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Wen Y, Zhou W, Zhao Z, Ma D, Mao J, Cai Y, Liu F, Zhou J, Lv K, Gu W, Jiang L. Annexin A's Life in Pan-Cancer: Especially in Glioma Immune Cells. Neuromolecular Med 2025; 27:17. [PMID: 40011350 DOI: 10.1007/s12017-024-08827-9] [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: 10/16/2024] [Accepted: 12/23/2024] [Indexed: 02/28/2025]
Abstract
The Annexin A (ANXA) family plays a critical role in cancer, with particular emphasis on their prognostic significance in pan-cancer analyses and gliomas. By integrating multi-omics data from The Cancer Genome Atlas (TCGA) and single-cell sequencing analysis, we conducted a comprehensive evaluation of ANXA2 and ANXA4 to investigate their expression patterns and functional impacts across various cancers, with a focus on glioblastoma (GBM). Our analysis encompassed several key components, including literature review, identification of differentially expressed genes (DEGs) in cancer, survival analysis, co-expression studies, competing endogenous RNA networks, cellular functional analysis, tumor microenvironment response to chemotherapy, and tumor stemness. Special attention was given to glioblastoma and low-grade glioma. Notably, our findings highlighted discrepancies among the analytical tools used, underscoring the necessity of employing multiple methods for accurate identification of DEGs. Additionally, we determined that ANXA2 and ANXA4 are predominantly expressed by M2 macrophages in GBM, based on our characterization of human glioma macrophages. These results suggest a strong correlation between ANXA2 and ANXA4 expression levels and the presence of macrophages and CD4 + resting memory T cells in gliomas, offering valuable insights into the complex interplay between the ANXA family and cancer progression.
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Affiliation(s)
- Yujing Wen
- Anhui Province Key Laboratory of Non-Coding RNA Basic and Clinical Transformation (Wannan Medical College), Yijishan Hospital of Wannan Medical College, Wuhu, 241000, China
- Central Laboratory, Yijishan Hospital of Wannan Medical College, Wuhu, 241000, China
| | - Wenhao Zhou
- Anhui Province Key Laboratory of Non-Coding RNA Basic and Clinical Transformation (Wannan Medical College), Yijishan Hospital of Wannan Medical College, Wuhu, 241000, China
| | - Zhenzhen Zhao
- Anhui Province Key Laboratory of Non-Coding RNA Basic and Clinical Transformation (Wannan Medical College), Yijishan Hospital of Wannan Medical College, Wuhu, 241000, China
| | - Didi Ma
- Anhui Province Key Laboratory of Non-Coding RNA Basic and Clinical Transformation (Wannan Medical College), Yijishan Hospital of Wannan Medical College, Wuhu, 241000, China
| | - Jian Mao
- Yangtze River Delta Information Intelligence Innovation Research Institute, Wuhu, 241000, Anhui, China
| | - Yingjie Cai
- Anhui Province Key Laboratory of Non-Coding RNA Basic and Clinical Transformation (Wannan Medical College), Yijishan Hospital of Wannan Medical College, Wuhu, 241000, China
| | - Fugui Liu
- Anhui Province Key Laboratory of Non-Coding RNA Basic and Clinical Transformation (Wannan Medical College), Yijishan Hospital of Wannan Medical College, Wuhu, 241000, China
| | - Juan Zhou
- Anhui Province Key Laboratory of Non-Coding RNA Basic and Clinical Transformation (Wannan Medical College), Yijishan Hospital of Wannan Medical College, Wuhu, 241000, China
| | - Kun Lv
- Anhui Province Key Laboratory of Non-Coding RNA Basic and Clinical Transformation (Wannan Medical College), Yijishan Hospital of Wannan Medical College, Wuhu, 241000, China.
- Central Laboratory, Yijishan Hospital of Wannan Medical College, Wuhu, 241000, China.
| | - Wenchao Gu
- Department of Diagnostic and Interventional Radiology, University of Tsukuba, Faculty of Medicine, lbaraki, Tsukuba, Japan.
| | - Lan Jiang
- Anhui Province Key Laboratory of Non-Coding RNA Basic and Clinical Transformation (Wannan Medical College), Yijishan Hospital of Wannan Medical College, Wuhu, 241000, China.
- Central Laboratory, Yijishan Hospital of Wannan Medical College, Wuhu, 241000, China.
