|
1
|
Martinez-Seidel F, Suwanchaikasem P, Gentry-Torfer D, Rajarathinam Y, Ebert A, Erban A, Firmino A, Nie S, Leeming M, Williamson N, Roessner U, Kopka J, Boughton BA. Remodelled ribosomal populations synthesize a specific proteome in proliferating plant tissue during cold. Philos Trans R Soc Lond B Biol Sci 2025; 380:20230384. [PMID: 40045790 PMCID: PMC11883437 DOI: 10.1098/rstb.2023.0384] [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: 12/15/2023] [Revised: 06/21/2024] [Accepted: 09/11/2024] [Indexed: 03/09/2025] Open
Abstract
Plant acclimation occurs through system-wide mechanisms that include proteome shifts, some of which occur at the level of protein synthesis. All proteins are synthesized by ribosomes. Rather than being monolithic, transcript-to-protein translation machines, ribosomes can be selective and cause proteome shifts. In this study, we use apical root meristems of germinating seedlings of the monocotyledonous plant barley as a model to examine changes in protein abundance and synthesis during cold acclimation. We measured metabolic and physiological parameters that allowed us to compare protein synthesis in the cold to optimal rearing temperatures. We demonstrated that the synthesis and assembly of ribosomal proteins are independent processes in root proliferative tissue. We report the synthesis and accumulation of various macromolecular complexes and propose how ribosome compositional shifts may be associated with functional proteome changes that are part of successful cold acclimation. Our study indicates that translation initiation is limiting during cold acclimation while the ribosome population is remodelled. The distribution of the triggered ribosomal protein heterogeneity suggests that altered compositions may confer 60S subunits selective association capabilities towards translation initiation complexes. To what extent selective translation depends on heterogeneous ribo-proteome compositions in barley proliferative root tissue remains a yet unresolved question.This article is part of the discussion meeting issue 'Ribosome diversity and its impact on protein synthesis, development and disease'.
Collapse
Affiliation(s)
- Federico Martinez-Seidel
- Molecular Physiology Department, Max Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany
- Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, USA
- RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO, USA
- School of BioSciences, The University of Melbourne, Parkville, Victoria, Australia
| | - Pipob Suwanchaikasem
- School of BioSciences, The University of Melbourne, Parkville, Victoria, Australia
| | - Dione Gentry-Torfer
- Molecular Physiology Department, Max Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany
- School of BioSciences, The University of Melbourne, Parkville, Victoria, Australia
| | - Yogeswari Rajarathinam
- Molecular Physiology Department, Max Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany
| | - Alina Ebert
- Molecular Physiology Department, Max Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany
- School of BioSciences, The University of Melbourne, Parkville, Victoria, Australia
| | - Alexander Erban
- Molecular Physiology Department, Max Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany
| | - Alexandre Firmino
- Molecular Physiology Department, Max Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany
| | - Shuai Nie
- Bio21 Institute of Molecular Science and Biotechnology, The University of Melbourne, Parkville, Victoria, Australia
| | - Michael Leeming
- Bio21 Institute of Molecular Science and Biotechnology, The University of Melbourne, Parkville, Victoria, Australia
- School of Chemistry, The University of Melbourne, Parkville, Victoria, Australia
| | - Nicholas Williamson
- Bio21 Institute of Molecular Science and Biotechnology, The University of Melbourne, Parkville, Victoria, Australia
- Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Ute Roessner
- School of BioSciences, The University of Melbourne, Parkville, Victoria, Australia
- Research School of Biology, The Australian National University, Acton, Australia
| | - Joachim Kopka
- Molecular Physiology Department, Max Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany
| | - Berin A. Boughton
- School of BioSciences, The University of Melbourne, Parkville, Victoria, Australia
- La Trobe Institute of Sustainable Agriculture and Food, La Trobe University, Bundoora, Victoria3083, Australia
| |
Collapse
|
|
2
|
Wang R, Deng J, Zhang M, Wang Z, Wu S, Liu S, Qi L. Overexpression of HYOU1 is associated with cisplatin resistance and may depend on m 6A modification in patients with cervical cancer. Oncol Lett 2025; 29:77. [PMID: 39650230 PMCID: PMC11622003 DOI: 10.3892/ol.2024.14823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 11/01/2024] [Indexed: 12/11/2024] Open
