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Serra F, Nieto-Aliseda A, Fanlo-Escudero L, Rovirosa L, Cabrera-Pasadas M, Lazarenkov A, Urmeneta B, Alcalde-Merino A, Nola EM, Okorokov AL, Fraser P, Graupera M, Castillo SD, Sardina JL, Valencia A, Javierre BM. p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response. Nat Commun 2024; 15:2821. [PMID: 38561401 PMCID: PMC10984980 DOI: 10.1038/s41467-024-46666-1] [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: 06/15/2023] [Accepted: 03/04/2024] [Indexed: 04/04/2024] Open
Abstract
Activation of the p53 tumor suppressor triggers a transcriptional program to control cellular response to stress. However, the molecular mechanisms by which p53 controls gene transcription are not completely understood. Here, we uncover the critical role of spatio-temporal genome architecture in this process. We demonstrate that p53 drives direct and indirect changes in genome compartments, topologically associating domains, and DNA loops prior to one hour of its activation, which escort the p53 transcriptional program. Focusing on p53-bound enhancers, we report 340 genes directly regulated by p53 over a median distance of 116 kb, with 74% of these genes not previously identified. Finally, we showcase that p53 controls transcription of distal genes through newly formed and pre-existing enhancer-promoter loops in a cohesin dependent manner. Collectively, our findings demonstrate a previously unappreciated architectural role of p53 as regulator at distinct topological layers and provide a reliable set of new p53 direct target genes that may help designs of cancer therapies.
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Affiliation(s)
- François Serra
- Josep Carreras Leukaemia Research Institute, Barcelona, Spain
| | | | | | | | - Mónica Cabrera-Pasadas
- Josep Carreras Leukaemia Research Institute, Barcelona, Spain
- Barcelona Supercomputing Center, Barcelona, Spain
| | | | - Blanca Urmeneta
- Josep Carreras Leukaemia Research Institute, Barcelona, Spain
| | | | - Emanuele M Nola
- Josep Carreras Leukaemia Research Institute, Barcelona, Spain
| | - Andrei L Okorokov
- Wolfson Institute for Biomedical Research, University College London, London, UK
| | - Peter Fraser
- Department of Biological Science, Florida State University, Tallahassee, FL, USA
| | - Mariona Graupera
- Josep Carreras Leukaemia Research Institute, Barcelona, Spain
- Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
- CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | | | - Jose L Sardina
- Josep Carreras Leukaemia Research Institute, Barcelona, Spain
| | - Alfonso Valencia
- Barcelona Supercomputing Center, Barcelona, Spain
- Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
| | - Biola M Javierre
- Josep Carreras Leukaemia Research Institute, Barcelona, Spain.
- Institute for Health Science Research Germans Trias i Pujol, Barcelona, Spain.
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2
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Gao D, Liao H, Junaid M, Chen X, Kong C, Wang Q, Pan T, Chen G, Wang X, Wang J. Polystyrene nanoplastics' accumulation in roots induces adverse physiological and molecular effects in water spinach Ipomoea aquatica Forsk. THE SCIENCE OF THE TOTAL ENVIRONMENT 2023; 872:162278. [PMID: 36801319 DOI: 10.1016/j.scitotenv.2023.162278] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 02/06/2023] [Accepted: 02/12/2023] [Indexed: 06/18/2023]
Abstract
The ubiquity of plastic pollution has emerged as a perplexing issue for aquatic and terrestrial plants. To assess the toxic effects of polystyrene NPs (PS-NPs, 80 nm), we conducted a hydroponic experiment in which water spinach (Ipomoea aquatica Forsk) was subjected to low (0.5 mg/L), medium (5 mg/L), and high (10 mg/L) concentrations of fluorescent PS-NPs for 10 days to examine their accumulation and transportation in water spinach and associated impacts on growth, photosynthesis, antioxidant defense systems. Laser confocal scanning microscopy (LCSM) observations at 10 mg/L PS-NPs exposure indicated that PS-NPs only adhered to the root surface of water spinach and were not transported upward, indicating that short-term exposure to high concentrations of PS-NPs (10 mg/L) did not cause the internalization of PS-NPs in the water spinach. However, this high concentration of PS-NPs (10 mg/L) discernibly inhibited the growth parameters (fresh weight, root length and shoot length), albeit failed to induce any significant impact on chlorophyll a and chlorophyll b concentrations. Meanwhile, high concentration of PS-NPs (10 mg/L) significantly decreased the SOD and CAT activities in leaves (p < 0.05). At the molecular level, low and medium concentrations of PS-NPs (0.5, 5 mg/L) significantly promoted the expression of photosynthesis (PsbA and rbcL) and antioxidant-related (SIP) genes in leaves (p < 0.05), and high concentration of PS-NPs (10 mg/L) significantly increased the transcription levels of antioxidant-related (APx) genes (p < 0.01). Our results imply that PS-NPs accumulate in the roots of water spinach, compromising the upward transport of water and nutrients and undermining the antioxidant defense system of the leaves at the physiological and molecular levels. These results provide a fresh perspective to examine the implications of PS-NPs on edible aquatic plants, and future efforts should be focused intensively on the impacts of PS-NPs on agricultural sustainability and food security.
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Affiliation(s)
- Dandan Gao
- College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China
| | - Hongping Liao
- College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China
| | - Muhammad Junaid
- College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China
| | - Xikun Chen
- College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China
| | - Chunmiao Kong
- College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China
| | - Qiuping Wang
- College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China
| | - Ting Pan
- College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China
| | - Guanglong Chen
- Institute of Eco-Environmental Research, Guangxi Academy of Sciences, Nanning 530007, China
| | - Xu Wang
- Institute of Quality Standard and Monitoring Technology for Agro-Products of Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China.
| | - Jun Wang
- College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China; Institute of Eco-Environmental Research, Guangxi Academy of Sciences, Nanning 530007, China; Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Guangzhou 510006, China.
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3
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Zhao W, Zhang Y, Zhang W, Sun Y, Zheng B, Wang J, Gu Y, Qi J, Li J, Wang XJ, Chen J, Yang F. Exosomal LINC00355 promotes the malignant progression of gastric cancer through histone deacetylase HDAC3-mediated TP53INP1 transcriptional inhibition. Life Sci 2023; 315:121387. [PMID: 36640904 DOI: 10.1016/j.lfs.2023.121387] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 01/06/2023] [Accepted: 01/09/2023] [Indexed: 01/13/2023]
Abstract
AIMS Exosomes are a subpopulation of extracellular vesicles (EV) derived from multivesicular body (MVB) that transmit various cellular molecular constituents, including long noncoding RNAs (lncRNAs), to promote intercellular communication. Our aim was to investigate the function and mechanism of exosomal LINC00355 in gastric cancer cells. MAIN METHODS Exosomal levels of LINC00355 in GC patients and healthy controls were measured by RT-qPCR. The effects of exosomal LINC00355 on GC cell viability, proliferation, migration and invasion were evaluated by CCK8, colony formation, Transwell and wound healing assays. The expression levels of Ki67 in xenograft tumor tissues were confirmed by immunohistochemistry assay, and apoptosis was analyzed by TUNEL apoptosis assay. Western blotting was used to monitor protein expression. RNA immunoprecipitation and RNA pulldown were performed to detect the interaction between LINC00355 and HDAC3. Chromatin immunoprecipitation was used to assess the interaction of HDAC3 with the TP53INP1 promoter. KEY FINDINGS Exosomal LINC00355 levels were higher in plasma from gastric cancer patients than in plasma from healthy volunteers. Exosomal LINC00355 promoted the proliferation, migration and invasion of gastric cancer cell lines. RNA sequence analysis demonstrated that LINC00355 knockdown downregulated histone deacetylase HDAC3 and upregulated TP53INP1. Mechanistic investigation indicated that exosomal LINC00355 interacted with HDAC3 to suppress TP53INP1 transcription, which promoted epithelial-mesenchymal transition (EMT). SIGNIFICANCE Exosomal LINC00355 plays a pivotal role in regulating EMT to induce the malignant progression of GC. Exosomal LINC00355 could be a promising biomarker in the early diagnosis and prognosis of GC.
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Affiliation(s)
- Wenjing Zhao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China
| | - Yunan Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China
| | - Wei Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China
| | - Yiming Sun
- Department of Pharmacy, the First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, Anhui, PR China
| | - Beiyao Zheng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China
| | - Junbin Wang
- Department of Oncology, the First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, Anhui, PR China
| | - Yazhou Gu
- Nanjing Heron Pharmaceutical Science and Technology Co., Ltd, Nanjing 211166, Jiangsu, PR China
| | - Junxia Qi
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China
| | - Juxue Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China
| | - Xue Jun Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China.
| | - Jinfei Chen
- Department of Oncology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, PR China; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China.
| | - Fen Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China.
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Nuclear corepressors NCOR1/NCOR2 regulate B cell development, maintain genomic integrity and prevent transformation. Nat Immunol 2022; 23:1763-1776. [PMID: 36316474 PMCID: PMC9772092 DOI: 10.1038/s41590-022-01343-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 09/16/2022] [Indexed: 12/15/2022]
Abstract
The nuclear corepressors NCOR1 and NCOR2 interact with transcription factors involved in B cell development and potentially link these factors to alterations in chromatin structure and gene expression. Herein, we demonstrate that Ncor1/2 deletion limits B cell differentiation via impaired recombination, attenuates pre-BCR signaling and enhances STAT5-dependent transcription. Furthermore, NCOR1/2-deficient B cells exhibited derepression of EZH2-repressed gene modules, including the p53 pathway. These alterations resulted in aberrant Rag1 and Rag2 expression and accessibility. Whole-genome sequencing of Ncor1/2 DKO B cells identified increased number of structural variants with cryptic recombination signal sequences. Finally, deletion of Ncor1 alleles in mice facilitated leukemic transformation, whereas human leukemias with less NCOR1 correlated with worse survival. NCOR1/2 mutations in human leukemia correlated with increased RAG expression and number of structural variants. These studies illuminate how the corepressors NCOR1/2 regulate B cell differentiation and provide insights into how NCOR1/2 mutations may promote B cell transformation.
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Changes in the Transcriptome Caused by Mutations in the Ribosomal Protein uS10 Associated with a Predisposition to Colorectal Cancer. Int J Mol Sci 2022; 23:ijms23116174. [PMID: 35682850 PMCID: PMC9181716 DOI: 10.3390/ijms23116174] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/24/2022] [Accepted: 05/30/2022] [Indexed: 02/05/2023] Open
Abstract
A number of mutations in the RPS20 gene encoding the ribosomal protein uS10 have been found to be associated with a predisposition to hereditary non-polyposis colorectal carcinoma (CRC). We transfected HEK293T cells with constructs carrying the uS10 minigene with mutations identical to those mentioned above and examined the effects of the produced proteins on the cellular transcriptome. We showed that uS10 with mutations p.V50SfsX23 or p.L61EfsX11 cannot be incorporated into 40S ribosomal subunits, while the protein with the missense mutation p.V54L functionally replaces the respective endogenous protein in the 40S subunit assembly and the translation process. The comparison of RNA-seq data obtained from cells producing aberrant forms of uS10 with data for those producing the wild-type protein revealed overlapping sets of upregulated and downregulated differently expressed genes (DEGs) related to several pathways. Among the limited number of upregulated DEGs, there were genes directly associated with the progression of CRC, e.g., PPM1D and PIGN. Our findings indicate that the accumulation of the mutant forms of uS10 triggers a cascade of cellular events, similar to that which is triggered when the cell responds to a large number of erroneous proteins, suggesting that this may increase the risk of cancer.
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Chen J, Li H, Yao J, Guo H, Zhang H, Guo Y, Sheng N, Wang J, Dai J. Chronic exposure to PFO4DA and PFO5DoDA, two perfluoroalkyl ether carboxylic acids (PFECAs), suppresses hepatic stress signals and disturbs glucose and lipid metabolism in male mice. JOURNAL OF HAZARDOUS MATERIALS 2021; 411:124963. [PMID: 33440278 DOI: 10.1016/j.jhazmat.2020.124963] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 12/21/2020] [Accepted: 12/23/2020] [Indexed: 05/27/2023]
Abstract
Perfluoroalkyl ether carboxylic acids (PFECAs), including PFO4DA and PFO5DoDA, have been found in both surface water and volunteer blood samples from polluted regions. However, little knowledge is available on their potential bioaccumulation and health risk. In the present study, the half-lives of PFO4DA and PFO5DoDA in male mouse serum were 24 h and nearly 43 d, respectively, indicating markedly increased difficulty in eliminating PFO5DoDA from the body. After 140 d daily exposure both PFO4DA and PFO5DoDA (10 μg/kg/d) increased body weight. Hepatomegaly was the most sensitive phenomenon after exposure treatment, with occurrence even in the 2 μg/kg/d exposure groups. RNA-seq analysis supported a similar but stronger effect of PFO5DoDA compared with PFO4DA. A wide array of genes involved in stimulus sensing and response were suppressed. In addition to weight gain, hyperglycemia was also observed after treatment. Increased glucose and decreased pyruvate and lactate levels in the liver supported a reduction in glycolysis, consistent with the reduction in the key regulator Pfkfb3. In conclusion, chronic PFO4DA and PFO5DoDA exposure suppressed stress signals and disturbed glucose and lipid metabolism in the liver. The longer serum half-life and stronger hepatic bioaccumulation of PFO5DoDA, at least partially, contributed to its stronger hepatotoxicity than that of PFO4DA.