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Zheng H, Liu M, Shi S, Huang H, Yang X, Luo Z, Song Y, Xu Q, Li T, Xue L, Lu F, Wang J. MAP4K4 and WT1 mediate SOX6-induced cellular senescence by synergistically activating the ATF2-TGFβ2-Smad2/3 signaling pathway in cervical cancer. Mol Oncol 2024; 18:1327-1346. [PMID: 38383842 PMCID: PMC11076992 DOI: 10.1002/1878-0261.13613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 01/18/2024] [Accepted: 02/04/2024] [Indexed: 02/23/2024] Open
Abstract
SRY-box transcription factor 6 (SOX6) is a member of the SOX gene family and inhibits the proliferation of cervical cancer cells by inducing cell cycle arrest. However, the final cell fate and significance of these cell-cycle-arrested cervical cancer cells induced by SOX6 remains unclear. Here, we report that SOX6 inhibits the proliferation of cervical cancer cells by inducing cellular senescence, which is mainly mediated by promoting transforming growth factor beta 2 (TGFB2) gene expression and subsequently activating the TGFβ2-Smad2/3-p53-p21WAF1/CIP1-Rb pathway. SOX6 promotes TGFB2 gene expression through the MAP4K4-MAPK (JNK/ERK/p38)-ATF2 and WT1-ATF2 pathways, which is dependent on its high-mobility group (HMG) domain. In addition, the SOX6-induced senescent cervical cancer cells are resistant to cisplatin treatment. ABT-263 (navitoclax) and ABT-199 (venetoclax), two classic senolytics, can specifically eliminate the SOX6-induced senescent cervical cancer cells, and thus significantly improve the chemosensitivity of cisplatin-resistant cervical cancer cells. This study uncovers that the MAP4K4/WT1-ATF2-TGFβ2 axis mediates SOX6-induced cellular senescence, which is a promising therapeutic target in improving the chemosensitivity of cervical cancer.
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Affiliation(s)
- Han Zheng
- Department of Microbiology and Infectious Disease Center, School of Basic Medical SciencesPeking University Health Science CenterBeijingChina
- NHC Key Laboratory of Medical ImmunologyPeking UniversityBeijingChina
| | - Mingchen Liu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical SciencesPeking University Health Science CenterBeijingChina
| | - Shu Shi
- Department of Microbiology and Infectious Disease Center, School of Basic Medical SciencesPeking University Health Science CenterBeijingChina
| | - Hongxin Huang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical SciencesPeking University Health Science CenterBeijingChina
| | - Xingwen Yang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical SciencesPeking University Health Science CenterBeijingChina
- NHC Key Laboratory of Medical ImmunologyPeking UniversityBeijingChina
| | - Ziheng Luo
- Department of Microbiology and Infectious Disease Center, School of Basic Medical SciencesPeking University Health Science CenterBeijingChina
- NHC Key Laboratory of Medical ImmunologyPeking UniversityBeijingChina
| | - Yarong Song
- Department of Microbiology and Infectious Disease Center, School of Basic Medical SciencesPeking University Health Science CenterBeijingChina
- NHC Key Laboratory of Medical ImmunologyPeking UniversityBeijingChina
| | - Qiang Xu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical SciencesPeking University Health Science CenterBeijingChina
| | - Tingting Li
- Department of Biomedical Informatics, School of Basic Medical SciencesPeking University Health Science CenterBeijingChina
| | - Lixiang Xue
- Department of Radiation OncologyCancer Center of Peking University Third Hospital, Peking University Third HospitalBeijingChina
| | - Fengmin Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical SciencesPeking University Health Science CenterBeijingChina
| | - Jie Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical SciencesPeking University Health Science CenterBeijingChina
- NHC Key Laboratory of Medical ImmunologyPeking UniversityBeijingChina
