, Seoul, Republic of Korea
- Division of Oncology and Hematology, Department of Internal Medicine, College of Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
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22
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Ruan H, Luo H, Wang J, Ji X, Zhang Z, Wu J, Zhang X, Wu X. Smoothened-independent activation of hedgehog signaling by rearranged during transfection promotes neuroblastoma cell proliferation and tumor growth. Biochim Biophys Acta Gen Subj 2016; 1860:1961-72. [PMID: 27316313 DOI: 10.1016/j.bbagen.2016.06.017] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2016] [Revised: 06/09/2016] [Accepted: 06/13/2016] [Indexed: 11/25/2022]
Abstract
BACKGROUND Rearranged during transfection (RET) proto-oncogene encodes a receptor tyrosine kinase for glial cell line-derived neurotrophic factor (GDNF) signaling, and high RET expression is closely related to the tumorigenesis and malignancy of neuroblastoma(NB). METHODS We have investigated whether RET signals through hedgehog (HH) pathway in NB cell proliferation and tumor growth by in vitro cell culture and in vivo xenograft approaches. RESULTS The key members of both GDNF/RET and HH/GLI pathways are expressed in NB cell lines to different extents. Knockdown of RET in NB cells significantly attenuates the activity of HH signaling, whereas overexpression of RET robustly enhances the output of transcriptional activation by HH. Likewise, activation of RET by GDNF induces HH signaling, whereas knockdown of RET attenuates both basal and GDNF-induced activities of HH signaling. Moreover, protein kinase B lies on the downstream of GDNF/RET signaling module to inhibit the GSK3β, resulting in activation of HH signaling. Furthermore, either knockdown of RET by shRNA or inhibition of HH pathway by cyclopamine attenuates not only basal but also GDNF-induced proliferation of SH-SY5Y cells, and knockdown of either RET or smoothened in SH-SY5Y cell xenografts significantly attenuated the tumor growth. Finally, inhibition of HH signaling by GLI1 and GLI2 inhibitor, Gant61, reduces not only basal but also RET-induced proliferation of SH-SY5Y cells and outgrowth of xenografts. CONCLUSION GDNF/RET/AKT/GSK3β signaling module activates HH pathway to stimulate NB cells proliferation and tumor outgrowth. GENERAL SIGNIFICANCE Targeting HH pathway is a rational approach for therapeutic intervention of NB with high RET expression.
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Affiliation(s)
- Hongfeng Ruan
- Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China; Department of Genetics, School of Medicine, Zhejiang University, Hangzhou 310058, China; Institute of Orthopaedics and Traumatology, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Huan Luo
- Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China; Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Jirong Wang
- Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Xing Ji
- Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Zhongmiao Zhang
- Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Junsong Wu
- Department of Emergence, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Xianning Zhang
- Department of Genetics, School of Medicine, Zhejiang University, Hangzhou 310058, China.
| | - Ximei Wu
- Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
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Bonilla X, Parmentier L, King B, Bezrukov F, Kaya G, Zoete V, Seplyarskiy VB, Sharpe HJ, McKee T, Letourneau A, Ribaux PG, Popadin K, Basset-Seguin N, Ben Chaabene R, Santoni FA, Andrianova MA, Guipponi M, Garieri M, Verdan C, Grosdemange K, Sumara O, Eilers M, Aifantis I, Michielin O, de Sauvage FJ, Antonarakis SE, Nikolaev SI. Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma. Nat Genet 2016; 48:398-406. [PMID: 26950094 DOI: 10.1038/ng.3525] [Citation(s) in RCA: 359] [Impact Index Per Article: 39.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Accepted: 02/11/2016] [Indexed: 12/13/2022]
Abstract
Basal cell carcinoma (BCC) of the skin is the most common malignant neoplasm in humans. BCC is primarily driven by the Sonic Hedgehog (Hh) pathway. However, its phenotypic variation remains unexplained. Our genetic profiling of 293 BCCs found the highest mutation rate in cancer (65 mutations/Mb). Eighty-five percent of the BCCs harbored mutations in Hh pathway genes (PTCH1, 73% or SMO, 20% (P = 6.6 × 10(-8)) and SUFU, 8%) and in TP53 (61%). However, 85% of the BCCs also harbored additional driver mutations in other cancer-related genes. We observed recurrent mutations in MYCN (30%), PPP6C (15%), STK19 (10%), LATS1 (8%), ERBB2 (4%), PIK3CA (2%), and NRAS, KRAS or HRAS (2%), and loss-of-function and deleterious missense mutations were present in PTPN14 (23%), RB1 (8%) and FBXW7 (5%). Consistent with the mutational profiles, N-Myc and Hippo-YAP pathway target genes were upregulated. Functional analysis of the mutations in MYCN, PTPN14 and LATS1 suggested their potential relevance in BCC tumorigenesis.