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Affiliation(s)
- Jiamiao Chen
- Key Laboratory of Zoological Systematics and Application, School of Life Science, Institute of Life Science and Green Development, Hebei University, Hebei Province, Baoding 071002, PR China; Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China
| | - Hongyuan Li
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China
| | - Jingzhi Yao
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China
| | - Hua Guo
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China
| | - Hongxia Zhang
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China
| | - Yong Guo
- Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, PR China
| | - Nan Sheng
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China
| | - Jianshe Wang
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China; School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, Shandong Province, PR China.
| | - Jiayin Dai
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China
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Tu Y, Xie L, Chen L, Yuan Y, Qin B, Wang K, Zhu Q, Ji N, Zhu M, Guan H. Long non-coding RNA MEG3 promotes cataractogenesis by upregulating TP53INP1 expression in age-related cataract. Exp Eye Res 2020; 199:108185. [PMID: 32841649 DOI: 10.1016/j.exer.2020.108185] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 07/04/2020] [Accepted: 08/01/2020] [Indexed: 01/02/2023]
Abstract
Age-related cataract (ARC) is the leading cause of visual impairment or even blindness among the aged population globally. Long non-coding RNA (LncRNA) has been proven to be the potential regulator of ARC. The latest study reveals that maternally expressed gene 3 (MEG3) promotes the apoptosis and inhibits the proliferation of multiple cancer cells. However, the expression and role of MEG3 in ARC are unclear. In this study, we investigated the effects of MEG3 in ARC and explored the regulatory mechanisms underlying these effects. We observed that MEG3 expression was up-regulated in the age-related cortical cataract (ARCC) lens capsules and positively correlated with the histological degree of ARCC. The pro-apoptosis protein, active caspase-3 and Bax increased in the anterior lens capsules of ARCC tissue, while the anti-apoptotic protein Bcl-2 decreased compared to normal lens. Knockdown of MEG3 increased the viability and inhibited the apoptosis of LECs upon the oxidative stress induced by H2O2. MEG3 was localized in both nucleus and cytoplasm in LECs. MEG3 facilitated TP53INP1 expression via acting as miR-223 sponge and promoting P53 expression. Additionally, TP53INP1 knockdown alleviated H2O2-induced lens turbidity. In summary, MEG3 promoted ARC progression by up-regulating TP53INP1 expression through suppressing miR-223 and promoting P53 expression, which would provide a novel insight into the pathogenesis of ARC.
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Affiliation(s)
- Yuanyuan Tu
- Department of Ophthalmology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China; Department of Ophthalmology, Lixiang Eye Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Laiqing Xie
- Department of Ophthalmology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Lili Chen
- Department of Ophthalmology, Lixiang Eye Hospital of Soochow University, Suzhou, Jiangsu, China
| | - You Yuan
- Department of Ophthalmology, Lixiang Eye Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Bai Qin
- Department of Ophthalmology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Kun Wang
- Department of Ophthalmology, Lixiang Eye Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Qiujian Zhu
- Department of Ophthalmology, Lixiang Eye Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Na Ji
- Department of Ophthalmology, The Affiliated Eye Hospital of Suzhou Vocational Health College, Suzhou, Jiangsu, China
| | - Manhui Zhu
- Department of Ophthalmology, Lixiang Eye Hospital of Soochow University, Suzhou, Jiangsu, China.
| | - Huaijin Guan
- Department of Ophthalmology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.
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Yu J, Chen S, Niu Y, Liu M, Zhang J, Yang Z, Gao P, Wang W, Han X, Sun G. Functional Significance and Therapeutic Potential of miRNA-20b-5p in Esophageal Squamous Cell Carcinoma. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 21:315-331. [PMID: 32622332 PMCID: PMC7334444 DOI: 10.1016/j.omtn.2020.05.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 04/15/2020] [Accepted: 05/15/2020] [Indexed: 12/26/2022]
Abstract
Novel therapies tailored to the molecular composition mechanism of esophageal squamous cell carcinoma (ESCC) are needed to improve patient survival. miR-20b-5p expression was significantly upregulated in cancerous tissues and associated with lymph node metastasis, clinical stage, and overall survival (OS). An analysis of the methylation status of the miR-20b-5p gene indicated that the hypomethylation of the CpG sites located upstream of the miR-20b-5p gene in the ESCC tissues was more frequent than in the adjacent normal tissues, and the methylation status of miR-20b-5p correlated inversely with its expression levels. Notably, a series of gain- and loss-of-function assays elucidated that miR-20b-5p promoted ESCC cell proliferation, migration, and invasion both in vitro and in vivo. Luciferase reporter assays, western blot, and qRT-PCR revealed that RB1 and TP53INP1 were the direct targets of miR-20b-5p. Moreover, the effects of ectopic miR-20b-5p expression were abrogated by RB1 and TP53INP1 overexpression. In contrast, the effects of miR-20b-5p depletion were impaired by RB1 and TP53INP1 knockdown. Treatment with a miR-20b-5p antagomir dramatically increased tumor growth and inhibited RB1 and TP53INP1 protein expression in nude mice. This work provided novel insights on the molecular mechanism of ESCC and further provided suggestions for therapy development.
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Affiliation(s)
- Jiarui Yu
- School of Clinical Medicine, Affiliated Hospital, School of Public Health, North China University of Science and Technology, Tangshan, Hebei 063210, China; Department of Radiation Oncology, North China University of Science and Technology Affiliated People's Hospital, Tangshan 063000, China
| | - Siyuan Chen
- Department of Radiation Oncology, North China University of Science and Technology Affiliated People's Hospital, Tangshan 063000, China
| | - Yi Niu
- Department of Radiation Oncology, North China University of Science and Technology Affiliated People's Hospital, Tangshan 063000, China
| | - Meiyue Liu
- School of Clinical Medicine, Affiliated Hospital, School of Public Health, North China University of Science and Technology, Tangshan, Hebei 063210, China; Department of Radiation Oncology, North China University of Science and Technology Affiliated People's Hospital, Tangshan 063000, China
| | - Jie Zhang
- Department of pathology, North China University of Science and Technology Affiliated People's Hospital, Tangshan 063000, China
| | - Zhao Yang
- Department of Radiation Oncology, North China University of Science and Technology Affiliated People's Hospital, Tangshan 063000, China
| | - Peng Gao
- Department of Radiation Oncology, North China University of Science and Technology Affiliated People's Hospital, Tangshan 063000, China
| | - Wei Wang
- Department of Radiation Oncology, North China University of Science and Technology Affiliated People's Hospital, Tangshan 063000, China
| | - Xiaochen Han
- Department of Radiation Oncology, North China University of Science and Technology Affiliated People's Hospital, Tangshan 063000, China.
| | - Guogui Sun
- School of Clinical Medicine, Affiliated Hospital, School of Public Health, North China University of Science and Technology, Tangshan, Hebei 063210, China; Department of Radiation Oncology, North China University of Science and Technology Affiliated People's Hospital, Tangshan 063000, China.
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Lacroix M, Riscal R, Arena G, Linares LK, Le Cam L. Metabolic functions of the tumor suppressor p53: Implications in normal physiology, metabolic disorders, and cancer. Mol Metab 2020; 33:2-22. [PMID: 31685430 PMCID: PMC7056927 DOI: 10.1016/j.molmet.2019.10.002] [Citation(s) in RCA: 221] [Impact Index Per Article: 44.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 09/24/2019] [Accepted: 10/05/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The TP53 gene is one of the most commonly inactivated tumor suppressors in human cancers. p53 functions during cancer progression have been linked to a variety of transcriptional and non-transcriptional activities that lead to the tight control of cell proliferation, senescence, DNA repair, and cell death. However, converging evidence indicates that p53 also plays a major role in metabolism in both normal and cancer cells. SCOPE OF REVIEW We provide an overview of the current knowledge on the metabolic activities of wild type (WT) p53 and highlight some of the mechanisms by which p53 contributes to whole body energy homeostasis. We will also pinpoint some evidences suggesting that deregulation of p53-associated metabolic activities leads to human pathologies beyond cancer, including obesity, diabetes, liver, and cardiovascular diseases. MAJOR CONCLUSIONS p53 is activated when cells are metabolically challenged but the origin, duration, and intensity of these stresses will dictate the outcome of the p53 response. p53 plays pivotal roles both upstream and downstream of several key metabolic regulators and is involved in multiple feedback-loops that ensure proper cellular homeostasis. The physiological roles of p53 in metabolism involve complex mechanisms of regulation implicating both cell autonomous effects as well as autocrine loops. However, the mechanisms by which p53 coordinates metabolism at the organismal level remain poorly understood. Perturbations of p53-regulated metabolic activities contribute to various metabolic disorders and are pivotal during cancer progression.
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Affiliation(s)
- Matthieu Lacroix
- Institut de Recherche en Cancérologie de Montpellier, INSERM, Université de Montpellier, Institut Régional du Cancer de Montpellier, Montpellier, France; Equipe labélisée Ligue Contre le Cancer, France
| | - Romain Riscal
- Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Giuseppe Arena
- Gustave Roussy Cancer Campus, INSERM U1030, Villejuif, France
| | - Laetitia Karine Linares
- Institut de Recherche en Cancérologie de Montpellier, INSERM, Université de Montpellier, Institut Régional du Cancer de Montpellier, Montpellier, France; Equipe labélisée Ligue Contre le Cancer, France
| | - Laurent Le Cam
- Institut de Recherche en Cancérologie de Montpellier, INSERM, Université de Montpellier, Institut Régional du Cancer de Montpellier, Montpellier, France; Equipe labélisée Ligue Contre le Cancer, France.
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10
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Nishimoto M, Nishikawa S, Kondo N, Wanifuchi-Endo Y, Hato Y, Hisada T, Dong Y, Okuda K, Sugiura H, Kato H, Takahashi S, Toyama T. Prognostic impact of TP53INP1 gene expression in estrogen receptor α-positive breast cancer patients. Jpn J Clin Oncol 2019; 49:567-575. [PMID: 30855679 DOI: 10.1093/jjco/hyz029] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 02/01/2019] [Accepted: 02/13/2019] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Tumor protein 53-induced nuclear protein 1 (TP53INP1) is a key stress protein with tumor suppressor function. Several studies have demonstrated TP53INP1 downregulation in many cancers. In this study, we investigated the correlations of TP53INP1 mRNA expression in breast cancer tissues with prognosis and the correlations of microRNAs that regulate TP53INP1 expression in breast cancer patients with long follow-up. METHODS A total of 453 invasive breast cancer tissues were analyzed for TP53INP1 mRNA expression. We examined correlations of clinicopathological factors and expression levels of TP53INP1 mRNA in these samples. The expressions of miR-155, miR-569 and markers associated with tumor-initiating capacity were also analyzed. The median follow-up period was 9.0 years. RESULTS We found positive correlations between low expression of TP53INP1 mRNA and shorter disease-free survival and overall survival in breast cancer patients (P = 0.0002 and P < 0.0001, respectively), as well as in estrogen receptor α (ERα)-positive patients receiving adjuvant endocrine therapy (P = 0.01 and P = 0.0008, respectively). No correlations were found in ERα-negative patients. Low TP53INP1 mRNA levels positively correlated with higher grade and ERα-negativity. Multivariate analysis indicated that TP53INP1 mRNA level was an independent risk factor for overall survival both in overall breast cancer patients (hazard ratio, 2.13; 95% confidence interval, 1.17-3.92) and ERα-positive patients (hazard ratio, 2.34; 95% confidence interval, 1.18-4.64). CONCLUSIONS We show that low expression of TP53INP1 is an independent factor of poor prognosis in breast cancer patients, especially ERα-positive patients. TP53INP1 might be a promising candidate biomarker and therapeutic target in ERα-positive breast cancer patients.