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Kolenda T, Graczyk Z, Żarska B, Łosiewski W, Smolibowski M, Wartecki A, Kozłowska-Masłoń J, Guglas K, Florczak A, Kazimierczak U, Teresiak A, Lamperska K. SRY-Related Transcription Factors in Head and Neck Squamous Cell Carcinomas: In Silico Based Analysis. Curr Issues Mol Biol 2023; 45:9431-9449. [PMID: 38132438 PMCID: PMC10742289 DOI: 10.3390/cimb45120592] [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: 07/07/2023] [Revised: 11/15/2023] [Accepted: 11/17/2023] [Indexed: 12/23/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer and the fifth cause of cancer-related deaths worldwide with a poor 5-year survival. SOX family genes play a role in the processes involved in cancer development such as epithelial-mesenchymal transition (EMT), the maintenance of cancer stem cells (CSCs) and the regulation of drug resistance. We analyzed the expression of SOX2-OT, SOX6, SOX8, SOX21, SOX30 and SRY genes in HNSCC patients using the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, to assess their biological role and their potential utility as biomarkers. We demonstrated statistically significant differences in expression between normal and primary tumor tissues for SOX6, SOX8, SOX21 and SOX30 genes and pointed to SOX6 as the one that met the independent diagnostic markers criteria. SOX21 or SRY alone, or the panel of six SRY-related genes, could be used to estimate patient survival. SRY-related genes are positively correlated with immunological processes, as well as with keratinization and formation of the cornified envelope, and negatively correlated with DNA repair and response to stress. Moreover, except SRY, all analyzed genes were associated with a different tumor composition and immunological profiles. Based on validation results, the expression of SOX30 is higher in HPV(+) patients and is associated with patients' survival. SRY-related transcription factors have vast importance in HNSCC biology. SOX30 seems to be a potential biomarker of HPV infection and could be used as a prognostic marker, but further research is required to fully understand the role of SOX family genes in HNSCC.
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Affiliation(s)
- Tomasz Kolenda
- Laboratory of Cancer Genetics, Greater Poland Cancer Centre, Garbary 15, 61-866 Poznan, Poland
- Research and Implementation Unit, Greater Poland Cancer Centre, Garbary 15, 61-866 Poznan, Poland
| | - Zuzanna Graczyk
- Department of Cancer Immunology, Poznan University of Medical Sciences, 8 Rokietnicka Street, 60-806 Poznan, Poland (A.W.); (A.F.)
- Institute of Human Genetics, Polish Academy of Sciences, Strzeszynska 32, 60-479 Poznan, Poland
| | - Barbara Żarska
- Department of Cancer Immunology, Poznan University of Medical Sciences, 8 Rokietnicka Street, 60-806 Poznan, Poland (A.W.); (A.F.)
| | - Wojciech Łosiewski
- Department of Cancer Immunology, Poznan University of Medical Sciences, 8 Rokietnicka Street, 60-806 Poznan, Poland (A.W.); (A.F.)
| | - Mikołaj Smolibowski
- Department of Cancer Immunology, Poznan University of Medical Sciences, 8 Rokietnicka Street, 60-806 Poznan, Poland (A.W.); (A.F.)
| | - Adrian Wartecki
- Department of Cancer Immunology, Poznan University of Medical Sciences, 8 Rokietnicka Street, 60-806 Poznan, Poland (A.W.); (A.F.)
| | - Joanna Kozłowska-Masłoń
- Laboratory of Cancer Genetics, Greater Poland Cancer Centre, Garbary 15, 61-866 Poznan, Poland
- Research and Implementation Unit, Greater Poland Cancer Centre, Garbary 15, 61-866 Poznan, Poland
- Institute of Human Biology and Evolution, Faculty of Biology, Adam Mickiewicz University, Uniwersytetu Poznańskiego 6, 61-614 Poznan, Poland
| | - Kacper Guglas
- Laboratory of Cancer Genetics, Greater Poland Cancer Centre, Garbary 15, 61-866 Poznan, Poland
- Research and Implementation Unit, Greater Poland Cancer Centre, Garbary 15, 61-866 Poznan, Poland
- Postgraduate School of Molecular Medicine, Medical University of Warsaw, Żwirki i Wigury 61, 02-091 Warsaw, Poland
| | - Anna Florczak
- Department of Cancer Immunology, Poznan University of Medical Sciences, 8 Rokietnicka Street, 60-806 Poznan, Poland (A.W.); (A.F.)
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, Garbary 15, 61-688 Poznan, Poland
| | - Urszula Kazimierczak
- Department of Cancer Immunology, Poznan University of Medical Sciences, 8 Rokietnicka Street, 60-806 Poznan, Poland (A.W.); (A.F.)
