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Carvalho D, Diaz-Amarilla P, Dapueto R, Santi MD, Duarte P, Savio E, Engler H, Abin-Carriquiry JA, Arredondo F. Transcriptomic Analyses of Neurotoxic Astrocytes Derived from Adult Triple Transgenic Alzheimer's Disease Mice. J Mol Neurosci 2023; 73:487-515. [PMID: 37318736 DOI: 10.1007/s12031-023-02105-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 02/03/2023] [Indexed: 06/16/2023]
Abstract
Neurodegenerative diseases such as Alzheimer's disease have been classically studied from a purely neuronocentric point of view. More recent evidences support the notion that other cell populations are involved in disease progression. In this sense, the possible pathogenic role of glial cells like astrocytes is increasingly being recognized. Once faced with tissue damage signals and other stimuli present in disease environments, astrocytes suffer many morphological and functional changes, a process referred as reactive astrogliosis. Studies from murine models and humans suggest that these complex and heterogeneous responses could manifest as disease-specific astrocyte phenotypes. Clear understanding of disease-associated astrocytes is a necessary step to fully disclose neurodegenerative processes, aiding in the design of new therapeutic and diagnostic strategies. In this work, we present the transcriptomics characterization of neurotoxic astrocytic cultures isolated from adult symptomatic animals of the triple transgenic mouse model of Alzheimer's disease (3xTg-AD). According to the observed profile, 3xTg-AD neurotoxic astrocytes show various reactivity features including alteration of the extracellular matrix and release of pro-inflammatory and proliferative factors that could result in harmful effects to neurons. Moreover, these alterations could be a consequence of stress responses at the endoplasmic reticulum and mitochondria as well as of concomitant metabolic adaptations. Present results support the hypothesis that adaptive changes of astrocytic function induced by a stressed microenvironment could later promote harmful astrocyte phenotypes and further accelerate or induce neurodegenerative processes.
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Affiliation(s)
- Diego Carvalho
- Departamento de Neuroquímica, Instituto de Investigaciones Biológicas Clemente Estable, 11600, Montevideo, Uruguay
| | - Pablo Diaz-Amarilla
- Área I+D Biomédica, Centro Uruguayo de Imagenología Molecular, 11600, Montevideo, Uruguay
| | - Rosina Dapueto
- Área I+D Biomédica, Centro Uruguayo de Imagenología Molecular, 11600, Montevideo, Uruguay
| | - María Daniela Santi
- Área I+D Biomédica, Centro Uruguayo de Imagenología Molecular, 11600, Montevideo, Uruguay
- College of Dentistry, Bluestone Center for Clinical Research, New York University, New York, 10010, USA
| | - Pablo Duarte
- Área I+D Biomédica, Centro Uruguayo de Imagenología Molecular, 11600, Montevideo, Uruguay
| | - Eduardo Savio
- Área I+D Biomédica, Centro Uruguayo de Imagenología Molecular, 11600, Montevideo, Uruguay
| | - Henry Engler
- Área I+D Biomédica, Centro Uruguayo de Imagenología Molecular, 11600, Montevideo, Uruguay
- Facultad de Medicina, Universidad de la República, 1800, Montevideo, Uruguay
| | - Juan A Abin-Carriquiry
- Departamento de Neuroquímica, Instituto de Investigaciones Biológicas Clemente Estable, 11600, Montevideo, Uruguay.
- Laboratorio de Biofármacos, Institut Pasteur de Montevideo, 11600, Montevideo, Uruguay.
| | - Florencia Arredondo
- Departamento de Neuroquímica, Instituto de Investigaciones Biológicas Clemente Estable, 11600, Montevideo, Uruguay.
- Área I+D Biomédica, Centro Uruguayo de Imagenología Molecular, 11600, Montevideo, Uruguay.