Abstract
Cervical cancer (CC) is the fourth leading cause of cancer-associated mortalities among women worldwide. The chemotherapeutical platinum-based agent cisplatin (DDP) is the standard therapy for locally advanced or recurrent CC; however, platinum resistance limits its clinical benefit. Therefore, the present study aimed to identify key genes associated with DDP resistance in patients with CC and investigate the underlying molecular mechanisms. Firstly, using the CRISPR-Cas9 dataset of CC cells derived from DepMap portal, 699 genes associated with CC cell survival were identified. Subsequently, using the gene expression profiles of normal and CC samples with a response status to DDP, derived from The Cancer Genome Atlas (TCGA), hypoxia upregulated 1 (HYOU1) was further identified as significantly upregulated in CC samples and patients that did not respond to DDP (non-responders) when compared with healthy controls and patients that did respond to DDP (responders), respectively, using unpaired student's t-tests. Additionally, the log-rank test revealed that the high expression of HYOU1 was significantly associated with the poor survival of patients receiving DDP. The association between the high HYOU1 expression levels and the poor survival of patients receiving DDP was validated in the remaining TCGA dataset of patients with CC. HYOU1 expression levels were positively associated with the half-maximal inhibitory concentration value of DDP in CC cells using data derived from the Genomics of Drug Sensitivity in Cancer database. In vitro, western blotting experiments revealed high HYOU1 protein expression levels in DDP-resistant HeLa cells compared with their parental HeLa cells. Furthermore, the knockdown of HYOU1 resulted in an increased sensitivity of HeLa cells to DDP. Finally, using the sequence-based RNA adenosine methylation site predictor program, it was found that N6-methyladenosine (m6A) was highly enriched in HYOU1. The expression levels of the m6A reader, EIF3A, was positively correlated with the expression levels of HYOU1 and was upregulated in the non-response group compared with the response group in a dataset from TCGA database. Additionally, EIF3A had the highest probability of binding to the m6A motifs of HYOU1 compared with other genes. In GSE56363 obtained from the Gene Expression Omnibus, the non-responders had significantly increased expression levels of EIF3A compared with the responders. In conclusion, high expression levels of HYOU1, which may be regulated by EIF3A due to m6A modifications, was associated with DDP resistance in patients with CC and could potentially be used as an indicator of DDP treatment resistance.
Collapse
Affiliation(s)
- Ruixue Wang
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Jiaxing Deng
- Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Meng Zhang
- Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Zhihui Wang
- Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Shangjie Wu
- Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Shilong Liu
- Department of Thoracic Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150086, P.R. China
| | - Lishuang Qi
- Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| |
Collapse
|
|
3
|
Dong Z, Ojha A, Barlow L, Luo L, Liu JY, Zhang JT. The eIF3a translational control axis in the Wnt/β-catenin signaling pathway and colon tumorigenesis. Cancer Lett 2024; 605:217303. [PMID: 39413959 PMCID: PMC11646415 DOI: 10.1016/j.canlet.2024.217303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 10/10/2024] [Accepted: 10/13/2024] [Indexed: 10/18/2024]
Abstract
Translational initiation in protein synthesis is an important regulatory step in gene expression and its dysregulation may result in diseases such as cancer. Translational control by eIF4E/4E-BP has been well studied and contributes to mTOR signaling in various biological processes. Here, we report a novel translational control axis in the Wnt/β-catenin signaling pathway in colon tumorigenesis by eIF3a, a Yin-Yang factor in tumorigenesis and prognosis. We show that eIF3a expression is upregulated in human colon cancer tissues, pre-cancerous adenoma polyps, and associates with β-catenin level and APC mutation in human samples, and that eIF3a overexpression transforms intestinal epithelial cells. We also show that eIF3a expression is regulated by the Wnt/β-catenin signaling pathway with an active TCF/LEF binding site in its promoter and that eIF3a knockdown inhibits APC mutation-induced spontaneous colon tumorigenesis in APCmin/+ mice. Together, we conclude that eIF3a upregulation in colon cancer is due to APC mutation and it participates in colon tumorigenesis by adding a translational control axis in the Wnt/β-catenin signaling pathway and that it can serve as a potential target for colon cancer intervention.