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, Garbary 15, 61-688 Poznan, Poland
| | - Anna Teresiak
- Laboratory of Cancer Genetics, Greater Poland Cancer Centre, Garbary 15, 61-866 Poznan, Poland
- Research and Implementation Unit, Greater Poland Cancer Centre, Garbary 15, 61-866 Poznan, Poland
| | - Katarzyna Lamperska
- Laboratory of Cancer Genetics, Greater Poland Cancer Centre, Garbary 15, 61-866 Poznan, Poland
- Research and Implementation Unit, Greater Poland Cancer Centre, Garbary 15, 61-866 Poznan, Poland
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Jiang L, Yang J, Xu Q, Lv K, Cao Y. Machine learning for the micropeptide encoded by LINC02381 regulates ferroptosis through the glucose transporter SLC2A10 in glioblastoma. BMC Cancer 2022; 22:882. [PMID: 35962317 PMCID: PMC9373536 DOI: 10.1186/s12885-022-09972-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 08/03/2022] [Indexed: 11/10/2022] Open
Abstract
Glioblastoma (GBM) is the most common primary intracranial tumor in the central nervous system, and resistance to temozolomide is an important reason for the failure of GBM treatment. We screened out that Solute Carrier Family 2 Member 10 (SLC2A10) is significantly highly expressed in GBM with a poor prognosis, which is also enriched in the NF-E2 p45-related factor 2 (NRF2) signalling pathway. The NRF2 signalling pathway is an important defence mechanism against ferroptosis. SLC2A10 related LINC02381 is highly expressed in GBM, which is localized in the cytoplasm/exosomes, and LINC02381 encoded micropeptides are localized in the exosomes. The micropeptide encoded by LINC02381 may be a potential treatment strategy for GBM, but the underlying mechanism of its function is not precise yet. We put forward the hypothesis: “The micropeptide encoded by LINC02381 regulates ferroptosis through the glucose transporter SLC2A10 in GBM.” This study innovatively used machine learning for micropeptide to provide personalized diagnosis and treatment plans for precise treatment of GBM, thereby promoting the development of translational medicine. The study aimed to help find new disease diagnoses and prognostic biomarkers and provide a new strategy for experimental scientists to design the downstream validation experiments.
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Affiliation(s)
- Lan Jiang
- Key Laboratory of Non-Coding RNA Transformation Research of Anhui Higher Education Institution, Yijishan Hospital of Wannan Medical College, Wuhu, China.,Central Laboratory, Yijishan Hospital of Wannan Medical College, Wuhu, China.,Anhui Provincial Clinical Research Center for Critical Respiratory Disease, Wuhu, China
| | - Jianke Yang
- School of Preclinical Medicine, Wannan Medical College, Wuhu, China
| | - Qiancheng Xu
- Anhui Provincial Clinical Research Center for Critical Respiratory Disease, Wuhu, China
| | - Kun Lv
- Key Laboratory of Non-Coding RNA Transformation Research of Anhui Higher Education Institution, Yijishan Hospital of Wannan Medical College, Wuhu, China. .,Central Laboratory, Yijishan Hospital of Wannan Medical College, Wuhu, China. .,Anhui Provincial Clinical Research Center for Critical Respiratory Disease, Wuhu, China.
| | - Yunpeng Cao
- Wuhan Botanical Garden, Chinese Academy of Sciences, Wuhan, 430074, China.
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Rodriguez SMB, Staicu GA, Sevastre AS, Baloi C, Ciubotaru V, Dricu A, Tataranu LG. Glioblastoma Stem Cells-Useful Tools in the Battle against Cancer. Int J Mol Sci 2022; 23:ijms23094602. [PMID: 35562993 PMCID: PMC9100635 DOI: 10.3390/ijms23094602] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/13/2022] [Accepted: 04/19/2022] [Indexed: 02/01/2023] Open
Abstract
Glioblastoma stem cells (GSCs) are cells with a self-renewal ability and capacity to initiate tumors upon serial transplantation that have been linked to tumor cell heterogeneity. Most standard treatments fail to completely eradicate GSCs, causing the recurrence of the disease. GSCs could represent one reason for the low efficacy of cancer therapy and for the short relapse time. Nonetheless, experimental data suggest that the presence of therapy-resistant GSCs could explain tumor recurrence. Therefore, to effectively target GSCs, a comprehensive understanding of their biology and the survival and developing mechanisms during treatment is mandatory. This review provides an overview of the molecular features, microenvironment, detection, and targeting strategies of GSCs, an essential information required for an efficient therapy. Despite the outstanding results in oncology, researchers are still developing novel strategies, of which one could be targeting the GSCs present in the hypoxic regions and invasive edge of the glioblastoma.
