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Saloni, Sachan M, Rahul, Verma RS, Patel GK. SOXs: Master architects of development and versatile emulators of oncogenesis. Biochim Biophys Acta Rev Cancer 2025; 1880:189295. [PMID: 40058508 DOI: 10.1016/j.bbcan.2025.189295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 02/26/2025] [Accepted: 03/03/2025] [Indexed: 03/22/2025]
Abstract
Transcription factors regulate a variety of events and maintain cellular homeostasis. Several transcription factors involved in embryonic development, has been shown to be closely associated with carcinogenesis when deregulated. Sry-like high mobility group box (SOX) proteins are potential transcription factors which are evolutionarily conserved. They regulate downstream genes to determine cell fate, via various signaling pathways and cellular processes essential for tissue and organ development. Dysregulation of SOXs has been reported to promote or suppress tumorigenesis by modulating cellular reprogramming, growth, proliferation, angiogenesis, metastasis, apoptosis, immune modulation, lineage plasticity, maintenance of the stem cell pool, therapy resistance and cancer relapse. This review provides a crucial understanding of the molecular mechanism by which SOXs play multifaceted roles in embryonic development and carcinogenesis. It also highlights their potential in advancing therapeutic strategies aimed at targeting SOXs and their downstream effectors in various malignancies.
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Affiliation(s)
- Saloni
- Cancer and Stem Cell Laboratory, Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj 211004, India
| | - Manisha Sachan
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj 211004, India
| | - Rahul
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India
| | - Rama Shanker Verma
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj 211004, India.
| | - Girijesh Kumar Patel
- Cancer and Stem Cell Laboratory, Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj 211004, India.
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Steen S, Horn D, Flechtenmacher C, Hoffmann J, Freier K, Ristow O, Hess J, Moratin J. Expression analysis of SOX2 and SOX9 in patients with oral squamous cell carcinoma. Head Neck 2025; 47:437-451. [PMID: 39180200 PMCID: PMC11717967 DOI: 10.1002/hed.27925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 08/12/2024] [Accepted: 08/15/2024] [Indexed: 08/26/2024] Open
Abstract
BACKGROUND Lately SOX2 and SOX9, transcription factors associated with stemness-like phenotypes of cancer cells, have been linked to tumor growth, metastasis, and resistance to therapy. METHODS This study aimed on evaluating the expression of SOX2 and SOX9 in a large cohort of patients with OSCC including primary and recurrent tumors and corresponding lymph node metastases. Semiautomatic digital pathology scoring was used to determine protein expression and survival analysis was performed to evaluate its prognostic significance. RESULTS We found a significant downregulation of SOX9 from primary disease to lymph node metastases (p < 0.001). SOX9 expression and the subgroup SOX2lowSOX9high were significantly correlated with worse overall survival (p < 0.05). Additionally, SOX2lowSOX9high expression pattern was confirmed as independent prognosticator for overall survival. CONCLUSIONS These results indicate the relevant role of SOX2 and SOX9 in patients with OSCC and show the clinical relevance for further investigation on the molecular mechanisms underlying SOX-related gene expression.
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Affiliation(s)
- Sonja Steen
- Department of Oral and Cranio‐Maxillofacial SurgeryUniversity of HeidelbergHeidelbergGermany
| | - Dominik Horn
- Department of Oral and Cranio‐Maxillofacial SurgerySaarland University HospitalHomburgGermany
| | - Christa Flechtenmacher
- Tissue Bank of the National Center for Tumor Diseases (NCT)HeidelbergGermany
- Institute of PathologyUniversity of HeidelbergHeidelbergGermany
| | - Jürgen Hoffmann
- Department of Oral and Cranio‐Maxillofacial SurgeryUniversity of HeidelbergHeidelbergGermany
| | - Kolja Freier
- Department of Oral and Cranio‐Maxillofacial SurgerySaarland University HospitalHomburgGermany
| | - Oliver Ristow
- Department of Oral and Cranio‐Maxillofacial SurgeryUniversity of HeidelbergHeidelbergGermany
| | - Jochen Hess
- Department of Otorhinolaryngology – Head and Neck SurgeryUniversity of HeidelbergHeidelbergGermany
| | - Julius Moratin
- Department of Oral and Cranio‐Maxillofacial SurgeryUniversity of HeidelbergHeidelbergGermany
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3
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Robinson L, Smit C, van Heerden MB, Moolla H, Afrogheh AH, Opperman JF, Ambele MA, van Heerden WFP. Surrogate Immunohistochemical Markers of Proliferation and Embryonic Stem Cells in Distinguishing Ameloblastoma from Ameloblastic Carcinoma. Head Neck Pathol 2024; 18:92. [PMID: 39365497 PMCID: PMC11452366 DOI: 10.1007/s12105-024-01704-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 09/13/2024] [Indexed: 10/05/2024]
Abstract
PURPOSE The current study aimed to investigate the use of surrogate immunohistochemical (IHC) markers of proliferation and stem cells to distinguish ameloblastoma (AB) from ameloblastic carcinoma (AC). METHODS The study assessed a total of 29 ACs, 6 ABs that transformed into ACs, and a control cohort of 20 ABs. The demographics and clinicopathologic details of the included cases of AC were recorded. The Ki-67 proliferation index was scored through automated methods with the QuPath open-source software platform. For SOX2, OCT4 and Glypican-3 IHC, each case was scored using a proportion of positivity score combined with an intensity score to produce a total score. RESULTS All cases of AC showed a relatively high median proliferation index of 41.7%, with statistically significant higher scores compared to ABs. ABs that transformed into ACs had similar median proliferation scores to the control cohort of ABs. Most cases of AC showed some degree of SOX2 expression, with 58.6% showing high expression. OCT4 expression was not seen in any case of AC. GPC-3 expression in ACs was limited, with high expression in 17.2% of ACs. Primary ACs showed higher median proliferation scores and degrees of SOX2 and GPC-3 expression than secondary cases. Regarding SOX2, OCT4 and GPC-3 IHC expression, no statistically significant differences existed between the cohort of ABs and ACs. CONCLUSION Ki-67 IHC as a proliferation marker, particularly when assessed via automated methods, was helpful in distinguishing AC from AB cases. In contrast to other studies, surrogate IHC markers of embryonic stem cells, SOX2, OCT4 and GPC-3, were unreliable in distinguishing the two entities.
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Affiliation(s)
- Liam Robinson
- Department of Oral and Maxillofacial Pathology, Faculty of Health Sciences, University of Pretoria, Pretoria Oral Health Care Centre, Office 6-11, Corner of Steve Biko and Dr Savage Roads, Pretoria, 0084, South Africa.
| | - Chané Smit
- Department of Oral and Maxillofacial Pathology, Faculty of Health Sciences, University of Pretoria, Pretoria Oral Health Care Centre, Office 6-11, Corner of Steve Biko and Dr Savage Roads, Pretoria, 0084, South Africa
| | - Marlene B van Heerden
- Department of Oral and Maxillofacial Pathology, Faculty of Health Sciences, University of Pretoria, Pretoria Oral Health Care Centre, Office 6-11, Corner of Steve Biko and Dr Savage Roads, Pretoria, 0084, South Africa
| | - Haroon Moolla
- Centre for Infectious Disease Epidemiology and Research, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Amir H Afrogheh
- Department of Oral and Maxillofacial Pathology, Faculty of Dentistry, University of the Western Cape, Cape Town, South Africa
- Division of Anatomical Pathology, Faculty of Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Johan F Opperman
- Department of Oral and Maxillofacial Pathology, Faculty of Dentistry, University of the Western Cape, Cape Town, South Africa
- Division of Anatomical Pathology, Faculty of Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Melvin A Ambele
- Department of Oral and Maxillofacial Pathology, Faculty of Health Sciences, University of Pretoria, Pretoria Oral Health Care Centre, Office 6-11, Corner of Steve Biko and Dr Savage Roads, Pretoria, 0084, South Africa
- Institute for Cellular and Molecular Medicine, Extramural Unit for Stem Cell Research and Therapy, Faculty of Health Sciences, South African Medical Research Council, University of Pretoria, Pretoria, South Africa
| | - Willie F P van Heerden
- Department of Oral and Maxillofacial Pathology, Faculty of Health Sciences, University of Pretoria, Pretoria Oral Health Care Centre, Office 6-11, Corner of Steve Biko and Dr Savage Roads, Pretoria, 0084, South Africa
- PathCare Vermaak Histopathology Laboratory, Pretoria, South Africa
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Niharika, Ureka L, Roy A, Patra SK. Dissecting SOX2 expression and function reveals an association with multiple signaling pathways during embryonic development and in cancer progression. Biochim Biophys Acta Rev Cancer 2024; 1879:189136. [PMID: 38880162 DOI: 10.1016/j.bbcan.2024.189136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/03/2024] [Accepted: 06/10/2024] [Indexed: 06/18/2024]
Abstract
SRY (Sex Determining Region) box 2 (SOX2) is an essential transcription factor that plays crucial roles in activating genes involved in pre- and post-embryonic development, adult tissue homeostasis, and lineage specifications. SOX2 maintains the self-renewal property of stem cells and is involved in the generation of induced pluripotency stem cells. SOX2 protein contains a particular high-mobility group domain that enables SOX2 to achieve the capacity to participate in a broad variety of functions. The information about the involvement of SOX2 with gene regulatory elements, signaling networks, and microRNA is gradually emerging, and the higher expression of SOX2 is functionally relevant to various cancer types. SOX2 facilitates the oncogenic phenotype via cellular proliferation and enhancement of invasive tumor properties. Evidence are accumulating in favor of three dimensional (higher order) folding of chromatin and epigenetic control of the SOX2 gene by chromatin modifications, which implies that the expression level of SOX2 can be modulated by epigenetic regulatory mechanisms, specifically, via DNA methylation and histone H3 modification. In view of this, and to focus further insights into the roles SOX2 plays in physiological functions, involvement of SOX2 during development, precisely, the advances of our knowledge in pre- and post-embryonic development, and interactions of SOX2 in this scenario with various signaling pathways in tumor development and cancer progression, its potential as a therapeutic target against many cancers are summarized and discussed in this article.
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Affiliation(s)
- Niharika
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Lina Ureka
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Ankan Roy
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Samir Kumar Patra
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India.
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Cook SR, Hugen S, Hayward JJ, Famula TR, Belanger JM, McNiel E, Fieten H, Oberbauer AM, Leegwater PA, Ostrander EA, Mandigers PJ, Evans JM. Genomic analyses identify 15 susceptibility loci and reveal HDAC2, SOX2-OT, and IGF2BP2 in a naturally-occurring canine model of gastric cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.14.604426. [PMID: 39372775 PMCID: PMC11451740 DOI: 10.1101/2024.08.14.604426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/08/2024]
Abstract
Gastric cancer (GC) is the fifth most common human cancer worldwide, but the genetic etiology is largely unknown. We performed a Bayesian genome-wide association study and selection analyses in a naturally-occurring canine model of GC, the Belgian Tervuren and Sheepdog breeds, to elucidate underlying genetic risk factors. We identified 15 loci with over 90% predictive accuracy for the GC phenotype. Variant filtering revealed germline putative regulatory variants for the EPAS1 (HIF2A) and PTEN genes and a coding variant in CD101. Although closely related to Tervuren and Sheepdogs, Belgian Malinois rarely develop GC. Across-breed analyses uncovered protective haplotypes under selection in Malinois at SOX2-OT and IGF2BP2. Among Tervuren and Sheepdogs, HDAC2 putative regulatory variants were present at comparatively high frequency and were associated with GC. Here, we describe a complex genetic architecture governing GC in a dog model, including genes such as PDZRN3, that have not been associated with human GC.
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Affiliation(s)
- Shawna R. Cook
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Sanne Hugen
- Expertisecentre of Genetics, Department of Clinical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Jessica J. Hayward
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Thomas R. Famula
- Department of Animal Science, University of California, Davis, CA, USA
| | | | - Elizabeth McNiel
- Cummings School of Veterinary Medicine, Tufts University, Grafton, Massachusetts, USA
| | - Hille Fieten
- Expertisecentre of Genetics, Department of Clinical Sciences, Utrecht University, Utrecht, The Netherlands
| | | | - Peter A.J. Leegwater
- Expertisecentre of Genetics, Department of Clinical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Elaine A. Ostrander
- Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Center, National Institutes of Health, Bethesda, MD, USA
| | - Paul J.J. Mandigers
- Expertisecentre of Genetics, Department of Clinical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Jacquelyn M. Evans
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
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Tekin C, Ercelik M, Dunaev P, Galembikova A, Tezcan G, Aksoy SA, Budak F, Isık O, Ugras N, Boichuk S, Tunca B. Leaf Extract from European Olive (Olea europaea L.) Post-Transcriptionally Suppresses the Epithelial-Mesenchymal Transition and Sensitizes Gastric Cancer Cells to Chemotherapy. BIOCHEMISTRY. BIOKHIMIIA 2024; 89:97-115. [PMID: 38467548 DOI: 10.1134/s0006297924010061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 11/21/2023] [Accepted: 11/30/2023] [Indexed: 03/13/2024]
Abstract
The overall survival of patients with the advanced and recurrent gastric cancer (GC) remains unfavorable. In particular, this is due to cancer spreading and resistance to chemotherapy associated with the epithelial-mesenchymal transition (EMT) of tumor cells. EMT can be identified by the transcriptome profiling of GC for EMT markers. Indeed, analysis of the TCGA and GTEx databases (n = 408) and a cohort of GC patients (n = 43) revealed that expression of the CDH2 gene was significantly decreased in the tumors vs. non-tumor tissues and correlated with the overall survival of GC patients. Expression of the EMT-promoting transcription factors SNAIL and ZEB1 was significantly increased in GC. These data suggest that targeting the EMT might be an attractive therapeutic approach for patients with GC. Previously, we demonstrated a potent anti-cancer activity of the olive leaf extract (OLE). However, its effect on the EMT regulation in GC remained unknown. Here, we showed that OLE efficiently potentiated the inhibitory effect of the chemotherapeutic agents 5-fluorouracil (5-FU) and cisplatin (Cis) on the EMT and their pro-apoptotic activity, as was demonstrated by changes in the expression of the EMT markers (E- and N-cadherins, vimentin, claudin-1) in GC cells treated with the aforementioned chemotherapeutic agents in the presence of OLE. Thus, culturing GC cells with 5-FU + OLE or Cis + OLE attenuated the invasive properties of cancer cells. Importantly, upregulation of expression of the apoptotic markers (PARP cleaved form) and increase in the number of cells undergoing apoptosis (annexin V-positive) were observed for GC cells treated with a combination of OLE and 5-FU or Cis. Collectively, our data illustrate that OLE efficiently interferes with the EMT in GC cells and potentiates the pro-apoptotic activity of certain chemotherapeutic agents used for GC therapy.