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Affiliation(s)
- Ximena Bonilla
- Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
| | | | - Bryan King
- Department of Pathology, New York University School of Medicine, New York, New York, USA
| | - Fedor Bezrukov
- Department of Physics, University of Connecticut, Storrs, Connecticut, USA
- RIKEN BNL Research Center, Brookhaven National Laboratory, Upton, New York, USA
| | - Gürkan Kaya
- Department of Dermatology, University Hospitals of Geneva, Geneva, Switzerland
| | - Vincent Zoete
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Vladimir B Seplyarskiy
- Institute of Information Transmission Problems, Russian Academy of Sciences, Moscow, Russia
- Pirogov Russian National Research Medical University, Moscow, Russia
- Lomonosov Moscow State University, Moscow, Russia
| | - Hayley J Sharpe
- Department of Molecular Oncology, Genentech, Inc., South San Francisco, California, USA
| | - Thomas McKee
- Service of Clinical Pathology, University Hospitals of Geneva, Geneva, Switzerland
| | - Audrey Letourneau
- Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
| | - Pascale G Ribaux
- Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
| | - Konstantin Popadin
- Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
| | - Nicole Basset-Seguin
- Department of Dermatology, Saint Louis Hospital, Paris 7 University, Paris, France
| | - Rouaa Ben Chaabene
- Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
| | - Federico A Santoni
- Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
- Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland
| | - Maria A Andrianova
- Institute of Information Transmission Problems, Russian Academy of Sciences, Moscow, Russia
- Pirogov Russian National Research Medical University, Moscow, Russia
- Lomonosov Moscow State University, Moscow, Russia
| | - Michel Guipponi
- Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland
| | - Marco Garieri
- Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
| | - Carole Verdan
- Service of Clinical Pathology, University Hospitals of Geneva, Geneva, Switzerland
| | - Kerstin Grosdemange
- Department of Dermatology, University Hospitals of Geneva, Geneva, Switzerland
| | - Olga Sumara
- Department of Biochemistry and Molecular Biology, University of Würzburg, Würzburg, Germany
| | - Martin Eilers
- Department of Biochemistry and Molecular Biology, University of Würzburg, Würzburg, Germany
- Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany
| | - Iannis Aifantis
- Department of Pathology, New York University School of Medicine, New York, New York, USA
| | - Olivier Michielin
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
- Department of Oncology, University of Lausanne and Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
| | - Frederic J de Sauvage
- Department of Molecular Oncology, Genentech, Inc., South San Francisco, California, USA
| | - Stylianos E Antonarakis
- Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
- Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland
- Institute of Genetics and Genomics of Geneva (iGE3), Geneva, Switzerland
| | - Sergey I Nikolaev
- Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
- Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland
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24
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Wang M, Liu Y, Zou J, Yang R, Xuan F, Wang Y, Gao N, Cui H. Transcriptional co-activator TAZ sustains proliferation and tumorigenicity of neuroblastoma by targeting CTGF and PDGF-β. Oncotarget 2016; 6:9517-30. [PMID: 25940705 PMCID: PMC4496235 DOI: 10.18632/oncotarget.3367] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/1969] [Accepted: 02/11/2015] [Indexed: 01/22/2023] Open
Abstract
Neuroblastoma is a common childhood malignant tumor originated from the neural crest-derived sympathetic nervous system. A crucial event in the pathogenesis of neuroblastoma is to promote proliferation of neuroblasts, which is closely related to poor survival. However, mechanisms for regulation of cell proliferation and tumorigenicity in neuroblastoma are not well understood. Here, we report that overexpression of TAZ in neuroblastoma BE(2)-C cells causes increases in cell proliferation, self renewal and colony formation, which was restored back to its original levels by knockdown of TAZ in TAZ-overexpression cells. Inhibition of endogenous TAZ attenuated cell proliferation, colony formation and tumor development in neuroblastoma SK-N-AS cell, which could be rescued by re-introduction of TAZ into TAZ-knockdown cells. In addition, we found that overexpressing TAZ-mediated induction of CTGF and PDGF-β expression, cell proliferation and colony formation were inhibited by knocking down CTGF and PDGF-β with siRNA in TAZ-overexpressing cell. Overall, our findings suggested that TAZ plays an essential role in regulating cell proliferation and tumorigenesis in neuroblastoma cells. Thus, TAZ seems to be a novel and promising target for the treatment of neuroblastoma.