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Affiliation(s)
- Silvia Mara Baez Rodriguez
- Neurosurgical Department, Clinical Hospital “Bagdasar-Arseni”, 041915 Bucharest, Romania; (S.M.B.R.); (V.C.); (L.G.T.)
| | - Georgiana-Adeline Staicu
- Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy, 200349 Craiova, Romania; (G.-A.S.); (C.B.)
| | - Ani-Simona Sevastre
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Medicine and Pharmacy, 200349 Craiova, Romania;
| | - Carina Baloi
- Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy, 200349 Craiova, Romania; (G.-A.S.); (C.B.)
| | - Vasile Ciubotaru
- Neurosurgical Department, Clinical Hospital “Bagdasar-Arseni”, 041915 Bucharest, Romania; (S.M.B.R.); (V.C.); (L.G.T.)
| | - Anica Dricu
- Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy, 200349 Craiova, Romania; (G.-A.S.); (C.B.)
- Correspondence:
| | - Ligia Gabriela Tataranu
- Neurosurgical Department, Clinical Hospital “Bagdasar-Arseni”, 041915 Bucharest, Romania; (S.M.B.R.); (V.C.); (L.G.T.)
- Department 6—Clinical Neurosciences, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
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Arunachalam E, Rogers W, Simpson GR, Möller-Levet C, Bolton G, Ismael M, Smith C, Keegen K, Bagwan I, Brend T, Short SC, Hong B, Otani Y, Kaur B, Annels N, Morgan R, Pandha H. HOX and PBX gene dysregulation as a therapeutic target in glioblastoma multiforme. BMC Cancer 2022; 22:400. [PMID: 35418059 PMCID: PMC9006463 DOI: 10.1186/s12885-022-09466-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 03/21/2022] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND Glioblastoma multiforme (GBM) is the most common high-grade malignant brain tumour in adults and arises from the glial cells in the brain. The prognosis of treated GBM remains very poor with 5-year survival rates of 5%, a figure which has not improved over the last few decades. Currently, there is a modest 14-month overall median survival in patients undergoing maximum safe resection plus adjuvant chemoradiotherapy. HOX gene dysregulation is now a widely recognised feature of many malignancies. METHODS In this study we have focused on HOX gene dysregulation in GBM as a potential therapeutic target in a disease with high unmet need. RESULTS We show significant dysregulation of these developmentally crucial genes and specifically that HOX genes A9, A10, C4 and D9 are strong candidates for biomarkers and treatment targets for GBM and GBM cancer stem cells. We evaluated a next generation therapeutic peptide, HTL-001, capable of targeting HOX gene over-expression in GBM by disrupting the interaction between HOX proteins and their co-factor, PBX. HTL-001 induced both caspase-dependent and -independent apoptosis in GBM cell lines. CONCLUSION In vivo biodistribution studies confirmed that the peptide was able to cross the blood brain barrier. Systemic delivery of HTL-001 resulted in improved control of subcutaneous murine and human xenograft tumours and improved survival in a murine orthotopic model.
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Affiliation(s)
- Einthavy Arunachalam
- Targeted Cancer Therapy, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7WG, UK
| | - William Rogers
- Targeted Cancer Therapy, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7WG, UK
| | - Guy R Simpson
- Targeted Cancer Therapy, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7WG, UK
| | - Carla Möller-Levet
- Targeted Cancer Therapy, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7WG, UK
| | - Gemma Bolton
- Targeted Cancer Therapy, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7WG, UK
- Surrey Technology Centre, HOX Therapeutics Ltd, Unit 2440 Occam Rd, Guildford, GU2 7YG, UK
| | - Mohammed Ismael
- Targeted Cancer Therapy, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7WG, UK
- Surrey Technology Centre, HOX Therapeutics Ltd, Unit 2440 Occam Rd, Guildford, GU2 7YG, UK
| | - Christopher Smith
- Targeted Cancer Therapy, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7WG, UK
| | - Karl Keegen
- Surrey Technology Centre, HOX Therapeutics Ltd, Unit 2440 Occam Rd, Guildford, GU2 7YG, UK
| | - Izhar Bagwan
- Department of Pathology, Royal Surrey County Hospital, Egerton Road, Guildford, GU2 7XX, Surrey, UK
| | - Tim Brend
- Faculty of Medicine and Health, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, LS9 7TF, UK
| | - Susan C Short
- Faculty of Medicine and Health, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, LS9 7TF, UK
| | - Bangxing Hong
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Centre at Houston, 7000 Fannin Street, Houston, TX, 77030, USA
| | - Yoshihiro Otani
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Centre at Houston, 7000 Fannin Street, Houston, TX, 77030, USA
| | - Balveen Kaur
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Centre at Houston, 7000 Fannin Street, Houston, TX, 77030, USA
| | - Nicola Annels
- Targeted Cancer Therapy, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7WG, UK
| | - Richard Morgan
- School of Biomedical Sciences, University of West London, St Mary's Road, Ealing, London, W5 5RF, UK
| | - Hardev Pandha
- Targeted Cancer Therapy, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, GU2 7WG, UK.