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Affiliation(s)
- Cagla Tekin
- Department of Medical Biology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Melis Ercelik
- Department of Medical Biology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Pavel Dunaev
- Department of Pathology, Kazan State Medical University, Kazan, Russia
| | - Aigul Galembikova
- Department of Pathology, Kazan State Medical University, Kazan, Russia
| | - Gulcin Tezcan
- Department of Fundamental Sciences, Faculty of Dentistry, Bursa Uludag University, Bursa, Turkey
| | - Secil Ak Aksoy
- Inegol Vocation School, Bursa Uludag University, Bursa, Turkey
- Experimental Animal Breeding and Research Unit, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Ferah Budak
- Department of Immunology, Medical Faculty, Bursa Uludag University Bursa, Turkey
| | - Ozgen Isık
- Department of General Surgery, Medical Faculty, Bursa Uludag University Bursa, Turkey
| | - Nesrin Ugras
- Department of Pathology, Medical Faculty, Bursa Uludag University, Bursa, Turkey
| | - Sergei Boichuk
- Department of Pathology, Kazan State Medical University, Kazan, Russia.
- Department of Radiotherapy and Radiology, Russian Medical Academy of Continuous Professional Education, Moscow, Russia
- "Biomarker" Research Laboratory, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Berrin Tunca
- Department of Medical Biology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey.
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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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Bode AM, Zhang T. Recent Advances in Carcinogenesis Transcription Factors: Biomarkers and Targeted Therapies. Cancers (Basel) 2023; 15:4673. [PMID: 37835367 PMCID: PMC10571516 DOI: 10.3390/cancers15194673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 09/20/2023] [Indexed: 10/15/2023] Open
Abstract
Carcinogenesis, the process by which normal cells transform into cancer cells, is complex and multifaceted [...].
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Affiliation(s)
- Ann M. Bode
- The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
| | - Tianshun Zhang
- The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
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Fleifel D, Cook JG. G1 Dynamics at the Crossroads of Pluripotency and Cancer. Cancers (Basel) 2023; 15:4559. [PMID: 37760529 PMCID: PMC10526231 DOI: 10.3390/cancers15184559] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 08/29/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
G1 cell cycle phase dynamics are regulated by intricate networks involving cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors, which control G1 progression and ensure proper cell cycle transitions. Moreover, adequate origin licensing in G1 phase, the first committed step of DNA replication in the subsequent S phase, is essential to maintain genome integrity. In this review, we highlight the intriguing parallels and disparities in G1 dynamics between stem cells and cancer cells, focusing on their regulatory mechanisms and functional outcomes. Notably, SOX2, OCT4, KLF4, and the pluripotency reprogramming facilitator c-MYC, known for their role in establishing and maintaining stem cell pluripotency, are also aberrantly expressed in certain cancer cells. In this review, we discuss recent advances in understanding the regulatory role of these pluripotency factors in G1 dynamics in the context of stem cells and cancer cells, which may offer new insights into the interconnections between pluripotency and tumorigenesis.
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Affiliation(s)
| | - Jeanette Gowen Cook
- Department of Biochemistry & Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;
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Zhang J, Wang Z, Zhao H, Wei Y, Zhou Y, Zhang S, Zhao J, Li X, Lin Y, Liu K. The roles of the SOX2 protein in the development of esophagus and esophageal squamous cell carcinoma, and pharmacological target for therapy. Biomed Pharmacother 2023; 163:114764. [PMID: 37100016 DOI: 10.1016/j.biopha.2023.114764] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/16/2023] [Accepted: 04/20/2023] [Indexed: 04/28/2023] Open
Abstract
SOX2 is a transcription factor belonging to the SOX gene family, whose activity has been associated with the maintenance of the stemness and self-renewal of embryonic stem cells (ESCs), as well as the induction of differentiated cells into induced pluripotent stem cells (iPSCs). Moreover, accumulating studies have shown that SOX2 is amplified in various cancers, notably in esophageal squamous cell carcinoma (ESCC). In addition, SOX2 expression is linked to multiple malignant processes, including proliferation, migration, invasion, and drug resistance. Taken together, targeting SOX2 might shed light on novel approaches for cancer therapy. In this review, we aim to summarize the current knowledge regarding SOX2 in the development of esophagus and ESCC. We also highlight several therapeutic strategies for targeting SOX2 in different cancer types, which can provide new tools to treat cancers possessing abnormal levels of SOX2 protein.
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Affiliation(s)
- Jiaying Zhang
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China; School of Life Science, Xiamen University, Xiamen, Fujian 361102, China; Fujian Health College, Fuzhou, Fujian, 350101, China
| | - 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; Fujian Health College, Fuzhou, Fujian, 350101, 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; Fujian Health College, Fuzhou, Fujian, 350101, China
| | - 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; Fujian Health College, Fuzhou, Fujian, 350101, 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; Fujian Health College, Fuzhou, Fujian, 350101, China
| | - Shihui Zhang
- Centre for Translational Stem Cell Biology, School of Biomedical Sciences, The University of Hong Kong, Pokfulam 999077, Hong Kong, China; Fujian Health College, Fuzhou, Fujian, 350101, China
| | - Jing 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; Fujian Health College, Fuzhou, Fujian, 350101, China
| | - Xinxin Li
- 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; Fujian Health College, Fuzhou, Fujian, 350101, China
| | - Yong Lin
- Centre for Translational Stem Cell Biology, School of Biomedical Sciences, The University of Hong Kong, Pokfulam 999077, Hong Kong, China; Fujian Health College, Fuzhou, Fujian, 350101, China.
| | - 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; Fujian Health College, Fuzhou, Fujian, 350101, China.
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11
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Chang SY, Wu TH, Shih YL, Chen YC, Su HY, Chian CF, Lin YW. SOX1 Functions as a Tumor Suppressor by Repressing HES1 in Lung Cancer. Cancers (Basel) 2023; 15:cancers15082207. [PMID: 37190139 DOI: 10.3390/cancers15082207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 03/25/2023] [Accepted: 03/31/2023] [Indexed: 05/17/2023] Open
Abstract
The development of lung cancer is a complex process that involves many genetic and epigenetic changes. Sex-determining region Y (SRY)-box (SOX) genes encode a family of proteins that are involved in the regulation of embryonic development and cell fate determination. SOX1 is hypermethylated in human cancers. However, the role of SOX1 in the development of lung cancer is unclear. We used quantitative methylation-specific polymerase chain reaction (MSP), quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis, and web tools to confirm the frequent epigenetic silencing of SOX1 in lung cancer. Stable overexpression of SOX1 repressed cell proliferation, anchorage-independent growth, and invasion in vitro as well as cancer growth and metastasis in a xenograft mouse model. Knockdown of SOX1 by the withdrawal of doxycycline partly restored the malignant phenotype of inducible SOX1-expressing NSCLC cells. Next, we discovered the potential downstream pathways of SOX1 using RNA-seq analysis and identified HES1 as a direct target of SOX1 using chromatin immunoprecipitation (ChIP)-PCR. Furthermore, we performed phenotypic rescue experiments to prove that overexpression of HES1-FLAG in SOX1-expressing H1299 cells partly reversed the tumor-suppressive effect. Taken together, these data demonstrated that SOX1 acts as a tumor suppressor by directly inhibiting HES1 during the development of NSCLC.
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Affiliation(s)
- Shan-Yueh Chang
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
| | - Ti-Hui Wu
- Division of Thoracic Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
| | - Yu-Lueng Shih
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
| | - Ying-Chieh Chen
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
| | - Her-Young Su
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan
| | - Chih-Feng Chian
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan
| | - Ya-Wen Lin
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei 11490, Taiwan
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan
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12
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Ding LN, Yu YY, Ma CJ, Lei CJ, Zhang HB. SOX2-associated signaling pathways regulate biological phenotypes of cancers. Biomed Pharmacother 2023; 160:114336. [PMID: 36738502 DOI: 10.1016/j.biopha.2023.114336] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 01/20/2023] [Accepted: 01/27/2023] [Indexed: 02/05/2023] Open
Abstract
SOX2 is a transcription factor involved in multiple stages of embryonic development. In related reports, SOX2 was found to be abnormally expressed in tumor tissues and correlated with clinical features such as TNM staging, tumor grade, and prognosis in patients with various cancer types. In most cancer types, SOX2 is a tumor-promoting factor that regulates tumor progression and metastasis primarily by maintaining the stemness of cancer cells. In addition, SOX2 also regulates the proliferation, apoptosis, invasion, migration, ferroptosis and drug resistance of cancer cells. However, SOX2 acts as a tumor suppressor in some cases in certain cancer types, such as gastric and lung cancer. These key regulatory functions of SOX2 involve complex regulatory networks, including protein-protein and protein-nucleic acid interactions through signaling pathways and noncoding RNA interactions, modulating SOX2 expression may be a potential therapeutic strategy for clinical cancer patients. Therefore, we sorted out the phenotypes related to SOX2 in cancer, hoping to provide a basis for further clinical translation.
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Affiliation(s)
- L N Ding
- Department of Oncology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Y Y Yu
- Department of Oncology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - C J Ma
- Department of Oncology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - C J Lei
- Department of Oncology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - H B Zhang
- Department of Oncology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Department of Oncology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou, China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
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13
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Lin X, Li G, Yan X, Fu W, Ruan J, Ding H, Yu H, Chen X, Lan L, Dai Y, Pan K, Liu X, Zhang H. Long non-coding RNA BC002811 Promotes Gastric Cancer Metastasis by Regulating SOX2 Binding to the PTEN Promoter. Int J Biol Sci 2023; 19:967-980. [PMID: 36778127 PMCID: PMC9909995 DOI: 10.7150/ijbs.76407] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 12/23/2022] [Indexed: 02/04/2023] Open
Abstract
There is increasing evidence that long non-coding RNAs (lncRNAs) are involved in the pathogenesis and progression of gastric cancer (GC), however, the underlying mechanisms remain poorly understood. In this study, we identified lncRNA BC002811 as a critical regulator of GC development and progression. BC002811 was upregulated in GC tissues and cell lines, and that high expression of BC002811 was indicative of a reduction in overall survival of GC patients. Our research reveals that BC002811 promoted GC cell proliferation, migration, invasion, and inhibition of apoptosis in vitro, as well as accelerated tumor growth and metastasis in vivo. We also found that BC002811 upregulated MMP2 and MMP9 and promoted GC cell metastasis partially through downregulating PTEN expression. BC002811 may act as a molecular decoy for the transcription factor SOX2, thereby inhibiting the transcription of PTEN by blocking SOX2 binding to the PTEN promoter. Our study advances the understanding of the role of BC002811 in the pathogenesis of GC and provides new molecular targets for therapeutic intervention against GC metastasis.
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Affiliation(s)
- Xiaocong Lin
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, Guangdong, China.,Peptide and Protein Research and Application Key Laboratory of Guangdong Medical University, Zhanjiang 524023, Guangdong, China
| | - Guodan Li
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, Guangdong, China.,Peptide and Protein Research and Application Key Laboratory of Guangdong Medical University, Zhanjiang 524023, Guangdong, China
| | - Xiuwen Yan
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, Guangdong, China.,Peptide and Protein Research and Application Key Laboratory of Guangdong Medical University, Zhanjiang 524023, Guangdong, China
| | - Weiyu Fu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, Guangdong, China.,Peptide and Protein Research and Application Key Laboratory of Guangdong Medical University, Zhanjiang 524023, Guangdong, China
| | - Jie Ruan
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, Guangdong, China
| | - Hang Ding
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, Guangdong, China.,Peptide and Protein Research and Application Key Laboratory of Guangdong Medical University, Zhanjiang 524023, Guangdong, China
| | - Huajun Yu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, Guangdong, China.,Peptide and Protein Research and Application Key Laboratory of Guangdong Medical University, Zhanjiang 524023, Guangdong, China
| | - Xiaoyi Chen
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, Guangdong, China.,Peptide and Protein Research and Application Key Laboratory of Guangdong Medical University, Zhanjiang 524023, Guangdong, China
| | - Liubo Lan
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, Guangdong, China.,Peptide and Protein Research and Application Key Laboratory of Guangdong Medical University, Zhanjiang 524023, Guangdong, China
| | - Yong Dai
- Clinical Medical Research Center, Shenzhen People's Hospital, Shenzhen 518020, Guangdong, China
| | - Kai Pan
- Department of Gastrointestinal Surgery, Shenzhen People's Hospital, Shenzhen 518020, Guangdong, China
| | - Xinguang Liu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, Guangdong, China
| | - Haitao Zhang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang 524023, Guangdong, China.,Peptide and Protein Research and Application Key Laboratory of Guangdong Medical University, Zhanjiang 524023, Guangdong, China
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14
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Li N, Pang Y, Sang J, Sun Y, Hou W. The controversial expression of SOX2 in gastric cancer and its correlation with Helicobacter pylori infection: A meta-analysis. Medicine (Baltimore) 2022; 101:e30886. [PMID: 36221360 PMCID: PMC9542901 DOI: 10.1097/md.0000000000030886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND The expression of sex-determining region Y (SRY)-like high-mobility group (HMG) box 2 (SOX2) in gastric cancer and the prognosis of patients are controversial. This study analyzed the relationship between SOX2 expression and baseline data, clinicopathological parameters, prognosis, and Helicobacter pylori infection in patients with gastric cancer, and provided new supplements for the diagnosis and treatment of gastric cancer. METHODS The articles which reported SOX2 expression in gastric cancer from medical database was collected. The literature search was conducted in PubMed, Google Scholar, Cochrane library, SpringerLink, China National Knowledge Infrastructure, Web of Science, and Wanfang databases, which were written in English and Chinese. RESULTS A total of 32 articles, including 4641 gastric cancer patients. The results showed that SOX2 expression in gastric cancer group was lower than that in the para-cancerous control group (P < .001). Statistical difference was found between the SOX2 expression and differentiation (Well/Moderate vs Poor), TNM stage (I/II vs III/IV), lymphatic invasion (N0 vs N+), edge infiltration (R0 vs R1), and H pylori infection in the pathological parameters. The prognosis analysis showed that the level of SOX2 expression was unrelated to the overall survival of patients (P = .329). No statistical difference was observed between the SOX2 expression and the baseline data of the patients (all P > .05). CONCLUSIONS Although downregulation expression of SOX2 are related to clinicopathological parameters in gastric cancer, which is not correlated with prognosis. This controversy over the expression of SOX2 will provide a new idea for the study of gastric cancer.
