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Ogden J, Sellers R, Sahoo S, Oojageer A, Chaturvedi A, Dive C, Lopez-Garcia C. A human model to deconvolve genotype-phenotype causations in lung squamous cell carcinoma. Nat Commun 2025; 16:3215. [PMID: 40185723 PMCID: PMC11971459 DOI: 10.1038/s41467-025-58343-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 03/18/2025] [Indexed: 04/07/2025] Open
Abstract
Tractable, patient-relevant models are needed to investigate cancer progression and heterogeneity. Here, we report an alternative in vitro model of lung squamous cell carcinoma (LUSC) using primary human bronchial epithelial cells (hBECs) from three healthy donors. The co-operation of ubiquitous alterations (TP53 and CDKN2A loss) and components of commonly deregulated pathways including squamous differentiation (SOX2), PI3K signalling (PTEN) and the oxidative stress response (KEAP1) is investigated by generating hBECs harbouring cumulative alterations. Our analyses confirms that SOX2-overexpression initiates early preinvasive LUSC stages, and co-operation with the oxidative stress response and PI3K pathways to drive more aggressive phenotypes, with expansion of cells expressing LUSC biomarkers and invasive properties. This cooperation is consistent with the classical LUSC subtype. Importantly, we connect pathway dysregulation with gene expression changes associated with cell-intrinsic processes and immunomodulation. Our approach constitutes a powerful system to model LUSC and unravel genotype-phenotype causations of clinical relevance.
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Affiliation(s)
- Julia Ogden
- Cancer Research UK Manchester Institute, Wilmslow Road, M20 4BX, Manchester, United Kingdom
| | - Robert Sellers
- Cancer Research UK Manchester Institute, Wilmslow Road, M20 4BX, Manchester, United Kingdom
| | - Sudhakar Sahoo
- Cancer Research UK Manchester Institute, Wilmslow Road, M20 4BX, Manchester, United Kingdom
| | - Anthony Oojageer
- Cancer Research UK Manchester Institute, Wilmslow Road, M20 4BX, Manchester, United Kingdom
| | - Anshuman Chaturvedi
- Department of Histopathology, The Christie Hospital, Wilmslow Road, Manchester, M20 4BX, United Kingdom
| | - Caroline Dive
- Cancer Research UK Manchester Institute, Wilmslow Road, M20 4BX, Manchester, United Kingdom
- Cancer Research UK, National Biomarker Centre, Wilmslow Road, M20 4BX, Manchester, United Kingdom
- Cancer Research UK Lung Cancer Centre of Excellence, Wilmslow Road, M20 4BX, Manchester, United Kingdom
| | - Carlos Lopez-Garcia
- Cancer Research UK Manchester Institute, Wilmslow Road, M20 4BX, Manchester, United Kingdom.
- Cancer Research UK Lung Cancer Centre of Excellence, Wilmslow Road, M20 4BX, Manchester, United Kingdom.
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2
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Ormsbee Golden BD, Gonzalez DV, Yochum GS, Coulter DW, Rizzino A. SOX2 represses c-MYC transcription by altering the co-activator landscape of the c-MYC super-enhancer and promoter regions. J Biol Chem 2024; 300:107642. [PMID: 39122009 PMCID: PMC11408076 DOI: 10.1016/j.jbc.2024.107642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 07/05/2024] [Accepted: 07/22/2024] [Indexed: 08/12/2024] Open
Abstract
Our previous studies determined that elevating SOX2 in a wide range of tumor cells leads to a reversible state of tumor growth arrest. Efforts to understand how tumor cell growth is inhibited led to the discovery of a SOX2:MYC axis that is responsible for downregulating c-MYC (MYC) when SOX2 is elevated. Although we had determined that elevating SOX2 downregulates MYC transcription, the mechanism responsible was not determined. Given the challenges of targeting MYC clinically, we set out to identify how elevating SOX2 downregulates MYC transcription. In this study, we focused on the MYC promoter region and an upstream region of the MYC locus that contains a MYC super-enhancer encompassing five MYC enhancers and which is associated with several cancers. Here we report that BRD4 and p300 associate with each of the MYC enhancers in the upstream MYC super-enhancer as well as the MYC promoter region and that elevating SOX2 decreases the recruitment of BRD4 and p300 to these sites. Additionally, we determined that elevating SOX2 leads to increases in the association of SOX2 and H3K27me3 within the MYC super-enhancer and the promoter region of MYC. Importantly, we conclude that the increases in SOX2 within the MYC super-enhancer precipitate a cascade of events that culminates in the repression of MYC transcription. Together, our studies identify a novel molecular mechanism able to regulate MYC transcription in two distinctly different tumor types and provide new mechanistic insights into the molecular interrelationships between two master regulators, SOX2 and MYC, widely involved in multiple cancers.
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Affiliation(s)
- Briana D Ormsbee Golden
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Daisy V Gonzalez
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Gregory S Yochum
- Department of Surgery & Biochemistry & Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - Donald W Coulter
- Hematology and Oncology Division, Department of Pediatrics, Nebraska Medical Center, Omaha, Nebraska, USA; Child Health Research Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Angie Rizzino
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA.
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3
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Zhang S, Yang R, Ouyang Y, Shen Y, Hu L, Xu C. Cancer stem cells: a target for overcoming therapeutic resistance and relapse. Cancer Biol Med 2023; 20:j.issn.2095-3941.2023.0333. [PMID: 38164743 PMCID: PMC10845928 DOI: 10.20892/j.issn.2095-3941.2023.0333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 11/20/2023] [Indexed: 01/03/2024] Open
Abstract
Cancer stem cells (CSCs) are a small subset of cells in cancers that are thought to initiate tumorous transformation and promote metastasis, recurrence, and resistance to treatment. Growing evidence has revealed the existence of CSCs in various types of cancers and suggested that CSCs differentiate into diverse lineage cells that contribute to tumor progression. We may be able to overcome the limitations of cancer treatment with a comprehensive understanding of the biological features and mechanisms underlying therapeutic resistance in CSCs. This review provides an overview of the properties, biomarkers, and mechanisms of resistance shown by CSCs. Recent findings on metabolic features, especially fatty acid metabolism and ferroptosis in CSCs, are highlighted, along with promising targeting strategies. Targeting CSCs is a potential treatment plan to conquer cancer and prevent resistance and relapse in cancer treatment.
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Affiliation(s)
- Shuo Zhang
- Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610042, China
| | - Rui Yang
- Department of Ultrasound in Medicine, Chengdu Wenjiang District People’s Hospital, Chengdu 611130, China
| | - Yujie Ouyang
- Acupuncture and Massage College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yang Shen
- Department of Oncology & Cancer Institute, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- School of Pharmacy, Macau University of Science and Technology, Macau SAR 999078, China
| | - Lanlin Hu
- Department of Oncology & Cancer Institute, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Yu-Yue Pathology Scientific Research Center, Chongqing 400039, China
- Jinfeng Laboratory, Chongqing 401329, China
| | - Chuan Xu
- Department of Oncology & Cancer Institute, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Yu-Yue Pathology Scientific Research Center, Chongqing 400039, China
- Jinfeng Laboratory, Chongqing 401329, China
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4
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Abatti LE, Lado-Fernández P, Huynh L, Collado M, Hoffman M, Mitchell J. Epigenetic reprogramming of a distal developmental enhancer cluster drives SOX2 overexpression in breast and lung adenocarcinoma. Nucleic Acids Res 2023; 51:10109-10131. [PMID: 37738673 PMCID: PMC10602899 DOI: 10.1093/nar/gkad734] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 08/18/2023] [Accepted: 08/24/2023] [Indexed: 09/24/2023] Open
Abstract
Enhancer reprogramming has been proposed as a key source of transcriptional dysregulation during tumorigenesis, but the molecular mechanisms underlying this process remain unclear. Here, we identify an enhancer cluster required for normal development that is aberrantly activated in breast and lung adenocarcinoma. Deletion of the SRR124-134 cluster disrupts expression of the SOX2 oncogene, dysregulates genome-wide transcription and chromatin accessibility and reduces the ability of cancer cells to form colonies in vitro. Analysis of primary tumors reveals a correlation between chromatin accessibility at this cluster and SOX2 overexpression in breast and lung cancer patients. We demonstrate that FOXA1 is an activator and NFIB is a repressor of SRR124-134 activity and SOX2 transcription in cancer cells, revealing a co-opting of the regulatory mechanisms involved in early development. Notably, we show that the conserved SRR124 and SRR134 regions are essential during mouse development, where homozygous deletion results in the lethal failure of esophageal-tracheal separation. These findings provide insights into how developmental enhancers can be reprogrammed during tumorigenesis and underscore the importance of understanding enhancer dynamics during development and disease.
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Affiliation(s)
- Luis E Abatti
- Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada
| | - Patricia Lado-Fernández
- Laboratory of Cell Senescence, Cancer and Aging, Health Research Institute of Santiago de Compostela (IDIS), Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain
- Department of Physiology and Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain
| | - Linh Huynh
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Manuel Collado
- Laboratory of Cell Senescence, Cancer and Aging, Health Research Institute of Santiago de Compostela (IDIS), Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain
| | - Michael M Hoffman
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- Department of Computer Science, University of Toronto, Toronto, Ontario, Canada
- Vector Institute for Artificial Intelligence, Toronto, Ontario, Canada
| | - Jennifer A Mitchell
- Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada
- Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
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5
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Roberts M, Ogden J, Hossain ASM, Chaturvedi A, Kerr ARW, Dive C, Beane JE, Lopez-Garcia C. Interrogating the precancerous evolution of pathway dysfunction in lung squamous cell carcinoma using XTABLE. eLife 2023; 12:e77507. [PMID: 36892933 PMCID: PMC10038660 DOI: 10.7554/elife.77507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 03/09/2023] [Indexed: 03/10/2023] Open
Abstract
Lung squamous cell carcinoma (LUSC) is a type of lung cancer with a dismal prognosis that lacks adequate therapies and actionable targets. This disease is characterized by a sequence of low- and high-grade preinvasive stages with increasing probability of malignant progression. Increasing our knowledge about the biology of these premalignant lesions (PMLs) is necessary to design new methods of early detection and prevention, and to identify the molecular processes that are key for malignant progression. To facilitate this research, we have designed XTABLE (Exploring Transcriptomes of Bronchial Lesions), an open-source application that integrates the most extensive transcriptomic databases of PMLs published so far. With this tool, users can stratify samples using multiple parameters and interrogate PML biology in multiple manners, such as two- and multiple-group comparisons, interrogation of genes of interests, and transcriptional signatures. Using XTABLE, we have carried out a comparative study of the potential role of chromosomal instability scores as biomarkers of PML progression and mapped the onset of the most relevant LUSC pathways to the sequence of LUSC developmental stages. XTABLE will critically facilitate new research for the identification of early detection biomarkers and acquire a better understanding of the LUSC precancerous stages.
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Affiliation(s)
- Matthew Roberts
- Cancer Biomarker Centre, Cancer Research UK Manchester Institute, The University of ManchesterMacclesfieldUnited Kingdom
- Cancer Research UK Lung Cancer Centre of ExcellenceAlderley ParkUnited Kingdom
| | - Julia Ogden
- Cancer Research UK Lung Cancer Centre of ExcellenceAlderley ParkUnited Kingdom
- Translational Lung Cancer Biology Laboratory, Cancer Research UK Manchester Institute, University of ManchesterMacclesfieldUnited Kingdom
| | - AS Mukarram Hossain
- Cancer Biomarker Centre, Cancer Research UK Manchester Institute, The University of ManchesterMacclesfieldUnited Kingdom
- Cancer Research UK Lung Cancer Centre of ExcellenceAlderley ParkUnited Kingdom
| | - Anshuman Chaturvedi
- Cancer Research UK Lung Cancer Centre of ExcellenceAlderley ParkUnited Kingdom
- Department of Histopathology, The Christie HospitalManchesterUnited Kingdom
| | - Alastair RW Kerr
- Cancer Biomarker Centre, Cancer Research UK Manchester Institute, The University of ManchesterMacclesfieldUnited Kingdom
- Cancer Research UK Lung Cancer Centre of ExcellenceAlderley ParkUnited Kingdom
| | - Caroline Dive
- Cancer Biomarker Centre, Cancer Research UK Manchester Institute, The University of ManchesterMacclesfieldUnited Kingdom
- Cancer Research UK Lung Cancer Centre of ExcellenceAlderley ParkUnited Kingdom
| | | | - Carlos Lopez-Garcia
- Cancer Research UK Lung Cancer Centre of ExcellenceAlderley ParkUnited Kingdom
- Translational Lung Cancer Biology Laboratory, Cancer Research UK Manchester Institute, University of ManchesterMacclesfieldUnited Kingdom
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6
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Mirzaei S, Paskeh MDA, Entezari M, Mirmazloomi SR, Hassanpoor A, Aboutalebi M, Rezaei S, Hejazi ES, Kakavand A, Heidari H, Salimimoghadam S, Taheriazam A, Hashemi M, Samarghandian S. SOX2 function in cancers: Association with growth, invasion, stemness and therapy response. Biomed Pharmacother 2022; 156:113860. [DOI: 10.1016/j.biopha.2022.113860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 09/30/2022] [Accepted: 10/08/2022] [Indexed: 11/29/2022] Open
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7
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Hagey DW, Bergsland M, Muhr J. SOX2 transcription factor binding and function. Development 2022; 149:276045. [DOI: 10.1242/dev.200547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
ABSTRACT
The transcription factor SOX2 is a vital regulator of stem cell activity in various developing and adult tissues. Mounting evidence has demonstrated the importance of SOX2 in regulating the induction and maintenance of stemness as well as in controlling cell proliferation, lineage decisions and differentiation. Recent studies have revealed that the ability of SOX2 to regulate these stem cell features involves its function as a pioneer factor, with the capacity to target nucleosomal DNA, modulate chromatin accessibility and prepare silent genes for subsequent activation. Moreover, although SOX2 binds to similar DNA motifs in different stem cells, its multifaceted and cell type-specific functions are reliant on context-dependent features. These cell type-specific properties include variations in partner factor availability and SOX2 protein expression levels. In this Primer, we discuss recent findings that have increased our understanding of how SOX2 executes its versatile functions as a master regulator of stem cell activities.