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Liu B, Zhang G, Cui S, Du G. Upregulation of KIF11 in TP53 Mutant Glioma Promotes Tumor Stemness and Drug Resistance. Cell Mol Neurobiol 2022; 42:1477-1485. [PMID: 33491154 PMCID: PMC11421707 DOI: 10.1007/s10571-020-01038-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 12/31/2020] [Indexed: 12/21/2022]
Abstract
Glioma is the most common type of primary brain malignancy with high morbidity and mortality, but little is known about its pathological mechanisms. Kinesin family member 11 (KIF11) is a key driver of malignancy in glioblastoma, a grade IV glioma, but its involvement in glioma chemoresistance remains to be determined. We accessed the TCGA open datasets, collected glioma tumor tissue samples, and analyzed the expression of KIF11 in glioma patients. Meanwhile, the correlation between KIF11 and survival outcomes was determined by the Kaplan-Meier analysis. The role of KIF11 in glioma tumor cell function was assessed in an in vitro knockdown and overexpressing system. Here, we found that KIF11 was upregulated in glioma tumors and negatively correlated with overall survival outcomes via analyzing the open datasets. KIF11 was negatively correlated with TP53 expression. Furthermore, KIF11 promoted the stemness in glioma cells, accompanied by increased cell proliferation and chemoresistance. Mechanistically, we found that KIF11 promoted cell cycle progression via upregulating cyclin expression.
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Affiliation(s)
- Bin Liu
- Department of Neurosurgery Six, Cangzhou Central Hospital, Xinhua West Road, Cangzhou, 061000, Hebei, China.
| | - Gang Zhang
- Department of Neurosurgery Six, Cangzhou Central Hospital, Xinhua West Road, Cangzhou, 061000, Hebei, China
| | - Shukun Cui
- Department of Neurosurgery Six, Cangzhou Central Hospital, Xinhua West Road, Cangzhou, 061000, Hebei, China
| | - Guoliang Du
- Department of Neurosurgery Six, Cangzhou Central Hospital, Xinhua West Road, Cangzhou, 061000, Hebei, China
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Xiao Y, Yang K, Wang Z, Zhao M, Deng Y, Ji W, Zou Y, Qian C, Liu Y, Xiao H, Liu H. CD44-Mediated Poor Prognosis in Glioma Is Associated With M2-Polarization of Tumor-Associated Macrophages and Immunosuppression. Front Surg 2022; 8:775194. [PMID: 35187044 PMCID: PMC8850306 DOI: 10.3389/fsurg.2021.775194] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 12/29/2021] [Indexed: 12/31/2022] Open
Abstract
Background Glioma is the most common primary brain tumor with a poor prognosis. Key genes that are negatively related to prognosis may provide the therapy targets to cure glioma. To clarify the role of CD44 in glioma, we explored its function at bulk-transcriptome, spatial and single-cell transcriptome levels. Methods In total, expression profiles with survival data of whole-grade glioma from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA), RNA-seq data with anatomic information of glioblastoma (GBM) from the Ivy Glioblastoma Atlas Project, RNA-sequencing (RNA-seq) data from recurrent GBM receiving adjuvant anti-PD-1 immunotherapy accessed through GSE121810, and single-cell RNA-seq data of GBM under accession GSE103224 were enrolled in this study. CD44-specific findings were further analyzed by R language. Results CD44 is positively correlated with WHO grade of malignancy and is negatively related to prognosis in glioma. Meanwhile, CD44 predominantly expresses in GBM mesenchymal subtype, and gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses reveal that CD44 positively coexpressed genes are closely related to glioma immunity. Moreover, CD44+ cells mainly distribute in perinecrotic region with high expression of immune factors. At single-cell resolution, only malignant tumor cells, tumor-associated macrophages (TAMs), and T cells express CD44 in GBM. CD44+ malignant tumor cells are in mesenchymal-1-like (MES1-like) cellular state, and CD44+ TAMs are in M2 phenotype. CD44+ T cells have high expression of both PD-1 and PD-L1. CD44 and its directly interacted inhibitory immunomodulators are upregulated in patients with nonresponder recurrent GBM treated with PD-1 blockade therapy. Conclusion Our work demonstrates that CD44, a new M2 TAM biomarker, is involved in immune suppressor and promote glioma progression in glioma microenvironment. These results expand our understanding of CD44-specific clinical and immune features in glioma.