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Affiliation(s)
- Ning Li
- Department of Pathology, Tai’an City Central Hospital, Tai’an, Shandong, China
| | - Yu Pang
- Department of Pathology, Tai’an City Central Hospital, Tai’an, Shandong, China
| | - Jing Sang
- Department of Pathology, Tai’an City Central Hospital, Tai’an, Shandong, China
| | - Yong Sun
- Department of Pediatrics, Tai’an City Central Hospital, Tai’an, Shandong, China
| | - Weiwei Hou
- Department of Pathology, Tai’an City Central Hospital, Tai’an, Shandong, China
- *Correspondence: Weiwei Hou, Department of Pathology, Tai’an City Central Hospital, Tai’an, Shandong 271000, China (e-mail: )
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15
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A Deep Neural Network for Gastric Cancer Prognosis Prediction Based on Biological Information Pathways. JOURNAL OF ONCOLOGY 2022; 2022:2965166. [PMID: 36117847 PMCID: PMC9481367 DOI: 10.1155/2022/2965166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 07/09/2022] [Accepted: 07/22/2022] [Indexed: 11/18/2022]
Abstract
Background Gastric cancer (GC) is one of the deadliest cancers in the world, with a 5-year overall survival rate of lower than 20% for patients with advanced GC. Genomic information is now frequently employed for precision cancer treatment due to the rapid advancements of high-throughput sequencing technologies. As a result, integrating multiomics data to construct predictive models for the GC patient prognosis is critical for tailored medical care. Results In this study, we integrated multiomics data to design a biological pathway-based gastric cancer sparse deep neural network (GCS-Net) by modifying the P-NET model for long-term survival prediction of GC. The GCS-Net showed higher accuracy (accuracy = 0.844), area under the curve (AUC = 0.807), and F1 score (F1 = 0.913) than traditional machine learning models. Furthermore, the GCS-Net not only enables accurate patient survival prognosis but also provides model interpretability capabilities lacking in most traditional deep neural networks to describe the complex biological process of prognosis. The GCS-Net suggested the importance of genes (UBE2C, JAK2, RAD21, CEP250, NUP210, PTPN1, CDC27, NINL, NUP188, and PLK4) and biological pathways (Mitotic Anaphase, Resolution of Sister Chromatid Cohesion, and SUMO E3 ligases) to GC, which is consistent with the results revealed in biological- and medical-related studies of GC. Conclusion The GCS-Net is an interpretable deep neural network built using biological pathway information whose structure represents a nonlinear hierarchical representation of genes and biological pathways. It can not only accurately predict the prognosis of GC patients but also suggest the importance of genes and biological pathways. The GCS-Net opens up new avenues for biological research and could be adapted for other cancer prediction and discovery activities as well.
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16
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Tang K, Liu J, Liu B, Meng C, Liao J. SOX2 contributes to invasion and poor prognosis of gastric cancer: A meta-analysis. Medicine (Baltimore) 2022; 101:e30559. [PMID: 36086709 PMCID: PMC10980484 DOI: 10.1097/md.0000000000030559] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 08/11/2022] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND The sex-determining region Y-box 2 (SOX2) has been identified to be involved in tumor progression and prognosis in patients with gastric cancer (GC). However, its action is paradoxical. Thus, we conducted the first meta-analysis based on eligible studies to evaluate the clinical utility of SOX2 in GC only. METHODS A thorough electronic search was performed to collect eligible studies. The hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were generated from included studies to assess the strength of the association between SOX2 and prognosis and clinicopathological characteristics in GC. RESULTS A total of 10 studies comprising 1321 patients with GC were identified for the meta-analysis. The pooled results revealed that high SOX2 expression was significantly associated with poor overall survival compared to low SOX2 expression (pooled HR = 1.485; 95% CI: 1.022-2.160; 𝑃 = .04). The statistical significance between SOX2 expression and overall survival was also established in univariate analysis (pooled HR = 1.606; 95% CI: 1.134-2.274; 𝑃 < .01), as well as recruitment time exceeding 2010 (pooled HR = 1.873; 95% CI: 1.041-3.371; 𝑃 = .04), follow-up time more than 5 years (pooled HR = 1.642; 95% CI: 1.066-2.527; 𝑃 = .02), and cutoff value of more than 5% of cells stained (pooled HR = 1.730; 95% CI: 1.162-2.577; 𝑃 < .01). Moreover, we verified that positive SOX2 expression was correlated with advanced tumor invasion depth (pooled OR = 0.494; 95% CI: 0.362-0.675; 𝑃 < .01) and positive vascular invasion (pooled OR = 1.515; 95% CI: 1.078-2.130; 𝑃 = .02). CONCLUSION SOX2 could not only be an independent prognostic marker in GC but might also be a novel target for cancer therapy.
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Affiliation(s)
- Kaifeng Tang
- Department of Surgery, Zhejiang Hospital, Hangzhou, China
| | - Jingting Liu
- Department of Health Management, Sir Run Run Shaw International Medical Centre, Hangzhou, China
| | - Baoqing Liu
- Department of Surgery, Zhejiang Hospital, Hangzhou, China
| | - Chunyan Meng
- Department of Surgery, Zhejiang Hospital, Hangzhou, China
| | - Jianhua Liao
- Department of Surgery, Zhejiang Hospital, Hangzhou, China
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17
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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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18
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Gharib AF, Elsawy WH, Alrehaili AA, Amin HS, Alhuthali HM, Bakhuraysah MM, El Askary A. The Application of Molecular Techniques for Assessment of SOX2 and miR126 Expression as Prognostic Markers in Esophageal Carcinoma. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:1514412. [PMID: 39290848 PMCID: PMC11407893 DOI: 10.1155/2022/1514412] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 01/27/2022] [Accepted: 02/10/2022] [Indexed: 09/19/2024]
Abstract
Objective To study the problem in esophageal cancer, the function of SOX2 and miR-126 has not been completely explored. The objective of this study was to find out how SOX2 and miR-126 act in esophageal cancer and their relation to the clinical and prognostic features. Methods The expression of SOX2 and miR-126 was properly assessed in the carcinoma of the esophagus, and the nearby healthy tissues surgically excised from 35 included patients. Results SOX2 was elevated in esophageal cancer relative to normal tissues contrary to the miR-126 levels. This inverse relationship was linked to adverse clinical features. Background SOX2 has been involved as an oncogene in various types of malignant tumors; microRNA-126 (miR-126) is extensively expressed in vascular endothelial cells, which control angiogenesis. Furthermore, many published reports reasonably concluded that based on the prime characteristic of malignant cells, miR-126 may act appropriately as a promotor or a suppressor for the malignant growth. Conclusion In esophageal cancer, SOX2 works as an oncogene, whereas miR-126 acts as a tumor suppressor gene. SOX2 overexpression and miR-126 downregulation were shown to be linked to a poor prognosis.
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Affiliation(s)
- Amal F Gharib
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O.Box 11099, Taif 21944, Saudi Arabia
| | - Wael H Elsawy
- Department of Clinical Oncology, Faculty of Medicine, Zagazig University, Egypt
| | - Amani A Alrehaili
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O.Box 11099, Taif 21944, Saudi Arabia
| | - Hanan S Amin
- Department of Clinical Chemistry, Theodor Bilharz Research Institute, Cairo, Egypt
| | - Hayaa M Alhuthali
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O.Box 11099, Taif 21944, Saudi Arabia
| | - Maha M Bakhuraysah
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O.Box 11099, Taif 21944, Saudi Arabia
| | - Ahmad El Askary
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O.Box 11099, Taif 21944, Saudi Arabia
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19
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BRD4-directed super-enhancer organization of transcription repression programs links to chemotherapeutic efficacy in breast cancer. Proc Natl Acad Sci U S A 2022; 119:2109133119. [PMID: 35105803 PMCID: PMC8832982 DOI: 10.1073/pnas.2109133119] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/15/2021] [Indexed: 12/11/2022] Open
Abstract
BRD4 is well known for its role in super-enhancer organization and transcription activation of several prominent oncogenes including c-MYC and BCL2 As such, BRD4 inhibitors are being pursued as promising therapeutics for cancer treatment. However, drug resistance also occurs for BRD4-targeted therapies. Here, we report that BRD4 unexpectedly interacts with the LSD1/NuRD complex and colocalizes with this repressive complex on super-enhancers. Integrative genomic and epigenomic analyses indicate that the BRD4/LSD1/NuRD complex restricts the hyperactivation of a cluster of genes that are functionally linked to drug resistance. Intriguingly, treatment of breast cancer cells with a small-molecule inhibitor of BRD4, JQ1, results in no immediate activation of the drug-resistant genes, but long-time treatment or destabilization of LSD1 by PELI1 decommissions the BRD4/LSD1/NuRD complex, leading to resistance to JQ1 as well as to a broad spectrum of therapeutic compounds. Consistently, PELI1 is up-regulated in breast carcinomas, its level is negatively correlated with that of LSD1, and the expression level of the BRD4/LSD1/NuRD complex-restricted genes is strongly correlated with a worse overall survival of breast cancer patients. Together, our study uncovers a functional duality of BRD4 in super-enhancer organization of transcription activation and repression linking to oncogenesis and chemoresistance, respectively, supporting the pursuit of a combined targeting of BRD4 and PELI1 in effective treatment of breast cancer.
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20
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Chen QY, Huang XB, Zhao YJ, Wang HG, Wang JB, Liu LC, Wang LQ, Zhong Q, Xie JW, Lin JX, Lu J, Cao LL, Lin M, Tu RH, Zheng CH, Li P, Huang CM. The peroxisome proliferator-activated receptor agonist rosiglitazone specifically represses tumour metastatic potential in chromatin inaccessibility-mediated FABP4-deficient gastric cancer. Theranostics 2022; 12:1904-1920. [PMID: 35198079 PMCID: PMC8825587 DOI: 10.7150/thno.66814] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 12/07/2021] [Indexed: 11/05/2022] Open
Abstract
Background: Efforts to prevent recurrence in gastric cancer (GC) patients are limited by current incomplete understanding of the pathological mechanisms. The present study aimed to identify novel tumour metastasis-associated genes and investigate potential value of these genes in clinical diagnosis and therapy. Methods: RNA sequencing was performed to identify differentially expressed genes related to GC metastasis. The expression and prognostic significance of fatty acid binding protein 4 (FABP4) were evaluated in two independent cohorts of GC patients. Chromatin immunoprecipitation sequencing, diverse mouse models and assays for transposase-accessible chromatin with high-throughput sequencing were used to investigate the roles and mechanisms of action of FABP4. Results: The results of the present multicentre study confirmed an association between a decrease in the expression of FABP4 and poor outcomes in GC patients. FABP4 inhibited GC metastasis but did not influence tumour growth in vitro and in vivo. Mechanistically, FABP4 binding with peroxisome proliferator-activated receptor γ (PPAR-γ) facilitated the translocation of PPAR-γ to the nucleus. FABP4 depletion suppressed PPAR-γ-mediated transcription of cell adhesion molecule 3 (CADM3), which preferentially governed GC metastasis. Notably, the PPAR-γ agonist rosiglitazone reversed the metastatic properties of FABP4-deficient GC cells in vitro and demonstrated viable therapeutic potential in multiple mouse models. For GC patients with diabetes, low FABP4 portends better prognosis than high FABP4 after receipt of rosiglitazone treatment. Additionally, chromatin inaccessibility induced by HDAC1 reduced FABP4 expression at the epigenetic level. Conclusions: Our findings suggest that chromatin inaccessibility orchestrates a reduction in FABP4 expression, which inhibits CADM3 transcription via PPAR-γ, thereby resulting in GC metastasis. The antidiabetic drug rosiglitazone restores PPAR-γ/CADM3 activation in FABP4-deficient GC and thus has promising therapeutic potential.