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Affiliation(s)
- Daniel W. Hagey
- Karolinska Institutet 1 Department of Laboratory Medicine , , SE-171 77 Stockholm , Sweden
| | - Maria Bergsland
- Karolinska Institutet 2 Department of Cell and Molecular Biology , , Solnavägen 9, SE-171 65 Stockholm , Sweden
| | - Jonas Muhr
- Karolinska Institutet 2 Department of Cell and Molecular Biology , , Solnavägen 9, SE-171 65 Stockholm , Sweden
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Wang Z, Wang J, Zhao H, Zhao T, Chen Y, Jiang M, Zhang S, Wei Y, Zhang J, Zhou Y, Shi S, Fu Z, Yang Y, Zhang Y, Yang L, Que J, Liu K. Targeting the SOX2/PARP1 complex to intervene in the growth of esophageal squamous cell carcinoma. Biomed Pharmacother 2022; 153:113309. [PMID: 35738180 DOI: 10.1016/j.biopha.2022.113309] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/10/2022] [Accepted: 06/14/2022] [Indexed: 11/30/2022] Open
Abstract
Elevated SOX2 protein levels are closely correlated with the increased incidence of esophageal squamous cell carcinoma (ESCC). However, establishing effective target measures for ESCC treatments continue to be researched. It has been previously proposed that SOX2 represents a potential therapeutic target for ESCC. Here, we found that the enzyme Poly(ADP-Ribose) polymerase 1 (PARP1) enriched in ESCCs interact with SOX2. Inhibition of PARP1 with 3-aminobenzamide (3-ABA) or shRNA knockdown reduced the proliferation of ESCCs, accompanied by decreased protein levels of SOX2. RNA sequencing demonstrated that PARP1 inhibition affected multiple signaling pathways involved in cancer cell proliferation. Additionally, 3-ABA synergistically suppressed the growth of ESCC cells when combined with cisplatin, and metformin potentiated the suppressive effect of 3-ABA on ESCC cell growth. Together these findings suggest that targeting SOX2 binding partner PARP1 provides a possible avenue to treat patients with high levels of SOX2.
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Affiliation(s)
- Zhuo Wang
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China; School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Junkai Wang
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Hongzhou Zhao
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China; School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Tingting Zhao
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China; School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Yunyun Chen
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China; School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Ming Jiang
- Department of Gastroenterology of The Children's Hospital, Institute of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Shihui Zhang
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh EH16 4UU, UK
| | - Yuxuan Wei
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China; School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Jiaying Zhang
- School of Life Science, Xiamen University, Xiamen, Fujian 361102, China
| | - Yijian Zhou
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China; School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Songlin Shi
- School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Zhichao Fu
- Department of radiotherapy, 900 Hospital of the Joint Logistics Team (Dongfang Hospital, Xiamen University), Fuzhou, Fujian 350025, China
| | - Yaxin Yang
- Department of Biology, University of Rochester, NY 14627, USA
| | - Yujun Zhang
- School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Ling Yang
- School of Medicine, Xiamen University, Xiamen, Fujian 361102, China
| | - Jianwen Que
- Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
| | - Kuancan Liu
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China; School of Medicine, Xiamen University, Xiamen, Fujian 361102, China.
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9
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Metz EP, Wilder PJ, Popay TM, Wang J, Liu Q, Kalluchi A, Rowley MJ, Tansey WP, Rizzino A. Elevating SOX2 Downregulates MYC through a SOX2:MYC Signaling Axis and Induces a Slowly Cycling Proliferative State in Human Tumor Cells. Cancers (Basel) 2022; 14:1946. [PMID: 35454854 PMCID: PMC9025961 DOI: 10.3390/cancers14081946] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 03/29/2022] [Accepted: 04/07/2022] [Indexed: 02/05/2023] Open
Abstract
Slowly cycling/infrequently proliferating tumor cells present a clinical challenge due to their ability to evade treatment. Previous studies established that high levels of SOX2 in both fetal and tumor cells restrict cell proliferation and induce a slowly cycling state. However, the mechanisms through which elevated SOX2 levels inhibit tumor cell proliferation have not been identified. To identify common mechanisms through which SOX2 elevation restricts tumor cell proliferation, we initially performed RNA-seq using two diverse tumor cell types. SOX2 elevation in both cell types downregulated MYC target genes. Consistent with these findings, elevating SOX2 in five cell lines representing three different human cancer types decreased MYC expression. Importantly, the expression of a dominant-negative MYC variant, omomyc, recapitulated many of the effects of SOX2 on proliferation, cell cycle, gene expression, and biosynthetic activity. We also demonstrated that rescuing MYC activity in the context of elevated SOX2 induces cell death, indicating that the downregulation of MYC is a critical mechanistic step necessary to maintain survival in the slowly cycling state induced by elevated SOX2. Altogether, our findings uncover a novel SOX2:MYC signaling axis and provide important insights into the molecular mechanisms through which SOX2 elevation induces a slowly cycling proliferative state.
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Affiliation(s)
- Ethan P. Metz
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA; (E.P.M.); (P.J.W.)
| | - Phillip J. Wilder
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA; (E.P.M.); (P.J.W.)
| | - Tessa M. Popay
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; (T.M.P.); (W.P.T.)
| | - Jing Wang
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; (J.W.); (Q.L.)
- Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Qi Liu
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; (J.W.); (Q.L.)
- Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Achyuth Kalluchi
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA; (A.K.); (M.J.R.)
| | - M. Jordan Rowley
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA; (A.K.); (M.J.R.)
| | - William P. Tansey
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; (T.M.P.); (W.P.T.)
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Angie Rizzino
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA; (E.P.M.); (P.J.W.)
- Department of Pathology and Microbiology, University of Nebraska Medical Center Fred & Pamela Buffett Cancer Center, Omaha, NE 68198, USA
- Department of Biochemistry and Molecular Biology, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
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10
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Pouremamali F, Vahedian V, Hassani N, Mirzaei S, Pouremamali A, Kazemzadeh H, Faridvand Y, Jafari-gharabaghlou D, Nouri M, Maroufi NF. The role of SOX family in cancer stem cell maintenance: With a focus on SOX2. Pathol Res Pract 2022; 231:153783. [DOI: 10.1016/j.prp.2022.153783] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/17/2022] [Accepted: 01/25/2022] [Indexed: 02/06/2023]
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11
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Ray S, Chaturvedi NK, Bhakat KK, Rizzino A, Mahapatra S. Subgroup-Specific Diagnostic, Prognostic, and Predictive Markers Influencing Pediatric Medulloblastoma Treatment. Diagnostics (Basel) 2021; 12:diagnostics12010061. [PMID: 35054230 PMCID: PMC8774967 DOI: 10.3390/diagnostics12010061] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/11/2021] [Accepted: 12/18/2021] [Indexed: 12/24/2022] Open
Abstract
Medulloblastoma (MB) is the most common malignant central nervous system tumor in pediatric patients. Mainstay of therapy remains surgical resection followed by craniospinal radiation and chemotherapy, although limitations to this therapy are applied in the youngest patients. Clinically, tumors are divided into average and high-risk status on the basis of age, metastasis at diagnosis, and extent of surgical resection. However, technological advances in high-throughput screening have facilitated the analysis of large transcriptomic datasets that have been used to generate the current classification system, dividing patients into four primary subgroups, i.e., WNT (wingless), SHH (sonic hedgehog), and the non-SHH/WNT subgroups 3 and 4. Each subgroup can further be subdivided on the basis of a combination of cytogenetic and epigenetic events, some in distinct signaling pathways, that activate specific phenotypes impacting patient prognosis. Here, we delve deeper into the genetic basis for each subgroup by reviewing the extent of cytogenetic events in key genes that trigger neoplastic transformation or that exhibit oncogenic properties. Each of these discussions is further centered on how these genetic aberrations can be exploited to generate novel targeted therapeutics for each subgroup along with a discussion on challenges that are currently faced in generating said therapies. Our future hope is that through better understanding of subgroup-specific cytogenetic events, the field may improve diagnosis, prognosis, and treatment to improve overall quality of life for these patients.
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Affiliation(s)
- Sutapa Ray
- Department of Pediatrics, University of Nebraska Medical Center, 601 S Saddle Creek Road, Omaha, NE 68198, USA; (S.R.); (N.K.C.)
- Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA; (K.K.B.); (A.R.)
| | - Nagendra K. Chaturvedi
- Department of Pediatrics, University of Nebraska Medical Center, 601 S Saddle Creek Road, Omaha, NE 68198, USA; (S.R.); (N.K.C.)
- Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA; (K.K.B.); (A.R.)
| | - Kishor K. Bhakat
- Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA; (K.K.B.); (A.R.)
- Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Angie Rizzino
- Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA; (K.K.B.); (A.R.)
- Eppley Institute for Research in Cancer and Allied Disease, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Sidharth Mahapatra
- Department of Pediatrics, University of Nebraska Medical Center, 601 S Saddle Creek Road, Omaha, NE 68198, USA; (S.R.); (N.K.C.)
- Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68105, USA; (K.K.B.); (A.R.)
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Correspondence: ; Tel.: +1-(402)-599-7754
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12
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Stevanovic M, Kovacevic-Grujicic N, Mojsin M, Milivojevic M, Drakulic D. SOX transcription factors and glioma stem cells: Choosing between stemness and differentiation. World J Stem Cells 2021; 13:1417-1445. [PMID: 34786152 PMCID: PMC8567447 DOI: 10.4252/wjsc.v13.i10.1417] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 07/15/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
Glioblastoma (GBM) is the most common, most aggressive and deadliest brain tumor. Recently, remarkable progress has been made towards understanding the cellular and molecular biology of gliomas. GBM tumor initiation, progression and relapse as well as resistance to treatments are associated with glioma stem cells (GSCs). GSCs exhibit a high proliferation rate and self-renewal capacity and the ability to differentiate into diverse cell types, generating a range of distinct cell types within the tumor, leading to cellular heterogeneity. GBM tumors may contain different subsets of GSCs, and some of them may adopt a quiescent state that protects them against chemotherapy and radiotherapy. GSCs enriched in recurrent gliomas acquire more aggressive and therapy-resistant properties, making them more malignant, able to rapidly spread. The impact of SOX transcription factors (TFs) on brain tumors has been extensively studied in the last decade. Almost all SOX genes are expressed in GBM, and their expression levels are associated with patient prognosis and survival. Numerous SOX TFs are involved in the maintenance of the stemness of GSCs or play a role in the initiation of GSC differentiation. The fine-tuning of SOX gene expression levels controls the balance between cell stemness and differentiation. Therefore, innovative therapies targeting SOX TFs are emerging as promising tools for combatting GBM. Combatting GBM has been a demanding and challenging goal for decades. The current therapeutic strategies have not yet provided a cure for GBM and have only resulted in a slight improvement in patient survival. Novel approaches will require the fine adjustment of multimodal therapeutic strategies that simultaneously target numerous hallmarks of cancer cells to win the battle against GBM.