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Affiliation(s)
- Yong Xiao
- Department of Neurosurgery, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Kun Yang
- Department of Neurosurgery, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Zhen Wang
- Department of Neurosurgery, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Mengjie Zhao
- Department of Neuro-Psychiatric Institute, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Yanxiang Deng
- Department of Biomedical Engineering, Yale University, New Haven, CT, United States
| | - Wei Ji
- Department of Neurosurgery, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China
- Department of Neurosurgery, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Yuanjie Zou
- Department of Neurosurgery, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Chunfa Qian
- Department of Neurosurgery, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Yong Liu
- Department of Neurosurgery, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Hong Xiao
- Department of Neuro-Psychiatric Institute, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China
- *Correspondence: Hong Xiao
| | - Hongyi Liu
- Department of Neurosurgery, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China
- Hongyi Liu
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Ma K, Chen X, Liu W, Yang Y, Chen S, Sun J, Ma C, Wang T, Yang J. ANXA2 is correlated with the molecular features and clinical prognosis of glioma, and acts as a potential marker of immunosuppression. Sci Rep 2021; 11:20839. [PMID: 34675316 PMCID: PMC8531374 DOI: 10.1038/s41598-021-00366-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 10/11/2021] [Indexed: 12/15/2022] Open
Abstract
Recent studies have shown that ANXA2 is important in the development of many cancers, while its role in glioma-related immune response remains unclear. We aimed to comprehensively investigate its biological characteristics and clinical value in glioma. We analyzed 699 glioma samples from The Cancer Genome Atlas as training cohort and 325 samples from the Chinese Glioma Genome Atlas as validation cohort. All the statistical analyses and figures were generated with R. ANXA2 was overexpressed significantly in high-grade glioma, isocitrate dehydrogenase wild-type and mesenchymal-subtype glioma. ANXA2 was a special indicator of mesenchymal subtype. The survival analysis showed that highly-expressed ANXA2 was related to worse survival status as an independent factor of poor prognosis. Further gene ontology analysis showed that ANXA2 was mainly involved in immune response and inflammatory activities of glioma. Subsequent correlation analysis showed that ANXA2 was positively correlated with HCK, LCK, MHC II, STAT1 and interferon but negatively with IgG. Meanwhile, ANXA2 was positively related to the infiltration of tumor-related macrophages, regulatory T cells and myeloid-derived suppressor cells. Our study revealed that ANXA2 is a biomarker closely related to the malignant phenotype and poor prognosis of glioma, and plays an important role in immune response, inflammatory activity and immunosuppression.
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Affiliation(s)
- Kaiming Ma
- Department of Neurosurgery, Peking University Third Hospital, 49 North Garden Rd, Haidian District, Beijing, 100191, China
- Center for Precision Neurosurgery and Oncology of Peking University Health Science Center, Beijing, China
| | - Xin Chen
- Department of Neurosurgery, Peking University Third Hospital, 49 North Garden Rd, Haidian District, Beijing, 100191, China
- Center for Precision Neurosurgery and Oncology of Peking University Health Science Center, Beijing, China
| | - Weihai Liu
- Department of Neurosurgery, Peking University Third Hospital, 49 North Garden Rd, Haidian District, Beijing, 100191, China
- Center for Precision Neurosurgery and Oncology of Peking University Health Science Center, Beijing, China
| | - Yang Yang
- Department of Neurosurgery, Peking University Third Hospital, 49 North Garden Rd, Haidian District, Beijing, 100191, China
- Center for Precision Neurosurgery and Oncology of Peking University Health Science Center, Beijing, China
| | - Suhua Chen
- Department of Neurosurgery, Peking University Third Hospital, 49 North Garden Rd, Haidian District, Beijing, 100191, China
- Center for Precision Neurosurgery and Oncology of Peking University Health Science Center, Beijing, China
| | - Jianjun Sun
- Department of Neurosurgery, Peking University Third Hospital, 49 North Garden Rd, Haidian District, Beijing, 100191, China
- Center for Precision Neurosurgery and Oncology of Peking University Health Science Center, Beijing, China
| | - Changcheng Ma
- Department of Neurosurgery, Peking University Third Hospital, 49 North Garden Rd, Haidian District, Beijing, 100191, China
- Center for Precision Neurosurgery and Oncology of Peking University Health Science Center, Beijing, China
| | - Tao Wang
- Department of Neurosurgery, Peking University Third Hospital, 49 North Garden Rd, Haidian District, Beijing, 100191, China
- Center for Precision Neurosurgery and Oncology of Peking University Health Science Center, Beijing, China
| | - Jun Yang
- Department of Neurosurgery, Peking University Third Hospital, 49 North Garden Rd, Haidian District, Beijing, 100191, China.
- Center for Precision Neurosurgery and Oncology of Peking University Health Science Center, Beijing, China.