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The Dysregulation of SOX Family Correlates with DNA Methylation and Immune Microenvironment Characteristics to Predict Prognosis in Hepatocellular Carcinoma. DISEASE MARKERS 2022; 2022:2676114. [PMID: 35465267 PMCID: PMC9020970 DOI: 10.1155/2022/2676114] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 03/23/2022] [Indexed: 12/24/2022]
Abstract
Background Due to the molecular heterogeneity of hepatocellular carcinoma (HCC), majority of patients respond poorly among various of therapy. This study is aimed at conducting a comprehensive analysis about roles of SOX family in HCC for obtaining more therapeutic targets and biomarkers which may bring new ideas for the treatment of HCC. Methods UALCAN, Kaplan Meier plotter, cBioPortal, STRING, WebGestalt, Metascape, TIMER 2.0, DiseaseMeth, MethSurv, HPA, CCLE database, and Cytoscape software were used to comprehensively analyze the bioinformatic data. Results SOX2, SOX4, SOX8, SOX10, SOX11, SOX12, SOX17, and SOX18 were significantly differentially expressed in HCC and normal tissues and were valuable for the grade and survival of HCC patients. In addition, the gene alterations of SOX family happened frequently, and SOX4 and SOX17 had the highest mutation rate. The function of SOX family on HCC may be closely correlated with the regulation of angiogenesis-related signaling pathways. Moreover, SOX4, SOX8, SOX11, SOX12, SOX17, and SOX18 were correlation with 8 types of immune cells (including CD8+ T cell, CD4+ T cell, B cell, Tregs, neutrophil, macrophage, myeloid DC, and NK cell), and we found that most types of immune cells had a positive correlation with SOX family. Notably, CD4+ T cell and macrophage were positively related with all these SOX family. NK cells were negatively related with most SOX family genes. DNA methylation levels in promoter area of SOX2, SOX4, and SOX10 were lower in HCC than normal tissues, while SOX8, SOX11, SOX17, and SOX18 had higher DNA methylation levels than normal tissues. Moreover, higher DNA methylation level of SOX12 and SOX18 demonstrated worse survival rates in patients with HCC. Conclusion SOX family genes could predict the prognosis of HCC. In addition, the regulation of angiogenesis-related signaling pathways may participate in the development of HCC. DNA methylation level and immune microenvironment characteristics (especially CD4+ T cell and macrophage immune cell infiltration) could be a novel insight for predicting prognosis in HCC.