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Affiliation(s)
- Qi-Yue Chen
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian, P. R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
| | - Xiao-Bo Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian, P. R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
| | - Ya-Jun Zhao
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, P. R. China
| | - Hua-Gen Wang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian, P. R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
| | - Jia-Bin Wang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian, P. R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
| | - Li-Chao Liu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian, P. R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
| | - Ling-Qian Wang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian, P. R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
| | - Qing Zhong
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian, P. R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
| | - Jian-Wei Xie
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian, P. R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
| | - Jian-Xian Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian, P. R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
| | - Jun Lu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian, P. R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
| | - Long-Long Cao
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian, P. R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
| | - Mi Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian, P. R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
| | - Ru-Hong Tu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian, P. R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
| | - Chao-Hui Zheng
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian, P. R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
| | - Ping Li
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian, P. R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
| | - Chang-Ming Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian, P. R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
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21
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Singh N, Sharma R, Bose S. Meta-analysis of transcriptomics data identifies potential biomarkers and their associated regulatory networks in gallbladder cancer. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2022; 15:311-325. [PMID: 36762219 PMCID: PMC9876761 DOI: 10.22037/ghfbb.v15i4.2292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 09/21/2022] [Indexed: 02/11/2023]
Abstract
Aim This study aimed to identify key genes, non-coding RNAs, and their possible regulatory interactions during gallbladder cancer (GBC). Background The early detection of GBC, i.e. before metastasis, is restricted by our limited knowledge of molecular markers and mechanism(s) involved during carcinogenesis. Therefore, identifying important disease-associated transcriptome-level alterations can be of clinical importance. Methods In this study, six NCBI-GEO microarray dataseries of GBC and control tissue samples were analyzed to identify differentially expressed genes (DEGs) and non-coding RNAs {microRNAs (DEmiRNAs) and long non-coding RNAs (DElncRNAs)} with a computational meta-analysis approach. A series of bioinformatic methods were applied to enrich functional pathways, create protein-protein interaction networks, identify hub genes, and screen potential targets of DEmiRNAs and DElncRNAs. Expression and interaction data were consolidated to reveal putative DElncRNAs:DEmiRNAs:DEGs interactions. Results In total, 351 DEGs (185 downregulated, 166 upregulated), 787 DEmiRNAs (299 downregulated, 488 upregulated), and 7436 DElncRNAs (3127 downregulated, 4309 upregulated) were identified. Eight genes (FGF, CDK1, RPN2, SEC61A1, SOX2, CALR, NGFR, and NCAM) were identified as hub genes. Genes associated with ubiquitin ligase activity, N-linked glycosylation, and blood coagulation were upregulated, while those for cell-cell adhesion, cell differentiation, and surface receptor-linked signaling were downregulated. DEGs-DEmiRNAs-DElncRNAs interaction network identified 46 DElncRNAs to be associated with 28 DEmiRNAs, consecutively regulating 27 DEGs. DEmiRNAs-hsa-miR-26b-5p and hsa-miR-335-5p; and DElnRNAs-LINC00657 and CTB-89H12.4 regulated the highest number of DEGs and DEmiRNAs, respectively. Conclusion The current study has identified meaningful transcriptome-level changes and gene-miRNA-lncRNA interactions during GBC and laid a platform for future studies on novel prognostic and diagnostic markers in GBC.
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Affiliation(s)
- Nidhi Singh
- Department of Biotechnology, Gauhati University, Guwahati, Assam, India
| | - Rinku Sharma
- Department of Life Sciences, Shiv Nadar University, Noida, Uttar Pradesh, India
| | - Sujoy Bose
- Department of Biotechnology, Gauhati University, Guwahati, Assam, India
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22
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Saberi S, Esmaeili M, Tashakoripour M, Eshagh Hosseini M, Baharvand H, Mohammadi M. Infection with a hypervirulent strain of Helicobacter pylori primes gastric cells toward intestinal transdifferentiation. Microb Pathog 2021; 162:105353. [PMID: 34896202 DOI: 10.1016/j.micpath.2021.105353] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 12/05/2021] [Accepted: 12/05/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND Intestinal metaplasia, gastric-to-intestinal transdifferentiation, occurs as a result of the misexpression of certain regulatory factors, leading to genetic reprogramming. Here, we have evaluated the H. pylori-induced expression patterns of these candidate genes. METHODS The expression levels of 1) tissue-specific transcription factors (RUNX3, KLF5, SOX2, SALL4, CDX1 and CDX2), 2) stemness factors (TNFRSF19, LGR5, VIL1) and 3) tissue-specific mucins (MUC5AC, MUC2) were evaluated by quantitative real-time PCR in gastric primary cells (GPCs), in parallel with two gastric cancer (MKN45 and AGS) cell lines, up to 96h following H. pylori infection. RESULTS Following H. pylori infection of GPCs, RUNX3 declined at 24h post infection (-6.2 ± 0.3) and remained downregulated for up to 96h. Subsequently, overexpression of self-renewal and pluripotency transcription factors, KLF5 (3.6 ± 0.2), SOX2 (7.6 ± 0.5) and SALL4 (4.3 ± 0.2) occurred. The expression of TNFRSF19 and LGR5, demonstrated opposing trends, with an early rise of the former (4.5 ± 0.3) at 8h, and a simultaneous fall of the latter (-1.8 ± 0.5). This trend was reversed at 96h, with the decline in TNFRSF19 (-5.5 ± 0.2), and escalation of LGR5 (2.6 ± 0.2) and VIL1 (1.8 ± 0.3). Ultimately, CDX1 and CDX2 were upregulated by 1.9 and 4.7-fold, respectively. The above scenario was, variably observed in MKN45 and AGS cells. CONCLUSION Our data suggests an interdependent gene regulatory network, induced by H. pylori infection. This interaction begins with the downregulation of RUNX3, upregulation of self-renewal and pluripotency transcription factors, KLF5, SOX2 and SALL4, leading to the downregulation of TNFRSF19, upregulation of LGR5 and aberrant expression of intestine-specific transcription factors, potentially facilitating the process of gastric-to-intestinal transdifferentiation.
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Affiliation(s)
- Samaneh Saberi
- HPGC Research Group, Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Maryam Esmaeili
- HPGC Research Group, Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Mohammad Tashakoripour
- Gastroenterology Department, Amiralam Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahmoud Eshagh Hosseini
- Gastroenterology Department, Amiralam Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Baharvand
- Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Department of Developmental Biology, University of Science and Culture, Tehran, Iran
| | - Marjan Mohammadi
- HPGC Research Group, Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
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23
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Pluripotency Stemness and Cancer: More Questions than Answers. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1376:77-100. [PMID: 34725790 DOI: 10.1007/5584_2021_663] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Embryonic stem cells and induced pluripotent stem cells provided us with fascinating new knowledge in recent years. Mechanistic insight into intricate regulatory circuitry governing pluripotency stemness and disclosing parallels between pluripotency stemness and cancer instigated numerous studies focusing on roles of pluripotency transcription factors, including Oct4, Sox2, Klf4, Nanog, Sall4 and Tfcp2L1, in cancer. Although generally well substantiated as tumour-promoting factors, oncogenic roles of pluripotency transcription factors and their clinical impacts are revealing themselves as increasingly complex. In certain tumours, both Oct4 and Sox2 behave as genuine oncogenes, and reporter genes driven by composite regulatory elements jointly recognized by both the factors can identify stem-like cells in a proportion of tumours. On the other hand, cancer stem cells seem to be biologically very heterogeneous both among different tumour types and among and even within individual tumours. Pluripotency transcription factors are certainly implicated in cancer stemness, but do not seem to encompass its entire spectrum. Certain cancer stem cells maintain their stemness by biological mechanisms completely different from pluripotency stemness, sometimes even by engaging signalling pathways that promote differentiation of pluripotent stem cells. Moreover, while these signalling pathways may well be antithetical to stemness in pluripotent stem cells, they may cooperate with pluripotency factors in cancer stem cells - a paradigmatic example is provided by the MAPK-AP-1 pathway. Unexpectedly, forced expression of pluripotency transcription factors in cancer cells frequently results in loss of their tumour-initiating ability, their phenotypic reversion and partial epigenetic normalization. Besides the very different signalling contexts operating in pluripotent and cancer stem cells, respectively, the pronounced dose dependency of reprogramming pluripotency factors may also contribute to the frequent loss of tumorigenicity observed in induced pluripotent cancer cells. Finally, contradictory cell-autonomous and non-cell-autonomous effects of various signalling molecules operate during pluripotency (cancer) reprogramming. The effects of pluripotency transcription factors in cancer are thus best explained within the concept of cancer stem cell heterogeneity.
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Wang P, Gong S, Pan J, Wang J, Zou D, Xiong S, Zhao L, Yan Q, Deng Y, Wu N, Liao B. Hyperbaric oxygen promotes not only glioblastoma proliferation but also chemosensitization by inhibiting HIF1α/HIF2α-Sox2. Cell Death Discov 2021; 7:103. [PMID: 33986256 PMCID: PMC8119469 DOI: 10.1038/s41420-021-00486-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 03/20/2021] [Accepted: 04/16/2021] [Indexed: 12/17/2022] Open
Abstract
There exists a consensus that combining hyperbaric oxygen (HBO) and chemotherapy promotes chemotherapy sensitivity in GBM cells. However, few studies have explored the mechanism involved. HIF1α and HIF2α are the two main molecules that contribute to GBM malignant progression by inhibiting apoptosis or maintaining stemness under hypoxic conditions. Moreover, Sox2, a marker of stemness, also contributes to GBM malignant progression through stemness maintenance or cell cycle arrest. Briefly, HIF1α, HIF2α and Sox2 are highly expressed under hypoxia and contribute to GBM growth and chemoresistance. However, after exposure to HBO for GBM, whether the expression of the above factors is decreased, resulting in chemosensitization, remains unknown. Therefore, we performed a series of studies and determined that the expression of HIF1α, HIF2α and Sox2 was decreased after HBO and that HBO promoted GBM cell proliferation through cell cycle progression, albeit with a decrease in stemness, thus contributing to chemosensitization via the inhibition of HIF1α/HIF2α-Sox2.
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Affiliation(s)
- Pan Wang
- Department of Neurosurgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 401147, China.,Chongqing Medical University, Chongqing, China
| | - Sheng Gong
- Department of Neurosurgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 401147, China
| | - Jinyu Pan
- Department of Neurosurgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 401147, China
| | - Junwei Wang
- Department of Neurosurgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 401147, China
| | - Dewei Zou
- Department of Neurosurgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 401147, China
| | - Shuanglong Xiong
- Department of Oncology, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Lu Zhao
- Department of Neurosurgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 401147, China
| | - Qian Yan
- Department of Neurosurgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 401147, China
| | - Yangming Deng
- Department of Neurosurgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 401147, China
| | - Nan Wu
- Department of Neurosurgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 401147, China.
| | - Bin Liao
- Department of Neurosurgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 401147, China.
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HIF1α/HIF2α-Sox2/Klf4 promotes the malignant progression of glioblastoma via the EGFR-PI3K/AKT signalling pathway with positive feedback under hypoxia. Cell Death Dis 2021; 12:312. [PMID: 33762574 PMCID: PMC7990922 DOI: 10.1038/s41419-021-03598-8] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 02/23/2021] [Accepted: 02/25/2021] [Indexed: 12/12/2022]
Abstract
Previous studies have suggested that hypoxic responses are regulated by hypoxia-inducible factors (HIFs), which in turn promote the malignant progression of glioblastoma (GBM) by inhibiting apoptosis and increasing proliferation; these events lead to a poor prognosis of GBM patients. However, there are still no HIF-targeted therapies for the treatment of GBM. We have conducted series of experiments and discovered that GBM cells exhibit features indicative of malignant progression and are present in a hypoxic environment. Knocking out HIF1α or HIF2α alone resulted in no significant change in cell proliferation and cell cycle progression in response to acute hypoxia, but cells showed inhibition of stemness expression and chemosensitization to temozolomide (TMZ) treatment. However, simultaneously knocking out HIF1α and HIF2α inhibited cell cycle arrest and promoted proliferation with decreased stemness, making GBM cells more sensitive to chemotherapy, which could improve patient prognosis. Thus, HIF1α and HIF2α regulate each other with negative feedback. In addition, HIF1α and HIF2α are upstream regulators of epidermal growth factor (EGF), which controls the malignant development of GBM through the EGFR-PI3K/AKT-mTOR-HIF1α signalling pathway. In brief, the HIF1α/HIF2α-EGF/EGFR-PI3K/AKT-mTOR-HIF1α signalling axis contributes to the growth of GBM through a positive feedback mechanism. Finally, HIF1α and HIF2α regulate Sox2 and Klf4, contributing to stemness expression and inducing cell cycle arrest, thus increasing malignancy in GBM. In summary, HIF1α and HIF2α regulate glioblastoma malignant progression through the EGFR-PI3K/AKT pathway via a positive feedback mechanism under the effects of Sox2 and Klf4, which provides a new tumour development model and strategy for glioblastoma treatment.
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Zhu Z, Lin S, Wu X, Xu J, Li L, Ye W, Li J, Huang Z. Decitabine and Cisplatin are Synergistic to Exert Anti-Tumor Effect on Gastric Cancer via Inducing Sox2 DNA Demethylation. Onco Targets Ther 2021; 14:623-636. [PMID: 33519210 PMCID: PMC7837578 DOI: 10.2147/ott.s276168] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 12/10/2020] [Indexed: 01/30/2023] Open
Abstract
Background Cisplatin is a vital chemotherapy regimen for gastric cancer (GC), while partial response is observed (approximately 40%) because of drug resistance. Thus, it is urgent to improve drug sensitivity to improve the therapeutic effect of cisplatin on GC. Purpose The study was performed to explore the synergistic effect of decitabine and cisplatin in GC. Materials and Methods Cancer and matched adjacent tissues from patients with GC were obtained and quantitative real-time PCR (qRT-PCR), Western blot and immunohistochemistry were performed to evaluate Sox2 expression level. Methylation-specific PCR (MSP) was performed to assess the effect of 5-aza-2ʹ-deoxycytidine (5-Aza-CdR) on Sox2 promoter. Cell proliferation assay, scratch-wound migration assay and Transwell invasion ability were performed to assess the effect of 5-Aza-CdR on proliferation, migration and invasion ability. Meantime, the effect of 5-Aza-CdR was also investigated in gastric cell lines BGC-823 and nude mouse xenograft tumor model. Finally, the anti-cancer effect of decitabine, cisplatin and their combination treatment were investigated in a BGC-823 and nude mouse xenograft tumor model, Sox2 methylation level, Sox2 expression of BGC-823 and xenograft tumors were analyzed by MSP, qRT-PCR and Western blot. Results Sox2 expression was significantly associated with different differentiated degrees, depth of invasion (0.0011), lymph node metastasis (0.0013), and TNM stage (0.0002). Next, methylation inhibitor 5-Aza-CdR restored Sox2 expression to promote proliferation, migration and invasion in vitro and in vivo. Finally, cisplatin and decitabine was found to be synergistic to inhibit proliferation of xenograft tumors. Likewise, cisplatin and decitabine were also synergistic to induce Sox2 DNA demethylation to promote Sox2 mRNA and protein expression in BGC-823 and xenograft tumors. Conclusion Cisplatin and decitabine could be synergistic to induce Sox2 DNA demethylation to promote expression of the Sox2 gene, which exerted an anti-tumor effect on GC. It may suggest an insight for innovative therapeutics of GC.