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Affiliation(s)
- Milena Stevanovic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
- Chair Biochemistry and Molecular Biology, Faculty of Biology, University of Belgrade, Belgrade 11158, Serbia
- Department of Chemical and Biological Sciences, Serbian Academy of Sciences and Arts, Belgrade 11000, Serbia.
| | - Natasa Kovacevic-Grujicic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
| | - Marija Mojsin
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
| | - Milena Milivojevic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
| | - Danijela Drakulic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
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13
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Metz EP, Wuebben EL, Wilder PJ, Cox JL, Datta K, Coulter D, Rizzino A. Tumor quiescence: elevating SOX2 in diverse tumor cell types downregulates a broad spectrum of the cell cycle machinery and inhibits tumor growth. BMC Cancer 2020; 20:941. [PMID: 32998722 PMCID: PMC7528478 DOI: 10.1186/s12885-020-07370-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 08/31/2020] [Indexed: 11/17/2022] Open
Abstract
Background Quiescent tumor cells pose a major clinical challenge due to their ability to resist conventional chemotherapies and to drive tumor recurrence. Understanding the molecular mechanisms that promote quiescence of tumor cells could help identify therapies to eliminate these cells. Significantly, recent studies have determined that the function of SOX2 in cancer cells is highly dose dependent. Specifically, SOX2 levels in tumor cells are optimized to promote tumor growth: knocking down or elevating SOX2 inhibits proliferation. Furthermore, recent studies have shown that quiescent tumor cells express higher levels of SOX2 compared to adjacent proliferating cells. Currently, the mechanisms through which elevated levels of SOX2 restrict tumor cell proliferation have not been characterized. Methods To understand how elevated levels of SOX2 restrict the proliferation of tumor cells, we engineered diverse types of tumor cells for inducible overexpression of SOX2. Using these cells, we examined the effects of elevating SOX2 on their proliferation, both in vitro and in vivo. In addition, we examined how elevating SOX2 influences their expression of cyclins, cyclin-dependent kinases (CDKs), and p27Kip1. Results Elevating SOX2 in diverse tumor cell types led to growth inhibition in vitro. Significantly, elevating SOX2 in vivo in pancreatic ductal adenocarcinoma, medulloblastoma, and prostate cancer cells induced a reversible state of tumor growth arrest. In all three tumor types, elevation of SOX2 in vivo quickly halted tumor growth. Remarkably, tumor growth resumed rapidly when SOX2 returned to endogenous levels. We also determined that elevation of SOX2 in six tumor cell lines decreased the levels of cyclins and CDKs that control each phase of the cell cycle, while upregulating p27Kip1. Conclusions Our findings indicate that elevating SOX2 above endogenous levels in a diverse set of tumor cell types leads to growth inhibition both in vitro and in vivo. Moreover, our findings indicate that SOX2 can function as a master regulator by controlling the expression of a broad spectrum of cell cycle machinery. Importantly, our SOX2-inducible tumor studies provide a novel model system for investigating the molecular mechanisms by which elevated levels of SOX2 restrict cell proliferation and tumor growth.
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Affiliation(s)
- Ethan P Metz
- Eppley Institute for Research in Cancer and Allied Diseases Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198-6805, USA
| | - Erin L Wuebben
- Eppley Institute for Research in Cancer and Allied Diseases Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198-6805, USA
| | - Phillip J Wilder
- Eppley Institute for Research in Cancer and Allied Diseases Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198-6805, USA
| | - Jesse L Cox
- Department of Pathology and Microbiology, University of Nebraska Medical Center Fred & Pamela Buffett Cancer Center, Omaha, NE, 68198-6805, USA
| | - Kaustubh Datta
- Department of Biochemistry and Molecular Biology Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198-6805, USA
| | - Donald Coulter
- Department of Pediatrics, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198-6805, USA
| | - Angie Rizzino
- Eppley Institute for Research in Cancer and Allied Diseases Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198-6805, USA. .,Department of Pathology and Microbiology, University of Nebraska Medical Center Fred & Pamela Buffett Cancer Center, Omaha, NE, 68198-6805, USA. .,Department of Biochemistry and Molecular Biology Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198-6805, USA.
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14
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Targeting Glioblastoma: Advances in Drug Delivery and Novel Therapeutic Approaches. ADVANCED THERAPEUTICS 2020. [DOI: 10.1002/adtp.202000124] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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15
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Dalmo E, Johansson P, Niklasson M, Gustavsson I, Nelander S, Westermark B. Growth-Inhibitory Activity of Bone Morphogenetic Protein 4 in Human Glioblastoma Cell Lines Is Heterogeneous and Dependent on Reduced SOX2 Expression. Mol Cancer Res 2020; 18:981-991. [PMID: 32234828 DOI: 10.1158/1541-7786.mcr-19-0638] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 02/13/2020] [Accepted: 03/25/2020] [Indexed: 11/16/2022]
Abstract
Glioblastoma multiforme continues to have a dismal prognosis. Even though detailed information on the genetic aberrations in cell signaling and cell-cycle checkpoint control is available, no effective targeted treatment has been developed. Despite the advanced molecular defects, glioblastoma cells may have remnants of normal growth-inhibitory pathways, such as the bone morphogenetic protein (BMP) signaling pathway. We have evaluated the growth-inhibitory effect of BMP4 across a broad spectrum of patient samples, using a panel of 40 human glioblastoma initiating cell (GIC) cultures. A wide range of responsiveness was observed. BMP4 sensitivity was positively correlated with a proneural mRNA expression profile, high SOX2 activity, and BMP4-dependent upregulation of genes associated with inhibition of the MAPK pathway, as demonstrated by gene set enrichment analysis. BMP4 response in sensitive cells was mediated by the canonical BMP receptor pathway involving SMAD1/5/9 phosphorylation and SMAD4 expression. SOX2 was consistently downregulated in BMP4-treated cells. Forced expression of SOX2 attenuated the BMP4 sensitivity including a reduced upregulation of MAPK-inhibitory genes, implying a functional relationship between SOX2 downregulation and sensitivity. The results show an extensive heterogeneity in BMP4 responsiveness among GICs and identify a BMP4-sensitive subgroup, in which SOX2 is a mediator of the response. IMPLICATIONS: Development of agonists targeting the BMP signaling pathway in glioblastoma is an attractive avenue toward a better treatment. Our study may help find biomarkers that predict the outcome of such treatment and enable stratification of patients.
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Affiliation(s)
- Erika Dalmo
- Department of Immunology, Genetics and Pathology, and Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Patrik Johansson
- Department of Immunology, Genetics and Pathology, and Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Mia Niklasson
- Department of Immunology, Genetics and Pathology, and Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Ida Gustavsson
- Department of Immunology, Genetics and Pathology, and Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Sven Nelander
- Department of Immunology, Genetics and Pathology, and Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Bengt Westermark
- Department of Immunology, Genetics and Pathology, and Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
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16
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Metz EP, Wilder PJ, Dong J, Datta K, Rizzino A. Elevating SOX2 in prostate tumor cells upregulates expression of neuroendocrine genes, but does not reduce the inhibitory effects of enzalutamide. J Cell Physiol 2019; 235:3731-3740. [PMID: 31587305 DOI: 10.1002/jcp.29267] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 09/18/2019] [Indexed: 01/02/2023]
Abstract
Prostate cancer (PCa) is one of the leading causes of cancer deaths in men. In this cancer, the stem cell transcription factor SOX2 increases during tumor progression, especially as the cancer progresses to the highly aggressive neuroendocrine-like phenotype. Other studies have shown that knockdown of RB1 and TP53 increases the expression of neuroendocrine markers, decreases the sensitivity to enzalutamide, and increases the expression of SOX2. Importantly, knockdown of SOX2 in the context of RB1 and TP53 depletion restored sensitivity to enzalutamide and reduced the expression of neuroendocrine markers. In this study, we examined whether elevating SOX2 is not only necessary, but also sufficient on its own to promote the expression of neuroendocrine markers and confer enzalutamide resistance. For this purpose, we engineered LNCaP cells for inducible overexpression of SOX2 (i-SOX2-LNCaP). As shown previously for other tumor cell types, inducible elevation of SOX2 in i-SOX2-LNCaP inhibited cell proliferation. SOX2 elevation also increased the expression of several neuroendocrine markers, including several neuropeptides and synaptophysin. However, SOX2 elevation did not decrease the sensitivity of i-SOX2-LNCaP cells to enzalutamide, which indicates that elevating SOX2 on its own is not sufficient to confer enzalutamide resistance. Furthermore, knocking down SOX2 in C4-2B cells, a derivative of LNCaP cells which is far less sensitive to enzalutamide and which expresses much higher levels of SOX2 than LNCaP cells, did not alter the growth response to this antiandrogen. Thus, our studies indicate that NE marker expression can increase independently of the sensitivity to enzalutamide.
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Affiliation(s)
- Ethan P Metz
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska
| | - Phillip J Wilder
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska
| | - Jixin Dong
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska
| | - Kaustubh Datta
- Department of Biochemistry and Molecular Biology, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska
| | - Angie Rizzino
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska.,Department of Biochemistry and Molecular Biology, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska
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17
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Alameda F, Velarde JM, Carrato C, Vidal N, Arumí M, Naranjo D, Martinez-Garcia M, Ribalta T, Balañá C. Prognostic value of stem cell markers in glioblastoma. Biomarkers 2019; 24:677-683. [DOI: 10.1080/1354750x.2019.1652345] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Francesc Alameda
- Department of Pathology, Hospital del Mar, Barcelona, Spain
- Universitat Autonoma, Barcelona, Spain
| | - José María Velarde
- Institute for Health Science Research Germans Trias i Pujol (IGTP), Badalona, Spain
| | - Cristina Carrato
- Department of Pathology, Hospital Germans Trias i Pujol, Badalona, Spain
| | - Noemí Vidal
- Department of Pathology, Hospital de Bellvitge, L'Hospitalet de Llobregat, Spain
| | | | | | | | - Teresa Ribalta
- Department of Pathology, Hospital Clinic i Provincial, Barcelona, Spain
| | - Carme Balañá
- Department of Medical Oncology, Catalan Institute of Oncology, Badalona, Spain
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18
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Metz EP, Rizzino A. Sox2 dosage: A critical determinant in the functions of Sox2 in both normal and tumor cells. J Cell Physiol 2019; 234:19298-19306. [PMID: 31344986 DOI: 10.1002/jcp.28610] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 03/21/2019] [Indexed: 01/01/2023]
Abstract
The stem cell transcription factor Sox2 is widely recognized for its many roles during normal development and cancer. Over the last several years, it has become increasingly evident that Sox2 dosage plays critical roles in both normal and malignant cells. The work described in this review indicates that the dosage of Sox2 influences cell fate decisions made during normal mammalian development, as well as cell fate decisions in cancer, including those that influence the tumor cell of origin and progression of the cancer. Equally important, Sox2 dosage is a key determinant in the proliferation of both normal cells and tumor cells, where proliferation is restricted in Sox2high cells. Collectively, the studies reviewed here indicate that tumor cells utilize the fundamental effects of Sox2 dosage to suit their own needs. Finally, we speculate that elevated expression of Sox2 helps establish and maintain tumor dormancy in Sox2-positive cancers.
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Affiliation(s)
- Ethan P Metz
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska
| | - Angie Rizzino
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska
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19
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Abdelrahman AE, Ibrahim HM, Elsebai EA, Ismail EI, Elmesallamy W. The clinicopathological significance of CD133 and Sox2 in astrocytic glioma. Cancer Biomark 2019; 23:391-403. [PMID: 30248046 DOI: 10.3233/cbm-181460] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND The treatment strategies of astrocytoma have not changed considerably due to the restricted appreciation of its biology. OBJECTIVES This study aimed to evaluate the expression of the stem cell-related proteins (CD133 and Sox2) and their prognostic value in astrocytic glioma. METHODS The immunohistochemical expression of CD133 and Sox2 in 40 patients with an astrocytic glioma of different grades was studied. The recorded data on the overall survival (OS), progression-free survival (PFS) and the response to the therapeutic protocol were collected and lastly analyzed. RESULTS CD133 expression was observed in 87.5% of the cases, while positive Sox2 expression was found in all the studied cases. There was a significant association of CD133 expression with the histological grade and the tumor size (p< 0.001). A significant association of Sox2 with the histological grade and the tumor size was noted (p= 0.004, p= 0.006 respectively). Up-regulation of both CD133 and Sox2 had a significant association with poor clinical response to the therapy (p< 0.001 for each). Shorter OS and PFS were related to CD133 and Sox2 overexpression. CONCLUSIONS Astrocytoma with CD133 and Sox2 overexpression had an unfavorable prognosis and poor clinical response to the current therapeutic protocol.