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Rocha MR, Morgado-Diaz JA. Epithelial-Mesenchymal Transition in colorectal cancer: Annexin A2 is caught in the crosshairs. J Cell Mol Med 2021; 25:10774-10777. [PMID: 34626069 PMCID: PMC8581319 DOI: 10.1111/jcmm.16962] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/09/2021] [Accepted: 09/19/2021] [Indexed: 11/28/2022] Open
Affiliation(s)
- Murilo Ramos Rocha
- Grupo de Estrutura e Dinâmica Celular, Programa de Oncobiologia Celular e Molecular, Instituto Nacional de Câncer, Rio de Janeiro, Brasil
| | - Jose Andres Morgado-Diaz
- Grupo de Estrutura e Dinâmica Celular, Programa de Oncobiologia Celular e Molecular, Instituto Nacional de Câncer, Rio de Janeiro, Brasil
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Huang SW, Chen YC, Lin YH, Yeh CT. Clinical Limitations of Tissue Annexin A2 Level as a Predictor of Postoperative Overall Survival in Patients with Hepatocellular Carcinoma. J Clin Med 2021; 10:jcm10184158. [PMID: 34575275 PMCID: PMC8465313 DOI: 10.3390/jcm10184158] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/07/2021] [Accepted: 09/13/2021] [Indexed: 11/20/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the second common cause of cancer-related death in Taiwan. Tumor recurrence is frequently observed in HCC patients receiving surgical resection, resulting in unsatisfactory overall survival (OS). Therefore, it is pivotal to identify effective prognostic makers, so that intensive surveillance or adjuvant treatments can be applied to predictively unfavorable patients. Previous studies indicated that Annexin A2 (ANXA2) was an effective prognostic marker in several cancers, including HCC. However, the prognostic value of ANXA2 in Taiwanese HCC patients remains unclear, where a great proportion of patients had chronic hepatitis B with liver cirrhosis. Here, ANXA2 was highly expressed in HCC tissues compared with para-neoplastic noncancerous tissues. Furthermore, high ANXA2 expression in HCC tissues independently predicted shorter OS. In subgroup analysis, however, ANXA2 expression could not effectively predict OS in the following subgroups: female, age > 65 years old, Child–Pugh classification B, hepatitis B virus surface antigen negative or anti-hepatitis C antibody positive, alcoholism, tumor number >1, presence of micro- or macrovascular invasion, absence of capsule, non-cirrhosis and high alpha-fetoprotein. In conclusion, ANXA2 expression in HCC tissues could predict postoperative OS. However, the predictive value was limited in patients with specific clinical conditions.
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Affiliation(s)
- Shu-Wei Huang
- Department of Gastroenterology and Hepatology, New Taipei Municipal Tucheng Hospital, New Taipei 236, Taiwan;
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan
| | - Yen-Chin Chen
- Graduate Institute of Clinical Medicine, Chang Gung University, Taoyuan 333, Taiwan;
| | - Yang-Hsiang Lin
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan
- Correspondence: (Y.-H.L.); (C.-T.Y.); Tel.: +886-3328-1200 (ext. 7785) (Y.-H.L.); +886-3328-1200 (ext. 8129) (C.-T.Y.); Fax: +886-3328-2824 (C.-T.Y.)
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan
- Correspondence: (Y.-H.L.); (C.-T.Y.); Tel.: +886-3328-1200 (ext. 7785) (Y.-H.L.); +886-3328-1200 (ext. 8129) (C.-T.Y.); Fax: +886-3328-2824 (C.-T.Y.)
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Li Y, Zhang Y, Wang X, Yang Q, Zhou X, Wu J, Yang X, Zhao Y, Lin R, Xie Y, Yuan J, Zheng X, Wang S. Bufalin induces mitochondrial dysfunction and promotes apoptosis of glioma cells by regulating Annexin A2 and DRP1 protein expression. Cancer Cell Int 2021; 21:424. [PMID: 34376212 PMCID: PMC8353806 DOI: 10.1186/s12935-021-02137-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 08/03/2021] [Indexed: 12/24/2022] Open
Abstract
Background Glioma is a common primary central nervous system tumour, and therapeutic drugs that can effectively improve the survival rate of patients in the clinic are lacking. Bufalin is effective in treating various tumours, but the mechanism by which it promotes the apoptosis of glioma cells is unclear. The aim of this study was to investigate the drug targets of bufalin in glioma cells and to clarify the apoptotic mechanism. Methods Cell viability and proliferation were evaluated by CCK-8 and colony formation assays. Then, the cell cycle and apoptosis, intracellular ion homeostasis, oxidative stress levels and mitochondrial damage were assessed after bufalin treatment. DARTS-PAGE technology was employed and LC–MS/MS was performed to explore the drug targets of bufalin in U251 cells. Molecular docking and western blotting were performed to identify potential targets. siRNA targeting Annexin A2 and the DRP1 protein inhibitor Mdivi-1 were used to confirm the targets of bufalin. Results Bufalin upregulated the expression of cytochrome C, cleaved caspase 3, p-Chk1 and p-p53 proteins to induce U251 cell apoptosis and cycle arrest in the S phase. Bufalin also induced oxidative stress in U251 cells, destroyed intracellular ion homeostasis, and caused mitochondrial damage. The expression of mitochondrial division-/fusion-related proteins in U251 cells was abnormal, the Annexin A2 and DRP1 proteins were translocated from the cytoplasm to mitochondria, and the MFN2 protein was released from mitochondria into the cytoplasm after bufalin treatment, disrupting the mitochondrial division/fusion balance in U251 cells. Conclusions Our research indicated that bufalin can cause Annexin A2 and DRP1 oligomerization on the surface of mitochondria and disrupt the mitochondrial division/fusion balance to induce U251 cell apoptosis. Graphic Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-02137-x.