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Affiliation(s)
- Zhipeng Zhu
- Department of Gastrointestinal Surgery, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, People's Republic of China
| | - Sihao Lin
- Department of Gastrointestinal Surgery, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, People's Republic of China
| | - Xiaofang Wu
- Department of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian 350004, People's Republic of China
| | - Jiuhua Xu
- Department of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian 350004, People's Republic of China
| | - Lulu Li
- Department of Gastrointestinal Surgery, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, People's Republic of China
| | - Weipeng Ye
- Department of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian 350004, People's Republic of China
| | - Jiayi Li
- Department of Medical Oncology, Xiamen Cancer center, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, People's Republic of China
| | - Zhengjie Huang
- Department of Gastrointestinal Surgery, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, People's Republic of China.,Department of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian 350004, People's Republic of China
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Gomaa W, Marouf A, Alamoudi A, Al-Maghrabi J. SOX2 Is a Potential Novel Marker of Undifferentiated Thyroid Carcinomas. Cureus 2020; 12:e12102. [PMID: 33489519 PMCID: PMC7805510 DOI: 10.7759/cureus.12102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/15/2020] [Indexed: 11/15/2022] Open
Abstract
Background Thyroid cancer is a very common endocrine malignancy. Cancer stem cells are attributable to initiation, progression, and treatment failure in thyroid carcinoma. In the current study, immunostaining of SRY-box 2 (SOX2) in thyroid carcinoma is investigated. Material and methods Tissue microarrays were generated from 219 thyroid carcinomas distributed as follows: papillary thyroid carcinoma (175), follicular thyroid carcinoma (11), medullary thyroid carcinoma (11), Hurthle cell carcinoma (three), poorly differentiated thyroid carcinoma (PTDC; nine), and anaplastic thyroid carcinoma (ATC; 10). Immunohistochemistry for SOX2 was done and examined for nuclear staining. The results were analysed. Results SOX2 immunostaining was positive in one PDTC (out of nine; 11.1%) and in three ATC (out of 10; 30%). The rest of the thyroid cancers showed no immunostaining for SOX2. Conclusion The study represents for the first time SOX2 immunostaining on a large number of thyroid carcinomas. We discovered that SOX2 immunostaining is found in PDTC and ATC while SOX2 immunostaining is lacking in other thyroid cancer. SOX2 may be a marker of loss of differentiation in thyroid carcinoma. In vitro as well as in vivo molecular studies are required to explore the possible role of SOX2 in thyroid carcinoma.
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Affiliation(s)
| | - Azmi Marouf
- Medicine, King Abdulaziz University, Jeddah, SAU
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28
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Basati G, Mohammadpour H, Emami Razavi A. Association of High Expression Levels of SOX2, NANOG, and OCT4 in Gastric Cancer Tumor Tissues with Progression and Poor Prognosis. J Gastrointest Cancer 2020; 51:41-47. [PMID: 30628031 DOI: 10.1007/s12029-018-00200-x] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Expression of the essential regulator genes, SOX2, NANOG, and OCT4, so-called as stemness factors, is prerequisite for the tumorigenic capability of cancer stem cells (CSCs) and their potential role in the formation and progression of various human cancers. METHODS In this study, the expression levels of SOX2, NANOG, and OCT4 were quantified by a qRT-PCR method in 100 gastric cancer tumor tissues vs the paired adjacent normal tissues. Then, the relationship between the expression of the three genes in gastric cancer tumor tissues and the clinicopathological characteristics and overall survival of patients was investigated. RESULTS Higher expression levels of SOX2, NANOG, and OCT4 were found in gastric cancer tumor tissues compared with those in paired adjacent normal tissues (P = 0.0001). Overexpression of the mentioned genes in gastric cancer tumor tissues was resolved to be significantly associated with tumor size (P < 0.05), TNM stage (P = 0.001), tumor grade (P < 0.01), and shortened overall survival time (P = 0.0001). CONCLUSIONS These findings indicted that the stemness factors SOX2, NANOG, and OCT4 are significantly overexpressed in gastric cancer and may serve as potential biomarkers of gastric cancer progression and prognosis.
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Affiliation(s)
- Gholam Basati
- Biotechnology and Medicinal Plants Research Center, Ilam University of Medical Sciences, Ilam, Iran
| | - Hadiseh Mohammadpour
- Cancer Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
| | - Amirnader Emami Razavi
- Iran National Tumor Bank, Cancer Biology Research Center, Cancer Institute of Iran., Tehran University of Medical Sciences, Keshavarz Boulevard, Tehran, Iran.
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29
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Olbromski M, Podhorska-Okołów M, Dzięgiel P. Role of SOX Protein Groups F and H in Lung Cancer Progression. Cancers (Basel) 2020; 12:cancers12113235. [PMID: 33152990 PMCID: PMC7692225 DOI: 10.3390/cancers12113235] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 10/24/2020] [Accepted: 10/27/2020] [Indexed: 12/15/2022] Open
Abstract
Simple Summary The expression of SOX proteins has been demonstrated in many tissues at various stages of embryogenesis, where they play the role of transcription factors. The SOX18 protein (along with SOX7 and SOX17) belongs to the SOXF group and is mainly involved in the development of the cardiovascular system, where its expression was found in the endothelium. SOX18 expression was also demonstrated in neoplastic lines of gastric, pancreatic and colon adenocarcinomas. The prognostic role of SOX30 expression has only been studied in lung adenocarcinomas, where a low expression of this factor in the stromal tumor was associated with a worse prognosis for patients. Because of the complexity of non-small-cell lung cancer (NSCLC) development, the role of the SOX proteins in this malignancy is still not fully understood. Many recently published papers show that SOX family protein members play a crucial role in the progression of NSCLC. Abstract The SOX family proteins are proved to play a crucial role in the development of the lymphatic ducts and the cardiovascular system. Moreover, an increased expression level of the SOX18 protein has been found in many malignances, such as melanoma, stomach, pancreatic breast and lung cancers. Another SOX family protein, the SOX30 transcription factor, is responsible for the development of male germ cells. Additionally, recent studies have shown its proapoptotic character in non-small cell lung cancer cells. Our preliminary studies showed a disparity in the amount of mRNA of the SOX18 gene relative to the amount of protein. This is why our attention has been focused on microRNA (miRNA) molecules, which could regulate the SOX18 gene transcript level. Recent data point to the fact that, in practically all types of cancer, hundreds of genes exhibit an abnormal methylation, covering around 5–10% of the thousands of CpG islands present in the promoter sequences, which in normal cells should not be methylated from the moment the embryo finishes its development. It has been demonstrated that in non-small-cell lung cancer (NSCLC) cases there is a large heterogeneity of the methylation process. The role of the SOX18 and SOX30 expression in non-small-cell lung cancers (NSCLCs) is not yet fully understood. However, if we take into account previous reports, these proteins may be important factors in the development and progression of these malignancies.
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Affiliation(s)
- Mateusz Olbromski
- Department of Histology and Embryology, Department of Human Morphology and Embryology, Medical University, 50-368 Wroclaw, Poland;
- Correspondence: ; Tel.: +48-717-841-354; Fax: +48-717-840-082
| | - Marzenna Podhorska-Okołów
- Department of Ultrastructural Research, Department of Human Morphology and Embryology, Medical University, 50-368 Wroclaw, Poland;
| | - Piotr Dzięgiel
- Department of Histology and Embryology, Department of Human Morphology and Embryology, Medical University, 50-368 Wroclaw, Poland;
- Department of Physiotherapy, University School of Physical Education, 51-612 Wroclaw, Poland
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30
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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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Yang KK, Xu HM, Huang JY, Guo YX, Wang ZN. Low SOX12 Expression Is Correlated With Poor Prognosis in Patients With Gastric Cancer. Technol Cancer Res Treat 2020; 19:1533033819901126. [PMID: 32019439 PMCID: PMC7003157 DOI: 10.1177/1533033819901126] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Background: SRY-related HMG box-12, which is associated with the prognosis of cancer, has been frequently described. However, both SRY-related HMG box-12 expression and its relationship with clinicopathological variables and patient survival have not been defined in gastric cancer. The aim of our study was to examine the prognostic value of SRY-related HMG box-12 expression in patients with gastric cancer. Methods: In this study, we determined SRY-related HMG box-12 expression in 79 primary gastric cancer tissues and 79 matched adjacent nontumor tissues by immunohistochemistry and then calculated the survival rate using the Kaplan-Meier method. Cox proportional hazard regression model was used to analyze predictors of gastric cancer. Western blot and quantitative real-time polymerase chain reaction were used to investigate the difference in SRY-related HMG box-12 expression between normal gastric epithelial cells and gastric cancer cells at the protein level and RNA level, respectively. Results: SRY-related HMG box-12 was downregulated in gastric cancer tissues. Low SRY-related HMG box-12 expression was significantly associated not only with lymph node metastasis (P = .027) and TNM stage (P = .021) but also with disease-specific survival in patients with gastric cancer. Multivariate analysis demonstrated TNM stage was an independent factor predicting poor survival (P = .034). Conclusions: Low SRY-related HMG box-12 expression is associated with poor clinical outcomes in gastric cancer.
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Affiliation(s)
- Kan-Kan Yang
- Department of Surgical Oncology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Hui-Mian Xu
- Department of Surgical Oncology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Jin-Yu Huang
- Department of Surgical Oncology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yu-Xuan Guo
- Department of Surgical Oncology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhen-Ning Wang
- Department of Surgical Oncology, First Affiliated Hospital of China Medical University, Shenyang, China
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32
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Functional characterization of SOX2 as an anticancer target. Signal Transduct Target Ther 2020; 5:135. [PMID: 32728033 PMCID: PMC7391717 DOI: 10.1038/s41392-020-00242-3] [Citation(s) in RCA: 124] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/01/2020] [Accepted: 06/22/2020] [Indexed: 02/07/2023] Open
Abstract
SOX2 is a well-characterized pluripotent factor that is essential for stem cell self-renewal, reprogramming, and homeostasis. The cellular levels of SOX2 are precisely regulated by a complicated network at the levels of transcription, post-transcription, and post-translation. In many types of human cancer, SOX2 is dysregulated due to gene amplification and protein overexpression. SOX2 overexpression is associated with poor survival of cancer patients. Mechanistically, SOX2 promotes proliferation, survival, invasion/metastasis, cancer stemness, and drug resistance. SOX2 is, therefore, an attractive anticancer target. However, little progress has been made in the efforts to discover SOX2 inhibitors, largely due to undruggable nature of SOX2 as a transcription factor. In this review, we first briefly introduced SOX2 as a transcription factor, its domain structure, normal physiological functions, and its involvement in human cancers. We next discussed its role in embryonic development and stem cell-renewal. We then mainly focused on three aspects of SOX2: (a) the regulatory mechanisms of SOX2, including how SOX2 level is regulated, and how SOX2 cross-talks with multiple signaling pathways to control growth and survival; (b) the role of SOX2 in tumorigenesis and drug resistance; and (c) current drug discovery efforts on targeting SOX2, and the future perspectives to discover specific SOX2 inhibitors for effective cancer therapy.
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Pádua D, Barros R, Luísa Amaral A, Mesquita P, Filipa Freire A, Sousa M, Filipe Maia A, Caiado I, Fernandes H, Pombinho A, Filipe Pereira C, Almeida R. A SOX2 Reporter System Identifies Gastric Cancer Stem-Like Cells Sensitive to Monensin. Cancers (Basel) 2020; 12:E495. [PMID: 32093282 PMCID: PMC7072720 DOI: 10.3390/cancers12020495] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 02/12/2020] [Accepted: 02/15/2020] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer remains a serious health burden with few therapeutic options. Therefore, the recognition of cancer stem cells (CSCs) as seeds of the tumorigenic process makes them a prime therapeutic target. Knowing that the transcription factors SOX2 and OCT4 promote stemness, our approach was to isolate stem-like cells in human gastric cancer cell lines using a traceable reporter system based on SOX2/OCT4 activity (SORE6-GFP). Cells transduced with the SORE6-GFP reporter system were sorted into SORE6+ and SORE6- cell populations, and their biological behavior characterized. SORE6+ cells were enriched for SOX2 and exhibited CSC features, including a greater ability to proliferate and form gastrospheres in non-adherent conditions, a larger in vivo tumor initiating capability, and increased resistance to 5-fluorouracil (5-FU) treatment. The overexpression and knockdown of SOX2 revealed a crucial role of SOX2 in cell proliferation and drug resistance. By combining the reporter system with a high-throughput screening of pharmacologically active small molecules we identified monensin, an ionophore antibiotic, displaying selective toxicity to SORE6+ cells. The ability of SORE6-GFP reporter system to recognize cancer stem-like cells facilitates our understanding of gastric CSC biology and serves as a platform for the identification of powerful therapeutics for targeting gastric CSCs.