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Affiliation(s)
- Aziza E Abdelrahman
- Pathology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Hanaa M Ibrahim
- Pathology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Eman A Elsebai
- Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Eman I Ismail
- Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Wael Elmesallamy
- Neurosurgery Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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20
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Srinivasan D, Senbanjo L, Majumdar S, Franklin RB, Chellaiah MA. Androgen receptor expression reduces stemness characteristics of prostate cancer cells (PC3) by repression of CD44 and SOX2. J Cell Biochem 2019; 120:2413-2428. [PMID: 30206982 PMCID: PMC6411465 DOI: 10.1002/jcb.27573] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 08/02/2018] [Indexed: 01/24/2023]
Abstract
Studies have shown that a subgroup of tumor cells possess stemness characteristics having self-renewal capacity and the ability to form new tumors. We sought to identify the plausible stemness factor that determines the "molecular signature" of prostate cancer (PCa) cells derived from different metastases (PC3, PCa2b, LNCaP, and DU145) and whether androgen receptor (AR) influences the maintenance of stemness features. Here we show sex-determining region Y (SRY)-box 2 (SOX2) as a putative stem cell marker in PC3 PCa cells and not in DU145, PCa2b, or LNCaP cells. PCa2b and PC3 cells were derived from bone metastases. PCa2b cells which are positive for the AR failed to demonstrate the expression of either cluster of differentiation 44 (CD44) or SOX2. Knockdown (KD) of AR in these cells did not affect the expression of either CD44 or SOX2. Conversely, PC3 cells, which are negative for AR, expressed both CD44 and SOX2. However, the expression of AR downregulated the expression of both CD44 and SOX2 in PC3 cells. CD44 regulates SOX2 expression as KD of CD44 and reduces SOX2 levels considerably. SOX2 KD attenuated not only the expression of SNAIL and SLUG but also the migration and tumorsphere formation in PC3 cells. Collectively, our findings underscore a novel role of CD44 signaling in the maintenance of stemness and progression of cancer through SOX2 in AR-independent PC3 cells. SOX2 has a role in the regulation of expression of SNAIL and SLUG. SOX2 could be a potential therapeutic target to thwart the progression of SOX2-positive cancer cells or recurrence of androgen-independent PCa.
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Affiliation(s)
- Deepa Srinivasan
- Department of Oncology and Diagnostic SciencesUniversity of Maryland Dental SchoolBaltimoreMaryland
| | - Linda Senbanjo
- Department of Oncology and Diagnostic SciencesUniversity of Maryland Dental SchoolBaltimoreMaryland
| | - Sunipa Majumdar
- Department of Oncology and Diagnostic SciencesUniversity of Maryland Dental SchoolBaltimoreMaryland
| | - Renty B. Franklin
- Department of Oncology and Diagnostic SciencesUniversity of Maryland Dental SchoolBaltimoreMaryland
| | - Meenakshi A. Chellaiah
- Department of Oncology and Diagnostic SciencesUniversity of Maryland Dental SchoolBaltimoreMaryland
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21
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Khan IN, Ullah N, Hussein D, Saini KS. Current and emerging biomarkers in tumors of the central nervous system: Possible diagnostic, prognostic and therapeutic applications. Semin Cancer Biol 2018; 52:85-102. [PMID: 28774835 DOI: 10.1016/j.semcancer.2017.07.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2017] [Accepted: 07/25/2017] [Indexed: 12/15/2022]
Abstract
Recent investments in research associated with the discovery of specific tumor biomarkers important for efficient diagnosis and prognosis are beginning to bear fruit. Key biomarkers could potentially outweigh traditional radiological or pathological methods by enabling specificity of early detection, when coupled with tumor molecular profiling and clinical associations. Only few biomarkers are approved by regulatory authorities for Central Nervous System Tumors (CNSTs), despite the evaluation of a large number of CNST related markers during clinical trials. Traditional CNSTs biomarkers include 1p/19q co-deletion, O6-Methylguanine-DNA Methyltransferase Methylation, and mutations in IDH1/IDH2. Recently tested CNSTs biomarkers include VEGFR-2, EGFRvIII, IL2, PDGFR, MMPs, BRAF, STAT3, PTEN, TERT, AKT, NF2, and BCL2. Additional studies have highlighted new and novel MicroRNAs, circular RNAs and long non-coding RNAs as promising biomarkers. Studies on microvesicles pinpoint exosomes as promising, less invasive biomarkers that could be isolated from the serum of cancer patients. Furthermore, Cancer Stem Cells (CSCs) related molecules, such as CD133, SOX2 and Nestin, utilized as CNST biomarkers, might enable efficient monitoring of cancer progression, and/or surveillance of emerging drug resistant cells. Approved protocols that implement novel molecular markers in diagnostics, prognostics and drug development will herald a new era of precision and personalized neuro-oncology. This review summarizes and discusses putative CNST biomarkers that are under clinical development, and are ready to move into diagnostic, prognostic and therapeutic applications. Data presented here is predicted to aid in streamlining the process of biomarker's research and development.
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Affiliation(s)
- Ishaq N Khan
- PK-Neurooncology Research Group, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar 25100, Pakistan; Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
| | - Najeeb Ullah
- Department of Anatomy, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar 25100, Pakistan.
| | - Deema Hussein
- Neurooncology Translational Group, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
| | - Kulvinder S Saini
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Department of Biotechnology, Eternal University, Baru Sahib, Himachal Pradesh 173101, India.
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22
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Lv K, Chen Z, Zhang X, Zhang Q, Liu L. Selective enrichment of CD133 +/SOX2 + glioblastoma stem cells via adherent culture. Oncol Lett 2018; 16:4567-4576. [PMID: 30197675 DOI: 10.3892/ol.2018.9154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 06/08/2018] [Indexed: 11/06/2022] Open
Abstract
Most of the brain tumors are malignant with an extremely poor survival rate. Recent progress in identifying cancer stem cells (CSCs) within the brain tumors is starting to revolutionize our understanding in the imitation and progression of tumors as well as relapse and the development of therapeutic strategies. Suspension spheroid body culture paradigm is a routine method in enriching CSCs. While, it was reported recently that CSCs within the brain tumor may also be enriched through adherent monolayer culture with optimized properties. In the present study, 18 surgically resected brain tumors were used for analyzing the feasibility of adherent enrichment of CSCs. The results indicated that 50% of glioblastomas were able to generate adherent CSCs, which were uniformly positive for Sox2, CD133, GFAP and Nestin. However, adherent culture paradigm failed to yield CSCs in secondary brain tumors, including neurocytomas, ependymomas, germ cell tumors or low-grade astrocytomas, which is most likely due to a lack of CD133+/Sox2+ cells within the original biopsies. Therefore, it was concluded that the adherent culture paradigm may serve as a reliable method in enriching brain CSCs, but this method is more suitable for enriching CD133+/Sox2+ CSCs in glioblastomas.
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Affiliation(s)
- Ke Lv
- Neurosurgical Department, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200092, P.R. China.,Neuroregeneration Key Laboratory of Shanghai Universities, Tongji University School of Medicine, Shanghai 200092, P.R. China
| | - Zhenyu Chen
- Neuroregeneration Key Laboratory of Shanghai Universities, Tongji University School of Medicine, Shanghai 200092, P.R. China.,Institute of Translational Research, Tongji Hospital, Tongji University School of Medicine, Shanghai 200092, P.R. China.,The Collaborative Innovation Center for Brain Science, Tongji University, Shanghai 200092, P.R. China
| | - Xiaoqing Zhang
- Neuroregeneration Key Laboratory of Shanghai Universities, Tongji University School of Medicine, Shanghai 200092, P.R. China.,Institute of Translational Research, Tongji Hospital, Tongji University School of Medicine, Shanghai 200092, P.R. China.,The Collaborative Innovation Center for Brain Science, Tongji University, Shanghai 200092, P.R. China
| | - Quanbin Zhang
- Neurosurgical Department, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200092, P.R. China
| | - Ling Liu
- Neuroregeneration Key Laboratory of Shanghai Universities, Tongji University School of Medicine, Shanghai 200092, P.R. China.,Institute of Translational Research, Tongji Hospital, Tongji University School of Medicine, Shanghai 200092, P.R. China
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23
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Wuebben EL, Rizzino A. The dark side of SOX2: cancer - a comprehensive overview. Oncotarget 2018; 8:44917-44943. [PMID: 28388544 PMCID: PMC5546531 DOI: 10.18632/oncotarget.16570] [Citation(s) in RCA: 168] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 03/16/2017] [Indexed: 12/14/2022] Open
Abstract
The pluripotency-associated transcription factor SOX2 is essential during mammalian embryogenesis and later in life, but SOX2 expression can also be highly detrimental. Over the past 10 years, SOX2 has been shown to be expressed in at least 25 different cancers. This review provides a comprehensive overview of the roles of SOX2 in cancer and focuses on two broad topics. The first delves into the expression and function of SOX2 in cancer focusing on the connection between SOX2 levels and tumor grade as well as patient survival. As part of this discussion, we address the developing connection between SOX2 expression and tumor drug resistance. We also call attention to an under-appreciated property of SOX2, its levels in actively proliferating tumor cells appear to be optimized to maximize tumor growth - too little or too much SOX2 dramatically alters tumor growth. The second topic of this review focuses on the exquisite array of molecular mechanisms that control the expression and transcriptional activity of SOX2. In addition to its complex regulation at the transcriptional level, SOX2 expression and activity are controlled carefully by microRNAs, long non-coding RNAs, and post-translational modifications. In the Conclusion and Future Perspectives section, we point out that there are still important unanswered questions. Addressing these questions is expected to lead to new insights into the functions of SOX2 in cancer, which will help design novels strategies for more effectively treating some of the most deadly cancers.
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Affiliation(s)
- Erin L Wuebben
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Angie Rizzino
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.,Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
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Wuebben EL, Wilder PJ, Cox JL, Grunkemeyer JA, Caffrey T, Hollingsworth MA, Rizzino A. SOX2 functions as a molecular rheostat to control the growth, tumorigenicity and drug responses of pancreatic ductal adenocarcinoma cells. Oncotarget 2017; 7:34890-906. [PMID: 27145457 PMCID: PMC5085197 DOI: 10.18632/oncotarget.8994] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 04/16/2016] [Indexed: 12/16/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly deadly malignancy. Expression of the stem cell transcription factor SOX2 increases during progression of PDAC. Knockdown of SOX2 in PDAC cell lines decreases growth in vitro; whereas, stable overexpression of SOX2 in one PDAC cell line reportedly increases growth in vitro. Here, we reexamined the role of SOX2 in PDAC cells, because inducible SOX2 overexpression in other tumor cell types inhibits growth. In this study, four PDAC cell lines were engineered for inducible overexpression of SOX2 or inducible knockdown of SOX2. Remarkably, inducible overexpression of SOX2 in PDAC cells inhibits growth in vitro and reduces tumorigenicity. Additionally, inducible knockdown of SOX2 in PDAC cells reduces growth in vitro and in vivo. Thus, growth and tumorigenicity of PDAC cells is highly dependent on the expression of optimal levels of SOX2 – a hallmark of molecular rheostats. We also determined that SOX2 alters the responses of PDAC cells to drugs used in PDAC clinical trials. Increasing SOX2 reduces growth inhibition mediated by MEK and AKT inhibitors; whereas knockdown of SOX2 further reduces growth when PDAC cells are treated with these inhibitors. Thus, targeting SOX2, or its mode of action, could improve the treatment of PDAC.
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Affiliation(s)
- Erin L Wuebben
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA
| | - Phillip J Wilder
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA
| | - Jesse L Cox
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-3135, USA
| | - James A Grunkemeyer
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA
| | - Thomas Caffrey
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA
| | - Michael A Hollingsworth
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA
| | - Angie Rizzino
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA.,Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5870, USA
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25
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Tatè R, Zona E, De Cicco R, Trotta V, Urciuoli M, Morelli A, Baiano S, Carnuccio R, Fuggetta MP, Morelli F. Simvastatin inhibits the expression of stemness-related genes and the metastatic invasion of human cancer cells via destruction of the cytoskeleton. Int J Oncol 2017; 51:1851-1859. [DOI: 10.3892/ijo.2017.4158] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Accepted: 09/15/2017] [Indexed: 11/06/2022] Open
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Glioblastoma entities express subtle differences in molecular composition and response to treatment. Oncol Rep 2017; 38:1341-1352. [PMID: 28714013 PMCID: PMC5549060 DOI: 10.3892/or.2017.5799] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 06/06/2017] [Indexed: 12/15/2022] Open
Abstract
Glioblastoma (GBM) is a grade IV astrocytoma. GBM patients show resistance to chemotherapy such as temozolomide (TMZ), the gold standard treatment. In order to simulate the molecular mechanisms behind the different chemotherapeutic responses in GBM patients we compared the cellular heterogeneity and chemotherapeutic resistance mechanisms in different GBM cell lines. We isolated and characterized a human GBM cell line obtained from a GBM patient, named GBM11. We studied the GBM11 behaviour when treated with Tamoxifen (TMX) that, among other functions, is a protein kinase C (PKC) inhibitor, alone and in combination with TMZ in comparison with the responses of U87 and U118 human GBM cell lines. We evaluated the cell death, cell cycle arrest and cell proliferation, mainly through PKC expression, by flow cytometry and western blot analysis and, ultimately, cell migration capability and f-actin filament disorganization by fluorescence microscopy. We demonstrated that the constitutive activation of p-PKC seems to be one of the main metabolic implicated on GBM malignancy. Despite of its higher resistance, possibly due to the overexpression of P-glycoprotein and stem-like cell markers, GBM11 cells presented a subtle different chemotherapeutic response compared to U87 and U118 cells. The GBM11, U87, U118 cell lines show subtle molecular differences, which clearly indicate the characterization of GBM heterogeneity, one of the main reasons for tumor resistance. The adding of cellular heterogeneity in molecular behaviour constitutes a step closer in the understanding of resistant molecular mechanisms in GBM, and can circumvents the eventual impaired therapy.