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Affiliation(s)
- Yao Li
- Faculty of Life Science & Medicine, Key Laboratory Resource Biology & Biotechnology in Western China, Ministry of Education, Northwest University, Xi'an, 710069, Shaanxi, China
| | - Yan Zhang
- Department of Acupuncture, Xi'an Hospital of Traditional Chinese Medicine, Xi'an, 710021, Shaanxi, China
| | - Xufang Wang
- Faculty of Life Science & Medicine, Key Laboratory Resource Biology & Biotechnology in Western China, Ministry of Education, Northwest University, Xi'an, 710069, Shaanxi, China
| | - Qian Yang
- Department of Chinese Materia Medica and Natural Medicines, Air Force Medical University, Xi'an, 710032, Shaanxi, China
| | - Xuanxuan Zhou
- Department of Chinese Materia Medica and Natural Medicines, Air Force Medical University, Xi'an, 710032, Shaanxi, China
| | - Junsheng Wu
- Faculty of Life Science & Medicine, Key Laboratory Resource Biology & Biotechnology in Western China, Ministry of Education, Northwest University, Xi'an, 710069, Shaanxi, China
| | - Xu Yang
- Faculty of Life Science & Medicine, Key Laboratory Resource Biology & Biotechnology in Western China, Ministry of Education, Northwest University, Xi'an, 710069, Shaanxi, China
| | - Yani Zhao
- Department of Acupuncture, Xi'an Hospital of Traditional Chinese Medicine, Xi'an, 710021, Shaanxi, China
| | - Rui Lin
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Yanhua Xie
- Faculty of Life Science & Medicine, Key Laboratory Resource Biology & Biotechnology in Western China, Ministry of Education, Northwest University, Xi'an, 710069, Shaanxi, China
| | - Jiani Yuan
- Air Force Hospital of Western Theater Command, Chengdu, 610083, Sichuan, China.
| | - Xiaohui Zheng
- Faculty of Life Science & Medicine, Key Laboratory Resource Biology & Biotechnology in Western China, Ministry of Education, Northwest University, Xi'an, 710069, Shaanxi, China.
| | - Siwang Wang
- Faculty of Life Science & Medicine, Key Laboratory Resource Biology & Biotechnology in Western China, Ministry of Education, Northwest University, Xi'an, 710069, Shaanxi, China.