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Affiliation(s)
- Mayumi Nishimoto
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences
| | - Sayaka Nishikawa
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences
| | - Naoto Kondo
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences
| | - Yumi Wanifuchi-Endo
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences
| | - Yukari Hato
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences
| | - Tomoka Hisada
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences
| | - Yu Dong
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences
| | - Katsuhiro Okuda
- Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences
| | - Hiroshi Sugiura
- Department of Education and Research Center for Advanced Medicine, Nagoya City University Graduate School of Medical Sciences
| | - Hiroyuki Kato
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Japan
| | - Satoru Takahashi
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Japan
| | - Tatsuya Toyama
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences
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11
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SUMOylation Evoked by Oxidative Stress Reduced Lens Epithelial Cell Antioxidant Functions by Increasing the Stability and Transcription of TP53INP1 in Age-Related Cataracts. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:7898069. [PMID: 31281592 PMCID: PMC6590620 DOI: 10.1155/2019/7898069] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 05/05/2019] [Indexed: 01/13/2023]
Abstract
Oxidative stress plays an important role in the pathogenesis of cataracts. Small ubiquitin-like modifier (SUMO) proteins have great effects on cell stress response. Previous studies have shown that TP53INP1 can arrest cell growth and induce apoptosis by modulating p53 transcriptional activity and that both TP53INP1 and p53 are substrates of SUMOylation. However, no previous research has studied the effect of SUMOylation on the oxidative stress response in cataracts. This is the first study to investigate the effect of SUMOylation of TP53INP1 in oxidative stress-induced lens epithelial cell injury and age-related cataract formation. We found that the oxidative stress-induced endogenous SUMOylation of TP53INP1 promoted human lens epithelial cell (holed) apoptosis and regulated hLEC antioxidant effects by increasing the stability and transcription of TP53INP1 in age-related cataracts. SUMO-1, SUMOylation, and TP53INP1 were upregulated in lens tissues affected by age-related cataracts. A SUMO-1-specific protease, SENP1, acted as an oxidative stress-sensitive target gene in hLECs. This study identified for the first time that TP53INP1 can be SUMOylated in vivo, that the SUMOylation of TP53INP1 is induced by oxidative stress, and that SUMOylation/deSUMOylation can affect the stability and transcription of TP53INP1 in hLECs.
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12
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Zhang F, Yang C, Xing Z, Liu P, Zhang B, Ma X, Huang L, Zhuang L. LncRNA GAS5-mediated miR-1323 promotes tumor progression by targeting TP53INP1 in hepatocellular carcinoma. Onco Targets Ther 2019; 12:4013-4023. [PMID: 31190897 PMCID: PMC6535457 DOI: 10.2147/ott.s209439] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 04/29/2019] [Indexed: 12/19/2022] Open
Abstract
Background: MiR-1323 was identified in 2006. Until now, the roles and mechanisms of miR-1323 in the progression of cancers including hepatocellular carcinoma (HCC) remain unknown. The aim of this study was to investigate the expressions, roles and mechanisms of miR-1323 in HCC development. Methods: QRT-PCR was used to evaluate the expressions of miR-1323, GAS5 and TP53INP1 in HCC tissues and cell lines. CCK-8 assay, transwell invasion assay and flow cytometry assay were conducted to evaluate the proliferation, invasion and apoptosis of HCC cells. Luciferase assay was used to identify microRNA-target interaction. Results: Firstly, our results showed that miR-1323 promoted proliferation and invasion, and inhibited apoptosis of HCC cells. Secondly, we found that TP53INP1 was a direct target of miR-1323 and could reverse the effects of miR-1323 on proliferation, invasion and apoptosis of HCC cells. Thirdly, our results showed that long non-coding RNA (lncRNA) GAS5 and miR-1323 could interact with each other and affect biological processes of HCC cells. Furthermore, we identified the negative correlations between miR-1323 and TP53INP1, and between miR-1323 and GAS5 in tumor tissues of patients with HCC. Conclusion: Taken together, our study revealed the important roles of GAS5/miR-1323/TP53INP1 axis in HCC progression. This study also provided promising strategies for targeted therapy of patients with HCC.
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Affiliation(s)
- Fengjuan Zhang
- Department of Infectious Diseases, The Affiliated Hospital of Qingdao University, Qingdao 266003, People's Republic of China
| | - Chao Yang
- Department of Infectious Diseases, The Affiliated Hospital of Qingdao University, Qingdao 266003, People's Republic of China
| | - Zhiyuan Xing
- Department of General Surgery, The Second Affiliated Hospital of Qingdao University, Qingdao 266003, People's Republic of China
| | - Pei Liu
- Department of Infectious Diseases, The Affiliated Hospital of Qingdao University, Qingdao 266003, People's Republic of China
| | - Bo Zhang
- Department of Gastroenterology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, People's Republic of China
| | - Xiang Ma
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266003, People's Republic of China
| | - Liuye Huang
- Department of Gastroenterology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, People's Republic of China
| | - Likun Zhuang
- Institute of Transplantation Science, The Affiliated Hospital of Qingdao University, Qingdao 266003, People's Republic of China
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13
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Warnez‐Soulie J, Macia M, Lac S, Pecchi E, Bernard M, Bendahan D, Bartoli M, Carrier A, Giannesini B. Tumor protein 53-induced nuclear protein 1 deficiency alters mouse gastrocnemius muscle function and bioenergetics in vivo. Physiol Rep 2019; 7:e14055. [PMID: 31124296 PMCID: PMC6533175 DOI: 10.14814/phy2.14055] [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] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 03/14/2019] [Indexed: 12/06/2022] Open
Abstract
Tumor protein 53-induced nuclear protein 1 (TP53INP1) deficiency leads to oxidative stress-associated obesity and insulin resistance. Although skeletal muscle has a predominant role in the development of metabolic syndrome, the bioenergetics and functional consequences of TP53INP1 deficiency upon this tissue remain undocumented. To clarify this issue, gastrocnemius muscle mechanical performance, energy metabolism, and anatomy were investigated in TP53INP1-deficient and wild-type mice using a multidisciplinary approach implementing noninvasive multimodal-NMR techniques. TP53INP1 deficiency increased body adiposity but did not affect cytosolic oxidative stress, lipid content, and mitochondrial pool and capacity in myocyte. During a fatiguing bout of exercise, the in vivo oxidative ATP synthesis capacity was dramatically reduced in TP53INP1-deficient mice despite ADP level (the main in vivo stimulator of mitochondrial respiration) did not differ between both genotypes. Moreover, TP53INP1 deficiency did not alter fatigue resistance but paradoxically increased the contractile force, whereas there were no differences for muscle fiber-type distribution and calcium homeostasis between both genotypes. In addition, muscle proton efflux was decreased in TP53INP1-deficient mice, thereby indicating a reduced blood supply. In conclusion, TP53INP1 plays a role in muscle function and bioenergetics through oxidative capacity impairment possibly as the consequence of abnormal mitochondrial respiration regulation and/or defective blood supply.
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Affiliation(s)
| | | | - Sophie Lac
- Aix Marseille Univ, CNRS, INSERM, Institut Paoli‐Calmettes, CRCMMarseilleFrance
| | | | | | | | | | - Alice Carrier
- Aix Marseille Univ, CNRS, INSERM, Institut Paoli‐Calmettes, CRCMMarseilleFrance
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14
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Aning OA, Cheok CF. Drugging in the absence of p53. J Mol Cell Biol 2019; 11:255-264. [PMID: 30865230 PMCID: PMC6478123 DOI: 10.1093/jmcb/mjz012] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 12/29/2018] [Accepted: 01/04/2019] [Indexed: 01/01/2023] Open
Abstract
Inactivation of the p53 gene is a key driver of tumorigenesis in various cancer cohorts and types. The quest for a successful p53-based therapy that holds the promise of treating more than half of the cancer population has culminated in extensive knowledge about the role and function of p53 and led to new proposed innovative strategies against p53-defective cancers. We will discuss some of these latest studies with a focus on metabolic regulation and DNA damage response and also highlight novel functions of p53 in these pathways that may provide a contemporary rationale for targeting p53 loss in tumors.
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Affiliation(s)
| | - Chit Fang Cheok
- Institute of Molecular and Cell Biology, A*STAR, Singapore
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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15
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Zhao J, Fu Y, Wu J, Li J, Huang G, Qin L. The Diverse Mechanisms of miRNAs and lncRNAs in the Maintenance of Liver Cancer Stem Cells. BIOMED RESEARCH INTERNATIONAL 2018; 2018:8686027. [PMID: 29888282 PMCID: PMC5977062 DOI: 10.1155/2018/8686027] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 04/03/2018] [Indexed: 12/26/2022]
Abstract
Liver cancer is the second leading cause of cancer-related death worldwide. The high frequency of recurrence and metastasis is the main reason for poor prognosis. Liver cancer stem cells (CSCs) have unlimited self-renewal, differentiation, and tumor-regenerating capacities. The maintenance of CSCs may account for the refractory features of liver cancer. Despite extensive investigations, the underlying regulatory mechanisms of liver CSCs remain elusive. miRNA and lncRNA, two major classes of the ncRNA family, can exert important roles in various biological processes, and their diverse regulatory mechanisms in CSC maintenance have acquired increasing attention. However, to the best of our knowledge, there is a lack of reviews summarizing these findings. Therefore, we systematically recapitulated the latest studies on miRNAs and lncRNAs in sustaining liver CSCs. Moreover, we highlighted the potential clinical application of these dysregulated ncRNAs as novel diagnostic and prognostic biomarkers and therapeutic targets. This review not only sheds new light to fully understand liver CSCs but also provides valuable clues on targeting ncRNAs to block or eradicate CSCs in cancer treatment.
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Affiliation(s)
- Jing Zhao
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
| | - Yan Fu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Jing Wu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Juan Li
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Guangjian Huang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Lunxiu Qin
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
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16
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Wang Y, Sun H, Zhang D, Fan D, Zhang Y, Dong X, Liu S, Yang Z, Ni C, Li Y, Liu F, Zhao X. TP53INP1 inhibits hypoxia-induced vasculogenic mimicry formation via the ROS/snail signalling axis in breast cancer. J Cell Mol Med 2018; 22:3475-3488. [PMID: 29655255 PMCID: PMC6010892 DOI: 10.1111/jcmm.13625] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2017] [Accepted: 03/05/2018] [Indexed: 12/28/2022] Open
Abstract
Tumour protein p53‐inducible nuclear protein 1 (TP53INP1) is a tumour suppressor associated with malignant tumour metastasis. Vasculogenic mimicry (VM) is a new tumour vascular supply pattern that significantly influences tumour metastasis and contributes to a poor prognosis. However, the molecular mechanism of the relationship between TP53INP1 and breast cancer VM formation is unknown. Here, we explored the underlying mechanism by which TP53INP1 regulates VM formation in vitro and in vivo. High TP53INP1 expression was not only negatively correlated with a poor prognosis but also had a negative relationship with VE‐cadherin, HIF‐1α and Snail expression. TP53INP1 overexpression inhibited breast cancer invasion, migration, epithelial‐mesenchymal transition (EMT) and VM formation; conversely, TP53INP1 down‐regulation promoted these processes in vitro by functional experiments and Western blot analysis. We established a hypoxia model induced by CoCl2 and assessed the effects of TP53INP1 on hypoxia‐induced EMT and VM formation. In addition, we confirmed that a reactive oxygen species (ROS)‐mediated signalling pathway participated in TP53INP1‐mediated VM formation. Together, our results show that TP53INP1 inhibits hypoxia‐induced EMT and VM formation via the ROS/GSK‐3β/Snail pathway in breast cancer, which offers new insights into breast cancer clinical therapy.
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Affiliation(s)
- Yi Wang
- Department of Pathology, Tianjin Medical University, Tianjin, China
| | - Huizhi Sun
- Department of Pathology, Tianjin Medical University, Tianjin, China
| | - Danfang Zhang
- Department of Pathology, Tianjin Medical University, Tianjin, China.,Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China
| | - Dan Fan
- Department of Pathology, Tianjin Medical University, Tianjin, China
| | - Yanhui Zhang
- Department of Pathology, Cancer Hospital of Tianjin Medical University, Tianjin, China
| | - Xueyi Dong
- Department of Pathology, Tianjin Medical University, Tianjin, China
| | - Shiqi Liu
- Department of Pathology, Tianjin Medical University, Tianjin, China
| | - Zhao Yang
- Department of Pathology, Tianjin Medical University, Tianjin, China
| | - Chunsheng Ni
- Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China
| | - Yanlei Li
- Department of Pathology, Tianjin Medical University, Tianjin, China
| | - Fang Liu
- Department of Pathology, Tianjin Medical University, Tianjin, China
| | - Xiulan Zhao
- Department of Pathology, Tianjin Medical University, Tianjin, China.,Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China
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17
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Ng KY, Chan LH, Chai S, Tong M, Guan XY, Lee NP, Yuan Y, Xie D, Lee TK, Dusetti NJ, Carrier A, Ma S. TP53INP1 Downregulation Activates a p73-Dependent DUSP10/ERK Signaling Pathway to Promote Metastasis of Hepatocellular Carcinoma. Cancer Res 2017; 77:4602-4612. [PMID: 28674078 DOI: 10.1158/0008-5472.can-16-3456] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 05/26/2017] [Accepted: 06/27/2017] [Indexed: 11/16/2022]
Abstract
Identifying critical factors involved in the metastatic progression of hepatocellular carcinoma (HCC) may offer important therapeutic opportunities. Here, we report that the proapoptotic stress response factor TP53INP1 is often selectively downregulated in advanced stage IV and metastatic human HCC tumors. Mechanistic investigations revealed that TP53INP1 downregulation in early-stage HCC cells promoted metastasis via DUSP10 phosphatase-mediated activation of the ERK pathway. The DUSP10 promoter included putative binding sites for p73 directly implicated in modulation by TP53INP1. Overall, our findings show how TP53INP1 plays a critical role in limiting the progression of early-stage HCC, with implications for developing new therapeutic strategies to attack metastatic HCC. Cancer Res; 77(17); 4602-12. ©2017 AACR.