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Rizzino A, Wuebben EL. Sox2/Oct4: A delicately balanced partnership in pluripotent stem cells and embryogenesis. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2016; 1859:780-91. [PMID: 26992828 DOI: 10.1016/j.bbagrm.2016.03.006] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Revised: 03/10/2016] [Accepted: 03/11/2016] [Indexed: 11/25/2022]
Abstract
Considerable progress has been made in understanding the roles of Sox2 and Oct4 in embryonic stem cells and mammalian embryogenesis. Specifically, significant progress has been made in answering three questions about the functions of Sox2 and Oct4, which are the focus of this review. 1) Are the first or second cell lineage decisions during embryogenesis controlled by Oct4 and/or Sox2? 2) Do the levels of Oct4 and Sox2 need to be maintained within narrow limits to promote normal development and to sustain the self-renewal of pluripotent stem cells? 3) Do Oct4 and Sox2 work closely together or is the primary role of Sox2 in pluripotent cells to ensure the expression of Oct4? Although significant progress has been made in answering these questions, additional studies are needed to resolve several important remaining issues. Nonetheless, the preponderance of the evidence suggests there is considerable crosstalk between Sox2 and Oct4, and further suggests Sox2 and Oct4 function as molecular rheostats and utilize negative feedback loops to carefully balance their expression and other critical genes during embryogenesis. This article is part of a Special Issue entitled: The Oct transcription factor family, edited by Dr. Dean Tantin.
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Affiliation(s)
- Angie Rizzino
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, United States.
| | - Erin L Wuebben
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, United States
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Miconi G, Palumbo P, Dehcordi SR, La Torre C, Lombardi F, Evtoski Z, Cimini AM, Galzio R, Cifone MG, Cinque B. Immunophenotypic characterization of human glioblastoma stem cells: correlation with clinical outcome. J Cell Biochem 2015; 116:864-76. [PMID: 25559650 DOI: 10.1002/jcb.25043] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Accepted: 12/16/2014] [Indexed: 11/11/2022]
Abstract
Recently, glioma stem cells have been identified as the main cause of glioma propagation and recurrence and a number of several cell markers have been indicated as putative GSC markers. In the present work, a retrospective study to evaluate the prognostic potential of ability to generate GSCs in our series of 15 glioblastoma patients is described. β-tubulin III, nestin, CD133, GFAP, and SOX-2 marker expression, both in primary GBM cultures and in respective glioblastoma stem cells (GSCs), was evaluated by flow cytometric analysis. Our results demonstrated various expression levels of these markers in both cell cultures; of note, only those cells expressing SOX-2 at greater than 30% levels were able to produce in vitro neurospheres. Moreover, statistical analysis revealed that the GSCs generation negatively affected overall survival (OS) (P = 0.000) and progression-free survival (PFS) (P = 0.001). In addition, a very poor OS (P = 0.000) and PFS (P = 0.000) were observed among patients whose tumors expressed Ki67, evaluated by immunohistochemistry, and showed the ability to generate in vitro GSCs. Overall, the results suggest that in vitro GSCs generation associated to the expression of Ki67 and SOX-2 may be useful to identify patients at risk of disease progression.
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Affiliation(s)
- Gianfranca Miconi
- Department of Life, Health and Environmental Sciences, University of L'Aquila-Building Delta 6, Coppito, L'Aquila, 67100, Italy
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Abstract
In recent times, dozens of articles have been rushing to report the excellent performance of curcumin in inhibiting the proliferation of glioma cells and in inducing apoptosis and autophagy. However, in this study, we found that curcumin could not only effectively inhibit the proliferation of glioma cells but also induce glioma cells to be stem-like, which showed that it caused some glioma cells to form spheres with CD133 and Nestin positive markers. Further research on its underlying mechanism showed that curcumin suppressed transition of the cells from G1 to S phase and enhanced the expression of Sox4, Sox2, and Oct4, which were essential to retain the stemness properties of glioma-initiating cells. In conclusion, we believe these findings can complement our knowledge on curcumin and arouse our attention to use curcumin for further research on glioma treatment.
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30
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Singh SK, Chen NM, Hessmann E, Siveke J, Lahmann M, Singh G, Voelker N, Vogt S, Esposito I, Schmidt A, Brendel C, Stiewe T, Gaedcke J, Mernberger M, Crawford HC, Bamlet WR, Zhang JS, Li XK, Smyrk TC, Billadeau DD, Hebrok M, Neesse A, Koenig A, Ellenrieder V. Antithetical NFATc1-Sox2 and p53-miR200 signaling networks govern pancreatic cancer cell plasticity. EMBO J 2015; 34:517-30. [PMID: 25586376 DOI: 10.15252/embj.201489574] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
In adaptation to oncogenic signals, pancreatic ductal adenocarcinoma (PDAC) cells undergo epithelial-mesenchymal transition (EMT), a process combining tumor cell dedifferentiation with acquisition of stemness features. However, the mechanisms linking oncogene-induced signaling pathways with EMT and stemness remain largely elusive. Here, we uncover the inflammation-induced transcription factor NFATc1 as a central regulator of pancreatic cancer cell plasticity. In particular, we show that NFATc1 drives EMT reprogramming and maintains pancreatic cancer cells in a stem cell-like state through Sox2-dependent transcription of EMT and stemness factors. Intriguingly, NFATc1-Sox2 complex-mediated PDAC dedifferentiation and progression is opposed by antithetical p53-miR200c signaling, and inactivation of the tumor suppressor pathway is essential for tumor dedifferentiation and dissemination both in genetically engineered mouse models (GEMM) and human PDAC. Based on these findings, we propose the existence of a hierarchical signaling network regulating PDAC cell plasticity and suggest that the molecular decision between epithelial cell preservation and conversion into a dedifferentiated cancer stem cell-like phenotype depends on opposing levels of p53 and NFATc1 signaling activities.
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Affiliation(s)
- Shiv K Singh
- Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University, Marburg, Germany
| | - Nai-Ming Chen
- Department of Gastroenterology II, University Medical Center Goettingen, Goettingen, Germany
| | - Elisabeth Hessmann
- Department of Gastroenterology II, University Medical Center Goettingen, Goettingen, Germany
| | - Jens Siveke
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität, Munich, Germany
| | - Marlen Lahmann
- Institute for Molecular Tumor Biology, Philipps University, Marburg, Germany
| | - Garima Singh
- Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University, Marburg, Germany
| | - Nadine Voelker
- Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University, Marburg, Germany
| | - Sophia Vogt
- Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University, Marburg, Germany
| | - Irene Esposito
- Institute of Pathology, Helmholtz Zentrum, Munich, Germany
| | - Ansgar Schmidt
- Institute of Pathology, Philipps University, Marburg, Germany
| | - Cornelia Brendel
- Department of Hematology and Oncology, Philipps University, Marburg, Germany
| | - Thorsten Stiewe
- Institute for Molecular Tumor Biology, Philipps University, Marburg, Germany
| | - Jochen Gaedcke
- Department of Surgery, University Medical Center Goettingen, Goettingen, Germany
| | - Marco Mernberger
- Institute for Molecular Tumor Biology, Philipps University, Marburg, Germany
| | - Howard C Crawford
- Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, FL, USA
| | - William R Bamlet
- Division of Biostatistics, College of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Jin-San Zhang
- Division of Oncology Research, Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, USA School of Pharmaceutical Sciences and Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiao-Kun Li
- School of Pharmaceutical Sciences and Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Thomas C Smyrk
- Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA
| | - Daniel D Billadeau
- Division of Oncology Research, Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, USA
| | | | - Albrecht Neesse
- Department of Gastroenterology II, University Medical Center Goettingen, Goettingen, Germany
| | - Alexander Koenig
- Department of Gastroenterology II, University Medical Center Goettingen, Goettingen, Germany Division of Oncology Research, Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, USA
| | - Volker Ellenrieder
- Department of Gastroenterology II, University Medical Center Goettingen, Goettingen, Germany
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Swartling FJ, Čančer M, Frantz A, Weishaupt H, Persson AI. Deregulated proliferation and differentiation in brain tumors. Cell Tissue Res 2015; 359:225-54. [PMID: 25416506 PMCID: PMC4286433 DOI: 10.1007/s00441-014-2046-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2014] [Accepted: 10/22/2014] [Indexed: 01/24/2023]
Abstract
Neurogenesis, the generation of new neurons, is deregulated in neural stem cell (NSC)- and progenitor-derived murine models of malignant medulloblastoma and glioma, the most common brain tumors of children and adults, respectively. Molecular characterization of human malignant brain tumors, and in particular brain tumor stem cells (BTSCs), has identified neurodevelopmental transcription factors, microRNAs, and epigenetic factors known to inhibit neuronal and glial differentiation. We are starting to understand how these factors are regulated by the major oncogenic drivers in malignant brain tumors. In this review, we will focus on the molecular switches that block normal neuronal differentiation and induce brain tumor formation. Genetic or pharmacological manipulation of these switches in BTSCs has been shown to restore the ability of tumor cells to differentiate. We will discuss potential brain tumor therapies that will promote differentiation in order to reduce treatment resistance, suppress tumor growth, and prevent recurrence in patients.
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Affiliation(s)
- Fredrik J Swartling
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, SE-751 85, Sweden
| | - Matko Čančer
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, SE-751 85, Sweden
| | - Aaron Frantz
- Departments of Neurology and Neurological Surgery, Sandler Neurosciences Center, University of California, San Francisco, CA, 94158, USA
- Brain Tumor Research Center, University of California, San Francisco, CA, 94158, USA
| | - Holger Weishaupt
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, SE-751 85, Sweden
| | - Anders I Persson
- Departments of Neurology and Neurological Surgery, Sandler Neurosciences Center, University of California, San Francisco, CA, 94158, USA
- Brain Tumor Research Center, University of California, San Francisco, CA, 94158, USA
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32
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Sox2 Acts in a Dose-Dependent Fashion to Regulate Proliferation of Cortical Progenitors. Cell Rep 2014; 9:1908-1920. [DOI: 10.1016/j.celrep.2014.11.013] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Revised: 09/25/2014] [Accepted: 11/08/2014] [Indexed: 12/17/2022] Open
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Stoltz K, Sinyuk M, Hale JS, Wu Q, Otvos B, Walker K, Vasanji A, Rich JN, Hjelmeland AB, Lathia JD. Development of a Sox2 reporter system modeling cellular heterogeneity in glioma. Neuro Oncol 2014; 17:361-71. [PMID: 25416826 DOI: 10.1093/neuonc/nou320] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Accepted: 10/26/2014] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Malignant gliomas are complex systems containing a number of factors that drive tumor initiation and progression, including genetic aberrations that lead to extensive cellular heterogeneity within the neoplastic compartment. Mouse models recapitulate these genetic aberrations, but readily observable heterogeneity remains challenging. METHODS To interrogate cellular heterogeneity in mouse glioma models, we utilized a replication-competent avian sarcoma-leukosis virus long terminal repeat with splice acceptor/tumor virus A (RCAS-tva) system to generate spontaneous mouse gliomas that contained a Sox2-enhanced green fluorescent protein (EGFP) reporter. Glial fibrillary acidic protein-tva mice were crossed with Sox2-EGFP mice, and tumors were initiated that contained a subpopulation of Sox2-EGFP-high cells enriched for tumor-initiating cell properties such as self-renewal, multilineage differentiation potential, and perivascular localization. RESULTS Following implantation into recipient mice, Sox2-EGFP-high cells generated tumors containing Sox2-EGFP-high and Sox2-EGFP-low cells. Kinomic analysis of Sox2-EGFP-high cells revealed activation of known glioma signaling pathways that are strongly correlated with patient survival including platelet-derived growth factor receptor beta, phosphoinositide-3 kinase, and vascular endothelial growth factor. Our functional analysis identified active feline sarcoma (Fes) signaling in Sox2-EGFP-high cells. Fes negatively correlated with glioma patient survival and was coexpressed with Sox2-positive cells in glioma xenografts and primary patient-derived tissue. CONCLUSIONS Our RCAS-tva/Sox2-EGFP model will empower closer examination of cellular heterogeneity and will be useful for identifying novel glioma pathways as well as testing preclinical treatment efficacy.