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Yin D, Hu Z, Luo C, Wang X, Xin H, Sun R, Wang P, Li J, Fan J, Zhou Z, Zhou J, Zhou S. LINC01133 promotes hepatocellular carcinoma progression by sponging miR-199a-5p and activating annexin A2. Clin Transl Med 2021; 11:e409. [PMID: 34047479 PMCID: PMC8101537 DOI: 10.1002/ctm2.409] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 03/22/2021] [Accepted: 04/19/2021] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Long noncoding RNAs (lncRNAs) are functionally associated with cancer development and progression. Although gene copy number variation (CNV) is common in hepatocellular carcinoma (HCC), it is not known how CNV in lncRNAs affects HCC progression and recurrence. We aimed to identify a CNV-related lncRNA involved in HCC progression and recurrence and illustrate its underlying mechanisms and prognostic value. METHODS We analyzed the whole genome sequencing (WGS) data of matched cancerous and noncancerous liver samples from 49 patients with HCC to identify lncRNAs with CNV. The results were validated in another cohort of 238 paired HCC and nontumor samples by TaqMan copy number assay. We preformed Kaplan-Meier analysis and log-rank test to identify lncRNA CNV with prognostic value. We conducted loss- and gain-of-function studies to explore the biological functions of LINC01133 in vitro and in vivo. The competing endogenous RNAs (ceRNAs) mechanism was clarified by microRNA sequencing (miR-seq), quantitative real-time PCR (qRT-PCR), western blot, and dual-luciferase reporter assays. We confirmed the binding mechanism between lncRNA and protein by RNA pull-down, RNA immunoprecipitation, qRT-PCR, and western blot analyses. RESULTS Genomic copy numbers of LINC01133 were increased in HCC, which were positively related with the elevated expression of LINC01133. Increased copy number of LINC01133 predicted the poor prognosis in HCC patients. LINC01133 overexpression in HCC cells promoted proliferation and aggressive phenotypes in vitro, and facilitated tumor growth and lung metastasis in vivo, whereas LINC01133 knockdown had the opposite effects. LINC01133 sponged miR-199a-5p, resulting in enhanced expression of SNAI1, which induced epithelial-to-mesenchymal transition (EMT) in HCC cells. In addition, LINC01133 interacted with Annexin A2 (ANXA2) to activate the ANXA2/STAT3 signaling pathway. CONCLUSIONS LINC01133 promotes HCC progression by sponging miR-199a-5p and interacting with ANXA2. LINC01133 CNV gain is predictive of poor prognosis in patients with HCC.
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Affiliation(s)
- Dan Yin
- Institute of Biomedical SciencesFudan UniversityShanghaiPeople's Republic of China
- Department of Liver Surgery and Transplantation, Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiPeople's Republic of China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University)Ministry of EducationShanghaiPeople's Republic of China
| | - Zhi‐Qiang Hu
- Department of Liver Surgery and Transplantation, Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiPeople's Republic of China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University)Ministry of EducationShanghaiPeople's Republic of China
| | - Chu‐Bin Luo
- Department of Liver Surgery and Transplantation, Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiPeople's Republic of China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University)Ministry of EducationShanghaiPeople's Republic of China
| | - Xiao‐Yi Wang
- Department of Liver Surgery and Transplantation, Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiPeople's Republic of China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University)Ministry of EducationShanghaiPeople's Republic of China
| | - Hao‐Yang Xin
- Department of Liver Surgery and Transplantation, Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiPeople's Republic of China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University)Ministry of EducationShanghaiPeople's Republic of China
| | - Rong‐Qi Sun
- Department of Liver Surgery and Transplantation, Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiPeople's Republic of China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University)Ministry of EducationShanghaiPeople's Republic of China
| | - Peng‐Cheng Wang
- Department of Liver Surgery and Transplantation, Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiPeople's Republic of China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University)Ministry of EducationShanghaiPeople's Republic of China
| | - Jia Li
- Department of Liver Surgery and Transplantation, Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiPeople's Republic of China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University)Ministry of EducationShanghaiPeople's Republic of China
| | - Jia Fan
- Institute of Biomedical SciencesFudan UniversityShanghaiPeople's Republic of China
- Department of Liver Surgery and Transplantation, Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiPeople's Republic of China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University)Ministry of EducationShanghaiPeople's Republic of China
| | - Zheng‐Jun Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiPeople's Republic of China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University)Ministry of EducationShanghaiPeople's Republic of China
| | - Jian Zhou
- Institute of Biomedical SciencesFudan UniversityShanghaiPeople's Republic of China
- Department of Liver Surgery and Transplantation, Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiPeople's Republic of China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University)Ministry of EducationShanghaiPeople's Republic of China
| | - Shao‐Lai Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer InstituteZhongshan HospitalFudan UniversityShanghaiPeople's Republic of China
- Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University)Ministry of EducationShanghaiPeople's Republic of China
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Grewal T, Rentero C, Enrich C, Wahba M, Raabe CA, Rescher U. Annexin Animal Models-From Fundamental Principles to Translational Research. Int J Mol Sci 2021; 22:ijms22073439. [PMID: 33810523 PMCID: PMC8037771 DOI: 10.3390/ijms22073439] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 03/18/2021] [Accepted: 03/24/2021] [Indexed: 02/07/2023] Open
Abstract
Routine manipulation of the mouse genome has become a landmark in biomedical research. Traits that are only associated with advanced developmental stages can now be investigated within a living organism, and the in vivo analysis of corresponding phenotypes and functions advances the translation into the clinical setting. The annexins, a family of closely related calcium (Ca2+)- and lipid-binding proteins, are found at various intra- and extracellular locations, and interact with a broad range of membrane lipids and proteins. Their impacts on cellular functions has been extensively assessed in vitro, yet annexin-deficient mouse models generally develop normally and do not display obvious phenotypes. Only in recent years, studies examining genetically modified annexin mouse models which were exposed to stress conditions mimicking human disease often revealed striking phenotypes. This review is the first comprehensive overview of annexin-related research using animal models and their exciting future use for relevant issues in biology and experimental medicine.