Collapse
Affiliation(s)
- Zizheng Dong
- Department of Cell and Cancer Biology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Anuj Ojha
- Department of Cell and Cancer Biology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Lincoln Barlow
- Department of Cell and Cancer Biology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Liyun Luo
- Department of Cell and Cancer Biology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Jing-Yuan Liu
- Department of Cell and Cancer Biology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Jian-Ting Zhang
- Department of Cell and Cancer Biology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA.
| |
Collapse
|
|
4
|
Sun H, Shang J, Liu X, Ren S, Hu S, Wang X. Eukaryotic initiation factor 3a promotes the development of diffuse large B-cell lymphoma through regulating cell proliferation. BMC Cancer 2024; 24:432. [PMID: 38589831 PMCID: PMC11003032 DOI: 10.1186/s12885-024-12166-0] [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: 11/26/2023] [Accepted: 03/21/2024] [Indexed: 04/10/2024] Open
Abstract
BACKGROUND One-third of diffuse large B-cell lymphoma (DLBCL) patients suffer relapse after standard treatment. Eukaryotic initiation factor 3a (eIF3a) is a key player in the initial stage of translation, which has been widely reported to be correlated with tumorigenesis and therapeutic response. This study aimed to explore the biological role of eIF3a, evaluate its prognostic and therapeutic potential in DLBCL. METHODS RNA-seq datasets from GEO database were utilized to detect the expression and prognostic role of eIF3a in DLBCL patients. Protein level of eIF3a was estimated by western blot and immunohistochemical. Next, DLBCL cells were transfected with lentiviral vector either eIF3a-knockdown or empty to assess the biological role of eIF3a. Then, samples were divided into 2 clusters based on eIF3a expression and differentially expressed genes (DEGs) were identified. Function enrichment and mutation analysis of DEGs were employed to detect potential biological roles. Moreover, we also applied pan-cancer and chemosensitivity analysis for deep exploration. RESULTS eIF3a expression was found to be higher in DLBCL than healthy controls, which was associated with worse prognosis. The expression of eIF3a protein was significantly increased in DLBCL cell lines compared with peripheral blood mononuclear cells (PBMCs) from healthy donors. eIF3a knockdown inhibited the proliferation of DLBCL cells and the expression of proliferation-related proteins and increase cell apoptosis rate. Besides, 114 DEGs were identified which had a close linkage to cell cycle and tumor immune. eIF3a and DEGs mutations were found to be correlated to chemosensitivity and vital signal pathways. Pan-cancer analysis demonstrated that high eIF3a expression was associated with worse prognosis in several tumors. Moreover, eIF3a expression was found to be related to chemosensitivity of several anti-tumor drugs in DLBCL, including Vincristine and Wee1 inhibitor. CONCLUSIONS We firstly revealed the high expression and prognostic role of eIF3a in DLBCL, and eIF3a might promote the development of DLBCL through regulating cell proliferation and apoptosis. eIF3a expression was related to immune profile and chemosensitivity in DLBCL. These results suggest that eIF3a could serve as a potential prognostic biomarker and therapeutic target in DLBCL.
Collapse
Affiliation(s)
- Hongkun Sun
- Department of Hematology, Shandong Provincial Hospital, Shandong University, 250021, Jinan, Shandong, China
- Department of Hematology, Binzhou Medical University Hospital, 256603, Binzhou, Shandong, China
| | - Juanjuan Shang
- Department of Hematology, Shandong Provincial Hospital, Shandong University, 250021, Jinan, Shandong, China
| | - Xiao Liu
- Department of Hematology, Binzhou Medical University Hospital, 256603, Binzhou, Shandong, China
| | - Shuai Ren
- Department of Oncology, Zibo Central Hospital, 255016, Zibo, Shandong, China
| | - Shunfeng Hu
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Road, 250021, Jinan, Shandong, China.
| | - Xin Wang
- Department of Hematology, Shandong Provincial Hospital, Shandong University, 250021, Jinan, Shandong, China.
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Road, 250021, Jinan, Shandong, China.
| |
Collapse
|
|
5
|
Zuo Z, Zhou Z, Chang Y, Liu Y, Shen Y, Li Q, Zhang L. Ribonucleotide reductase M2 (RRM2): Regulation, function and targeting strategy in human cancer. Genes Dis 2024; 11:218-233. [PMID: 37588202 PMCID: PMC10425756 DOI: 10.1016/j.gendis.2022.11.022] [Citation(s) in RCA: 41] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 10/26/2022] [Accepted: 11/14/2022] [Indexed: 12/29/2022] Open
Abstract
Ribonucleotide reductase M2 (RRM2) is a small subunit in ribonucleotide reductases, which participate in nucleotide metabolism and catalyze the conversion of nucleotides to deoxynucleotides, maintaining the dNTP pools for DNA biosynthesis, repair, and replication. RRM2 performs a critical role in the malignant biological behaviors of cancers. The structure, regulation, and function of RRM2 and its inhibitors were discussed. RRM2 gene can produce two transcripts encoding the same ORF. RRM2 expression is regulated at multiple levels during the processes from transcription to translation. Moreover, this gene is associated with resistance, regulated cell death, and tumor immunity. In order to develop and design inhibitors of RRM2, appropriate strategies can be adopted based on different mechanisms. Thus, a greater appreciation of the characteristics of RRM2 is a benefit for understanding tumorigenesis, resistance in cancer, and tumor microenvironment. Moreover, RRM2-targeted therapy will be more attention in future therapeutic approaches for enhancement of treatment effects and amelioration of the dismal prognosis.