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Affiliation(s)
- Diana Pádua
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, 4200-465 Porto, Portugal
| | - Rita Barros
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, 4200-465 Porto, Portugal
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
| | - Ana Luísa Amaral
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, 4200-465 Porto, Portugal
| | - Patrícia Mesquita
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, 4200-465 Porto, Portugal
| | - Ana Filipa Freire
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, 4200-465 Porto, Portugal
| | - Mafalda Sousa
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IBMC—Institute of Molecular and Cell Biology, University of Porto, 4200-135 Porto, Portugal
| | - André Filipe Maia
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IBMC—Institute of Molecular and Cell Biology, University of Porto, 4200-135 Porto, Portugal
| | - Inês Caiado
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; (I.C.); (H.F.); (C.F.P.)
- Cell Reprogramming in Hematopoiesis and Immunity laboratory, Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, BMC A12, 221 84 Lund, Sweden
- Wallenberg Center for Molecular Medicine, Lund University, 221 84 Lund, Sweden
| | - Hugo Fernandes
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; (I.C.); (H.F.); (C.F.P.)
- Faculty of Medicine, University of Coimbra, 3000-354 Coimbra, Portugal
| | - António Pombinho
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IBMC—Institute of Molecular and Cell Biology, University of Porto, 4200-135 Porto, Portugal
| | - Carlos Filipe Pereira
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; (I.C.); (H.F.); (C.F.P.)
- Cell Reprogramming in Hematopoiesis and Immunity laboratory, Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, BMC A12, 221 84 Lund, Sweden
- Wallenberg Center for Molecular Medicine, Lund University, 221 84 Lund, Sweden
| | - Raquel Almeida
- i3S—Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (D.P.); (R.B.); (A.L.A.); (P.M.); (A.F.F.); (M.S.); (A.F.M.); (A.P.)
- IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, 4200-465 Porto, Portugal
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
- Biology Department, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
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Chuang HM, Huang MH, Chen YS, Harn HJ. SOX2 for Stem Cell Therapy and Medical Use: Pros or Cons? Cell Transplant 2020; 29:963689720907565. [PMID: 32233795 PMCID: PMC7444200 DOI: 10.1177/0963689720907565] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 01/14/2020] [Accepted: 01/27/2020] [Indexed: 11/15/2022] Open
Abstract
Stem cell transplantation is a fast-developing technique, which includes stem cell isolation, purification, and storage, and it is in high demand in the industry. In addition, advanced applications of stem cell transplantation, including differentiation, gene delivery, and reprogramming, are presently being studied in clinical trials. In contrast to somatic cells, stem cells are self-renewing and have the ability to differentiate; however, the molecular mechanisms remain unclear. SOX2 (sex-determining region Y [SRY]-box 2) is one of the well-known reprogramming factors, and it has been recognized as an oncogene associated with cancer induction. The exclusion of SOX2 in reprogramming methodologies has been used as an alternative cancer treatment approach. However, the manner by which SOX2 induces oncogenic effects remains unclear, with most studies demonstrating its regulation of the cell cycle and no insight into the maintenance of cellular stemness. For controlling certain critical pathways, including Shh and Wnt pathways, SOX2 is considered irreplaceable and is required for the normal functioning of stem cells, particularly neural stem cells. In this report, we discussed the functions of SOX2 in both stem and cancer cells, as well as how this powerful regulator can be used to control cell fate.
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Affiliation(s)
- Hong-Meng Chuang
- Buddhist Tzu Chi Bioinnovation Center, Tzu Chi Foundation, Hualien,
Republic of China
- Department of Medical Research, Hualien Tzu Chi Hospital, Hualien,
Republic of China
| | - Mao-Hsuan Huang
- Buddhist Tzu Chi Bioinnovation Center, Tzu Chi Foundation, Hualien,
Republic of China
- Department of Stem Cell Applied Technology, Gwo Xi Stem Cell Applied
Technology, Hsinchu, Republic of China
| | - Yu-Shuan Chen
- Buddhist Tzu Chi Bioinnovation Center, Tzu Chi Foundation, Hualien,
Republic of China
- Department of Medical Research, Hualien Tzu Chi Hospital, Hualien,
Republic of China
| | - Horng-Jyh Harn
- Buddhist Tzu Chi Bioinnovation Center, Tzu Chi Foundation, Hualien,
Republic of China
- Department of Pathology, Hualien Tzu Chi Hospital & Tzu Chi
University, Hualien, Republic of China
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35
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Schaefer T, Lengerke C. SOX2 protein biochemistry in stemness, reprogramming, and cancer: the PI3K/AKT/SOX2 axis and beyond. Oncogene 2020; 39:278-292. [PMID: 31477842 PMCID: PMC6949191 DOI: 10.1038/s41388-019-0997-x] [Citation(s) in RCA: 121] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Revised: 07/20/2019] [Accepted: 08/09/2019] [Indexed: 12/14/2022]
Abstract
Research of the past view years expanded our understanding of the various physiological functions the cell-fate determining transcription factor SOX2 exerts in ontogenesis, reprogramming, and cancer. However, while scientific reports featuring novel and exciting aspects of SOX2-driven biology are published in near weekly routine, investigations in the underlying protein-biochemical processes that transiently tailor SOX2 activity to situational demand are underrepresented and have not yet been comprehensively summarized. Largely unrecognizable to modern array or sequencing-based technology, various protein secondary modifications and concomitant function modulations have been reported for SOX2. The chemical modifications imposed onto SOX2 are inherently heterogeneous, comprising singular or clustered events of phosphorylation, methylation, acetylation, ubiquitination, SUMOylation, PARPylation, and O-glycosylation that reciprocally affect each other and critically impact SOX2 functionality, often in a tissue and species-specific manner. One recurring regulatory principle though is the canonical PI3K/AKT signaling axis to which SOX2 relates in various entangled, albeit not exclusive ways. Here we provide a comprehensive review of the current knowledge on SOX2 protein modifications, their proposed relationship to the PI3K/AKT pathway, and regulatory influence on SOX2 with regards to stemness, reprogramming, and cancer.
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Affiliation(s)
- Thorsten Schaefer
- University of Basel and University Hospital Basel, Department of Biomedicine, Basel, Switzerland.
| | - Claudia Lengerke
- University of Basel and University Hospital Basel, Department of Biomedicine, Basel, Switzerland
- University Hospital Basel, Division of Hematology, Basel, Switzerland
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Yu W, Ren X, Hu C, Tan Y, Shui Y, Chen Z, Zhang L, Peng J, Wei Q. Glioma SOX2 expression decreased after adjuvant therapy. BMC Cancer 2019; 19:1087. [PMID: 31718604 PMCID: PMC6849258 DOI: 10.1186/s12885-019-6292-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 10/25/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND SOX2 is regarded as an important marker in stem cell. The change of SOX2 expression after adjuvant therapy in high grade glioma (HGG) remains unknown so far. Few patients with recurrent glioma have opportunity to undergo operation once again, so the recurrent glioma samples are scarce. This study tries to analyze SOX2 expression in paired primary and recurrent HGG, aims to better understand the transformation law of SOX2 after adjuvant therapy in HGG. METHODS Twenty-four recurrent HGG patients who undergone a second resection were included. 16 patients received adjuvant therapy, the remaining 8 patients didn't receive any adjuvant therapy at all. The protein expression of SOX2 in paired primary and recurrent HGG was tested by immunohistochemistry. The statistical analysis was conducted by IBM SPSS Statistics 19.0. RESULTS In primary HGG, SOX2 expression of 3 + , 2 + , 1+ and 0+ were seen in 20 (83.3%), 1 (4.2%), 1 (4.2%) and 2 cases (8.3%), respectively. The expression of SOX2 was decreased in recurrent HGG compared to the paired primary sample (p = 0.001). The decrease of SOX2 was often seen in patients received chemotherapy, radiotherapy or both (p = 0.003). Patients with SOX2 high expression in primary glioma had a longer median PFS than those with SOX2 low expression with marginal statistic significance (12.7 vs. 5.4 months, p = 0.083). For cases with SOX2 high expression in the primary glioma, those had SOX2 low expression after recurrence seemed to have worse prognosis as compared to patients with stable SOX2 high expression (PFS: 10.4 vs. 14.9 months, p = 0.036; OS: 27.0 vs 49.5 months, p = 0.005). CONCLUSIONS This is the first study comparing the protein expression of SOX2 in recurrent HGG and its paired primary tumor. SOX2 high expression is common in brain HGG, a tendency of decreased SOX2 expression in recurrent gliomas was evidenced. Lower SOX2 expression was seen in those patients who received adjuvant chemotherapy and/or radiotherapy. Patients with low SOX2 expression in primary HGG usually have poorer prognosis, those with SOX2 expression decreased in recurrent HGG had worse outcome.
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Affiliation(s)
- Wei Yu
- Department of Radiation Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Jiefang Road 88, Hangzhou, 310009, People's Republic of China.,Cancer Institute (Ministry of Education Key Laboratory of Cancer Prevention and Intervention), Zhejiang University Cancer Institute, Hangzhou, 310009, People's Republic of China
| | - Xiaoqiu Ren
- Department of Radiation Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Jiefang Road 88, Hangzhou, 310009, People's Republic of China.,Cancer Institute (Ministry of Education Key Laboratory of Cancer Prevention and Intervention), Zhejiang University Cancer Institute, Hangzhou, 310009, People's Republic of China
| | - Chunxiu Hu
- Department of Radiation Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Jiefang Road 88, Hangzhou, 310009, People's Republic of China.,Department of Radiation Oncology, Zhejiang Quhua Hospital, Quzhou, 324000, People's Republic of China
| | - Yinuo Tan
- Department of Medical Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, People's Republic of China
| | - Yongjie Shui
- Department of Radiation Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Jiefang Road 88, Hangzhou, 310009, People's Republic of China
| | - Zexin Chen
- Center of Clinical Epidemiology and Biostatistics for statistical analysis, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, People's Republic of China
| | - Lili Zhang
- Department of Radiation Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Jiefang Road 88, Hangzhou, 310009, People's Republic of China.,Cancer Institute (Ministry of Education Key Laboratory of Cancer Prevention and Intervention), Zhejiang University Cancer Institute, Hangzhou, 310009, People's Republic of China
| | - Jiaping Peng
- Department of Radiation Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Jiefang Road 88, Hangzhou, 310009, People's Republic of China.,Cancer Institute (Ministry of Education Key Laboratory of Cancer Prevention and Intervention), Zhejiang University Cancer Institute, Hangzhou, 310009, People's Republic of China
| | - Qichun Wei
- Department of Radiation Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Jiefang Road 88, Hangzhou, 310009, People's Republic of China. .,Cancer Institute (Ministry of Education Key Laboratory of Cancer Prevention and Intervention), Zhejiang University Cancer Institute, Hangzhou, 310009, People's Republic of China.
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Wang L, Xing Q, Feng T, He M, Yu W, Chen H. SNP rs710886 A>G in long noncoding RNA PCAT1 is associated with the risk of endometriosis by modulating expression of multiple stemness‐related genes via microRNA‐145 signaling pathway. J Cell Biochem 2019; 121:1703-1715. [PMID: 31595574 DOI: 10.1002/jcb.29406] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 06/05/2019] [Indexed: 01/16/2023]
Affiliation(s)
- Liming Wang
- Department of Gynecology, Hubei Provincial Maternal and Child Health Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Qi Xing
- Department of Gynecology, Hubei Provincial Maternal and Child Health Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Tongfu Feng
- Department of Gynecology, Hubei Provincial Maternal and Child Health Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Ming He
- Department of Gynecology, Hubei Provincial Maternal and Child Health Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Weixu Yu
- Department of Gynecology, Hubei Provincial Maternal and Child Health Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China
| | - Hui Chen
- Department of Gynecology and Obstetrics, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China
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Chai Y, Li Q, Zhao H, Zhang Z, Yu X, Pang L, Liu Z, Zhao J, Wang L, Li F. SOX2 antagonizes WWC1 to drive YAP1 activation in esophageal squamous cell carcinoma. Cancer Med 2019; 8:7055-7064. [PMID: 31560173 PMCID: PMC6853808 DOI: 10.1002/cam4.2569] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Revised: 08/19/2019] [Accepted: 09/09/2019] [Indexed: 12/24/2022] Open
Abstract
Whether SOX2 and ACTL6A/TP63 interact with the Hippo-YAP1 pathway in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we reveal that SOX2, ACTL6A, and TP63 are co-amplified and upregulated in ESCC samples. Multiple SOX2 binding peaks in the locus of WWC1, a Hippo-YAP1 regulator, and an inverse correlation between the expression of SOX2 and WWC1 are identified, suggesting direct repression of WWC1 by SOX2. Expression scores of SOX2 are higher in tumors than normal tissues and positively correlated with nuclear YAP1 staining in primary ESCC. Moreover, SOX2 gain-of-function significantly promotes nuclear YAP1 expression in ESCC cells while silencing of SOX2 expression inhibits YAP1 activation. SOX2 overexpression leads to a significant enhancement of cell migration and invasion as well as chemoresistance to cisplatin, whereas knockdown of SOX2 or ectopic expression of WWC1 suppresses the SOX2-induced migration ability and invasive potential. Disruption of this SOX2-WWC1-YAP1 axis could be a therapeutic strategy for SOX2-dependent tumors.
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Affiliation(s)
- Yuhang Chai
- Department of Pathology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases/the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China
| | - Qihang Li
- Department of Pathology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases/the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China
| | - Hongying Zhao
- Department of Pathology and Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Zhiyu Zhang
- Department of Pathology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases/the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China.,Department of Pathology and Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Xiaodan Yu
- Department of Pathology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases/the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China.,Department of Stomatology, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China
| | - Lijuan Pang
- Department of Pathology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases/the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China
| | - Zheng Liu
- Department of Pathology and Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Jin Zhao
- Department of Pathology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases/the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China
| | - Lianghai Wang
- Department of Pathology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases/the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China
| | - Feng Li
- Department of Pathology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases/the First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China.,Department of Pathology and Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
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Novak D, Hüser L, Elton JJ, Umansky V, Altevogt P, Utikal J. SOX2 in development and cancer biology. Semin Cancer Biol 2019; 67:74-82. [PMID: 31412296 DOI: 10.1016/j.semcancer.2019.08.007] [Citation(s) in RCA: 216] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 08/05/2019] [Accepted: 08/08/2019] [Indexed: 01/06/2023]
Abstract
The transcription factor SOX2 is essential for embryonic development and plays a crucial role in maintaining the stemness of embryonic cells and various adult stem cell populations. On the other hand, dysregulation of SOX2 expression is associated with a multitude of cancer types and it has been shown that SOX2 positively affects cancer cell traits such as the capacity to proliferate, migrate, invade and metastasize. Moreover, there is growing evidence that SOX2 mediates resistance towards established cancer therapies and that it is expressed in cancer stem cells. These findings indicate that studying the role of SOX2 in the context of cancer progression could lead to the development of new therapeutic options. In this review, the current knowledge about the role of SOX2 in development, maintenance of stemness, cancer progression and the resistance towards cancer therapies is summarized.