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Affiliation(s)
- Kevin Stoltz
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio (K.S., M.S., J.S.H., B.O., J.D.L.); Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio (Q.W., J.N.R.); Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, Ohio (M.S., J.D.L.); Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama (K.W., A.B.H.); Image I.Q., Cleveland, Ohio (A.V.); Case Comprehensive Cancer Center, Cleveland, Ohio (J.N.R., J.D.L.)
| | - Maksim Sinyuk
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio (K.S., M.S., J.S.H., B.O., J.D.L.); Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio (Q.W., J.N.R.); Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, Ohio (M.S., J.D.L.); Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama (K.W., A.B.H.); Image I.Q., Cleveland, Ohio (A.V.); Case Comprehensive Cancer Center, Cleveland, Ohio (J.N.R., J.D.L.)
| | - James S Hale
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio (K.S., M.S., J.S.H., B.O., J.D.L.); Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio (Q.W., J.N.R.); Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, Ohio (M.S., J.D.L.); Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama (K.W., A.B.H.); Image I.Q., Cleveland, Ohio (A.V.); Case Comprehensive Cancer Center, Cleveland, Ohio (J.N.R., J.D.L.)
| | - Qiulian Wu
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio (K.S., M.S., J.S.H., B.O., J.D.L.); Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio (Q.W., J.N.R.); Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, Ohio (M.S., J.D.L.); Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama (K.W., A.B.H.); Image I.Q., Cleveland, Ohio (A.V.); Case Comprehensive Cancer Center, Cleveland, Ohio (J.N.R., J.D.L.)
| | - Balint Otvos
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio (K.S., M.S., J.S.H., B.O., J.D.L.); Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio (Q.W., J.N.R.); Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, Ohio (M.S., J.D.L.); Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama (K.W., A.B.H.); Image I.Q., Cleveland, Ohio (A.V.); Case Comprehensive Cancer Center, Cleveland, Ohio (J.N.R., J.D.L.)
| | - Kiera Walker
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio (K.S., M.S., J.S.H., B.O., J.D.L.); Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio (Q.W., J.N.R.); Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, Ohio (M.S., J.D.L.); Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama (K.W., A.B.H.); Image I.Q., Cleveland, Ohio (A.V.); Case Comprehensive Cancer Center, Cleveland, Ohio (J.N.R., J.D.L.)
| | - Amit Vasanji
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio (K.S., M.S., J.S.H., B.O., J.D.L.); Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio (Q.W., J.N.R.); Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, Ohio (M.S., J.D.L.); Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama (K.W., A.B.H.); Image I.Q., Cleveland, Ohio (A.V.); Case Comprehensive Cancer Center, Cleveland, Ohio (J.N.R., J.D.L.)
| | - Jeremy N Rich
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio (K.S., M.S., J.S.H., B.O., J.D.L.); Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio (Q.W., J.N.R.); Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, Ohio (M.S., J.D.L.); Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama (K.W., A.B.H.); Image I.Q., Cleveland, Ohio (A.V.); Case Comprehensive Cancer Center, Cleveland, Ohio (J.N.R., J.D.L.)
| | - Anita B Hjelmeland
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio (K.S., M.S., J.S.H., B.O., J.D.L.); Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio (Q.W., J.N.R.); Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, Ohio (M.S., J.D.L.); Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama (K.W., A.B.H.); Image I.Q., Cleveland, Ohio (A.V.); Case Comprehensive Cancer Center, Cleveland, Ohio (J.N.R., J.D.L.)
| | - Justin D Lathia
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio (K.S., M.S., J.S.H., B.O., J.D.L.); Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio (Q.W., J.N.R.); Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, Ohio (M.S., J.D.L.); Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama (K.W., A.B.H.); Image I.Q., Cleveland, Ohio (A.V.); Case Comprehensive Cancer Center, Cleveland, Ohio (J.N.R., J.D.L.)
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Lönnroth C, Andersson M, Asting AG, Nordgren S, Lundholm K. Preoperative low dose NSAID treatment influences the genes for stemness, growth, invasion and metastasis in colorectal cancer. Int J Oncol 2014; 45:2208-20. [PMID: 25340937 PMCID: PMC4215588 DOI: 10.3892/ijo.2014.2686] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Accepted: 08/21/2014] [Indexed: 02/06/2023] Open
Abstract
Preclinical data, and an increasing list of clinical investigations, show anti-inflammatory agents to favourably influence the biology of colorectal tumor. We have earlier reported on re-expression of activated immune cells after three days preoperative treatment of patients with colorectal carcinoma, randomized to receive oral NSAID (indomethacin or celebrex). Antisecretory prophylaxis (esomeprasol) was provided to all patients and served as sham treatment. Concomittant to MHC locus activation, Prominin1/CD133, a marker associated with stemness and poor prognosis in several solid tumors, was downregulated. The aim of the present study was to evaluate expression of additional regulators belonging to the stem cell niche, OCT4, SOX2 and BMP7, as well as some microRNAs, reported to act as tumor suppressors or oncomiRs. Peroperative tumor biopsies were analyzed by microarrays, quantitative real-time PCR and immunohistochemistry (IHC). The stem cell master regulator SOX2 was increased by NSAIDs (p<0.01), as well as the tumor suppressor miR-630 (p<0.01), while BMP7, a marker for poor prognosis in CRC, was downregulated by NSAID (indomethacin, p<0.02). The upregulation of SOX2, but not of its heterodimer binding partner OCT4, could imply a negative feed-back loop, with a switch‑off for stemness preservation of tumor cells. This is supported by the overall evaluation of gene expression profiles with subsequent events, indicating less aggressive tumors following NSAID treatment.
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Affiliation(s)
- Christina Lönnroth
- Department of Surgery, Surgical Metabolic Research Laboratory at Lundberg Laboratory for Cancer Research, Sahlgrenska University Hospital, University of Gothenburg, SE 413 45 Gothenburg, Sweden
| | - Marianne Andersson
- Department of Surgery, Surgical Metabolic Research Laboratory at Lundberg Laboratory for Cancer Research, Sahlgrenska University Hospital, University of Gothenburg, SE 413 45 Gothenburg, Sweden
| | - Annika G Asting
- Department of Surgery, Surgical Metabolic Research Laboratory at Lundberg Laboratory for Cancer Research, Sahlgrenska University Hospital, University of Gothenburg, SE 413 45 Gothenburg, Sweden
| | - Svante Nordgren
- Department of Surgery, Surgical Metabolic Research Laboratory at Lundberg Laboratory for Cancer Research, Sahlgrenska University Hospital, University of Gothenburg, SE 413 45 Gothenburg, Sweden
| | - Kent Lundholm
- Department of Surgery, Surgical Metabolic Research Laboratory at Lundberg Laboratory for Cancer Research, Sahlgrenska University Hospital, University of Gothenburg, SE 413 45 Gothenburg, Sweden
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35
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Shih J, Rahman M, Luong QT, Lomeli SH, Riss J, Prins RM, Gure AO, Zeng G. Dominant B-cell epitopes from cancer/stem cell antigen SOX2 recognized by serum samples from cancer patients. AMERICAN JOURNAL OF CLINICAL AND EXPERIMENTAL IMMUNOLOGY 2014; 3:84-90. [PMID: 25143868 PMCID: PMC4138131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Accepted: 07/10/2014] [Indexed: 06/03/2023]
Abstract
Human sex determining region Y-box 2 (SOX2) is an important transcriptional factor involved in the pluripotency and stemness of human embryonic stem cells. SOX2 plays important roles in maintaining cancer stem cell activities of melanoma and cancers of the brain, prostate, breast, and lung. SOX2 is also a lineage survival oncogene for squamous cell carcinoma of the lung and esophagus. Spontaneous cellular and humoral immune responses against SOX2 present in cancer patients classify it as a tumor-associated antigen (TAA) shared by lung cancer, glioblastoma, and prostate cancer among others. In this study, B-cell epitopes were predicted using computer-assisted algorithms. Synthetic peptides based on the prediction were screened for recognition by serum samples from cancer patients using ELISA. Two dominant B-cell epitopes, SOX2:52-87 and SOX2:98-124 were identified. Prostate cancer, glioblastoma and lung cancer serum samples that recognized the above SOX2 epitopes also recognized the full-length protein based on Western blot. These B-cell epitopes may be used in assessing humoral immune responses against SOX2 in cancer immunotherapy and stem cell-related transplantation.
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Affiliation(s)
- Julia Shih
- Department of Urology, David Geffen School of Medicine at UCLALos Angeles, CA 90095, USA
| | - Munira Rahman
- Western University of Health SciencesPomona, CA 91766, USA
| | - Quang T Luong
- Department of Medicine, David Geffen School of Medicine at UCLALos Angeles, CA 90095, USA
| | - Shirley H Lomeli
- Department of Urology, David Geffen School of Medicine at UCLALos Angeles, CA 90095, USA
| | - Joseph Riss
- Department of Urology, David Geffen School of Medicine at UCLALos Angeles, CA 90095, USA
| | - Robert M Prins
- Department of Neurosurgery, David Geffen School of Medicine at UCLALos Angeles, CA 90095, USA
| | - Ali O Gure
- Department of Molecular Biology and Genetics, Bilkent UniversityAnkara 06800, Turkey
| | - Gang Zeng
- Department of Urology, David Geffen School of Medicine at UCLALos Angeles, CA 90095, USA
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Askarian-Amiri ME, Seyfoddin V, Smart CE, Wang J, Kim JE, Hansji H, Baguley BC, Finlay GJ, Leung EY. Emerging role of long non-coding RNA SOX2OT in SOX2 regulation in breast cancer. PLoS One 2014; 9:e102140. [PMID: 25006803 PMCID: PMC4090206 DOI: 10.1371/journal.pone.0102140] [Citation(s) in RCA: 100] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Accepted: 06/13/2014] [Indexed: 02/02/2023] Open
Abstract
The transcription factor SOX2 is essential for maintaining pluripotency in a variety of stem cells. It has important functions during embryonic development, is involved in cancer stem cell maintenance, and is often deregulated in cancer. The mechanism of SOX2 regulation has yet to be clarified, but the SOX2 gene lies in an intron of a long multi-exon non-coding RNA called SOX2 overlapping transcript (SOX2OT). Here, we show that the expression of SOX2 and SOX2OT is concordant in breast cancer, differentially expressed in estrogen receptor positive and negative breast cancer samples and that both are up-regulated in suspension culture conditions that favor growth of stem cell phenotypes. Importantly, ectopic expression of SOX2OT led to an almost 20-fold increase in SOX2 expression, together with a reduced proliferation and increased breast cancer cell anchorage-independent growth. We propose that SOX2OT plays a key role in the induction and/or maintenance of SOX2 expression in breast cancer.
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Affiliation(s)
| | - Vahid Seyfoddin
- Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand
| | - Chanel E. Smart
- University of Queensland Centre for Clinical Research, Royal Brisbane & Women's Hospital Campus, Herston, Queensland, Australia
| | - Jingli Wang
- Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand
| | - Ji Eun Kim
- Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand
| | - Herah Hansji
- Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand
| | - Bruce C. Baguley
- Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand
| | - Graeme J. Finlay
- Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand
- * E-mail: (GJF); (EYL)
| | - Euphemia Y. Leung
- Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand
- * E-mail: (GJF); (EYL)
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Jensen SS, Aaberg-Jessen C, Andersen C, Schrøder HD, Kristensen BW. Glioma spheroids obtained via ultrasonic aspiration are viable and express stem cell markers: a new tissue resource for glioma research. Neurosurgery 2014; 73:868-86; discussion 886. [PMID: 23887192 DOI: 10.1227/neu.0000000000000118] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Ultrasonic aspirators allow safe, rapid, and accurate removal of brain tumors. However, the tissue fragments removed are used surprisingly little in research. OBJECTIVE To investigate whether such tissue fragments could be cultured as organotypic multicellular spheroids because access to biopsy tissue is often limited. METHODS Tissue fragments obtained by ultrasonic aspiration from 10 glioblastomas and tumor biopsy tissue from 7 of these tumors were cultured in serum-containing and serum-free medium. On culturing, the fragments formed spheroids, which were prepared for histology. Two glioblastoma cell lines from ultrasonic fragments and biopsy tissue were established as well. RESULTS Hematoxylin and eosin staining showed viable glioma spheroids obtained from both ultrasonic and biopsy tissue in both types of medium. Endothelial growth factor receptor and PTEN/chromosome 10 status was found to be preserved in most spheroids (7-8 of 10 tumors), together with the level of glial fibrillary acidic protein, von Willebrand factor, and Ki-67. The levels of stem cell markers CD133, Bmi-1, nestin, and Sox2 also were preserved. The ultrasonic spheroids had higher levels of glial fibrillary acidic protein and von Willebrand factor and lower levels of Bmi-1, nestin, Sox2, and Olig2 compared with conventional biopsy spheroids. For both types of spheroids, the stem cell medium seemed to favor expression of stem cell markers. The established cell lines were capable of both spheroid formation at clonal density and tumor formation in vivo. CONCLUSION Viable organotypic and proliferating spheroids were easily obtained from ultrasonic tissue fragments. The preservation of markers and the establishment of cell lines with tumor-initiating cell properties suggest ultrasonic spheroids as a new tissue resource for glioma research.