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Affiliation(s)
- Mei Wang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China
| | - Yang Liu
- Department of Respiration, the Third Hospital of Hebei Medical University, Shijiazhuang, China.,Cardiovascular Department, Second Affiliated Hospital of University of South China, Hengyang, China
| | - Jiahua Zou
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China
| | - Rui Yang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China
| | - Fan Xuan
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China
| | - Yi Wang
- Cardiovascular Department, Second Affiliated Hospital of University of South China, Hengyang, China
| | - Ning Gao
- Department of Pharmacognosy, College of Pharmacy, Third Military Medical University, Chongqing, China
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China
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25
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Garner EF, Beierle EA. Cancer Stem Cells and Their Interaction with the Tumor Microenvironment in Neuroblastoma. Cancers (Basel) 2015; 8:cancers8010005. [PMID: 26729169 PMCID: PMC4728452 DOI: 10.3390/cancers8010005] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2015] [Revised: 12/16/2015] [Accepted: 12/21/2015] [Indexed: 12/26/2022] Open
Abstract
Neuroblastoma, a solid tumor arising from neural crest cells, accounts for over 15% of all pediatric cancer deaths. The interaction of neuroblastoma cancer-initiating cells with their microenvironment likely plays an integral role in the maintenance of resistant disease and tumor relapse. In this review, we discuss the interaction between neuroblastoma cancer-initiating cells and the elements of the tumor microenvironment and how these interactions may provide novel therapeutic targets for this difficult to treat disease.
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Affiliation(s)
- Evan F Garner
- Department of Surgery, Division of Pediatric Surgery, University of Alabama, Birmingham, AL 35233, USA.
| | - Elizabeth A Beierle
- Department of Surgery, Division of Pediatric Surgery, University of Alabama, Birmingham, AL 35233, USA.
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26
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Zhou ZG, Zhang CY, Fei HX, Zhong LL, Bai Y. Phenolic alkaloids from Menispermum dauricum inhibits BxPC-3 pancreatic cancer cells by blocking of Hedgehog signaling pathway. Pharmacogn Mag 2015; 11:690-7. [PMID: 26600712 PMCID: PMC4621636 DOI: 10.4103/0973-1296.165548] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Background: The Hedgehog (Hh) signaling pathway plays an important role in pancreatic cancer (PC) cells. Phenolic alkaloids from Menispermum dauricum (PAMD), a traditional Chinese medicine used for the treatment of immune disorders, have been reported to have antitumor activity recently. Objective: To investigate the efficacy and mechanism of PAMD against PC cell BxPC-3. Materials and Methods: F assay was used to assess cell proliferation inhibition of PAMD; the apoptotic induction and cell cycle arrest was detected by flow cytometry; the BxPC-3 xenograft was established to evaluate the tumor growth inhibition of PAMD; hematoxylin-eosin staining was applied to analyze the pathological morphology of tumor tissues; immunohistochemistry (IHC) and Western blot was adopted to detect the protein levels; quantitative real-time polymerase chain reaction was used to determine the mRNA expressions. Results: PAMD shows time-and dose-dependent proliferation inhibition on the BxPC-3 cell, induced G0/G1 phase arrest and cell apoptosis in vitro. PAMD also showed better inhibition of tumor growth and a preferable safety profile compared with chemotherapeutic regimen 5-fluoro-2, 4 (1 H, 3 H) pyrimidinedione in BxPC-3 xenograft in vivo. Furthermore, PAMD directly decreases the protein and mRNA levels of Sonic Hedgehog (Shh) and its downstream transcription factor Gli-1 in the BxPC-3 tumor tissues. Conclusion: The treatment of PAMD displayed Hh signaling pathway blockade through decreasing the protein and mRNA levels of Shh and its downstream transcription factor Gli-1, suggesting a promising strategy in treating human PC.