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Affiliation(s)
- Kai-Yu Ng
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong
| | - Lok-Hei Chan
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong
| | - Stella Chai
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong
| | - Man Tong
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong
| | - Xin-Yuan Guan
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong.,State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Nikki P Lee
- Department of Surgery, The University of Hong Kong, Hong Kong
| | - Yunfei Yuan
- State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Dan Xie
- State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Terence K Lee
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong
| | - Nelson J Dusetti
- Aix Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France
| | - Alice Carrier
- Aix Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France
| | - Stephanie Ma
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong. .,State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
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18
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Deng Y, Li AM, Zhao XM, Song ZJ, Liu SD. Downregulation of tumor protein 53-inducible nuclear protein 1 expression in hepatocellular carcinoma correlates with poor prognosis. Oncol Lett 2016; 13:1228-1234. [PMID: 28454239 PMCID: PMC5403351 DOI: 10.3892/ol.2016.5537] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 11/07/2016] [Indexed: 01/12/2023] Open
Abstract
The expression of tumor protein 53-inducible nuclear protein 1 (TP53INP1) is upregulated in certain cancers and downregulated in others. However, its expression in hepatocellular carcinoma (HCC) is not clear. The present study aimed to investigate the expression and prognostic value of TP53INP1 and its association with clinicopathological parameters in HCC. TP53INP1 expression in HCC tissue samples was examined via immunohistochemistry, western blotting and reverse transcription-quantitative polymerase chain reaction. Expression was categorized as high or low. The correlations of TP53INP1 expression with clinical characteristics and patients' prognoses were determined. TP53INP1 was frequently decreased in HCC tissues compared with adjacent non-tumorous liver tissues. This decreased expression was significantly associated with American Joint Committee on Cancer stage (P=0.014) and vascular invasion (P=0.024). Kaplan-Meier analysis further revealed that recurrence-free survival (RFS) (P=0.001) and overall survival (OS) (P=0.002) were significantly worse among patients with low TP53INP1 expression than among those with high TP53INP1 expression. In addition, multivariate analyses revealed that TP53INP1 was an independent predictor of OS [hazard ratio (HR)=2.680, 95% confidence interval (CI)=1.087–6.608, P=0.032) and RFS (HR=2.284, 95% CI=1.157–4.511, P=0.017). In conclusion, the expression of TP53INP1 was decreased in HCC, and TP53INP1 downregulation was an independent predictor of poor prognosis in patients with HCC.
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Affiliation(s)
- Yan Deng
- Department of Gastroenterology, Southern Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.,Department of Gastroenterology, Haicang Hospital, Xiamen, Fujian 361000, P.R. China
| | - Ai-Min Li
- Department of Gastroenterology, Southern Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Xin-Mei Zhao
- Department of Gastroenterology, Southern Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Zhang-Juan Song
- Department of Gastroenterology, Southern Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Si-De Liu
- Department of Gastroenterology, Southern Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
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19
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Chen Q, Zhou Y, Richards AM, Wang P. Up-regulation of miRNA-221 inhibits hypoxia/reoxygenation-induced autophagy through the DDIT4/mTORC1 and Tp53inp1/p62 pathways. Biochem Biophys Res Commun 2016; 474:168-174. [DOI: 10.1016/j.bbrc.2016.04.090] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2016] [Accepted: 04/14/2016] [Indexed: 01/16/2023]
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20
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Wang X, Wang L, Mo Q, Jia A, Dong Y, Wang G. A positive feedback loop of p53/miR-19/TP53INP1 modulates pancreatic cancer cell proliferation and apoptosis. Oncol Rep 2015; 35:518-23. [PMID: 26531836 DOI: 10.3892/or.2015.4361] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 06/26/2015] [Indexed: 11/06/2022] Open
Abstract
Pancreatic cancer is a common malignancy whose prognosis and treatment of pancreatic cancer is extremely poor, with only 20% of patients reaching two years of survival. Previous findings have shown that the tumor suppressor p53 is involved in the development of various types of cancer, including pancreatic cancer. Additionally, p53 is able to activate TP53INP1 transcription by regulating several phenotypes of cancer cells. Using gain and loss-of-function assays, the aim of the present study was to examine the relationships between miR-19a/b and cancer development as well as potential underlying mechanisms. The results showed that miR-19a/b identified a positive feedback regulation of p53/TP53INP1 axis. Additionally, p53 upregulated the TP53INP1 level in pancreatic cancer cells. However, overexpressed miR-19a/b partially restored the TP53 function in the pancreatic cancer cells while miR-19a/b downregulated TP53INP1 protein by directly targeting 3'UTR of its mRNA at the post-transcriptional level. In addition, the patient tissues identified that the miR-19a/b level in pancreatic cancer tissues was conversely correlated with TP53 and TP53INP1 expression. The results provide evidence for revealing the molecular mechanism involved in the development of pancreatic cancer and may be useful in the identification of new therapeutic targets for pancreatic cancer.
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Affiliation(s)
- Xiaofang Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Lei Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Qingjiang Mo
- Department of Clinical Laboratory, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Ankui Jia
- Department of Clinical Laboratory, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Yuqian Dong
- Department of Clinical Laboratory, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Guoqiang Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
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21
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Sándor N, Schilling-Tóth B, Kis E, Fodor L, Mucsányi F, Sáfrány G, Hegyesi H. TP53inp1 Gene Is Implicated in Early Radiation Response in Human Fibroblast Cells. Int J Mol Sci 2015; 16:25450-65. [PMID: 26512655 PMCID: PMC4632809 DOI: 10.3390/ijms161025450] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Revised: 09/15/2015] [Accepted: 10/20/2015] [Indexed: 12/04/2022] Open
Abstract
Tumor protein 53-induced nuclear protein-1 (TP53inp1) is expressed by activation via p53 and p73. The purpose of our study was to investigate the role of TP53inp1 in response of fibroblasts to ionizing radiation. γ-Ray radiation dose-dependently induces the expression of TP53inp1 in human immortalized fibroblast (F11hT) cells. Stable silencing of TP53inp1 was done via lentiviral transfection of shRNA in F11hT cells. After irradiation the clonogenic survival of TP53inp1 knockdown (F11hT-shTP) cells was compared to cells transfected with non-targeting (NT) shRNA. Radiation-induced senescence was measured by SA-β-Gal staining and autophagy was detected by Acridine Orange dye and microtubule-associated protein-1 light chain 3 (LC3B) immunostaining. The expression of TP53inp1, GDF-15, and CDKN1A and alterations in radiation induced mitochondrial DNA deletions were evaluated by qPCR. TP53inp1 was required for radiation (IR) induced maximal elevation of CDKN1A and GDF-15 expressions. Mitochondrial DNA deletions were increased and autophagy was deregulated following irradiation in the absence of TP53inp1. Finally, we showed that silencing of TP53inp1 enhances the radiation sensitivity of fibroblast cells. These data suggest functional roles for TP53inp1 in radiation-induced autophagy and survival. Taken together, we suppose that silencing of TP53inp1 leads radiation induced autophagy impairment and induces accumulation of damaged mitochondria in primary human fibroblasts.
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Affiliation(s)
- Nikolett Sándor
- Division of Molecular Radiobiology, National Public Health Center-National Research Directorate for Radiobiology and Radiohygiene, Anna 5, Budapest 1221, Hungary.
- Doctoral School of Pathological Sciences, Semmelweis University, Üllői 26, Budapest 1089, Hungary.
| | - Boglárka Schilling-Tóth
- Division of Molecular Radiobiology, National Public Health Center-National Research Directorate for Radiobiology and Radiohygiene, Anna 5, Budapest 1221, Hungary.
| | - Enikő Kis
- Division of Molecular Radiobiology, National Public Health Center-National Research Directorate for Radiobiology and Radiohygiene, Anna 5, Budapest 1221, Hungary.
| | - Lili Fodor
- Department of Genetics, Cell and Immunobiology, Semmelweis University, Nagyvárad tér 4, Budapest 1089, Hungary.
| | - Fruzsina Mucsányi
- Department of Genetics, Cell and Immunobiology, Semmelweis University, Nagyvárad tér 4, Budapest 1089, Hungary.
| | - Géza Sáfrány
- Division of Molecular Radiobiology, National Public Health Center-National Research Directorate for Radiobiology and Radiohygiene, Anna 5, Budapest 1221, Hungary.
| | - Hargita Hegyesi
- Division of Molecular Radiobiology, National Public Health Center-National Research Directorate for Radiobiology and Radiohygiene, Anna 5, Budapest 1221, Hungary.
- Department of Morphology and Physiology, College of Health Care, Semmelweis University, Vas 17, Budapest 1089, Hungary.
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NIE GUOHUI, DUAN HONGFANG, LI XIAOQING, YU ZHENDONG, LUO LIANG, LU RUIJING, JI ZILIANG, ZHANG WEI. MicroRNA‑205 promotes the tumorigenesis of nasopharyngeal carcinoma through targeting tumor protein p53-inducible nuclear protein 1. Mol Med Rep 2015; 12:5715-22. [PMID: 26252115 PMCID: PMC4581759 DOI: 10.3892/mmr.2015.4181] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 07/07/2015] [Indexed: 02/05/2023] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a common type of cancer in southern China, miRNAs have been shown to be involved in the tumorigenesis of multiple cancer types. The present study aimed to explore the potential role of miR‑205 in NPC. Reverse transcription quantitative polymerase chain reaction was used to determine the expression levels of miR‑205 in 20 fresh NPC specimens and 20 normal nasopharyngeal tissues. The function of miR‑205 in the proliferation, migration, invasion and apoptosis of NPC‑derived cells was detected by MTT assay, colony formation assay, wound healing assay, Transwell assay and flow cytometry. Furthermore, a target gene of miR‑205 was identified using the luciferase reporter assay. The expression of miR‑205 was increased in NPC tissues compared with that in normal tissues. Overexpression of miR‑205 was found to promote the proliferation, migration and invasion of NPC‑derived cells, while apoptosis was suppressed. Tumor protein p53-inducible nuclear protein 1 was identified as a target gene of miR‑205. Overall, the present study demonstrated that miR‑205 may function as an oncogene in NPC tumorigenesis.