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Affiliation(s)
- Stine Skov Jensen
- *Department of Pathology and ‡Department of Neurosurgery, Odense University Hospital, and Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
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Thu KL, Becker-Santos DD, Radulovich N, Pikor LA, Lam WL, Tsao MS. SOX15 and other SOX family members are important mediators of tumorigenesis in multiple cancer types. Oncoscience 2014; 1:326-35. [PMID: 25594027 PMCID: PMC4278306 DOI: 10.18632/oncoscience.46] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Accepted: 05/31/2014] [Indexed: 12/12/2022] Open
Abstract
SOX genes are transcription factors with important roles in embryonic development and carcinogenesis. The SOX family of 20 genes is responsible for regulating lineage and tissue specific gene expression patterns, controlling numerous developmental processes including cell differentiation, sex determination, and organogenesis. As is the case with many genes involved in regulating development, SOX genes are frequently deregulated in cancer. In this perspective we provide a brief overview of how SOX proteins can promote or suppress cancer growth. We also present a pan-cancer analysis of aberrant SOX gene expression and highlight potential molecular mechanisms responsible for their disruption in cancer. Our analyses indicate the prominence of SOX deregulation in different cancer types and reveal potential roles for SOX genes not previously described in cancer. Finally, we summarize our recent identification of SOX15 as a candidate tumor suppressor in pancreatic cancer and propose several research avenues to pursue to further delineate the emerging role of SOX15 in development and carcinogenesis.
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Affiliation(s)
- Kelsie L Thu
- BC Cancer Research Centre, Vancouver, B.C., Canada
| | | | | | | | - Wan L Lam
- BC Cancer Research Centre, Vancouver, B.C., Canada
| | - Ming-Sound Tsao
- Ontario Cancer Institute, Princess Margaret Hospital, University Health Network at the University of Toronto
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Cox JL, Wilder PJ, Wuebben EL, Ouellette MM, Hollingsworth MA, Rizzino A. Context-dependent function of the deubiquitinating enzyme USP9X in pancreatic ductal adenocarcinoma. Cancer Biol Ther 2014; 15:1042-52. [PMID: 24841553 DOI: 10.4161/cbt.29182] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadly malignancies. Recently, the deubiquitinating protease USP9X has been shown to behave as an oncogene in a number of neoplasms, including those of breast, brain, colon, esophagus and lung, as well as KRAS wild-type PDAC. However, other studies suggest that USP9X may function as a tumor-suppressor in a murine PDAC model when USP9X expression is depleted during early pancreatic development. To address the conflicting findings surrounding the role of USP9X in PDAC, we examined the effects of knocking down USP9X in five human PDAC cell lines (BxPC3, Capan1, CD18, Hs766T, and S2-013). We demonstrate that knocking down USP9X in each of the PDAC cell lines reduces their anchorage-dependent growth. Using an inducible shRNA system to knock down USP9X in both BxPC3 and Capan1 cells, we also determined that USP9X is necessary for the anchorage-independent growth. In addition, knockdown of USP9X alters the cell cycle profile of BxPC3 cells and increases their invasive capacity. Finally, we show that an inhibitor of deubiquitinating proteases, WP1130, induces significant cytotoxicity in each of the five PDAC cell lines tested. Overall, our work and the work of others indicate that the function and role of USP9X is highly context-dependent. Although USP9X may function as a tumor-suppressor during the establishment of PDAC, data presented here argue that USP9X promotes cell growth in advanced PDAC cells when PDAC is typically diagnosed. Hence, USP9X may be a promising therapeutic target for the treatment of advanced PDAC.
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Affiliation(s)
- Jesse L Cox
- Eppley Institute for Research in Cancer and Allied Diseases; Fred & Pamela Buffett Cancer Center; University of Nebraska Medical Center; Omaha, NE USA
| | - Phillip J Wilder
- Eppley Institute for Research in Cancer and Allied Diseases; Fred & Pamela Buffett Cancer Center; University of Nebraska Medical Center; Omaha, NE USA
| | - Erin L Wuebben
- Eppley Institute for Research in Cancer and Allied Diseases; Fred & Pamela Buffett Cancer Center; University of Nebraska Medical Center; Omaha, NE USA
| | - Michel M Ouellette
- Eppley Institute for Research in Cancer and Allied Diseases; Fred & Pamela Buffett Cancer Center; University of Nebraska Medical Center; Omaha, NE USA
| | - Michael A Hollingsworth
- Eppley Institute for Research in Cancer and Allied Diseases; Fred & Pamela Buffett Cancer Center; University of Nebraska Medical Center; Omaha, NE USA
| | - Angie Rizzino
- Eppley Institute for Research in Cancer and Allied Diseases; Fred & Pamela Buffett Cancer Center; University of Nebraska Medical Center; Omaha, NE USA
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40
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Dai W, Tan X, Sun C, Zhou Q. High expression of SOX2 is associated with poor prognosis in patients with salivary gland adenoid cystic carcinoma. Int J Mol Sci 2014; 15:8393-406. [PMID: 24828201 PMCID: PMC4057738 DOI: 10.3390/ijms15058393] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2014] [Revised: 02/24/2014] [Accepted: 03/11/2014] [Indexed: 02/07/2023] Open
Abstract
Sex determining region Y-BOX2 (SOX2), one of the key members of the SOX family, is a transcription factor that is involved in the maintenance of embryonic stem cell pluripotency and in multiple developmental processes. Recent studies have shown that SOX2 is aberrantly expressed in several types of tumors. The present study aimed to investigate the clinicopathological and prognostic significance of SOX2 in adenoid cystic carcinoma (ACC) of salivary gland. In this study, the expression of SOX2 in ACC tissues and matched adjacent non-cancerous tissues was measured by immunohistochemistry, western blot, and quantitative polymerase chain reaction. High SOX2 expression occurred in approximately 62.6% of primary ACC. In addition, high expression of SOX2 was significantly associated with T classification (p=0.003) and distant metastasis (p=0.002). The 5-year overall survival (OS) and disease-free survival (DFS) in patients with high SOX2 expression is poorer than those with low SOX2 expression. When adjusted by multivariate analysis, high SOX2 expression, together with distant metastasis, was an independent prognostic factor. The findings of the present study provide evidence that SOX2 represents a potential novel prognostic biomarker for ACC patients.
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Affiliation(s)
- Wei Dai
- Department of Oromaxillofacial-Head and Neck Surgery & Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University, Shenyang 110002, China.
| | - Xuexin Tan
- Department of Oromaxillofacial-Head and Neck Surgery & Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University, Shenyang 110002, China.
| | - Changfu Sun
- Department of Oromaxillofacial-Head and Neck Surgery & Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University, Shenyang 110002, China.
| | - Qing Zhou
- Department of Oromaxillofacial-Head and Neck Surgery & Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University, Shenyang 110002, China.
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41
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Herreros-Villanueva M, Bujanda L, Billadeau DD, Zhang JS. Embryonic stem cell factors and pancreatic cancer. World J Gastroenterol 2014; 20:2247-2254. [PMID: 24605024 PMCID: PMC3942830 DOI: 10.3748/wjg.v20.i9.2247] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 12/15/2013] [Accepted: 01/14/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic tumor, is a highly aggressive human cancer with the lowest five-year survival rate of any human maligancy primarily due to its early- metastasis and lack of response to chemotherapy and radiation. Recent research suggests that PDAC cells comprise a hierarchy of tumor cells that develop around a population of cancer stem cells (CSCs), a small and distinct population of cancer cells that mediates tumoregenesis, metastasis and resistance to standard treatments. Thus, CSCs could be a target for more effective treatment options. Interestingly, pancreatic CSCs are subject to regulation by some of key embryonic stem cell (ESC) transctiption factors abberently expressed in PDAC, such as SOX2, OCT4 and NANOG. ESC transcription factors are important DNA-binding proteins present in both embryonic and adult somatic cells. The critical role of these factors in reprogramming processes makes them essential not only for embryonic development but also tumorigenesis. Here we provide an overview of stem cell transcription factors, particularly SOX2, OCT4, and NANOG, on their expression and function in pancreatic cancer. In contrast to embryonic stem cells, in which OCT4 and SOX2 are tightly regulated and physically interact to regulate a wide spectrum of target genes, de novo SOX2 expression alone in pancreatic cancer cells is sufficient to promote self-renewal, de-differentiation and imparting stemness characteristics via impacting specific cell cycle regulatory genes and epithelial-mesnechymal transtion driver genes. Thus, targeting ESC factors, particularly SOX2, could be a worthy strategy for pancreatic cancer therapy.
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42
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Cruceru ML, Enciu AM, Popa AC, Albulescu R, Neagu M, Tanase CP, Constantinescu SN. Signal transduction molecule patterns indicating potential glioblastoma therapy approaches. Onco Targets Ther 2013; 6:1737-1749. [PMID: 24348050 PMCID: PMC3848931 DOI: 10.2147/ott.s52365] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
PURPOSE The expression of an array of signaling molecules, along with the assessment of real-time cell proliferation, has been performed in U87 glioma cell line and in patients' glioblastoma established cell cultures in order to provide a better understanding of cellular and molecular events involved in glioblastoma pathogenesis. Experimental therapy was performed using a phosphatidylinositol-3'-kinase (PI3K) inhibitor. PATIENTS AND METHODS xMAP technology was employed to assess expression levels of several signal transduction molecules and real-time xCELLigence platform for cell behavior. RESULTS PI3K inhibition induced the most significant effects on global signaling pathways in patient-derived cell cultures, especially on members of the mitogen-activated protein-kinase family, P70S6 serine-threonine kinase, and cAMP response element-binding protein expression and further prevented tumor cell proliferation. CONCLUSION The PI3K pathway might be a prime target for glioblastoma treatment.