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Affiliation(s)
- Thomas Grewal
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia;
- Correspondence: (T.G.); (U.R.); Tel.: +61-(0)2-9351-8496 (T.G.); +49-(0)251-83-52121 (U.R.)
| | - Carles Rentero
- Departament de Biomedicina, Unitat de Biologia Cel·lular, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, 08036 Barcelona, Spain; (C.R.); (C.E.)
- Centre de Recerca Biomèdica CELLEX, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Carlos Enrich
- Departament de Biomedicina, Unitat de Biologia Cel·lular, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, 08036 Barcelona, Spain; (C.R.); (C.E.)
- Centre de Recerca Biomèdica CELLEX, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Mohamed Wahba
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia;
| | - Carsten A. Raabe
- Research Group Regulatory Mechanisms of Inflammation, Center for Molecular Biology of Inflammation (ZMBE) and Cells in Motion Interfaculty Center (CiM), Institute of Medical Biochemistry, University of Muenster, 48149 Muenster, Germany;
| | - Ursula Rescher
- Research Group Regulatory Mechanisms of Inflammation, Center for Molecular Biology of Inflammation (ZMBE) and Cells in Motion Interfaculty Center (CiM), Institute of Medical Biochemistry, University of Muenster, 48149 Muenster, Germany;
- Correspondence: (T.G.); (U.R.); Tel.: +61-(0)2-9351-8496 (T.G.); +49-(0)251-83-52121 (U.R.)
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10
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Li X, Nie S, Lv Z, Ma L, Song Y, Hu Z, Hu X, Liu Z, Zhou G, Dai Z, Song T, Liu J, Wang S. Overexpression of Annexin A2 promotes proliferation by forming a Glypican 1/c-Myc positive feedback loop: prognostic significance in human glioma. Cell Death Dis 2021; 12:261. [PMID: 33712571 PMCID: PMC7954792 DOI: 10.1038/s41419-021-03547-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 02/17/2021] [Accepted: 02/19/2021] [Indexed: 12/25/2022]
Abstract
In order to set up a reliable prediction system for the tumor grade and prognosis in glioma patients, we clarify the complicated crosstalk of Annexin A2 (ANXA2) with Glypican 1 (GPC1) and demonstrate whether combined indexes of ANXA2 and GPC1 could improve the prognostic evaluation for glioma patients. We found that ANXA2-induced glioma cell proliferation in a c-Myc-dependent manner. ANXA2 increased the expression of GPC1 via c-Myc and the upregulated GPC1 further promoted the c-Myc level, forming a positive feedback loop, which eventually led to enhanced proliferation of glioma cells. Both mRNA and protein levels of ANXA2 were upregulated in glioma tissues and coincided with the overexpression of GPC1. Besides, we utilized tissue microarrays (TMAs) and immunohistochemistry to demonstrate that glioma patients with both high expression of ANXA2 and GPC1 tended to have higher rate of tumor recurrence and shorter overall survival (OS). In conclusion, the overexpression of ANXA2 promotes proliferation of glioma cells by forming a GPC1/c-Myc positive feedback loop, and ANXA2 together with its downstream target GPC1 could be a potential "combination biomarker" for predicting prognosis of glioma patients.