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Affiliation(s)
- GUOHUI NIE
- Department of Otolaryngology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
- Correspondence to: Dr Guohui Nie, Department of Otolaryngology, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, Guangdong 518036, P.R. China, E-mail:
| | - HONGFANG DUAN
- Department of Otolaryngology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
- Department of Clinical Medicine, Guangzhou Medical University, Guangzhou, Guangdong 510000, P.R. China
| | - XIAOQING LI
- Department of Clinical Laboratory, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
- Department of Clinical Medicine, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - ZHENDONG YU
- Central Laboratory, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
| | - LIANG LUO
- Department of Otolaryngology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
- Department of Clinical Medicine, Guangzhou Medical University, Guangzhou, Guangdong 510000, P.R. China
| | - RUIJING LU
- Department of Clinical Laboratory, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China
- Department of Clinical Medicine, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - ZILIANG JI
- Department of Clinical Medicine, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - WEI ZHANG
- Shenzhen Key Laboratory for Translational Medicine of Dermatology, Biomedical Research Institute, Shenzhen Peking University - The Hong Kong University of Science and Technology Medical Center, Shenzhen, Guangdong 518036, P.R. China
- Dr Wei Zhang, Shenzhen Key Laboratory for Translational Medicine of Dermatology, Biomedical Research Institute, Shenzhen Peking University - The Hong Kong University of Science and Technology Medical Center, 1120 Lianhua Road, Shenzhen, Guangdong 518036, P.R. China, E-mail:
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23
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Li Q, Han Y, Wang C, Shan S, Wang Y, Zhang J, Ren T. MicroRNA-125b promotes tumor metastasis through targeting tumor protein 53-induced nuclear protein 1 in patients with non-small-cell lung cancer. Cancer Cell Int 2015; 15:84. [PMID: 26388699 PMCID: PMC4573481 DOI: 10.1186/s12935-015-0233-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Accepted: 08/24/2015] [Indexed: 01/22/2023] Open
Abstract
Background Lung cancer, predominantly non-small-cell lung cancer (NSCLC), is the leading cause of cancer deaths worldwide. There is a great need to identify critical effectors involved in metastasis of NSCLC that will facilitate the development of new therapeutic strategies. Here we evaluated the potential role of miR-125b in the metastasis of NSCLC cells. Methods Human NSCLC cells were isolated from surgical tissues with Cancer Cell Isolation Kit. Expressions of miR-125b and TP53INP1 were detected with real-time PCR and western blot. Human miR-125b mimics, miR-125b inhibitor, TP53INP1 expression plasmid and TP53INP1 siRNA were transfected into NSCLC cells with nucleofector transfection kit. NSCLC metastasis was determined with adhesion assay, invasive assay and lung tumor metastasis model. Results The expression of miR-125b was significantly higher in poorly differentiated NSCLC cells that are endowed with high metastatic potentials. Up-regulation of miR-125b could enhance the metastatic potential of NSCLC cells in vitro and in vivo, while down-regulation of miR-125b resulted in decreased metastatic potentials in vitro and in vivo. Further, tumor protein 53-induced nuclear protein 1 (TP53INP1) was an important target of miR-125b involved in metastasis of NSCLC cells. TP53INP1 served as a negative regulator of NSCLC metastasis. Decreased expression of TP53INP1 in tumor tissues was inversely associated with their expression of miR-125b, significantly lower in poorly differentiated tumors and inversely correlated with the clinical stages in patients with NSCLC. Conclusions These findings demonstrated that miR-125b promoted tumor metastasis via targeting TP53INP1 in human NSCLC cells, which uncovered a real clinical relevance of microRNAs in tumor biology, and provided novel potential candidates for NSCLC clinical practice. Electronic supplementary material The online version of this article (doi:10.1186/s12935-015-0233-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Qinchuan Li
- Department of Cardiothoracic Surgery, East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yang Han
- Department of Pathology, East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Chunhong Wang
- Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong New Area, 200120 Shanghai, China
| | - Shan Shan
- Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong New Area, 200120 Shanghai, China
| | - Yuanyuan Wang
- Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong New Area, 200120 Shanghai, China
| | - Jingang Zhang
- Service Center for Family planning, Maternal and Child Health Care, Lanshan, Linyi, Shandong China
| | - Tao Ren
- Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong New Area, 200120 Shanghai, China
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24
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Saadi H, Seillier M, Carrier A. The stress protein TP53INP1 plays a tumor suppressive role by regulating metabolic homeostasis. Biochimie 2015. [PMID: 26225460 DOI: 10.1016/j.biochi.2015.07.024] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
In the recent years, we have provided evidence that Tumor Protein 53-Induced Nuclear Protein 1 (TP53INP1) is a key stress protein with antioxidant-associated tumor suppressive function. The TP53INP1 gene, which is highly conserved in mammals, is over-expressed during stress responses including inflammation. This gene encodes two protein isoforms with nuclear or cytoplasmic subcellular localization depending on the context. TP53INP1 contributes to stress responses, thus preventing stress-induced dysfunctions leading to pathologies such as cancer. Two major mechanisms by which TP53INP1 functions have been unveiled. First, in the nucleus, TP53INP1 was shown to regulate the transcriptional activity of p53 and p73 by direct interaction, and to mediate the antioxidant activity of p53. Second, independently of p53, TP53INP1 contributes to autophagy and more particularly mitophagy through direct interaction with molecular actors of autophagy. TP53INP1 is thus required for the homeostasis of the mitochondrial compartment, and is therefore involved in the regulation of energetic metabolism. Finally, the antioxidant function of TP53INP1 stems from the control of mitochondrial reactive oxygen species production. In conclusion, TP53INP1 is a multifaceted protein endowed with multiple functions, including metabolic regulation, as is its main functional partner p53.
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Affiliation(s)
- Houda Saadi
- Inserm, U1068, CRCM, Marseille, F-13009, France; Institut Paoli-Calmettes, Marseille, F-13009, France; Aix-Marseille Université, UM 105, Marseille, F-13284, France; CNRS, UMR7258, CRCM, Marseille, F-13009, France
| | - Marion Seillier
- Inserm, U1068, CRCM, Marseille, F-13009, France; Institut Paoli-Calmettes, Marseille, F-13009, France; Aix-Marseille Université, UM 105, Marseille, F-13284, France; CNRS, UMR7258, CRCM, Marseille, F-13009, France
| | - Alice Carrier
- Inserm, U1068, CRCM, Marseille, F-13009, France; Institut Paoli-Calmettes, Marseille, F-13009, France; Aix-Marseille Université, UM 105, Marseille, F-13284, France; CNRS, UMR7258, CRCM, Marseille, F-13009, France.
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25
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Yang Y, Peng W, Tang T, Xia L, Wang XD, Duan BF, Shu Y. MicroRNAs as promising biomarkers for tumor-staging: evaluation of MiR21 MiR155 MiR29a and MiR92a in predicting tumor stage of rectal cancer. Asian Pac J Cancer Prev 2015; 15:5175-80. [PMID: 25040971 DOI: 10.7314/apjcp.2014.15.13.5175] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVE In this study, tumor-stage predictive abilities of miR21, miR155, miR29a and miR92a were evaluated in rectal cancer (RC). METHODS Expression of miR21, miR155, miR29a and miR92a was detected and quantitated in tumor tissue and in adjacent normal tissue from 40 patients by TaqMan MicroRNA assay. RESULTS Significant overexpression of miR21, miR155, miR29a and miR92a was observed in RC tissues. While high expression of miR21, miR155 and miR29a in N1-2 and C-D stages presented a potential correlation with N and Duke stages, partial correlation analysis suggested that only miR155 rather than miR21 and miR29a played a greater influencing role. Receiver operating characteristics (ROC) curve analysis showed that miR155 could discriminate N0 from N1-2 with 85.0% sensitivity and 85.0% specificity, N2 from N0-1 with 90.0% sensitivity and 96.7% specificity, and C-D stage from A-B stage with 81.0% sensitivity and 84.2% specificity. CONCLUSIONS Increase in expression of miR155 might represent a novel predictor for RC N and Dukes staging.
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Affiliation(s)
- Yun Yang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China E-mail :
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26
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Bonacci T, Peuget S, Soubeyran P, Iovanna J, Dusetti NJ. Redox-sensitive TP53INP1 SUMOylation as an oxidative stress sensor to activate TP53. Mol Cell Oncol 2014; 1:e964044. [PMID: 27308354 PMCID: PMC4905059 DOI: 10.4161/23723548.2014.964044] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 08/04/2014] [Accepted: 08/12/2014] [Indexed: 11/23/2022]
Abstract
Oxidative stress-induced sumoylation of TP53INP1 (tumor protein p53-induced nuclear protein 1) is essential to enhance the TP53 response. Sumoylation of TP53INP1 on the K113 residue, which is mediated by protein inhibitor of activated STAT 3 (PIAS3) and chromobox homolog 4 (CBX4) and removed by SUMO1/sentrin specific peptidase (SENP1, 2 and 6), favors its interaction with TP53 in the nucleus and enhances TP53-induced gene expression.
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Affiliation(s)
- Thomas Bonacci
- CRCM; Cancer Research Center of Marseille; INSERM U1068; Institut Paoli-Calmettes; Aix-Marseille University ; CNRS, UMR7258 ; Marseille, France
| | - Sylvain Peuget
- CRCM; Cancer Research Center of Marseille; INSERM U1068; Institut Paoli-Calmettes; Aix-Marseille University ; CNRS, UMR7258 ; Marseille, France
| | - Philippe Soubeyran
- CRCM; Cancer Research Center of Marseille; INSERM U1068; Institut Paoli-Calmettes; Aix-Marseille University ; CNRS, UMR7258 ; Marseille, France
| | - Juan Iovanna
- CRCM; Cancer Research Center of Marseille; INSERM U1068; Institut Paoli-Calmettes; Aix-Marseille University ; CNRS, UMR7258 ; Marseille, France
| | - Nelson J Dusetti
- CRCM; Cancer Research Center of Marseille; INSERM U1068; Institut Paoli-Calmettes; Aix-Marseille University ; CNRS, UMR7258 ; Marseille, France
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27
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Yang Y, Tang T, Peng W, Xia L, Wang X, Duan B, Shu Y. The comparison of miR-155 with computed tomography and computed tomography plus serum amyloid A protein in staging rectal cancer. J Surg Res 2014; 193:764-71. [PMID: 25261908 DOI: 10.1016/j.jss.2014.08.040] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Revised: 08/17/2014] [Accepted: 08/22/2014] [Indexed: 02/05/2023]
Abstract
BACKGROUND Recently identified class of microRNAs (miRNAs) provided a new insight in cancer research. As a member of miRNAs family, miR-155 expression demonstrated the correlation with tumor stage. Thus, its expression level can be potentially used for staging rectal tumors. The aim of this study was to systematically evaluate the potential abilities of miR-155 in preoperatively N staging. MATERIALS AND METHODS Expression of miR-155 was detected and quantitated in rectal cancer tissues and in adjacent nonmalignant tissues from 40 patients by TaqMan MicroRNA assays. Preoperative enhanced computed tomography (CT) scan, serum amyloid A protein (SAA), carcinoembryonic antigen (CEA), and postoperative pathologic biopsy were performed. RESULTS A significant overexpression of miR-155 was observed in rectal carcinoma tissues (0.137 ± 0.095 versus 0.093 ± 0.091, P = 0.043). High expression of miR-155 in N1-2 (0.09 ± 0.038 versus 0.183 ± 0.111, P = 0.001) and III and IV stages (0.091 ± 0.039 versus 0.178 ± 0.111, P = 0.002) presented its potential correlation with N and tumor-node-metastasis combined stages. Receiver operating characteristics curve analysis showed that miR-155 could discriminate N0 from N1-2 with 85.0% sensitivity and 85.0% specificity at the cutoff value of 0.125. miR-155 and CT had nearly equal performances in sensitivity (0.850 versus 0.700, P = 0.450) and specificity (0.850 versus 0.550, P = 0.077) in predicting N1-2 stage. Compared with CT + SAA, miR-155 had similar sensitivity (0.850 versus 0.950, P = 0.617) but higher specificity (0.750 versus 0.200, P = 0.015) for lymph node assessment. CONCLUSIONS Increase in the expression of miR-155 might represent a potential valuable marker for rectal carcinoma N and combined tumor-node-metastasis staging.
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Affiliation(s)
- Yun Yang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Tian Tang
- Department of Hepatic Surgery and Hepatic Transplantation Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China
| | - Wei Peng
- Department of Gynecology and Obstetrics, West China Women's and Children's Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China
| | - Lin Xia
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Xiaodong Wang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Baofeng Duan
- Department of Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Ye Shu
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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Induction of apoptosis through ER stress and TP53 in MCF-7 cells by the nanoparticle [Gd@C82(OH)22]n: A systems biology study. Methods 2014; 67:394-406. [DOI: 10.1016/j.ymeth.2014.01.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Revised: 12/10/2013] [Accepted: 01/05/2014] [Indexed: 01/20/2023] Open
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Oxidative stress-induced p53 activity is enhanced by a redox-sensitive TP53INP1 SUMOylation. Cell Death Differ 2014; 21:1107-18. [PMID: 24608790 DOI: 10.1038/cdd.2014.28] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Revised: 01/08/2014] [Accepted: 01/27/2014] [Indexed: 01/28/2023] Open
Abstract
Tumor Protein p53-Induced Nuclear Protein 1 (TP53INP1) is a tumor suppressor that modulates the p53 response to stress. TP53INP1 is one of the key mediators of p53 antioxidant function by promoting the p53 transcriptional activity on its target genes. TP53INP1 expression is deregulated in many types of cancers including pancreatic ductal adenocarcinoma in which its decrease occurs early during the preneoplastic development. In this work, we report that redox-dependent induction of p53 transcriptional activity is enhanced by the oxidative stress-induced SUMOylation of TP53INP1 at lysine 113. This SUMOylation is mediated by PIAS3 and CBX4, two SUMO ligases especially related to the p53 activation upon DNA damage. Importantly, this modification is reversed by three SUMO1-specific proteases SENP1, 2 and 6. Moreover, TP53INP1 SUMOylation induces its binding to p53 in the nucleus under oxidative stress conditions. TP53INP1 mutation at lysine 113 prevents the pro-apoptotic, antiproliferative and antioxidant effects of TP53INP1 by impairing the p53 response on its target genes p21, Bax and PUMA. We conclude that TP53INP1 SUMOylation is essential for the regulation of p53 activity induced by oxidative stress.