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Affiliation(s)
- Maria Linda Cruceru
- Carol Davila University of Medicine and Pharmacy, Department of Cellular and Molecular Medicine, Bucharest, Romania
| | - Ana-Maria Enciu
- Carol Davila University of Medicine and Pharmacy, Department of Cellular and Molecular Medicine, Bucharest, Romania
- Victor Babes National Institute of Pathology, Bucharest, Romania
- Operational Sectorial Programme for Competitive Economic Growth Canbioprot at Victor Babes National Institute of Pathology, Bucharest, Romania
| | - Adrian Claudiu Popa
- Carol Davila University of Medicine and Pharmacy, Department of Cellular and Molecular Medicine, Bucharest, Romania
- Army Centre for Medical Research, Bucharest, Romania
| | - Radu Albulescu
- Victor Babes National Institute of Pathology, Bucharest, Romania
- National Institute for Chemical Pharmaceutical R&D, Bucharest, Romania
- Operational Sectorial Programme for Competitive Economic Growth Canbioprot at Victor Babes National Institute of Pathology, Bucharest, Romania
| | - Monica Neagu
- Victor Babes National Institute of Pathology, Bucharest, Romania
- Operational Sectorial Programme for Competitive Economic Growth Canbioprot at Victor Babes National Institute of Pathology, Bucharest, Romania
| | - Cristiana Pistol Tanase
- Victor Babes National Institute of Pathology, Bucharest, Romania
- Operational Sectorial Programme for Competitive Economic Growth Canbioprot at Victor Babes National Institute of Pathology, Bucharest, Romania
| | - Stefan N Constantinescu
- de Duve Institute, Université Catholique de Louvain, Brussels, Belgium
- Ludwig Institute for Cancer Research, Brussels, Belgium
- Operational Sectorial Programme for Competitive Economic Growth Canbioprot at Victor Babes National Institute of Pathology, Bucharest, Romania
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SOX2 plays a critical role in EGFR-mediated self-renewal of human prostate cancer stem-like cells. Cell Signal 2013; 25:2734-42. [PMID: 24036214 DOI: 10.1016/j.cellsig.2013.08.041] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2013] [Revised: 08/20/2013] [Accepted: 08/20/2013] [Indexed: 01/04/2023]
Abstract
SOX2 is an essential transcription factor for stem cells and plays a role in tumorigenesis, however its role in prostate cancer stem cells (PCSCs) remains unclear. We report here a significant upregulation of SOX2 at both mRNA and protein levels in DU145 PCSCs propagated as suspension spheres in vitro. The expression of SOX2 in DU145 PCSCs is positively regulated by epidermal growth factor receptor (EGFR) signaling. Activation of EGFR signaling, following the addition of epidermal growth factor (EGF) or ectopic expression of a constitutively-active EGFR mutant (EGFRvIII), increased SOX2 expression and the self-renewal of DU145 PCSCs. Conversely, a small molecule EGFR inhibitor (AG1478) blocked EGFR activation, reduced SOX2 expression and inhibited PCSC self-renewal activity, implicating SOX2 in mediating EGFR-dependent self-renewal of PCSCs. In line with this notion, ectopic SOX2 expression enhanced EGF-induced self-renewal of DU145 PCSCs, while SOX2 knockdown reduced PCSC self-renewal with EGF treatment no longer capable of enhancing their propagation. Furthermore, SOX2 knockdown reduced the capacity of DU145 PCSCs to grow under anchorage-independent conditions. Finally, DU145 PCSCs generated xenograft tumors more aggressively with elevated levels of SOX2 expression compared to xenograft tumors derived from non-PCSCs. Collectively, we provide evidence that SOX2 plays a critical role in EGFR-mediated self-renewal of DU145 PCSCs.
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Herreros-Villanueva M, Zhang JS, Koenig A, Abel EV, Smyrk TC, Bamlet WR, de Narvajas AAM, Gomez TS, Simeone DM, Bujanda L, Billadeau DD. SOX2 promotes dedifferentiation and imparts stem cell-like features to pancreatic cancer cells. Oncogenesis 2013; 2:e61. [PMID: 23917223 PMCID: PMC3759123 DOI: 10.1038/oncsis.2013.23] [Citation(s) in RCA: 257] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2013] [Accepted: 06/26/2013] [Indexed: 12/15/2022] Open
Abstract
SOX2 (Sex-determining region Y (SRY)-Box2) has important functions during embryonic development and is involved in cancer stem cell (CSC) maintenance, in which it impairs cell growth and tumorigenicity. However, the function of SOX2 in pancreatic cancer cells is unclear. The objective of this study was to analyze SOX2 expression in human pancreatic tumors and determine the role of SOX2 in pancreatic cancer cells regulating CSC properties. In this report, we show that SOX2 is not expressed in normal pancreatic acinar or ductal cells. However, ectopic expression of SOX2 is observed in 19.3% of human pancreatic tumors. SOX2 knockdown in pancreatic cancer cells results in cell growth inhibition via cell cycle arrest associated with p21(Cip1) and p27(Kip1) induction, whereas SOX2 overexpression promotes S-phase entry and cell proliferation associated with cyclin D3 induction. SOX2 expression is associated with increased levels of the pancreatic CSC markers ALDH1, ESA and CD44. Importantly, we show that SOX2 is enriched in the ESA(+)/CD44(+) CSC population from two different patient samples. Moreover, we show that SOX2 directly binds to the Snail, Slug and Twist promoters, leading to a loss of E-Cadherin and ZO-1 expression. Taken together, our findings show that SOX2 is aberrantly expressed in pancreatic cancer and contributes to cell proliferation and stemness/dedifferentiation through the regulation of a set of genes controlling G1/S transition and epithelial-to-mesenchymal transition (EMT) phenotype, suggesting that targeting SOX2-positive cancer cells could be a promising therapeutic strategy.
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Affiliation(s)
- M Herreros-Villanueva
- Division of Oncology Research, Schulze Center for Novel Therapeutics, College of Medicine, Mayo Clinic, Rochester, MN, USA
- Department of Gastroenterology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Donostia/Instituto Biodonostia, Universidad del País Vasco UPV/EHU, San Sebastián, Spain
| | - J-S Zhang
- Division of Oncology Research, Schulze Center for Novel Therapeutics, College of Medicine, Mayo Clinic, Rochester, MN, USA
| | - A Koenig
- Division of Oncology Research, Schulze Center for Novel Therapeutics, College of Medicine, Mayo Clinic, Rochester, MN, USA
- Department of Gastroenterology and Endocrinology, Philipps-University of Marburg, Marburg, Germany
| | - E V Abel
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - T C Smyrk
- Division of Anatomic Pathology, College of Medicine, Mayo Clinic, Rochester, MN, USA
| | - W R Bamlet
- Division of Biostatistics, College of Medicine, Mayo Clinic, Rochester, MN, USA
| | - A A-M de Narvajas
- Division of Oncology Research, Schulze Center for Novel Therapeutics, College of Medicine, Mayo Clinic, Rochester, MN, USA
| | - T S Gomez
- Division of Oncology Research, Schulze Center for Novel Therapeutics, College of Medicine, Mayo Clinic, Rochester, MN, USA
| | - D M Simeone
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - L Bujanda
- Department of Gastroenterology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Donostia/Instituto Biodonostia, Universidad del País Vasco UPV/EHU, San Sebastián, Spain
| | - D D Billadeau
- Division of Oncology Research, Schulze Center for Novel Therapeutics, College of Medicine, Mayo Clinic, Rochester, MN, USA
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Fujiwara D, Kato K, Nohara S, Iwanuma Y, Kajiyama Y. The usefulness of three-dimensional cell culture in induction of cancer stem cells from esophageal squamous cell carcinoma cell lines. Biochem Biophys Res Commun 2013; 434:773-8. [PMID: 23602898 DOI: 10.1016/j.bbrc.2013.04.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Accepted: 04/07/2013] [Indexed: 01/16/2023]
Abstract
In recent years, research on resistance to chemotherapy and radiotherapy in cancer treatment has come under the spotlight, and researchers have also begun investigating the relationship between resistance and cancer stem cells. Cancer stem cells are assumed to be present in esophageal cancer, but experimental methods for identification and culture of these cells have not yet been established. To solve this problem, we created spheroids using a NanoCulture® Plate (NCP) for 3-dimensional (3-D) cell culture, which was designed as a means for experimentally reproducing the 3-D structures found in the body. We investigated the potential for induction of cancer stem cells from esophageal cancer cells. Using flow cytometry we analyzed the expression of surface antigen markers CD44, CD133, CD338 (ABCG2), CD318 (CDCP1), and CD326 (EpCAM), which are known cancer stem cell markers. None of these surface antigen markers showed enhanced expression in 3-D cultured cells. We then analyzed aldehyde dehydrogenase (ALDH) enzymatic activity using the ALDEFLUOR reagent, which can identify immature cells such as stem cells and precursor cells. 3-D-cultured cells were strongly positive for ALDH enzyme activity. We also analyzed the expression of the stem cell-related genes Sox-2, Nanog, Oct3/4, and Lin28 using RT-PCR. Expression of Sox-2, Nanog, and Lin28 was enhanced. Analysis of expression of the hypoxic surface antigen marker carbonic anhydrase-9 (CA-9), which is an indicator of cancer stem cell induction and maintenance, revealed that CA-9 expression was enhanced, suggesting that hypoxia had been induced. Comparison of cancer drug resistance using cisplatin and doxorubicin in 3-D-cultured esophageal cancer cells showed that cancer drug resistance had increased. These results indicate that 3-D culture of esophageal squamous cell carcinoma lines is a useful method for inducing cancer stem cells.
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Affiliation(s)
- Daisuke Fujiwara
- Department of Esophageal & Gastroenterological Surgery, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Tokyo 113-8421, Japan
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Caglayan D, Lundin E, Kastemar M, Westermark B, Ferletta M. Sox21 inhibits glioma progression in vivo by forming complexes with Sox2 and stimulating aberrant differentiation. Int J Cancer 2013; 133:1345-56. [PMID: 23463365 DOI: 10.1002/ijc.28147] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Accepted: 02/20/2013] [Indexed: 11/09/2022]
Abstract
Sox2 is a transcription factor in neural stem cells and keeps the cells immature and proliferative. Sox2 is expressed in primary human glioma such as glioblastoma multiforme (GBM), primary glioma cells and glioma cell lines and is implicated in signaling pathways in glioma connected to malignancy. Sox21, the counteracting partner of Sox2, has the same expression pattern as Sox2 in glioma but in general induces opposite effects. In this study, Sox21 was overexpressed by using a tetracycline-regulated expression system (tet-on) in glioma cells. The glioma cells were injected subcutaneously into immunodeficient mice. The control tumors were highly proliferative, contained microvascular proliferation and large necrotic areas typical of human GBM. Induction of Sox21 in the tumor cells resulted in a significant smaller tumor size, and the effect correlated with the onset of treatment, where earlier treatment gave smaller tumors. Mice injected with glioma cells orthotopically into the brain survived significantly longer when Sox21 expression was induced. Tumors originating from glioma cells with an induced expression of Sox21 exhibited an increased formation of Sox2:Sox21 complexes and an upregulation of S100β, CNPase and Tuj1. Sox21 appears to decrease the stem-like cell properties of the tumor cells and initiate aberrant differentiation of glioma cells in vivo. Taken together our results indicate that Sox21 can function as a tumor suppressor during gliomagenesis mediated by a shift in the balance between Sox2 and Sox21. The wide distribution of Sox2 and Sox21 in GBM makes the Sox2/Sox21 axis a very interesting target for novel therapy of gliomas.
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Affiliation(s)
- Demet Caglayan
- Department of Immunology, Genetics and Pathology, Rudbeck laboratory, Uppsala University, Uppsala, Sweden
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Zhu Y, Li Y, Wei J, Liu X. The role of Sox genes in lung morphogenesis and cancer. Int J Mol Sci 2012; 13:15767-83. [PMID: 23443092 PMCID: PMC3546660 DOI: 10.3390/ijms131215767] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Revised: 10/26/2012] [Accepted: 11/14/2012] [Indexed: 12/17/2022] Open
Abstract
The human lung consists of multiple cell types derived from early embryonic compartments. The morphogenesis of the lung, as well as the injury repair of the adult lung, is tightly controlled by a network of signaling pathways with key transcriptional factors. Lung cancer is the third most cancer-related death in the world, which may be developed due to the failure of regulating the signaling pathways. Sox (sex-determining region Y (Sry) box-containing) family transcriptional factors have emerged as potent modulators in embryonic development, stem cells maintenance, tissue homeostasis, and cancerogenesis in multiple processes. Recent studies demonstrated that the members of the Sox gene family played important roles in the development and maintenance of lung and development of lung cancer. In this context, we summarize our current understanding of the role of Sox family transcriptional factors in the morphogenesis of lung, their oncogenic potential in lung cancer, and their potential impact in the diagnosis, prognosis, and targeted therapy of lung cancer.
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Affiliation(s)
- Yongzhao Zhu
- Key Laboratory of the Ministry of Education for Conservation and Utilization of Special Biological Resources in Western China, College of Life science, Ningxia University, Yinchuan 750021, China; E-Mails: (Y.Z.); (Y.L.)
- Institute of Stem Cell Research, General Hospital of Ningxia Medical University, Yinchuan 750004, China
| | - Yong Li
- Key Laboratory of the Ministry of Education for Conservation and Utilization of Special Biological Resources in Western China, College of Life science, Ningxia University, Yinchuan 750021, China; E-Mails: (Y.Z.); (Y.L.)
| | - Jun Wei
- Institute of Stem Cell Research, General Hospital of Ningxia Medical University, Yinchuan 750004, China
- Authors to whom correspondence should be addressed; E-Mails: (J.W.); or (X.L.); Tel.: +86-951-674-3751 (J.W.); +86-951-206-2037 (X.L); Fax: +86-951-206-2699 (X.L.)
| | - Xiaoming Liu
- Key Laboratory of the Ministry of Education for Conservation and Utilization of Special Biological Resources in Western China, College of Life science, Ningxia University, Yinchuan 750021, China; E-Mails: (Y.Z.); (Y.L.)
- Authors to whom correspondence should be addressed; E-Mails: (J.W.); or (X.L.); Tel.: +86-951-674-3751 (J.W.); +86-951-206-2037 (X.L); Fax: +86-951-206-2699 (X.L.)
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