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Stevanovic M, Kovacevic-Grujicic N, Mojsin M, Milivojevic M, Drakulic D. SOX transcription factors and glioma stem cells: Choosing between stemness and differentiation. World J Stem Cells 2021; 13:1417-1445. [PMID: 34786152 PMCID: PMC8567447 DOI: 10.4252/wjsc.v13.i10.1417] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 07/15/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
Glioblastoma (GBM) is the most common, most aggressive and deadliest brain tumor. Recently, remarkable progress has been made towards understanding the cellular and molecular biology of gliomas. GBM tumor initiation, progression and relapse as well as resistance to treatments are associated with glioma stem cells (GSCs). GSCs exhibit a high proliferation rate and self-renewal capacity and the ability to differentiate into diverse cell types, generating a range of distinct cell types within the tumor, leading to cellular heterogeneity. GBM tumors may contain different subsets of GSCs, and some of them may adopt a quiescent state that protects them against chemotherapy and radiotherapy. GSCs enriched in recurrent gliomas acquire more aggressive and therapy-resistant properties, making them more malignant, able to rapidly spread. The impact of SOX transcription factors (TFs) on brain tumors has been extensively studied in the last decade. Almost all SOX genes are expressed in GBM, and their expression levels are associated with patient prognosis and survival. Numerous SOX TFs are involved in the maintenance of the stemness of GSCs or play a role in the initiation of GSC differentiation. The fine-tuning of SOX gene expression levels controls the balance between cell stemness and differentiation. Therefore, innovative therapies targeting SOX TFs are emerging as promising tools for combatting GBM. Combatting GBM has been a demanding and challenging goal for decades. The current therapeutic strategies have not yet provided a cure for GBM and have only resulted in a slight improvement in patient survival. Novel approaches will require the fine adjustment of multimodal therapeutic strategies that simultaneously target numerous hallmarks of cancer cells to win the battle against GBM.
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Affiliation(s)
- Milena Stevanovic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
- Chair Biochemistry and Molecular Biology, Faculty of Biology, University of Belgrade, Belgrade 11158, Serbia
- Department of Chemical and Biological Sciences, Serbian Academy of Sciences and Arts, Belgrade 11000, Serbia.
| | - Natasa Kovacevic-Grujicic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
| | - Marija Mojsin
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
| | - Milena Milivojevic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
| | - Danijela Drakulic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade 11042, Serbia
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FOXO3-induced lncRNA LOC554202 contributes to hepatocellular carcinoma progression via the miR-485-5p/BSG axis. Cancer Gene Ther 2021; 29:326-340. [PMID: 33654226 PMCID: PMC8940625 DOI: 10.1038/s41417-021-00312-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 01/30/2021] [Accepted: 02/16/2021] [Indexed: 02/06/2023]
Abstract
Long non-coding RNAs (LncRNAs) have played very important roles in the malignancy behaviors of hepatocellular carcinoma (HCC). LncRNA LOC554202 (LOC554202) was a newly identified tumor-related lncRNA. However, its expression and function in HCC remained unknown. In this study, we firstly reported that LOC554202 expression was distinctly upregulated in HCC specimens and cell lines. Clinical assays indicated that increased LOC554202 expression had a diagnostic value for HCC patients and was positively associated with advanced stages and poor clinical prognosis. Additionally, forkhead box O3(FOXO3) could bind directly to the LOC554202 promoter region and activate its transcription. Functionally, we observed that knockdown of LOC554202 suppressed the proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) progress of HCC cells, and promoted apoptosis. Mechanistically, LOC554202 competitively bound to miR-485-5p and prevented the suppressive effects of miR-485-5p on its target gene basigin (BSG), which finally led to HCC metastasis, EMT, and docetaxel chemoresistance. Our data demonstrated that FOXO3-induced LOC554202 contributed to HCC progression by upregulating BSG via competitively binding to miR-485-5p, which suggested that the regulation of the FOXO3/LOC554202/miR-485-5p/BSG axis may have beneficial effects in the treatment of HCC.
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Jiang L, Zhu X, Yang H, Chen T, Lv K. Bioinformatics Analysis Discovers Microtubular Tubulin Beta 6 Class V (TUBB6) as a Potential Therapeutic Target in Glioblastoma. Front Genet 2020; 11:566579. [PMID: 33193654 PMCID: PMC7531581 DOI: 10.3389/fgene.2020.566579] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 08/25/2020] [Indexed: 12/11/2022] Open
Abstract
Glioblastoma (GBM) has long been a major clinical research challenge to scientists. The pivotal role of the mitochondria related gene family in the promotion of GBM tumorigenesis is not clear. We detected that microtubular tubulin beta 6 class V (TUBB6) was one of 33 differentially expressed mitochondrial-focused genes (DEMFGs) in GBM, and considered that TUBB6 is a potential therapeutic target in GBM. TUBB6 was vital for GBM and marked as the key prognostic gene in primary GBM. Mutations of TUBB6 in GBM were rare. Only four TUBB6 co-expressed hub genes (ANXA2, S100A11, FLNA, and MSN) exhibited poorer overall survival rates in higher expression groups (p-value < 0.05). We have confirmed the up-regulation of TUBB6 and its partners, ANXA2 and S100A11 in GBM and validated their importance as prognostic factors in primary GBM. TUBB6 was significantly correlated with stromal score in GBM samples (p-value = 6.99E-04). This study aimed to assess the importance of novel hub genes by analyzing the expression, potential function and prognostic impact of TUBB6 in human primary GBM cancer.