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30
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Zhang CM, Zhao J, Deng HY. MiR-155 promotes proliferation of human breast cancer MCF-7 cells through targeting tumor protein 53-induced nuclear protein 1. J Biomed Sci 2013; 20:79. [PMID: 24152184 PMCID: PMC4015120 DOI: 10.1186/1423-0127-20-79] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Accepted: 10/21/2013] [Indexed: 12/12/2022] Open
Abstract
Background MiR-155 has emerged as an “oncomiR”, which is the most significantly up-regulated miRNA in breast cancer. However, the mechanisms of miR-155 functions as an oncomiR are mainly unknown. In this study, the aims were to investigate the effects of miR-155 on cell proliferation, cell cycle, and cell apoptosis of ERalpha (+) breast cancer cells and to verify whether TP53INP1 (tumor protein 53-induced nuclear protein 1) is a target of miR-155, and tried to explore the mechanisms of miR-155 in this process. Results The expression of miR-155 is significantly higher in MCF-7 cells compared with MDA-MB-231 cells. Ectopic expression of TP53INP1 inhibits growth of MCF-7 cells by inducing cell apoptosis and inhibiting cell cycle progression. Overexpression of miR-155 increases cell proliferation and suppress cell apoptosis, whereas abrogating expression of miR-155 suppress cell proliferation and promotes cell apoptosis of MCF-7 cells. In addition, miR-155 negatively regulates TP53INP1 mRNA expression and the protein expression of TP53INP1, cleaved-caspase-3, -8, -9, and p21, and luciferase reporter reveals that TP53INP1 is targeted by miR-155. Conclusions TP53INP1 is the direct target of miR-155. MiR-155, which is overexpressed in MCF-7 cells, contributes to proliferation of MCF-7 cells possibly through down-regulating target TP53INP1.
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Affiliation(s)
| | | | - Hua-Yu Deng
- Department of Pathophysiology, School of Basic Medicine, Chongqing Medical University, 1 Medical School Road, Chongqing 400016, China.
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31
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Garg N, Po A, Miele E, Campese AF, Begalli F, Silvano M, Infante P, Capalbo C, De Smaele E, Canettieri G, Di Marcotullio L, Screpanti I, Ferretti E, Gulino A. microRNA-17-92 cluster is a direct Nanog target and controls neural stem cell through Trp53inp1. EMBO J 2013; 32:2819-32. [PMID: 24076654 PMCID: PMC3817465 DOI: 10.1038/emboj.2013.214] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Accepted: 08/12/2013] [Indexed: 11/09/2022] Open
Abstract
The transcription factor Nanog plays a critical role in the self-renewal of embryonic stem cells as well as in neural stem cells (NSCs). microRNAs (miRNAs) are also involved in stemness regulation. However, the miRNA network downstream of Nanog is still poorly understood. High-throughput screening of miRNA expression profiles in response to modulated levels of Nanog in postnatal NSCs identifies miR-17-92 cluster as a direct target of Nanog. Nanog controls miR-17-92 cluster by binding to the upstream regulatory region and maintaining high levels of transcription in NSCs, whereas Nanog/promoter association and cluster miRNAs expression are lost alongside differentiation. The two miR-17 family members of miR-17-92 cluster, namely miR-17 and miR-20a, target Trp53inp1, a downstream component of p53 pathway. To support a functional role, the presence of miR-17/20a or the loss of Trp53inp1 is required for the Nanog-induced enhancement of self-renewal of NSCs. We unveil an arm of the Nanog/p53 pathway, which regulates stemness in postnatal NSCs, wherein Nanog counteracts p53 signals through miR-17/20a-mediated repression of Trp53inp1. Direct control of the miRNA-17/92 cluster enables Nanog to restrain p53 activity and thus to maintain pluripotency in neural stem cells.
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Affiliation(s)
- Neha Garg
- Department of Molecular Medicine, University of Rome 'La Sapienza', Rome, Italy
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Pax8 has a critical role in epithelial cell survival and proliferation. Cell Death Dis 2013; 4:e729. [PMID: 23868062 PMCID: PMC3730432 DOI: 10.1038/cddis.2013.262] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Revised: 05/28/2013] [Accepted: 06/13/2013] [Indexed: 01/01/2023]
Abstract
The transcription factor Pax8, a member of the Paired-box gene family, is a critical regulator required for proper development and differentiation of thyroid follicular cells. Despite being Pax8 well characterized with respect to its role in regulating genes responsible for thyroid differentiation, its involvement in cell survival and proliferation has been hypothesized but remains unclear. Here, we show that Pax8 overexpression significantly increases proliferation and colony-forming efficiency of Fischer rat thyroid line 5 epithelial cells, although it is not sufficient to overcome their hormone dependence. More interestingly, we show that Pax8-specific silencing induces apoptosis through a p53-dependent pathway that involves caspase-3 activation and cleavage of poly(ADP)ribose polymerase. Our data indicate that tumor protein 53 induced nuclear protein 1 (tp53inp1), a positive regulator of p53-dependent cell cycle arrest and apoptosis, is a transcriptional target of Pax8 and is upregulated by Pax8 knockdown. Remarkably, tp53inp1 silencing significantly abolishes Pax8-induced apoptosis thus suggesting that tp53inp1 may be the mediator of the observed effects. In conclusion, our data highlight that Pax8 is required for the survival of differentiated epithelial cells and its expression levels are able to modulate the proliferation rate of such cells.
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Saadi H, Seillier M, Sandi MJ, Peuget S, Kellenberger C, Gravis G, Dusetti NJ, Iovanna JL, Rocchi P, Amri M, Carrier A. Development of an ELISA detecting Tumor Protein 53-Induced Nuclear Protein 1 in serum of prostate cancer patients. RESULTS IN IMMUNOLOGY 2013; 3:51-6. [PMID: 24600558 DOI: 10.1016/j.rinim.2013.05.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2013] [Revised: 05/10/2013] [Accepted: 05/13/2013] [Indexed: 10/26/2022]
Abstract
Tumor Protein 53-Induced Nuclear Protein 1 (TP53INP1) plays an important role during cell stress response in synergy with the potent "genome-keeper" p53. In human, the gene encoding TP53INP1 is expressed at very high level in some pathological situations, such as inflammation and prostate cancer (PC). TP53INP1 overexpression in PC seems to be a worse prognostic factor, particularly predictive of biological cancer relapse, making TP53INP1 a relevant specific target for molecular therapy of Castration Resistant (CR) PC. In that context, detection of TP53INP1 in patient biological fluids is a promising diagnostic avenue. We report here successful development of a new Enzyme-Linked Immunosorbent Assay (ELISA) detecting TP53INP1, taking advantage of molecular tools (monoclonal antibodies (mAbs) and recombinant proteins) generated in the laboratory during the course of basic functional investigations devoted to TP53INP1. The ELISA principle is based on a sandwich immunoenzymatic system, TP53INP1 protein being trapped by a first specific mAb coated on microplate then recognized by a second specific mAb. This new assay allows specific detection of TP53INP1 in serum of several PC patients. This breakthrough paves the way towards investigation of a large cohort of patients and assessment of clinical applications of TP53INP1 dosage.
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Affiliation(s)
- Houda Saadi
- Inserm, U1068, CRCM, Marseille F-13009, France ; Institut Paoli-Calmettes, Marseille F-13009, France ; Aix-Marseille Université, Marseille F-13284, France ; CNRS, UMR7258, CRCM, Marseille F-13009, France ; Laboratoire de Neurophysiologie Fonctionnelle et Pathologies, Unité de Recherche 00/UR/08-01, Tunis, Tunisia ; Département des Sciences Biologiques, Faculté des Sciences de Tunis, Campus Universitaire, El Manar, Tunis 2092, Tunisia
| | - Marion Seillier
- Inserm, U1068, CRCM, Marseille F-13009, France ; Institut Paoli-Calmettes, Marseille F-13009, France ; Aix-Marseille Université, Marseille F-13284, France ; CNRS, UMR7258, CRCM, Marseille F-13009, France
| | - Maria José Sandi
- Inserm, U1068, CRCM, Marseille F-13009, France ; Institut Paoli-Calmettes, Marseille F-13009, France ; Aix-Marseille Université, Marseille F-13284, France ; CNRS, UMR7258, CRCM, Marseille F-13009, France
| | - Sylvain Peuget
- Inserm, U1068, CRCM, Marseille F-13009, France ; Institut Paoli-Calmettes, Marseille F-13009, France ; Aix-Marseille Université, Marseille F-13284, France ; CNRS, UMR7258, CRCM, Marseille F-13009, France
| | - Christine Kellenberger
- Aix-Marseille Université, Marseille F-13284, France ; CNRS, UMR6098, AFMB, Marseille, France
| | | | - Nelson J Dusetti
- Inserm, U1068, CRCM, Marseille F-13009, France ; Institut Paoli-Calmettes, Marseille F-13009, France ; Aix-Marseille Université, Marseille F-13284, France ; CNRS, UMR7258, CRCM, Marseille F-13009, France
| | - Juan L Iovanna
- Inserm, U1068, CRCM, Marseille F-13009, France ; Institut Paoli-Calmettes, Marseille F-13009, France ; Aix-Marseille Université, Marseille F-13284, France ; CNRS, UMR7258, CRCM, Marseille F-13009, France
| | - Palma Rocchi
- Inserm, U1068, CRCM, Marseille F-13009, France ; Institut Paoli-Calmettes, Marseille F-13009, France ; Aix-Marseille Université, Marseille F-13284, France ; CNRS, UMR7258, CRCM, Marseille F-13009, France
| | - Mohamed Amri
- Laboratoire de Neurophysiologie Fonctionnelle et Pathologies, Unité de Recherche 00/UR/08-01, Tunis, Tunisia ; Département des Sciences Biologiques, Faculté des Sciences de Tunis, Campus Universitaire, El Manar, Tunis 2092, Tunisia
| | - Alice Carrier
- Inserm, U1068, CRCM, Marseille F-13009, France ; Institut Paoli-Calmettes, Marseille F-13009, France ; Aix-Marseille Université, Marseille F-13284, France ; CNRS, UMR7258, CRCM, Marseille F-13009, France
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Shahbazi J, Lock R, Liu T. Tumor Protein 53-Induced Nuclear Protein 1 Enhances p53 Function and Represses Tumorigenesis. Front Genet 2013; 4:80. [PMID: 23717325 PMCID: PMC3652520 DOI: 10.3389/fgene.2013.00080] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Accepted: 04/19/2013] [Indexed: 12/19/2022] Open
Abstract
Tumor protein 53-induced nuclear protein 1 (TP53INP1) is a stress-induced p53-target gene whose expression is modulated by transcription factors such as p53, p73, and E2F1. TP53INP1 gene encodes two isoforms of TP53INP1 proteins, TP53INP1α and TP53INP1β, both of which appear to be key elements in p53 function. In association with homeodomain-interacting protein kinase-2 (HIPK2), TP53INP1 phosphorylates p53 protein at Serine-46. This enhances p53 protein stability and its transcriptional activity, leading to transcriptional activation of p53-target genes such as p21 and PIG3, cell growth arrest and apoptosis upon DNA damage stress. The anti-proliferative and pro-apoptotic activities of TP53INP1 indicate that TP53INP1 has an important role in cellular homeostasis and DNA damage response. Deficiency in TP53INP1 expression results in increased tumorigenesis, whereas TP53INP1 expression is repressed during early stages of cancer by factors such as miR-155. This review aims to summarize the roles of TP53INP1 in blocking tumor progression through p53-dependant and p53-independent pathways, as well as the elements which repress TP53INP1 expression, hence highlighting its potential as a therapeutic target in cancer treatment.