Collapse
Affiliation(s)
- Zanwen Zuo
- Innovative Drug R&D Center, College of Life Sciences, Huaibei Normal University, Huaibei, Anhui 235000, China
- National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Key Laboratory of Industrial Microbiology, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), and School of Food and Biological Engineering, Hubei University of Technology, Wuhan, Hubei 430068, China
| | - Zerong Zhou
- Innovative Drug R&D Center, College of Life Sciences, Huaibei Normal University, Huaibei, Anhui 235000, China
- National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Key Laboratory of Industrial Microbiology, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), and School of Food and Biological Engineering, Hubei University of Technology, Wuhan, Hubei 430068, China
| | - Yuzhou Chang
- Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA
| | - Yan Liu
- School of Agriculture and Biology, and Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Yuping Shen
- College of Chemistry and Bioengineering, Hunan University of Science and Engineering, Yongzhou, Hunan 425199, China
| | - Qizhang Li
- Innovative Drug R&D Center, College of Life Sciences, Huaibei Normal University, Huaibei, Anhui 235000, China
- National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Key Laboratory of Industrial Microbiology, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), and School of Food and Biological Engineering, Hubei University of Technology, Wuhan, Hubei 430068, China
| | - Lei Zhang
- Innovative Drug R&D Center, College of Life Sciences, Huaibei Normal University, Huaibei, Anhui 235000, China
- Department of Pharmaceutical Botany, School of Pharmacy, Naval Medical University, Shanghai 200433, China
| |
Collapse
|
|
6
|
Ma S, Liu JY, Zhang JT. eIF3d: A driver of noncanonical cap-dependent translation of specific mRNAs and a trigger of biological/pathological processes. J Biol Chem 2023; 299:104658. [PMID: 36997088 PMCID: PMC10165153 DOI: 10.1016/j.jbc.2023.104658] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 03/20/2023] [Accepted: 03/21/2023] [Indexed: 03/31/2023] Open
Abstract
Eukaryotic initiation factor 3d (eIF3d), a known RNA-binding subunit of the eIF3 complex, is a 66 to 68-kDa protein with an RNA-binding motif and a cap-binding domain. Compared with other eIF3 subunits, eIF3d is relatively understudied. However, recent progress in studying eIF3d has revealed a number of intriguing findings on its role in maintaining eIF3 complex integrity, global protein synthesis, and in biological and pathological processes. It has also been reported that eIF3d has noncanonical functions in regulating translation of a subset of mRNAs by binding to 5'-UTRs or interacting with other proteins independent of the eIF3 complex and additional functions in regulating protein stability. The noncanonical regulation of mRNA translation or protein stability may contribute to the role of eIF3d in biological processes such as metabolic stress adaptation and in disease onset and progression including severe acute respiratory syndrome coronavirus 2 infection, tumorigenesis, and acquired immune deficiency syndrome. In this review, we critically evaluate the recent studies on these aspects of eIF3d and assess prospects in understanding the function of eIF3d in regulating protein synthesis and in biological and pathological processes.
Collapse
Affiliation(s)
- Shijie Ma
- Department of Cell and Cancer Biology, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Jing-Yuan Liu
- Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Jian-Ting Zhang
- Department of Cell and Cancer Biology, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA.
| |
Collapse
|
|
7
|
Ma S, Dong Z, Huang Y, Liu JY, Zhang JT. Translation initiation factor eIF3a regulates glucose metabolism and cell proliferation via promoting small GTPase Rheb synthesis and AMPK activation. J Biol Chem 2022; 298:102044. [PMID: 35595099 PMCID: PMC9207673 DOI: 10.1016/j.jbc.2022.102044] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 05/10/2022] [Accepted: 05/11/2022] [Indexed: 12/05/2022] Open
Abstract
Eukaryotic translation initiation factor 3 subunit A (eIF3a), the largest subunit of the eIF3 complex, has been shown to be overexpressed in malignant cancer cells, potentially making it a proto-oncogene. eIF3a overexpression can drive cancer cell proliferation but contributes to better prognosis. While its contribution to prognosis was previously shown to be due to its function in suppressing synthesis of DNA damage repair proteins, it remains unclear how eIF3a regulates cancer cell proliferation. In this study, we show using genetic approaches that eIF3a controls cell proliferation by regulating glucose metabolism via the phosphorylation and activation of AMP-activated protein kinase alpha (AMPKα) at Thr172 in its kinase activation loop. We demonstrate that eIF3a regulates AMPK activation mainly by controlling synthesis of the small GTPase Rheb, largely independent of the well-known AMPK upstream liver kinase B1 and Ca2+/calmodulin-dependent protein kinase kinase 2, and also independent of mammalian target of rapamycin signaling and glucose levels. Our findings suggest that glucose metabolism in and proliferation of cancer cells may be translationally regulated via a novel eIF3a–Rheb–AMPK signaling axis.