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Affiliation(s)
- Zhong-Guang Zhou
- Research Institute of Traditional Chinese Medicine, Heilongjiang, China
| | - Chao-Ying Zhang
- The Fourth Affiliated Hospital, Harbin Medical University, Heilongjiang, China
| | - Hong-Xin Fei
- Research Institute of Traditional Chinese Medicine, Heilongjiang, China ; Department of Qiqihar Medical University, Basic Medicine, Heilongjiang, China
| | - Li-Li Zhong
- Department of Pathology, The First Affiliated Hospital, Heilongjiang, China
| | - Yun Bai
- Basic Medical College, Heilongjiang University of Chinese Medicine, Heilongjiang, China
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27
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Justilien V, Fields AP. Molecular pathways: novel approaches for improved therapeutic targeting of Hedgehog signaling in cancer stem cells. Clin Cancer Res 2015; 21:505-13. [PMID: 25646180 DOI: 10.1158/1078-0432.ccr-14-0507] [Citation(s) in RCA: 101] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The Hedgehog (Hh) signaling pathway is critical for embryonic development. In adult tissues, Hh signaling is relatively quiescent with the exception of roles in tissue maintenance and repair. Aberrant activation of Hh signaling is implicated in multiple aspects of transformation, including the maintenance of the cancer stem cell (CSC) phenotype. Preclinical studies indicate that CSCs from many tumor types are sensitive to Hh pathway inhibition and that Hh-targeted therapeutics block many aspects of transformation attributed to CSCs, including drug resistance, relapse, and metastasis. However, to date, Hh inhibitors, specifically those targeting Smoothened [such as vismodegib, BMS-833923, saridegib (IPI-926), sonidegib/erismodegib (LDE225), PF-04449913, LY2940680, LEQ 506, and TAK-441], have demonstrated good efficacy as monotherapy in patients with basal cell carcinoma and medulloblastoma, but have shown limited activity in other tumor types. This lack of success is likely due to many factors, including a lack of patient stratification in early trials, cross-talk between Hh and other oncogenic signaling pathways that can modulate therapeutic response, and a limited knowledge of Hh pathway activation mechanisms in CSCs from most tumor types. Here, we discuss Hh signaling mechanisms in the context of human cancer, particularly in the maintenance of the CSC phenotype, and consider new therapeutic strategies that hold the potential to expand considerably the scope and therapeutic efficacy of Hh-directed anticancer therapy.
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Affiliation(s)
- Verline Justilien
- Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida
| | - Alan P Fields
- Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida.
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28
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Wang J, Gu S, Huang J, Chen S, Zhang Z, Xu M. Inhibition of autophagy potentiates the efficacy of Gli inhibitor GANT-61 in MYCN-amplified neuroblastoma cells. BMC Cancer 2014; 14:768. [PMID: 25323222 PMCID: PMC4210511 DOI: 10.1186/1471-2407-14-768] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Accepted: 10/10/2014] [Indexed: 12/21/2022] Open
Abstract
Background Aberrant Hedgehog (Hh) signaling is often associated with neuroblastoma (NB), a childhood malignancy with varying clinical outcomes due to different molecular characteristics. Inhibition of Hh signaling with small molecule inhibitors, particularly with GANT-61, significantly suppresses NB growth. However, NB with MYCN amplification is less sensitive to GANT-61 than those without MYCN amplification. Methods Autophagic process was examined in two MYCN amplified and two MYCN non-amplified NB cells treated with GANT-61. Subsequently, chemical and genetic approaches were applied with GANT-61 together to evaluate the role of autophagy in GANT-61 induced cell death. Results Here we show that GANT-61 enhanced autophagy in MYCN amplified NB cells. Both an autophagic inhibitor 3-methyladenine (3-MA) and genetic disruption of ATG5 or ATG7 expression suppressed GANT-61 induced autophagy and significantly increased apoptotic cell death, whereas pre-treatment with an apoptotic inhibitor, Z-VAD-FMK, rescued GANT-61 induced cell death and had no effect on the autophagic process. In the other hand, GANT-61 barely induced autophagy in MYCN non-amplified NB cells, but overexpression of MYCN in MYCN non-amplified NB cells recapitulated GANT-61 induced autophagy seen in MYCN amplified NB cells, suggesting that the level of GANT-61 induced autophagy in NB cells is related to MYCN expression level in cells. Conclusion Aberrant Hh signaling activation as an oncogenic driver in NB renders inhibition of Hh signaling an effective measure to suppress NB growth. However, our data suggest that enhanced autophagy concomitant with Hh signaling inhibition acts as a pro-survival factor to maintain cell viability, which reduces GANT-61 efficacy. Besides, MYCN amplification is likely involved in the induction of the pro-survival autophagy. Overall, simultaneous inhibition of both Hh signaling and autophagy could be a better way to treat MYCN amplified NB. Electronic supplementary material The online version of this article (doi:10.1186/1471-2407-14-768) contains supplementary material, which is available to authorized users.