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Affiliation(s)
- Xin Li
- Department of Neurosurgery, Xiang-Ya Hospital, Central South University, Changsha, China.,Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, China
| | - Shengdan Nie
- Institute of Clinical Medicine, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Ziyang Lv
- Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, China
| | - Lingran Ma
- Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, China
| | - Yuxi Song
- Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, China
| | - Zhongxu Hu
- Department of Neurosurgery, Xiang-Ya Hospital, Central South University, Changsha, China
| | - Xin Hu
- Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, China
| | - Zhiqiang Liu
- Department of Neurosurgery, Xiang-Ya Hospital, Central South University, Changsha, China
| | - Gaoya Zhou
- Department of Neurology, Brain Hospital of Hunan Province, Changsha, China
| | - Zhijie Dai
- Department of Institute of Metabolism and Endocrinology, Second Xiang-Ya Hospital, Central South University, Changsha, China
| | - Tao Song
- Department of Neurosurgery, Xiang-Ya Hospital, Central South University, Changsha, China.
| | - Jiajia Liu
- Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, China.
| | - Shan Wang
- Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, China.
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11
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Qiu LW, Liu YF, Cao XQ, Wang Y, Cui XH, Ye X, Huang SW, Xie HJ, Zhang HJ. Annexin A2 promotion of hepatocellular carcinoma tumorigenesis via the immune microenvironment. World J Gastroenterol 2020; 26:2126-2137. [PMID: 32476780 PMCID: PMC7235202 DOI: 10.3748/wjg.v26.i18.2126] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 04/08/2020] [Accepted: 04/20/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer with a dismal prognosis, especially when diagnosed at advanced stages. Annexin A2 (ANXA2), is found to promote cancer progression and therapeutic resistance. However, the underlining mechanisms of ANXA2 in immune escape of HCC remain poorly understood up to now. Herein, we summarized the molecular function of ANXA2 in HCC and its relationship with prognosis. Furthermore, we tentatively elucidated the underlying mechanism of ANXA2 immune escape of HCC by upregulating the proportion of regulatory T cells and the expression of several inhibitory molecules, and by downregulating the proportion of natural killer cells and dendritic cells and the expression of several inhibitory molecules or effector molecules. We expect a lot of in-depth studies to further reveal the underlying mechanism of ANXA2 in immune escape of HCC in the future.
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Affiliation(s)
- Li-Wei Qiu
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Yi-Fei Liu
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Xiao-Qing Cao
- Department of Thoracic Surgery, Beijing Chest Hospital, Capital Medical University (Beijing Tuberculosis and Thoracic Tumor Research Institute), Beijing 101149, China
| | - Yan Wang
- Emergency Department, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Xiao-Hong Cui
- Department of General Surgery, Shanghai Electric Power Hospital, Shanghai 200050, China
| | - Xian Ye
- Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Shuo-Wen Huang
- Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Hong-Jun Xie
- Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Hai-Jian Zhang
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
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12
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Kernel Differential Subgraph Analysis to Reveal the Key Period Affecting Glioblastoma. Biomolecules 2020; 10:biom10020318. [PMID: 32079293 PMCID: PMC7072688 DOI: 10.3390/biom10020318] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 02/05/2020] [Accepted: 02/10/2020] [Indexed: 12/26/2022] Open
Abstract
Glioblastoma (GBM) is a fast-growing type of malignant primary brain tumor. To explore the mechanisms in GBM, complex biological networks are used to reveal crucial changes among different biological states, which reflect on the development of living organisms. It is critical to discover the kernel differential subgraph (KDS) that leads to drastic changes. However, identifying the KDS is similar to the Steiner Tree problem that is an NP-hard problem. In this paper, we developed a criterion to explore the KDS (CKDS), which considered the connectivity and scale of KDS, the topological difference of nodes and function relevance between genes in the KDS. The CKDS algorithm was applied to simulated datasets and three single-cell RNA sequencing (scRNA-seq) datasets including GBM, fetal human cortical neurons (FHCN) and neural differentiation. Then we performed the network topology and functional enrichment analyses on the extracted KDSs. Compared with the state-of-art methods, the CKDS algorithm outperformed on simulated datasets to discover the KDSs. In the GBM and FHCN, seventeen genes (one biomarker, nine regulatory genes, one driver genes, six therapeutic targets) and KEGG pathways in KDSs were strongly supported by literature mining that they were highly interrelated with GBM. Moreover, focused on GBM, there were fifteen genes (including ten regulatory genes, three driver genes, one biomarkers, one therapeutic target) and KEGG pathways found in the KDS of neural differentiation process from activated neural stem cells (aNSC) to neural progenitor cells (NPC), while few genes and no pathway were found in the period from NPC to astrocytes (Ast). These experiments indicated that the process from aNSC to NPC is a key differentiation period affecting the development of GBM. Therefore, the CKDS algorithm provides a unique perspective in identifying cell-type-specific genes and KDSs.
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