Collapse
Affiliation(s)
- Shijie Ma
- Department of Cell and Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Zizheng Dong
- Department of Cell and Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Yanfei Huang
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Jing-Yuan Liu
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Jian-Ting Zhang
- Department of Cell and Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA.
| |
Collapse
|
|
8
|
eIF3a regulation of mTOR signaling and translational control via HuR in cellular response to DNA damage. Oncogene 2022; 41:2431-2443. [PMID: 35279705 PMCID: PMC9035104 DOI: 10.1038/s41388-022-02262-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 02/16/2022] [Accepted: 02/23/2022] [Indexed: 01/29/2023]
Abstract
eIF3a (eukaryotic translation initiation factor 3a), a subunit of the eIF3 complex, has been suggested to play a regulatory role in protein synthesis and in cellular response to DNA-damaging treatments. S6K1 is an effector and a mediator of mTOR complex 1 (mTORC1) in regulating protein synthesis and integrating diverse signals into control of cell growth and response to stress. Here, we show that eIF3a regulates S6K1 activity by inhibiting mTORC1 kinase via regulating Raptor synthesis. The regulation of Raptor synthesis is via eIF3a interaction with HuR (human antigen R) and binding of the eIF3a-HuR complex to the 5'-UTR of Raptor mRNA. Furthermore, mTORC1 may mediate eIF3a function in cellular response to cisplatin by regulating synthesis of NER proteins and NER activity. Taken together, we conclude that the mTOR signaling pathway may also be regulated by translational control and mediate eIF3a regulation of cancer cell response to cisplatin by regulating NER protein synthesis.
Collapse
|
|
9
|
Mei C, Liu C, Gao Y, Dai WT, Zhang W, Li X, Liu ZQ. eIF3a Regulates Colorectal Cancer Metastasis via Translational Activation of RhoA and Cdc42. Front Cell Dev Biol 2022; 10:794329. [PMID: 35300416 PMCID: PMC8921074 DOI: 10.3389/fcell.2022.794329] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 01/21/2022] [Indexed: 11/13/2022] Open
Abstract
Tumor metastasis is the major cause of tumor relapse and cancer-associated mortality in colorectal cancer, leading to poor therapeutic responses and reduced survival. eIF3a was previously described as an oncogene. However, its role in colorectal cancer progression and metastasis has not yet been fully investigated. In this study, the expression specificity and predictive value of eIF3a were investigated in clinical samples. The effects of eIF3a on cell proliferation and migration were verified in vivo and in vitro, respectively. The underlying molecular mechanism was revealed by western blotting, immunofluorescence, RNA-binding protein immunoprecipitation, and dual-luciferase reporter gene assays. The results showed that eIF3a was significantly overexpressed in tumor tissues compared with adjacent normal tissues. High eIF3a expression was correlated with tumor metastasis and overall survival. Downregulation of eIF3a obviously inhibited the proliferation and motility of malignant cells in vitro and in vivo. Mechanistically, eIF3a regulates Cdc42 and RhoA expression at the translation level, which further affects pseudopodia formation and actin cytoskeleton remodeling. Taken together, eIF3a accelerates the acquisition of the migratory phenotype of cancer cells by activating Cdc42 and RhoA expression at the translational level. Our study identified eIF3a as a promising target for inhibiting colorectal cancer metastasis.