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Affiliation(s)
- Daniel Novak
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
| | - Laura Hüser
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
| | - Jonathan J Elton
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
| | - Viktor Umansky
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
| | - Peter Altevogt
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
| | - Jochen Utikal
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
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40
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Chaudhary S, Islam Z, Mishra V, Rawat S, Ashraf GM, Kolatkar PR. Sox2: A Regulatory Factor in Tumorigenesis and Metastasis. Curr Protein Pept Sci 2019; 20:495-504. [PMID: 30907312 DOI: 10.2174/1389203720666190325102255] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 02/17/2019] [Accepted: 03/12/2019] [Indexed: 01/29/2023]
Abstract
The transcription factor Sox2 plays an important role in various phases of embryonic development, including cell fate and differentiation. These key regulatory functions are facilitated by binding to specific DNA sequences in combination with partner proteins to exert their effects. Recently, overexpression and gene amplification of Sox2 has been associated with tumor aggression and metastasis in various cancer types, including breast, prostate, lung, ovarian and colon cancer. All the different roles for Sox2 involve complicated regulatory networks consisting of protein-protein and protein-nucleic acid interactions. Their involvement in the EMT modulation is possibly enabled by Wnt/ β-catenin and other signaling pathways. There are number of in vivo models which show Sox2 association with increased cancer aggressiveness, resistance to chemo-radiation therapy and decreased survival rate suggesting Sox2 as a therapeutic target. This review will focus on the different roles for Sox2 in metastasis and tumorigenesis. We will also review the mechanism of action underlying the cooperative Sox2- DNA/partner factors binding where Sox2 can be potentially explored for a therapeutic opportunity to treat cancers.
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Affiliation(s)
| | - Zeyaul Islam
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Vijaya Mishra
- RASA Life science Informatics, Pune, Maharashtra, India
| | - Sakshi Rawat
- RASA Life science Informatics, Pune, Maharashtra, India
| | - Ghulam Md Ashraf
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.,Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Prasanna R Kolatkar
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
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Mahmoudian J, Ghods R, Nazari M, Jeddi-Tehrani M, Ghahremani MH, Ghaffari-Tabrizi-Wizsy N, Ostad SN, Zarnani AH. PLAC1: biology and potential application in cancer immunotherapy. Cancer Immunol Immunother 2019; 68:1039-1058. [PMID: 31165204 PMCID: PMC11028298 DOI: 10.1007/s00262-019-02350-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 05/24/2019] [Indexed: 12/29/2022]
Abstract
The emergence of immunotherapy has revolutionized medical oncology with unprecedented advances in cancer treatment over the past two decades. However, a major obstacle in cancer immunotherapy is identifying appropriate tumor-specific antigens to make targeted therapy achievable with fewer normal cells being impaired. The similarity between placentation and tumor development and growth has inspired many investigators to discover antigens for effective immunotherapy of cancers. Placenta-specific 1 (PLAC1) is one of the recently discovered placental antigens with limited normal tissue expression and fundamental roles in placental function and development. There is a growing body of evidence showing that PLAC1 is frequently activated in a wide variety of cancer types and promotes cancer progression. Based on the restricted expression of PLAC1 in testis, placenta and a wide variety of cancers, we have designated this molecule with new terminology, cancer-testis-placenta (CTP) antigen, a feature that PLAC1 shares with many other cancer testis antigens. Recent reports from our lab provide compelling evidence on the preferential expression of PLAC1 in prostate cancer and its potential utility in prostate cancer immunotherapy. PLAC1 may be regarded as a potential CTP antigen for targeted cancer immunotherapy based on the available data on its promoting function in cancer development and also its expression in cancers of different histological origin. In this review, we will summarize current data on PLAC1 with emphasis on its association with cancer development and immunotherapy.
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Affiliation(s)
- Jafar Mahmoudian
- Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences (TUMS), Tehran, Iran
- Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Roya Ghods
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mahboobeh Nazari
- Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Mahmood Jeddi-Tehrani
- Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Mohammad Hossein Ghahremani
- Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences (TUMS), Tehran, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Pharmacology Building, Enghelab St., Tehran, 1417614411, Iran
| | | | - Seyed Nasser Ostad
- Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences (TUMS), Tehran, Iran.
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Pharmacology Building, Enghelab St., Tehran, 1417614411, Iran.
| | - Amir-Hassan Zarnani
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Nafisi Building, Enghelab St., Tehran, 1417613151, Iran.
- Reproductive Immunology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran.
- Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran.
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Javaeed A, Ghauri SK. Metastatic potential and prognostic significance of SOX2: A meta-analysis. World J Clin Oncol 2019; 10:234-246. [PMID: 31367532 PMCID: PMC6657218 DOI: 10.5306/wjco.v10.i6.234] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Revised: 03/31/2019] [Accepted: 04/09/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND SOX2 is a regulator of pluripotent cellular transcription, yet it has been recently integrated in cancer biology. The present study provides an analytic insight into the correlation of SOX2 overexpression with cancer metastasis and patient survival.
AIM To investigate the association of SOX2 overexpression with metastasis and its implication in the prognosis of cancer patients.
METHODS A meta-analysis was conducted including studies that compared the association of low or high SOX2 expression with lymph node metastasis (LNM) and/or distant metastasis (DM). The following data were additionally extracted: survival, including the overall survival (OS) and disease-free survival (DFS), and prevalence of high and low SOX2 expression. Odds ratios (commonly known as ORs) and their respective 95% confidence intervals (CIs) were used to investigate the association between SOX2 expression and LNM and DM, while hazard ratios (commonly known as HRs) and 95%CIs were applied to evaluate the prognostic markers.
RESULTS In a total of 2643 patients (60.88% males), the pooled prevalence of SOX2 overexpression was 46.22% (95%CI: 39.07%-53.38%) in different types of cancer. SOX2 overexpression significantly correlated with DM (OR = 1.79, 95%CI: 1.20-3.25, P < 0.008) compared to low SOX2 expression. In subgroups analyses, a high SOX2 expression was associated with LNM in cancers of the lung, breast, and colon and associated with DM in hepatic, head and neck, and colon cancers. SOX2 overexpression was also associated with a shorter OS (HR = 1.65, 95%CI: 1.34-2.04, P < 0.001) and DFS (HR = 1.54, 95%CI: 1.14-2.08, P = 0.005).
CONCLUSION A remarkable role of SOX2 overexpression was observed in cancer biology and metastasis. However, many questions in the regulatory pathways need to be addressed to reveal as many functional aspects as possible to tailor new targeted therapeutic strategies.
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Affiliation(s)
- Arslaan Javaeed
- Department of Pathology, Poonch Medical College, Azad Kashmir, Rawalakot 1235, Pakistan
| | - Sanniya Khan Ghauri
- Department of Emergency Medicine, Shifa International Hospital, Islamabad, 44000, Pakistan
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Han SH, Kim JW, Kim M, Kim JH, Lee KW, Kim BH, Oh HK, Kim DW, Kang SB, Kim H, Shin E. Prognostic implication of ABC transporters and cancer stem cell markers in patients with stage III colon cancer receiving adjuvant FOLFOX-4 chemotherapy. Oncol Lett 2019; 17:5572-5580. [PMID: 31186779 PMCID: PMC6507487 DOI: 10.3892/ol.2019.10234] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 02/20/2019] [Indexed: 01/15/2023] Open
Abstract
Cancer stem cell (CSC) and ATP-binding cassette (ABC) transporters are associated with treatment resistance and outcomes of patients with cancer. The present study investigated the prognostic implications of pre-therapeutic expression of ABC transporters and CSC markers in patients with colon cancer (CC) who received adjuvant 5-fluorouracil, leucovorin and oxaliplatin combination therapy (FOLFOX-4). The immunohistochemical expression of 3 ABC transporters, including ABC subfamily C member 2 (ABCC2), ABCC3 and ABC subfamily G member 2 (ABCG2), and 3 CSC markers, including sex determining region Y-box 2 (SOX2), leucine-rich repeat-containing G protein-coupled receptor 5 and aldehyde dehydrogenase 1, were determined in 164 CC tissues from patients with stage III CC, who underwent postoperative FOLFOX-4 chemotherapy. The association between the protein expression and patients' prognoses was statistically analyzed. ABCG2 was associated with favorable overall survival rate (OS; P=0.001), and ABCC2, ABCG2 and SOX2 were associated with increased disease-free survival rate (DFS; P=0.001, 0.002 and 0.013, respectively). In multivariate analyses, ABCG2 was an independent prognostic factor for OS [hazard ratio (HR)=2.877; P=0.046], and ABCC2 and SOX2 were independent prognostic factors for DFS (HR=2.831; P=0.014; HR=2.558, P=0.020, respectively). ABCC2, ABCG2 and SOX2 may be promising prognostic markers for patients with CC receiving FOLFOX-4 therapy.
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Affiliation(s)
- Song-Hee Han
- Department of Pathology, Dong-A University School of Medicine, Busan, South Gyeongsang 49201, Republic of Korea
| | - Jin Won Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi 13620, Republic of Korea
| | - Milim Kim
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi 13620, Republic of Korea
| | - Jee Hyun Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi 13620, Republic of Korea
| | - Keun-Wook Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi 13620, Republic of Korea
| | - Bo-Hyung Kim
- Department of Clinical Pharmacology and Therapeutics, Kyung Hee University College of Medicine and Hospital, Seoul 02447, Republic of Korea
| | - Heung-Kwon Oh
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Gyeonggi 13620, Republic of Korea
| | - Duck-Woo Kim
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Gyeonggi 13620, Republic of Korea
| | - Sung-Bum Kang
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Gyeonggi 13620, Republic of Korea
| | - Hyunchul Kim
- Department of Pathology, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Gyeonggi 18450, Republic of Korea
| | - Eun Shin
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi 13620, Republic of Korea.,Department of Pathology, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Gyeonggi 18450, Republic of Korea
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Yuan T, Ni Z, Han C, Min Y, Sun N, Liu C, Shi M, Lu W, Wang N, Du F, Wu Q, Xie N, Shi Y. SOX2 interferes with the function of CDX2 in bile acid-induced gastric intestinal metaplasia. Cancer Cell Int 2019; 19:24. [PMID: 30733645 PMCID: PMC6357452 DOI: 10.1186/s12935-019-0739-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 01/28/2019] [Indexed: 12/16/2022] Open
Abstract
Background Intestinal metaplasia (IM) is a premalignant lesion associated with gastric cancer. Both animal and clinical studies have revealed that bile acid reflux and subsequent chronic inflammation are key causal factors of IM. Previous studies indicated that SOX2, the key transcription factor in gastric differentiation, was downregulated during IM development while CDX2, the pivotal intestine-specific transcription factor was upregulated significantly. However, it remains unclear whether the downregulation of SOX2 promotes gastric IM emergence or is merely a concomitant phenomenon. In addition, the underlying mechanisms of SOX2 downregulation during IM development are unclear. Methods Gastric cell lines were treated with deoxycholic acid (DCA) in a dose-dependent manner. The expression of CDX2 and miR-21 in gastric tissue microarray were detected by immunohistochemistry and in situ hybridization. Coimmunoprecipitation and immunofluorescence were performed to ascertain the interaction of SOX2 and CDX2. Luciferase reporter assays were used to detect the transcriptional activity of CDX2, and confirm miR-21 binding to SOX2 3′-UTR. The protein level of SOX2, CDX2 and downstream IM-specific genes were investigated using western blotting. mRNA level of miR-21, SOX2, CDX2 and downstream IM-specific genes were detected by qRT-PCR. Results Bile acid treatment could suppress SOX2 expression and simultaneously induce expression of CDX2 in gastric cell lines. Furthermore, we demonstrated that SOX2 overexpression could significantly inhibit bile acid- and exogenous CDX2-induced IM-specific gene expression, including KLF4, cadherin 17 and HNF4α expression. In contrast, SOX2 knockdown had the opposite effect. A dual-luciferase reporter assay demonstrated that SOX2 overexpression could significantly suppress CDX2 transcriptional activity in HEK293T cells. CDX2 and SOX2 could form protein complexes in the nucleus. In addition, bile acid induced the expression of miR-21. The inhibition of SOX2 in bile acid-treated gastric cell lines was rescued by miR-21 knockdown. Conclusions These findings suggested that SOX2 can interfere with the transcriptional activity of CDX2 in bile acid-induced IM and that miR-21 might play a key role in this process, which shed new lights in the prevention of gastric cancer. Electronic supplementary material The online version of this article (10.1186/s12935-019-0739-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ting Yuan
- 1State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032 China.,The 150 Hospital of the People's Liberation Army, Luoyang, 471000 China
| | - Zhen Ni
- 1State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032 China.,Department of Gastroenterology, The General Hospital of Western Theater Command, Chengdu, 610083 China
| | - Chuan Han
- 1State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032 China.,Rocket Army Emei Sanatorium, Emei, 614200 China
| | - Yali Min
- 5Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Medical University, Xi'an, 710032 China
| | - Nina Sun
- 1State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032 China.,6College of Postgraduates, Xi'an Medical University, Xi'an, 710032 China
| | - Caifang Liu
- 1State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032 China.,6College of Postgraduates, Xi'an Medical University, Xi'an, 710032 China
| | - Miao Shi
- 1State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032 China.,6College of Postgraduates, Xi'an Medical University, Xi'an, 710032 China
| | - Wenquan Lu
- 1State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032 China.,7Department of Gastroenterology, First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450000 China
| | - Na Wang
- 1State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032 China
| | - Feng Du
- 1State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032 China
| | - Qiong Wu
- 1State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032 China
| | - Ning Xie
- 8Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710032 China
| | - Yongquan Shi
- 1State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032 China
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Hu M, Xiong S, Chen Q, Zhu S, Zhou X. Novel role of microRNA-126 in digestive system cancers: From bench to bedside. Oncol Lett 2019; 17:31-41. [PMID: 30655735 PMCID: PMC6313097 DOI: 10.3892/ol.2018.9639] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 09/28/2018] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs) are ubiquitously expressed, small, non-coding RNAs that regulate the expression of approximately 30% of the human genes at the post-transcriptional level. miRNAs have emerged as crucial modulators in the initiation and progression of various diseases, including numerous cancer types. The high incidence rate of cancer and the large number of cancer-associated cases of mortality are mostly due to a lack of effective treatments and biomarkers for early diagnosis. Therefore there is an urgent requirement to further understand the underlying mechanisms of tumorigenesis. MicroRNA-126 (miR-126) is significantly downregulated in a number of tumor types and is commonly identified as a tumor suppressor in digestive system cancers (DSCs). miR-126 downregulates various oncogenes, including disintegrin and metalloproteinase domain-containing protein 9, v-crk sarcoma virus CT10 oncogene homolog and phosphoinositide-3-kinase regulatory subunit 2. These genes are involved in a number of tumor-associated signaling pathways, including angiogenesis, epithelial-mensenchymal transition and metastasis pathways. The aim of the current review was to summarize the role of miR-126 in DSCs, in terms of its dysregulation, target genes and associated signaling pathways. In addition, the current review has discussed the potential clinical application of miR-126 as a biomarker and therapeutic target for DSCs.