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Affiliation(s)
| | | | | | | | - Zhen Zhang
- Department of Surgery, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China.
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29
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Planells-Ferrer L, Urresti J, Soriano A, Reix S, Murphy DM, Ferreres JC, Borràs F, Gallego S, Stallings RL, Moubarak RS, Segura MF, Comella JX. MYCN repression of Lifeguard/FAIM2 enhances neuroblastoma aggressiveness. Cell Death Dis 2014; 5:e1401. [PMID: 25188511 PMCID: PMC4540192 DOI: 10.1038/cddis.2014.356] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Revised: 07/15/2014] [Accepted: 07/22/2014] [Indexed: 01/20/2023]
Abstract
Neuroblastoma (NBL) is the most common solid tumor in infants and accounts for 15% of all pediatric cancer deaths. Several risk factors predict NBL outcome: age at the time of diagnosis, stage, chromosome alterations and MYCN (V-Myc Avian Myelocytomatosis Viral Oncogene Neuroblastoma-Derived Homolog) amplification, which characterizes the subset of the most aggressive NBLs with an overall survival below 30%. MYCN-amplified tumors develop exceptional chemoresistance and metastatic capacity. These properties have been linked to defects in the apoptotic machinery, either by silencing components of the extrinsic apoptotic pathway (e.g. caspase-8) or by overexpression of antiapoptotic regulators (e.g. Bcl-2, Mcl-1 or FLIP). Very little is known on the implication of death receptors and their antagonists in NBL. In this work, the expression levels of several death receptor antagonists were analyzed in multiple human NBL data sets. We report that Lifeguard (LFG/FAIM2 (Fas apoptosis inhibitory molecule 2)/NMP35) is downregulated in the most aggressive and undifferentiated tumors. Intringuingly, although LFG has been initially characterized as an antiapoptotic protein, we have found a new association with NBL differentiation. Moreover, LFG repression resulted in reduced cell adhesion, increased sphere growth and enhanced migration, thus conferring a higher metastatic capacity to NBL cells. Furthermore, LFG expression was found to be directly repressed by MYCN at the transcriptional level. Our data, which support a new functional role for a hitherto undiscovered MYCN target, provide a new link between MYCN overexpression and increased NBL metastatic properties.
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Affiliation(s)
- L Planells-Ferrer
- Cell Signaling and Apoptosis Group, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - J Urresti
- Cell Signaling and Apoptosis Group, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - A Soriano
- Laboratory of Translational Research in Pediatric Cancer, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - S Reix
- Cell Signaling and Apoptosis Group, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - D M Murphy
- Molecular and Cellular Therapeutics, Royal College of Surgeons and National Children's Research Centre Our Lady's Children's Hospital, Dublin, Ireland
| | - J C Ferreres
- Hospital Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - F Borràs
- Hospital Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - S Gallego
- 1] Laboratory of Translational Research in Pediatric Cancer, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain [2] Hospital Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - R L Stallings
- Molecular and Cellular Therapeutics, Royal College of Surgeons and National Children's Research Centre Our Lady's Children's Hospital, Dublin, Ireland
| | - R S Moubarak
- Cell Signaling and Apoptosis Group, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - M F Segura
- Laboratory of Translational Research in Pediatric Cancer, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - J X Comella
- Cell Signaling and Apoptosis Group, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
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30
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Wan J, Zhou J, Zhao H, Wang M, Wei Z, Gao H, Wang Y, Cui H. Sonic hedgehog pathway contributes to gastric cancer cell growth and proliferation. Biores Open Access 2014; 3:53-9. [PMID: 24804165 PMCID: PMC3995118 DOI: 10.1089/biores.2014.0001] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The Sonic Hedgehog (Shh) signaling pathway is commonly activated in gastrointestinal cancer. However, our understanding of the Shh pathway in gastric cancer remains limited. Here we examined the effects of cyclopamine, a specific inhibitor of the Shh signaling pathway, on cell growth and proliferation in gastric primary cancer cells GAM-016 and the MKN-45 cell line. The results showed that the Shh signaling molecules SHH, PTCH, SMO, GLI1, and GLI2 were intact and activated in both types of cells. Furthermore, we observed that cyclopamine inhibited gastric cancer cell proliferation through cell cycle arrest and apoptosis. An in vivo study using NOD/SCID mouse xenografts demonstrated that cyclopamine significantly prevented tumor growth and development. Our study indicated that Shh signaling pathway could promote gastric cancer cell proliferation and tumor development, and blocking this pathway may be a potential strategy in gastric cancer treatment.