Collapse
Affiliation(s)
- Chao Mei
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacology, Engineering Research Center for Applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha, China
| | - Chong Liu
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacology, Engineering Research Center for Applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha, China
| | - Ying Gao
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacology, Engineering Research Center for Applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha, China
| | - Wen-Ting Dai
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacology, Engineering Research Center for Applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha, China
| | - Wei Zhang
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacology, Engineering Research Center for Applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha, China
| | - Xi Li
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacology, Engineering Research Center for Applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha, China
| | - Zhao-Qian Liu
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacology, Engineering Research Center for Applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha, China
| |
Collapse
|
|
10
|
Tang Q, Wu W, Lu Y, Zhou Y, Wu W, Li J, Pan L, Ling X, Pan F. Joint analysis of m 6A and mRNA expression profiles in the testes of idiopathic nonobstructive azoospermia patients. Front Endocrinol (Lausanne) 2022; 13:1063929. [PMID: 36589848 PMCID: PMC9798116 DOI: 10.3389/fendo.2022.1063929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 11/30/2022] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Growing evidence has indicated that epigenetic factors might be associated with the pathophysiology of idiopathic nonobstructive azoospermia (iNOA). As the most common RNA modification, N6-methyladenosine (m6A) methylation has recently attracted more attention in the regulation of spermatogenesis; however, its role in the mechanisms of iNOA is still unclear. OBJECTIVE To determine the differential expression of mRNA and m6A methylation status in the testes of iNOA patients. METHODS Testes tissues from diagnosed iNOA and controlled obstructive azoospermia (OA) patients were collected and grouped according to the histological examinations. Total RNA was isolated and quantified by an m6A RNA Methylation Quantification Kit. The expression level of mRNAs was detected by qRT-PCR analysis. Differentially expressed m6A genes were analyzed using the human ArrayStar m6A epitranscriptomic microarray, and bioinformatics analyses were applied. RESULTS A total of 36 iNOA and 8 controlled patients were included. The global expression of m6A in the iNOA group was significantly decreased. A dosage relationship was observed between the m6A decline and the degree of impaired spermatogenesis, with the successive process of normal spermatogeneis, hypospermatogenesis (HP), maturation arrest (MA), and Sertoli cell-only syndrome (SO). Four down-expressed genes (BDNF, TMEM38B, RPL3L, and C22orf42) displayed significantly lower expression of m6A methylation. Additionally, they also showed a gradually down-expressed tendency in the three groups (OA, HP, SO/MA groups). Moreover, m6A reader EIF3A was approved to have differential expression through microarrays analysis, which was consistent with the result from the qRT-PCR test. CONCLUSIONS The m6A expression was gradually downregulated in the testes tissue from iNOA patients in accordance with the degree of spermatogenic dysfunction. The determined differential expression of mRNA and m6A methylation status may represent potentially novel molecular targets for the mechanism study of iNOA in the epigenetic level, which could benefit the understanding of the pathophysiology of iNOA.
Collapse
Affiliation(s)
- Qiuqin Tang
- Department of Obstetrics, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China
| | - Wei Wu
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yiwen Lu
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yijie Zhou
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China
- Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Wangfei Wu
- Department of Pathology, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China
| | - Jinhui Li
- Department of Urology, Stanford University Medical Center, Stanford, CA, United States
| | - Lianjun Pan
- Department of Andrology, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China
| | - Xiufeng Ling
- Department of Reproductive Medicine, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China
| | - Feng Pan
- Department of Andrology, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China
- Department of Reproductive Medicine, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China
- *Correspondence: Feng Pan,
| |
Collapse
|
|
11
|
Zhang Y, Hua X, Shi H, Zhang L, Xiao H, Liang C. Systematic analyses of the role of prognostic and immunological EIF3A, a reader protein, in clear cell renal cell carcinoma. Cancer Cell Int 2021; 21:680. [PMID: 34923969 PMCID: PMC8684683 DOI: 10.1186/s12935-021-02364-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 11/24/2021] [Indexed: 02/08/2023] Open
Abstract
Background Eukaryotic initiation factor 3a (EIF3A), a “reader” protein for RNA methylation, has been found to be involved in promoting tumorigenesis in a variety of cancers. The impact of EIF3A in clear cell renal cell carcinoma (ccRCC) has yet to be reported. This study aimed to identify the prognostic value of EIF3A in ccRCC and investigate the relationship between EIF3A expression and immune infiltration. Methods We collected 29 m6A-related mRNA data and clinicopathological parameters from The Cancer Genome Atlas (TCGA) database. Logistic regression analyses were used to analyse the correlation between EIF3A expression and clinical characteristics. Immunohistochemistry (IHC) was applied to examine EIF3A levels in normal and ccRCC tissues. Univariate and multivariate analyses were conducted to recognize independent factors associated with overall survival (OS) and disease-free survival (DFS). The nomogram aimed to predict the 1-, 3- and 5-year survival probabilities. Gene set enrichment analysis (GSEA) was carried out to determine the potential functions and related signalling pathways of EIF3A expression. To investigate EIF3A of coexpressed genes, we used LinkedOmics, and the results were subjected to enrichment analysis. Simultaneously, LinkedOmics and STRING datasets were used to identify EIF3A coexpressed genes that were visualized via Cytoscape. Finally, we evaluated whether EIF3A expression correlated with the infiltration of immune cells and the expression of marker genes in ccRCC by Tumour Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA). Result EIF3A expression was significantly different between ccRCC tissues and normal tissues. EIF3A expression was correlated with poor prognostic clinicopathological factors, and K–M analyses revealed that low EIF3A expression was correlated with a poor prognosis. The results of univariate and multivariate analyses proved that EIF3A was a prognostic factor in ccRCC patients. GSEA results indicated that EIF3A high expression was enriched in the renal cell carcinoma pathway. EIF3A expression was significantly positively correlated with B cells, CD8 + T cells, CD4 + T cells, neutrophils, macrophages, and dendritic cells. Furthermore, EIF3A expression was associated with most marker genes of immune cells. Conclusions EIF3A could serve as a potential biomarker for prognostic and diagnostic stratification of ccRCC and is related to immune cell infiltrates. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-02364-2.