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Affiliation(s)
- Mingli Hu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330000, P.R. China
| | - Shengwei Xiong
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330000, P.R. China
| | - Qiaofeng Chen
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330000, P.R. China
| | - Shixuan Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330000, P.R. China
| | - Xiaodong Zhou
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330000, P.R. China
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Blackburn PR, Chacon-Camacho OF, Ortiz-González XR, Reyes M, Lopez-Uriarte GA, Zarei S, Bhoj EJ, Perez-Solorzano S, Vaubel RA, Murphree MI, Nava J, Cortes-Gonzalez V, Parisi JE, Villanueva-Mendoza C, Tirado-Torres IG, Li D, Klee EW, Pichurin PN, Zenteno JC. Extension of the mutational and clinical spectrum of SOX2 related disorders: Description of six new cases and a novel association with suprasellar teratoma. Am J Med Genet A 2018; 176:2710-2719. [PMID: 30450772 DOI: 10.1002/ajmg.a.40644] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 08/26/2018] [Accepted: 09/04/2018] [Indexed: 01/05/2023]
Abstract
SOX2 is a transcription factor that is essential for maintenance of pluripotency and has several conserved roles in early embryonic development. Heterozygous loss-of-function variants in SOX2 are identified in approximately 40% of all cases of bilateral anophthalmia/micropthalmia (A/M). Increasingly SOX2 mutation-positive patients without major eye findings, but with a range of other developmental disorders including autism, mild to moderate intellectual disability with or without structural brain changes, esophageal atresia, urogenital anomalies, and endocrinopathy are being reported, suggesting that the clinical phenotype associated with SOX2 loss is much broader than previously appreciated. In this report we describe six new cases, four of which carry novel pathogenic SOX2 variants. Four cases presented with bilateral anophthalmia in addition to extraocular involvement. Another individual presented with only unilateral anophthalmia. One individual did not have any eye findings but presented with a suprasellar teratoma in infancy and was found to have the recurrent c.70del20 mutation in SOX2 (c.70_89del, p.Asn24Argfs*65). This is this first time this tumor type has been reported in the context of a de novo SOX2 mutation. Notably, individuals with hypothalamic hamartomas and slow-growing hypothalamo-pituitary tumors have been reported previously, but it is still unclear how SOX2 loss contributes to their formation.
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Affiliation(s)
- Patrick R Blackburn
- Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota
- Department of Health Sciences Research, Rochester, Minnesota
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Oscar F Chacon-Camacho
- Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico
| | - Xilma R Ortiz-González
- Department of Pediatrics, Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Mariana Reyes
- Department of Genetics, Hospital "Dr. Luis Sánchez Bulnes", Asociación para Evitar la Ceguera en México, Mexico City, Mexico
| | - Graciela A Lopez-Uriarte
- Genetics Department, University Hospital "Dr. José Eleuterio González" and Medical School, Universidad Autónoma de Nuevo León, Monterrey, Mexico
| | - Shabnam Zarei
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
- Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota
| | - Elizabeth J Bhoj
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Sofia Perez-Solorzano
- Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico
| | - Rachael A Vaubel
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
- Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota
| | | | - Jessica Nava
- Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico
| | - Vianney Cortes-Gonzalez
- Department of Genetics, Hospital "Dr. Luis Sánchez Bulnes", Asociación para Evitar la Ceguera en México, Mexico City, Mexico
| | - Joseph E Parisi
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
- Department of Neurology, Mayo Clinic, Rochester, Minnesota
| | - Cristina Villanueva-Mendoza
- Department of Genetics, Hospital "Dr. Luis Sánchez Bulnes", Asociación para Evitar la Ceguera en México, Mexico City, Mexico
| | - Iris G Tirado-Torres
- Genetics Department, University Hospital "Dr. José Eleuterio González" and Medical School, Universidad Autónoma de Nuevo León, Monterrey, Mexico
| | - Dong Li
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Eric W Klee
- Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota
- Department of Health Sciences Research, Rochester, Minnesota
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
- Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota
| | - Pavel N Pichurin
- Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota
| | - Juan C Zenteno
- Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico
- Department of Biochemistry, Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
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Hüser L, Novak D, Umansky V, Altevogt P, Utikal J. Targeting SOX2 in anticancer therapy. Expert Opin Ther Targets 2018; 22:983-991. [PMID: 30366514 DOI: 10.1080/14728222.2018.1538359] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION SOX2 is a transcription factor that is important in the development and maintenance of the stem cell state. Furthermore, SOX2 is associated with cancer progression because it promotes the migration, invasion, and proliferation of cancer cells. SOX2 is also expressed in cancer stem cells and appears to be involved in the resistance toward anticancer therapies. These features render SOX2 an attractive target for cancer therapy. Areas covered: In this review, we highlight the role of SOX2 in cancer and in the resistance toward anticancer therapies. We summarize recent studies dealing with SOX2 as a direct or indirect therapeutic target in cancer. Expert opinion: SOX2 is an attractive target in cancer therapy because of its role in cancer progression and therapy resistance. SOX2 is a transcription factor, hence direct targeting is difficult. Studies aimed at a functional depletion, for example by knock-down with siRNAs, are difficult to translate into clinical settings. Alternatively, the identification of SOX2 upstream or downstream regulators that are easier to target is of paramount importance.
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Affiliation(s)
- Laura Hüser
- a Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology , University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg , Mannheim , Germany
| | - Daniel Novak
- a Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology , University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg , Mannheim , Germany
| | - Viktor Umansky
- a Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology , University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg , Mannheim , Germany
| | - Peter Altevogt
- a Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology , University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg , Mannheim , Germany
| | - Jochen Utikal
- a Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology , University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg , Mannheim , Germany
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Fattahi S, Golpour M, Amjadi-Moheb F, Sharifi-Pasandi M, Khodadadi P, Pilehchian-Langroudi M, Ashrafi GH, Akhavan-Niaki H. DNA methyltransferases and gastric cancer: insight into targeted therapy. Epigenomics 2018; 10:1477-1497. [PMID: 30325215 DOI: 10.2217/epi-2018-0096] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Gastric cancer is a major health problem worldwide occupying most frequent causes of cancer-related mortality. In addition to genetic modifications, epigenetic alterations catalyzed by DNA methyltransferases (DNMTs) are a well-characterized epigenetic hallmark in gastric cancer. The reversible nature of epigenetic alterations and central role of DNA methylation in diverse biological processes provides an opportunity for using DNMT inhibitors to enhance the efficacy of chemotherapeutics. In this review, we discussed key factors or mechanisms such as SNPs, infections and genetic modifications that trigger DNMTs level modification in gastric cancer, and their potential roles in cancer progression. Finally, we focused on how inhibitors of the DNMTs can most effectively be used for the treatment of gastric cancer with multidrug resistance.
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Affiliation(s)
- Sadegh Fattahi
- Cellular & Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, 4717647745, Babol, Iran.,North Research Center, Pasteur Institute, Amol, 4615885399, Iran
| | - Monireh Golpour
- Molecular & Cell Biology Research Center, Student Research Committee, Faculty of Medicine, Mazandaran University of Medical Science, Sari, 4817844718, Iran
| | - Fatemeh Amjadi-Moheb
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, 4717647745, Babol, Iran
| | - Marzieh Sharifi-Pasandi
- Molecular & Cell Biology Research Center, Student Research Committee, Faculty of Medicine, Mazandaran University of Medical Science, Sari, 4817844718, Iran
| | - Parastesh Khodadadi
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, 4717647745, Babol, Iran
| | | | - Gholam Hossein Ashrafi
- School of Life Science, Pharmacy & Chemistry, SEC Faculty, Cancer Theme, Kingston University London, Kingston upon Thames, London KT1 2EE, UK
| | - Haleh Akhavan-Niaki
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, 4717647745, Babol, Iran
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Tissue-specific induced DNA methyltransferase 1 (Dnmt1) in endocrine pancreas by RCAS-TVA-based somatic gene transfer system promotes β-cell proliferation. Cancer Gene Ther 2018; 26:94-102. [PMID: 30190513 DOI: 10.1038/s41417-018-0046-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 07/31/2018] [Accepted: 08/05/2018] [Indexed: 12/13/2022]
Abstract
We reported that inactivation of menin (the protein product of MEN1) increases activity of Dnmt1 and mediates DNA hypermethylation in the development of multiple endocrine neoplasia type 1 (MEN1) syndrome. We have developed a RCAS-TVA-based somatic gene transfer system that enables tissue-specific delivery of Dnmt1 to individual β-cells of the pancreas in a RIP-TVA mouse model. In the present study, we mediated Dnmt1 expression in islet β-cells in RIP-TVA mice by utilizing the RCAS-TVA system to test if the upregulation of Dnmt1 can promote β-cell proliferation. In vitro, we demonstrated that upregulation of Dnmt1 increased β-cell proliferation. In vivo, our results showed that the levels of serum insulin were increased in the RIP-TVA mice with RCASBP-Dnmt1 infection compared with wild-type control mice with RCASBP-Dnmt1 infection. Furthermore, we confirmed that mRNA and protein expression of Dnmt1 as well as Dnmt1 enzyme activity were upregulated in the RIP-TVA mice with RCASBP-Dnmt1 infection compared with wild-type control mice with RCASBP-Dnmt1 infection. Finally, we demonstrated that upregulation of Dnmt1 resulted in hyperplasia through β-cell proliferation. We conclude that the upregulation of Dnmt1 promotes islet β-cell proliferation and targeting Dnmt1 may be a promising therapy for patients suffering from pancreatic neuroendocrine tumors.
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Li Y, Li Y, Wang D, Meng Q. Linc-POU3F3 is overexpressed in hepatocellular carcinoma and regulates cell proliferation, migration and invasion. Biomed Pharmacother 2018; 105:683-689. [PMID: 29906746 DOI: 10.1016/j.biopha.2018.06.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Revised: 05/31/2018] [Accepted: 06/02/2018] [Indexed: 02/06/2023] Open
Abstract
Linc-POU3F3 showed an up-regulated tendency and functioned as tumor promoter in glioma, esophageal cancer and colorectal cancer. There was no report about the expression pattern and clinical value of linc-POU3F3 in hepatocellular carcinoma. Thus, the purpose of our study is to explore the clinical significance and biological role of linc-POU3F3 in hepatocellular carcinoma. Our results suggested that levels of linc-POU3F3 were dramatically increased in hepatocellular carcinoma tissues and cell lines compared with paired normal hepatic tissues and normal hepatic cell line, respectively. Levels of linc-POU3F3 were positively correlated with clinical stage, tumor size, vascular invasion and metastasis. Moreover, high-expression of linc-POU3F3 was an independent prognostic factor for hepatocellular carcinoma patients. The gain- and loss-of-function experiments showed that linc-POU3F3 expression significantly promoted tumor cell proliferation, migration and invasion. In addition, linc-POU3F3 expression was negatively correlated with POU3F3 mRNA and protein expressions in hepatocellular carcinoma tissues, and negatively regulated POU3F3 mRNA and protein expressions in hepatocellular carcinoma cells. In conclusion, our study supports the first evidence that linc-POU3F3 plays an oncogenic role in hepatocellular carcinoma, and represents a potential therapeutic strategy for hepatocellular carcinoma patients.
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Affiliation(s)
- Yichun Li
- Department of Hepatobiliary Surgery, Jining No.1 People's Hospital, Jining 272000, Shandong, China
| | - Yannan Li
- Department of General Surgery, Jining Traditional Chinese Medicine Hospital, Jining 272000, Shandong, China
| | - Dan Wang
- Department of Gynecology, Jining No.1 People's Hospital, Jining 272000, Shandong, China
| | - Qingdong Meng
- Department of General Surgery, Shandong Institute of Parasitic Diseases, Third Affiliated Hospital of Shandong Academy of Medical Sciences, No.11 Taibai Road Middle, Jining 272000, Shandong, China.
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