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Affiliation(s)
- Jeyran Shahbazi
- Histone Modification Group, Children's Cancer Institute Australia for Medical Research Randwick, Sydney, NSW, Australia ; Faculty of Science, School of Biotechnology and Biomolecular Sciences, UNSW Science, University of New South Wales Kensington, Sydney, NSW, Australia
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17β-estradiol up-regulates miR-155 expression and reduces TP53INP1 expression in MCF-7 breast cancer cells. Mol Cell Biochem 2013; 379:201-11. [PMID: 23568502 DOI: 10.1007/s11010-013-1642-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2012] [Accepted: 03/28/2013] [Indexed: 02/07/2023]
Abstract
In estrogen responsive breast cancer cells, estradiol (E2) is a key regulator of cell proliferation and survival. MiR-155 has emerged as an "oncomiR", which is the most significantly up-regulated miRNA in breast cancer. Moreover, miR-155 is higher in ERα (+) breast tumors than ERα (-), but no one has examined whether E2 regulates miR-155 expression in MCF-7 cells. In this study, the aim was to explore whether miR-155 involved in E2 regulated expression of estrogen responsive genes. We evaluated miR-155 expression in human breast cancer cells by real-time PCR, finding out miR-155 was overexpressed in MCF-7 cells compared with MDA-MB-231 cells. Treatment with E2 in MCF-7 cells increased miR-155 expression, promoting proliferation and decreasing apoptosis, similarly, transfection of miR-155m to MCF-7 cells gave the similar results. In contrast, inhibited miR-155 expression by transfection with miR-155 inhibitors reduced proliferation and promoted apoptosis of MCF-7 cells. Moreover, TP53INP1 is one of the targets of miR-155. E2 negatively regulated TP53INP1 mRNA expression and the protein expression of TP53INP1, cleaved-caspase-3, -8, -9, and p21, whereas transfection with miR-155 inhibitors increased TP53INP1, cleaved-caspase-3, -8, -9, and p21 protein level. These results demonstrated that E2 promoted breast cancer development and progression possibly through increasing the expression of miR-155, which was overexpressed in MCF-7 cells, contributes to proliferation of MCF-7 cells possibly through down-regulating TP53INP1.
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Giusiano S, Baylot V, Andrieu C, Fazli L, Gleave M, Iovanna JL, Taranger-Charpin C, Garcia S, Rocchi P. TP53INP1 as new therapeutic target in castration-resistant prostate cancer. Prostate 2012; 72:1286-94. [PMID: 22213058 DOI: 10.1002/pros.22477] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2011] [Accepted: 12/01/2011] [Indexed: 11/09/2022]
Abstract
BACKGROUND Prostate cancer (PC) is one of the most common malignancies in industrialized countries, and the second leading cause of cancer-related death in the United States. We recently showed that over-expression of tumor protein 53-induced nuclear protein 1 (TP53INP1), a cell stress response protein, is a worse prognostic factor in PC, particularly predictive of biological cancer relapse. Moreover, treatment of castration-sensitive (CS) LNCaP tumor cells with a TP53INP1 antisense oligonucleotide (TP53INP1 ASO) inhibits proliferation and induces apoptosis. The aim of this study was to investigate variations of TP53INP1 expression in PC during androgen withdrawal therapy and in castration-resistant prostate cancer (CRPC). METHODS Quantitative measurements of immunohistochemical expression of TP53INP1 using high-throughput densitometry, assessed on digitized microscopic tissue micro-array images were correlated with hormone therapy (HT) status in human PC. Northern blot analysis of TP53INP1 after castration was performed in LNCaP xenograft. Treatment of CR C4-2 tumor cells in vitro with TP53INP1 ASO was analyzed. We also analyzed the effect of TP53INP1 ASO treatment in vivo on tumor xenograft growth. RESULTS TP53INP1 protein expression decreases during HT and increases after HT in human CRPC. TP53INP1 mRNA increases significantly in CR tumors of LNCaP xenograft. Moreover, treatment of CR C4-2 cells with TP53INP1 ASO downregulates TP53INP1 protein level, inhibits proliferation, and induces apoptosis. Finally, in vivo, TP53INP1 ASO treatment significantly inhibits the tumoral progression of CR C4-2 xenograft and enhances docetaxel cytotoxicity. CONCLUSIONS These results suggest that TP53INP1 could be considered as a relevant-specific target for molecular therapy of CRPC.
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Affiliation(s)
- Sophie Giusiano
- Department of Pathology, Hôpital Nord, Chemin des Bourrellys, 13915 Marseille, France.
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Nakaya N, Ishigaki Y, Nakajima H, Murakami M, Shimasaki T, Takata T, Ozaki M, Dusetti NJ, Iovanna JL, Motoo Y. Meaning of tumor protein 53-induced nuclear protein 1 in the molecular mechanism of gemcitabine sensitivity. Mol Clin Oncol 2012; 1:100-104. [PMID: 24649130 DOI: 10.3892/mco.2012.8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2012] [Accepted: 07/10/2012] [Indexed: 01/05/2023] Open
Abstract
Stress proteins of the pancreas, such as tumor protein 53-induced nuclear protein 1 (TP53INP1), are important factors in the invasion and metastasis of pancreatic cancer. TP53INP1 is a pro-apoptotic factor and is transcriptionally regulated in p53-dependent and -independent manners. A previous study proved that gemcitabine induces TP53INP1 expression in pancreatic cancer cells and the pancreatic cancer cell line (PANC-1). The present study aimed to clarify the association between TP53INP1 and gemcitabine sensitivity. The expression of TP53INP1 and its related factors, such as cell growth and cell cycle status in TP53INP1-knockout mouse embryonic fibroblasts [TP53INP1-/--mouse embryonic fibroblasts (MEFs)] to those in wild-type counterparts (TP53INP1+/+-MEFs) were compared. Flow cytometric analysis demonstrated no difference of the checkpoint function in TP53INP1-/--MEFs and TP53INP1+/+-MEFs when exposed to 10 ng/ml of gemcitabine. No significant difference was found in the level of p53 expression in the cell types, although the base level and gemcitabine-induced expression of p21 were significantly decreased in TP53INP1-/--MEFs, compared to those in wild-type counterparts. Results showed that gemcitabine induced the p21 expression in TP53INP1+/+-MEFs, although not in TP53INP1-/--MEFs. However, their respective cell-cycle checkpoints were not different. Therefore, TP53INP1 was found to be associated with drug sensitivity through control of the cell cycle.
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Affiliation(s)
| | - Yasuhito Ishigaki
- Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa
| | - Hideo Nakajima
- Department of Medical Oncology ; Department of Oncology, Ageo Central General Hospital, Ageo, Saitama, Japan
| | - Manabu Murakami
- Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa
| | | | - Takanobu Takata
- Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa
| | - Mamoru Ozaki
- Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa
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Wei Q, Li YX, Liu M, Li X, Tang H. MiR-17-5p targets TP53INP1 and regulates cell proliferation and apoptosis of cervical cancer cells. IUBMB Life 2012; 64:697-704. [PMID: 22730212 DOI: 10.1002/iub.1051] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2012] [Revised: 04/08/2012] [Accepted: 04/25/2012] [Indexed: 12/12/2022]
Abstract
MicroRNAs are a class of small endogenous noncoding RNAs that function as post-transcriptional regulators. Tumor protein p53-induced nuclear protein 1 (TP53INP1) is a p53 target gene and is a major player in the stress response. Here, we identified TP53INP1 as a target of miR-17-5p. miR-17-5p suppressed cell growth and promoted apoptosis of cervical cancer cells, whereas the effects of TP53INP1 were opposite, and ectopic expression of TP53INP1 counteracted the suppression of cell growth caused by miR-17-5p. The same correlations between miR-17-5p and TP53INP1 were observed in cervical cancer tissues. Together, these results indicated that miR-17-5p functions as a tumor suppressor in cervical cancer cells by targeting TP53INP1.
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Affiliation(s)
- Qian Wei
- Tianjin Life Science Research Center and Department of Microbiology, Basic Medical School, Tianjin Medical University, Tianjin, China
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TP53INP1, a tumor suppressor, interacts with LC3 and ATG8-family proteins through the LC3-interacting region (LIR) and promotes autophagy-dependent cell death. Cell Death Differ 2012; 19:1525-35. [PMID: 22421968 DOI: 10.1038/cdd.2012.30] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
TP53INP1 (tumor protein 53-induced nuclear protein 1) is a tumor suppressor, whose expression is downregulated in cancers from different organs. It was described as a p53 target gene involved in cell death, cell-cycle arrest and cellular migration. In this work, we show that TP53INP1 is also able to interact with ATG8-family proteins and to induce autophagy-dependent cell death. In agreement with this finding, we observe that TP53INP1, which is mainly nuclear, relocalizes in autophagosomes during autophagy where it is eventually degraded. TP53INP1-LC3 interaction occurs via a functional LC3-interacting region (LIR). Inactivating mutations of this sequence abolish TP53INP1-LC3 interaction, relocalize TP53INP1 in autophagosomes and decrease TP53INP1 ability to trigger cell death. Interestingly, TP53INP1 binds to ATG8-family proteins with higher affinity than p62, suggesting that it could partially displace p62 from autophagosomes, modifying thereby their composition. Moreover, silencing the expression of autophagy related genes (ATG5 or Beclin-1) or inhibiting caspase activity significantly decreases cell death induced by TP53INP1. These data indicate that cell death observed after TP53INP1-LC3 interaction depends on both autophagy and caspase activity. We conclude that TP53INP1 could act as a tumor suppressor by inducing cell death by caspase-dependent autophagy.
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Giusiano S, Garcia S, Andrieu C, Dusetti NJ, Bastide C, Gleave M, Taranger-Charpin C, Iovanna JL, Rocchi P. TP53INP1 overexpression in prostate cancer correlates with poor prognostic factors and is predictive of biological cancer relapse. Prostate 2012; 72:117-28. [PMID: 21538421 DOI: 10.1002/pros.21412] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2011] [Accepted: 04/05/2011] [Indexed: 12/31/2022]
Abstract
BACKGROUND Tumor protein 53-induced nuclear protein 1 (TP53INP1) is a proapoptotic protein involved in cell stress response. Whereas there is an overexpression of TP53INP1 in numerous tissues submitted to stress agents, TP53INP1 is down-expressed in stomach, pancreatic, and inflammation-mediated colic carcinomas. In medullary thyroid carcinomas, TP53INP1 overexpression correlates with poor prognosis. TP53INP1 expression has never been reported in Prostate Cancer (PC). Our aim was to investigate variations of TP53INP1 expression and their correlation to clinicopathological parameters in PC. METHODS Quantitative measurements of immunohistochemical expression of TP53INP1 using high-throughput densitometry, assessed on digitized microscopic tissue micro-array images, were correlated with clinicopathological parameters in 91 human PC. Treatment of LNCaP tumor cells in vitro with cytokines and with TP53INP1 antisense oligonucleotide (ASO) was also analyzed. RESULTS In normal prostate tissues, TP53INP1 is only expressed in prostate basal cells. There is a de novo TP53INP1 expression in prostate luminal cells in inflammatory prostate tissues, high grade PIN lesions and in PC. Stimulation of LNCaP cells with inflammatory cytokines enhances the level of TP53INP1 mRNA. In PC, TP53INP1 overexpression correlates with high Gleason grade, unfavorable D'Amico score and lymph node invasion, and is an independent factor of biological cancer relapse. Moreover, treatment of LNCaP cells with a TP53INP1 ASO down-regulates TP53INP1 protein level, inhibits proliferation, and induces apoptosis. CONCLUSION TP53INP1 overexpression in PC seems to be a worse prognostic factor, particularly predictive of biological cancer relapse. Results in vitro suggest that TP53INP1 could be considered as a relevant target for potential specific therapy.
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Affiliation(s)
- Sophie Giusiano
- Department of Pathology, Hôpital Nord, Chemin des Bourrellys, Marseille, France.
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Iovanna J, Calvo EL, Dagorn JC, Dusetti N. Pancreatic Cancer Genetics. DIAGNOSTIC, PROGNOSTIC AND THERAPEUTIC VALUE OF GENE SIGNATURES 2012:51-79. [DOI: 10.1007/978-1-61779-358-5_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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MiR-125b promotes proliferation and migration of type II endometrial carcinoma cells through targeting TP53INP1 tumor suppressor in vitro and in vivo. BMC Cancer 2011; 11:425. [PMID: 21970405 PMCID: PMC3210504 DOI: 10.1186/1471-2407-11-425] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2011] [Accepted: 10/05/2011] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Our previous studies have identified that miR-125b was overexpressed in type II endometrial carcinoma (EC) cells compared with type I using microRNAs microarray. Although recent studies have shown the important role of miR-125b in several tumors and overexpression of miR-125b in advanced EC, its function in this disease has not yet been defined. In the present study, we tried to confirm the result of microRNAs microarray and further investigated the functions of miR-125b in EC, and tried to find new downstream targets of miR-125b. METHODS Differential expression of miR-125b was detected between type II EC cells (KLE, AN3CA) with ER negative and type I EC cells (ishikawa, RL95-2) with ER positive by qRT-PCR and northern blotting. The effects of miR-125b of on proliferation, migration, and target protein expression were evaluated by CCK8 assay, wound healing assay, transwell migration assay, western blotting, and Tumorigenicity assays in nude mice. In addition, luciferase reporter plasmid was constructed to demonstrate the direct target of miR-125b. RESULTS MiR-125b was overexpressed in type II EC cells compared with type I. Exogenous miR-125b expression increased proliferation and migration of ishikawa cells and abrogating expression of miR-125b suppressed proliferation, and migration of AN3CA cells in vitro. In addition, in vivo tumor formation assay confirmed that forced miR-125b expression promoted proliferation potential of ishikawa cells, and tumor suppressor gene Tumor Protein 53-Induced Nuclear Protein 1 (TP53INP1) was identified to be the direct target of miR-125b. CONCLUSIONS TP53INP1 was newly identified to be the direct downstream target of miR-125b. MiR-125b, which was overexpressed in type II EC cells compared with type I, contributes to malignancy of type II EC possibly through down-regulating TP53INP1.