Collapse
Affiliation(s)
- Yi Zhang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, China
| | - Xiaoliang Hua
- Institute of Urology, Anhui Medical University, Hefei, Anhui, China
| | - Haoqiang Shi
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, China.,Institute of Urology, Anhui Medical University, Hefei, Anhui, China.,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, China
| | - Li Zhang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, China.,Institute of Urology, Anhui Medical University, Hefei, Anhui, China.,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, China
| | - Haibing Xiao
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, China. .,Institute of Urology, Anhui Medical University, Hefei, Anhui, China. .,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, China.
| | - Chaozhao Liang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, China. .,Institute of Urology, Anhui Medical University, Hefei, Anhui, China. .,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, Anhui, China.
| |
Collapse
|
|
12
|
Zheng F, Du F, Zhao J, Wang X, Si Y, Jin P, Qian H, Xu B, Yuan P. The emerging role of RNA N6-methyladenosine methylation in breast cancer. Biomark Res 2021; 9:39. [PMID: 34044876 PMCID: PMC8161983 DOI: 10.1186/s40364-021-00295-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 05/18/2021] [Indexed: 02/07/2023] Open
Abstract
N6-methyladenosine (m6A) modification is the most prevalent internal mRNA modification and is involved in many biological processes in eukaryotes. Accumulating evidence has demonstrated that m6A may play either a promoting or suppressing role in breast cancer, including in tumorigenesis, metastasis and angiogenesis. In this review, we summarize the latest research progress on the biological function and prognostic value of m6A modification in breast cancer, as well as potential related therapeutic strategies.
Collapse
Affiliation(s)
- Fangchao Zheng
- Department of Medical Oncology, National Cancer Centre/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Beijing, 100021, China
| | - Feng Du
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), The VIPII Gastrointestinal Cancer Division of Medical Department, Peking University Cancer Hospital and Institute, Beijing, 100021, China
| | - Jiuda Zhao
- Breast Disease Diagnosis and Treatment Center, Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining, 810000, China
| | - Xue Wang
- Department of VIP Medical Services, National Cancer Centre/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yiran Si
- Department of Medical Oncology, National Cancer Centre/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Beijing, 100021, China
| | - Peng Jin
- Department of Surgery, National Cancer Centre/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Haili Qian
- State Key Laboratory of Molecular Oncology, Cancer Hospital/Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Binghe Xu
- Department of Medical Oncology, National Cancer Centre/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Beijing, 100021, China
| | - Peng Yuan
- Department of Medical Oncology, National Cancer Centre/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Beijing, 100021, China. .,Department of VIP Medical Services, National Cancer Centre/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| |
Collapse
|
|
13
|
Ma S, Dong Z, Cui Q, Liu JY, Zhang JT. eIF3i regulation of protein synthesis, cell proliferation, cell cycle progression, and tumorigenesis. Cancer Lett 2020; 500:11-20. [PMID: 33301799 DOI: 10.1016/j.canlet.2020.12.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 11/22/2020] [Accepted: 12/06/2020] [Indexed: 02/07/2023]
Abstract
eIF3i, a 36-kDa protein, is a putative subunit of the eIF3 complex important for translation initiation of mRNAs. It is a WD40 domain-containing protein with seven WD40 repeats that forms a β-propeller structure with an important function in pre-initiation complex formation and mRNA translation initiation. In addition to participating in the eIF3 complex formation for global translational control, eIF3i may bind to specific mRNAs and regulate their translation individually. Furthermore, eIF3i has been shown to bind to TGF-β type II receptor and participate in TGF-β signaling. It may also participate in and regulate other signaling pathways including Wnt/β-catenin pathway via translational regulation of COX-2 synthesis. These multiple canonical and noncanonical functions of eIF3i in translational control and in regulating signal transduction pathways may be responsible for its role in cell differentiation, cell cycle regulation, proliferation, and tumorigenesis. In this review, we will critically evaluate recent progresses and assess future prospects in studying eIF3i.