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Affiliation(s)
- Jianhua Wan
- State Key Laboratory of Silkworm Genome Biology, Southwest University , Chongqing, China
| | - Ji Zhou
- Department of Neurosurgery, Daping Hospital, Third Military Medical University , PLA, Chongqing, China
| | - Hailong Zhao
- State Key Laboratory of Silkworm Genome Biology, Southwest University , Chongqing, China
| | - Mei Wang
- State Key Laboratory of Silkworm Genome Biology, Southwest University , Chongqing, China
| | - Zhuanqin Wei
- State Key Laboratory of Silkworm Genome Biology, Southwest University , Chongqing, China
| | - Hongyan Gao
- State Key Laboratory of Silkworm Genome Biology, Southwest University , Chongqing, China
| | - Yongzhong Wang
- Department of Radiology, Fourth Hospital of Hebei Medical University , Shijiazhuang, Hebei Province, China
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, Southwest University , Chongqing, China
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31
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Hagiwara K, Obayashi T, Sakayori N, Yamanishi E, Hayashi R, Osumi N, Nakazawa T, Nishida K. Molecular and cellular features of murine craniofacial and trunk neural crest cells as stem cell-like cells. PLoS One 2014; 9:e84072. [PMID: 24465393 PMCID: PMC3896334 DOI: 10.1371/journal.pone.0084072] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2013] [Accepted: 11/11/2013] [Indexed: 11/18/2022] Open
Abstract
The outstanding differentiation capacities and easier access from adult tissues, cells derived from neural crest cells (NCCs) have fascinated scientists in developmental biology and regenerative medicine. Differentiation potentials of NCCs are known to depend on their originating regions. Here, we report differential molecular features between craniofacial (cNCCs) and trunk (tNCCs) NCCs by analyzing transcription profiles and sphere forming assays of NCCs from P0-Cre/floxed-EGFP mouse embryos. We identified up-regulation of genes linked to carcinogenesis in cNCCs that were not previously reported to be related to NCCs, which was considered to be, an interesting feature in regard with carcinogenic potentials of NCCs such as melanoma and neuroblastoma. Wnt signal related genes were statistically up-regulated in cNCCs, also suggesting potential involvement of cNCCs in carcinogenesis. We also noticed intense expression of mesenchymal and neuronal markers in cNCCs and tNCCs, respectively. Consistent results were obtained from in vitro sphere-forming and differentiation assays. These results were in accordance with previous notion about differential potentials of cNCCs and tNCCs. We thus propose that sorting NCCs from P0-Cre/floxed-EGFP mice might be useful for the basic and translational research of NCCs. Furthermore, these newly-identified genes up-regulated in cNCC would provide helpful information on NC-originating tumors, developmental disorders in NCC derivatives, and potential applications of NCCs in regenerative medicine.
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Affiliation(s)
- Kunie Hagiwara
- Department of Ophthalmology, Tohoku University Graduate School of Medicine, Seiryo-cho, Aoba-ku, Sendai, Japan
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Japan
| | - Takeshi Obayashi
- Division of Applied Informatics for Human and Life Science, Tohoku University Graduate School of Information Science, Aramaki-Aza-Aoba, Aoba-ku, Sendai, Japan
| | - Nobuyuki Sakayori
- Division of Developmental Neuroscience, Tohoku University Graduate School of Medicine, Seiryo-cho, Aoba-ku, Sendai, Japan
| | - Emiko Yamanishi
- Division of Developmental Neuroscience, Tohoku University Graduate School of Medicine, Seiryo-cho, Aoba-ku, Sendai, Japan
| | - Ryuhei Hayashi
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Japan
| | - Noriko Osumi
- Division of Developmental Neuroscience, Tohoku University Graduate School of Medicine, Seiryo-cho, Aoba-ku, Sendai, Japan
- * E-mail:
| | - Toru Nakazawa
- Department of Ophthalmology, Tohoku University Graduate School of Medicine, Seiryo-cho, Aoba-ku, Sendai, Japan
| | - Kohji Nishida
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Japan
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