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Affiliation(s)
- Lan Jiang
- Central Laboratory, Yijishan Hospital of Wannan Medical College, Wuhu, China.,Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Xiaolong Zhu
- Central Laboratory, Yijishan Hospital of Wannan Medical College, Wuhu, China.,Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Hui Yang
- Central Laboratory, Yijishan Hospital of Wannan Medical College, Wuhu, China.,Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Tianbing Chen
- Central Laboratory, Yijishan Hospital of Wannan Medical College, Wuhu, China.,Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Kun Lv
- Central Laboratory, Yijishan Hospital of Wannan Medical College, Wuhu, China.,Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Yijishan Hospital of Wannan Medical College, Wuhu, China
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Jiang L, Zhong M, Chen T, Zhu X, Yang H, Lv K. Gene regulation network analysis reveals core genes associated with survival in glioblastoma multiforme. J Cell Mol Med 2020; 24:10075-10087. [PMID: 32696617 PMCID: PMC7520335 DOI: 10.1111/jcmm.15615] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/16/2020] [Accepted: 06/23/2020] [Indexed: 01/01/2023] Open
Abstract
Glioblastoma multiforme (GBM) is a very serious mortality of central nervous system cancer. The microarray data from GSE2223, GSE4058, GSE4290, GSE13276, GSE68848 and GSE70231 (389 GBM tumour and 67 normal tissues) and the RNA-seq data from TCGA-GBM dataset (169 GBM and five normal samples) were chosen to find differentially expressed genes (DEGs). RRA (Robust rank aggregation) method was used to integrate seven datasets and calculate 133 DEGs (82 up-regulated and 51 down-regulated genes). Subsequently, through the PPI (protein-protein interaction) network and MCODE/ cytoHubba methods, we finally filtered out ten hub genes, including FOXM1, CDK4, TOP2A, RRM2, MYBL2, MCM2, CDC20, CCNB2, MYC and EZH2, from the whole network. Functional enrichment analyses of DEGs were conducted to show that these hub genes were enriched in various cancer-related functions and pathways significantly. We also selected CCNB2, CDC20 and MYBL2 as core biomarkers, and further validated them in CGGA, HPA and CCLE database, suggesting that these three core hub genes may be involved in the origin of GBM. All these potential biomarkers for GBM might be helpful for illustrating the important role of molecular mechanisms of tumorigenesis in the diagnosis, prognosis and targeted therapy of GBM cancer.
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Affiliation(s)
- Lan Jiang
- Central LaboratoryYijishan Hospital of Wannan Medical CollegeWuhuChina
- Key Laboratory of Non‐coding RNA Transformation Research of Anhui Higher Education InstitutionWannan Medical CollegeWuhuChina
| | - Min Zhong
- Central LaboratoryYijishan Hospital of Wannan Medical CollegeWuhuChina
- Key Laboratory of Non‐coding RNA Transformation Research of Anhui Higher Education InstitutionWannan Medical CollegeWuhuChina
| | - Tianbing Chen
- Central LaboratoryYijishan Hospital of Wannan Medical CollegeWuhuChina
- Key Laboratory of Non‐coding RNA Transformation Research of Anhui Higher Education InstitutionWannan Medical CollegeWuhuChina
| | - Xiaolong Zhu
- Central LaboratoryYijishan Hospital of Wannan Medical CollegeWuhuChina
- Key Laboratory of Non‐coding RNA Transformation Research of Anhui Higher Education InstitutionWannan Medical CollegeWuhuChina
| | - Hui Yang
- Central LaboratoryYijishan Hospital of Wannan Medical CollegeWuhuChina
- Key Laboratory of Non‐coding RNA Transformation Research of Anhui Higher Education InstitutionWannan Medical CollegeWuhuChina
| | - Kun Lv
- Central LaboratoryYijishan Hospital of Wannan Medical CollegeWuhuChina
- Key Laboratory of Non‐coding RNA Transformation Research of Anhui Higher Education InstitutionWannan Medical CollegeWuhuChina
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