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Ladelfa MF, Toledo MF, Laiseca JE, Monte M. Interaction of p53 with tumor suppressive and oncogenic signaling pathways to control cellular reactive oxygen species production. Antioxid Redox Signal 2011; 15:1749-61. [PMID: 20919943 DOI: 10.1089/ars.2010.3652] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
p53 is a crucial transcription factor with tumor suppressive properties that elicits its function through specific target genes. It constitutes a pivotal system that integrates information received by many signaling pathways and subsequently orchestrates cell fate decisions, namely, growth-arrest, senescence, or apoptosis. Reactive oxygen species (ROS) production in cells can play a key role in signal transduction, being able to trigger different processes as cell death or cell proliferation. Sustained oxidative stress can induce genomic instability and collaborates with cancer development, whereas acute enhancement of high ROS levels leads to toxic oxidative cell damage and cell death. Here, it has been considered p53 broad potential contribution through its ability to regulate selected key cancer signaling pathways, where ROS participate as inductors or effectors of the final biological outcome. Further, we have discussed how p53 could play a role in preventing potentially harmful oxidative state and cell proliferation by pro-oncogenic pathways such as PI3K/AKT/mTOR and WNT/β-catenin or under hypoxia state. In addition, we have considered potential mechanisms by which p53 could collaborate with signal transduction pathways such as transforming growth factor-β (TGF-β) and stress-activated protein kinases (SAPK) that produce ROS, to stop or eliminate uncontrolled proliferating cells.
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Affiliation(s)
- María Fátima Ladelfa
- Laboratorio de Biología Celular y Molecular, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires , Buenos Aires, Argentina
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N'guessan P, Pouyet L, Gosset G, Hamlaoui S, Seillier M, Cano CE, Seux M, Stocker P, Culcasi M, Iovanna JL, Dusetti NJ, Pietri S, Carrier A. Absence of tumor suppressor tumor protein 53-induced nuclear protein 1 (TP53INP1) sensitizes mouse thymocytes and embryonic fibroblasts to redox-driven apoptosis. Antioxid Redox Signal 2011; 15:1639-53. [PMID: 21235351 DOI: 10.1089/ars.2010.3553] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The p53-transcriptional target TP53INP1 is a potent stress-response protein promoting p53 activity. We previously showed that ectopic overexpression of TP53INP1 facilitates cell cycle arrest as well as cell death. Here we report a study investigating cell death in mice deficient for TP53INP1. Surprisingly, we found enhanced stress-induced apoptosis in TP53INP1-deficient cells. This observation is underpinned in different cell types in vivo (thymocytes) and in vitro (thymocytes and MEFs), following different types of injury inducing either p53-dependent or -independent cell death. Nevertheless, absence of TP53INP1 is unable to overcome impaired cell death of p53-deficient thymocytes. Stress-induced ROS production is enhanced in the absence of TP53INP1, and antioxidant NAC complementation abolishes increased sensitivity to apoptosis of TP53INP1-deficient cells. Furthermore, antioxidant defenses are defective in TP53INP1-deficient mice in correlation with ROS dysregulation. Finally, we show that autophagy is reduced in TP53INP1-deficient cells both at the basal level and upon stress. Altogether, these data show that impaired ROS regulation in TP53INP1-deficient cells is responsible for their sensitivity to induced apoptosis. In addition, they suggest that this sensitivity could rely on a defect of autophagy. Therefore, these data emphasize the role of TP53INP1 in protection against cell injury.
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Affiliation(s)
- Prudence N'guessan
- INSERM U624 Stress cellulaire, Case 915 Parc Scientifique de Luminy, Marseille Cedex 9, France
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Enomoto Y, Kitaura J, Hatakeyama K, Watanuki J, Akasaka T, Kato N, Shimanuki M, Nishimura K, Takahashi M, Taniwaki M, Haferlach C, Siebert R, Dyer MJS, Asou N, Aburatani H, Nakakuma H, Kitamura T, Sonoki T. Eμ/miR-125b transgenic mice develop lethal B-cell malignancies. Leukemia 2011; 25:1849-56. [DOI: 10.1038/leu.2011.166] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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Ma S, Tang KH, Chan YP, Lee TK, Kwan PS, Castilho A, Ng I, Man K, Wong N, To KF, Zheng BJ, Lai PBS, Lo CM, Chan KW, Guan XY. miR-130b Promotes CD133(+) liver tumor-initiating cell growth and self-renewal via tumor protein 53-induced nuclear protein 1. Cell Stem Cell 2011; 7:694-707. [PMID: 21112564 DOI: 10.1016/j.stem.2010.11.010] [Citation(s) in RCA: 322] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2010] [Revised: 07/09/2010] [Accepted: 09/02/2010] [Indexed: 12/17/2022]
Abstract
A novel paradigm in tumor biology suggests that cancer growth is driven by stem-like cells within a tumor, called tumor-initiating cells (TICs) or cancer stem cells (CSCs). Here we describe the identification and characterization of such cells from hepatocellular carcinoma (HCC) using the marker CD133. CD133 accounts for approximately 1.3%-13.6% of the cells in the bulk tumor of human primary HCC samples. When compared with their CD133⁻ counterparts, CD133(+) cells not only possess the preferential ability to form undifferentiated tumor spheroids in vitro but also express an enhanced level of stem cell-associated genes, have a greater ability to form tumors when implanted orthotopically in immunodeficient mice, and can be serially passaged into secondary animal recipients. Xenografts resemble the original human tumor and maintain a similar percentage of tumorigenic CD133(+) cells. Quantitative PCR analysis of 41 separate HCC tissue specimens with follow-up data found that CD133(+) tumor cells were frequently detected at low quantities in HCC, and their presence was also associated with worse overall survival and higher recurrence rates. Subsequent differential microRNA expression profiling of CD133(+) and CD133⁻ cells from human HCC clinical specimens and cell lines identified an overexpression of miR-130b in CD133(+) TICs. Functional studies on miR-130b lentiviral-transduced CD133⁻ cells demonstrated superior resistance to chemotherapeutic agents, enhanced tumorigenicity in vivo, and a greater potential for self renewal. Conversely, antagonizing miR-130b in CD133(+) TICs yielded an opposing effect. The increased miR-130b paralleled the reduced TP53INP1, a known miR-130b target. Silencing TP53INP1 in CD133⁻ cells enhanced both self renewal and tumorigenicity in vivo. Collectively, miR-130b regulates CD133(+) liver TICs, in part, via silencing TP53INP1.
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Affiliation(s)
- Stephanie Ma
- Department of Pathology, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
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Shibuya H, Iinuma H, Shimada R, Horiuchi A, Watanabe T. Clinicopathological and prognostic value of microRNA-21 and microRNA-155 in colorectal cancer. Oncology 2011; 79:313-20. [PMID: 21412018 DOI: 10.1159/000323283] [Citation(s) in RCA: 197] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2010] [Accepted: 11/02/2010] [Indexed: 12/16/2022]
Abstract
OBJECTIVE The clinical significance of microRNA-21 (miR-21) and miR-155 in colorectal cancer (CRC) patients remains elusive. In this study, we established the prognostic value of miR-21 and miR-155 using clinical samples from CRC patients. Furthermore, relationships between these microRNAs and target genes (PDCD4 and TP53INP1 mRNAs) were examined. METHODS miR-21 and miR-155 expression was assessed in tumor tissue and in adjacent normal tissue of 156 CRC patients by TaqMan MicroRNA assays, and PDCD4 and TP53INP1 mRNA levels were measured by quantitative real-time reverse transcriptase PCR (RT-PCR). RESULTS High miR-21 expression was significantly associated with venous invasion, liver metastasis and tumor stage, and high miR-155 expression was significantly correlated with lymph node metastases. The overall (OS) and disease-free survival (DFS) rates of patients with high miR-21 expression were significantly worse than those of patients with low miR-21 expression. The OS and DFS of patients with high miR-155 expression were also significantly worse than those in patients with low miR-155 expression. miR-21 and miR-155 expression levels in CRC tissue were independent prognostic factors for OS and DFS. Significant inverse correlations were demonstrated between miR-21 and PDCD4 mRNA, and miR-155 and TP53INP1 mRNA. CONCLUSION Increases in miR-21 and miR-155 expression may represent effective biomarkers for the prediction of a poor prognosis.
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Affiliation(s)
- Hajime Shibuya
- Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan
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Park JY, Helm J, Coppola D, Kim D, Malafa M, Kim SJ. MicroRNAs in pancreatic ductal adenocarcinoma. World J Gastroenterol 2011; 17:817-27. [PMID: 21412491 PMCID: PMC3051132 DOI: 10.3748/wjg.v17.i7.817] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2010] [Revised: 11/25/2010] [Accepted: 12/02/2010] [Indexed: 02/06/2023] Open
Abstract
Ductal adenocarcinoma of the pancreas is a lethal cancer for which the only chance of long-term survival belongs to the patient with localized disease in whom a potentially curative resection can be done. Therefore, biomarkers for early detection and new therapeutic strategies are urgently needed. miRNAs are a recently discovered class of small endogenous non-coding RNAs of about 22 nucleotides that have gained attention for their role in downregulation of mRNA expression at the post-transcriptional level. miRNAs regulate proteins involved in critical cellular processes such as differentiation, proliferation, and apoptosis. Evidence suggests that deregulated miRNA expression is involved in carcinogenesis at many sites, including the pancreas. Aberrant expression of miRNAs may upregulate the expression of oncogenes or downregulate the expression of tumor suppressor genes, as well as play a role in other mechanisms of carcinogenesis. The purpose of this review is to summarize our knowledge of deregulated miRNA expression in pancreatic cancer and discuss the implication for potential translation of this knowledge into clinical practice.
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Seux M, Peuget S, Montero MP, Siret C, Rigot V, Clerc P, Gigoux V, Pellegrino E, Pouyet L, N'Guessan P, Garcia S, Dufresne M, Iovanna JL, Carrier A, André F, Dusetti NJ. TP53INP1 decreases pancreatic cancer cell migration by regulating SPARC expression. Oncogene 2011; 30:3049-61. [PMID: 21339733 DOI: 10.1038/onc.2011.25] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Tumor protein 53 induced nuclear protein 1 (TP53INP1) is a p53 target gene that induces cell growth arrest and apoptosis by modulating p53 transcriptional activity. TP53INP1 interacts physically with p53 and is a major player in the p53-driven oxidative stress response. Previously, we demonstrated that TP53INP1 is downregulated in an early stage of pancreatic cancerogenesis and when restored is able to suppress pancreatic tumor development. TP53INP1 downregulation in pancreas is associated with an oncogenic microRNA miR-155. In the present work, we studied the effects of TP53INP1 on cell migration. We found that TP53INP1 inactivation correlates with increased cell migration both in vivo and in vitro. The impact of TP53INP1 expression on cell migration was studied in different cellular contexts: mouse embryonic fibroblast and different pancreatic cancer cell lines. Its expression decreases cell migration by the transcriptional downregulation of secreted protein acidic and rich in cysteine (SPARC). SPARC is a matrix cellular protein, which governs diverse cellular functions and has a pivotal role in regulating cell-matrix interactions, cellular proliferation and migration. SPARC was also showed to be upregulated in normal pancreas and in pancreatic intraepithelial neoplasia lesions in a pancreatic adenocarcinoma mouse model only in the TP53INP1-deficient animals. This novel TP53INP1 activity on the regulation of SPARC expression could explain in part its tumor suppressor function in pancreatic adenocarcinoma by modulating cellular spreading during the metastatic process.
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Affiliation(s)
- M Seux
- INSERM, U624 Stress cellulaire, Marseille, France
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Preconditioning with Maillard reaction products improves antioxidant defence leading to increased stress tolerance in cardiac cells. Exp Gerontol 2010; 45:752-62. [DOI: 10.1016/j.exger.2010.08.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2010] [Revised: 07/14/2010] [Accepted: 08/03/2010] [Indexed: 12/24/2022]
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