Collapse
Affiliation(s)
- Shijie Ma
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, China.
| | - Zizheng Dong
- Department of Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA
| | - Qingbin Cui
- Department of Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA
| | - Jing-Yuan Liu
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
| | - Jian-Ting Zhang
- Department of Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
| |
Collapse
|
|
14
|
Translational regulation of Chk1 expression by eIF3a via interaction with the RNA-binding protein HuR. Biochem J 2020; 477:1939-1950. [PMID: 32391557 DOI: 10.1042/bcj20200025] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 05/04/2020] [Accepted: 05/07/2020] [Indexed: 01/10/2023]
Abstract
eIF3a is a putative subunit of the eukaryotic translation initiation factor 3 complex. Accumulating evidence suggests that eIF3a may have a translational regulatory function by suppressing translation of a subset of mRNAs while accelerating that of other mRNAs. Albeit the suppression of mRNA translation may derive from eIF3a binding to the 5'-UTRs of target mRNAs, how eIF3a may accelerate mRNA translation remains unknown. In this study, we show that eIF3a up-regulates translation of Chk1 but not Chk2 mRNA by interacting with HuR, which binds directly to the 3'-UTR of Chk1 mRNA. The interaction between eIF3a and HuR occurs at the 10-amino-acid repeat domain of eIF3a and the RNA recognition motif domain of HuR. This interaction may effectively circularize Chk1 mRNA to form an end-to-end complex that has recently been suggested to accelerate mRNA translation. Together with previous findings, we conclude that eIF3a may regulate mRNA translation by directly binding to the 5'-UTR to suppress or by interacting with RNA-binding proteins at 3'-UTRs to accelerate mRNA translation.
Collapse
|
|
15
|
Tumia R, Wang CJ, Dong T, Ma S, Beebe J, Chen J, Dong Z, Liu JY, Zhang JT. eIF3a Regulation of NHEJ Repair Protein Synthesis and Cellular Response to Ionizing Radiation. Front Cell Dev Biol 2020; 8:753. [PMID: 32974334 PMCID: PMC7466773 DOI: 10.3389/fcell.2020.00753] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 07/20/2020] [Indexed: 11/21/2022] Open
Abstract
Translation initiation in protein synthesis regulated by eukaryotic initiation factors (eIFs) is a crucial step in controlling gene expression. eIF3a has been shown to regulate protein synthesis and cellular response to treatments by anticancer agents including cisplatin by regulating nucleotide excision repair. In this study, we tested the hypothesis that eIF3a regulates the synthesis of proteins important for the repair of double-strand DNA breaks induced by ionizing radiation (IR). We found that eIF3a upregulation sensitized cellular response to IR while its downregulation caused resistance to IR. eIF3a increases IR-induced DNA damages and decreases non-homologous end joining (NHEJ) activity by suppressing the synthesis of NHEJ repair proteins. Furthermore, analysis of existing patient database shows that eIF3a expression associates with better overall survival of breast, gastric, lung, and ovarian cancer patients. These findings together suggest that eIF3a plays an important role in cellular response to DNA-damaging treatments by regulating the synthesis of DNA repair proteins and, thus, eIIF3a likely contributes to the outcome of cancer patients treated with DNA-damaging strategies including IR.
Collapse
Affiliation(s)
- Rima Tumia
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Chao J Wang
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Tianhan Dong
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Shijie Ma
- Department of Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States
| | - Jenny Beebe
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Juan Chen
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Zizheng Dong
- Department of Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States
| | - Jing-Yuan Liu
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States
| | - Jian-Ting Zhang
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, United States.,Department of Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States
| |
Collapse
|
|
16
|
Chen T, Sun L, Yao B, Wang L, Wang Y, Niu Y, Liu R, Mo H, Liu Z, Tu K, Liu Q. MicroRNA‑875‑5p inhibits tumor growth and metastasis of hepatocellular carcinoma by targeting eukaryotic translation initiation factor 3 subunit a. Oncol Rep 2020; 44:2067-2079. [PMID: 33000235 PMCID: PMC7551348 DOI: 10.3892/or.2020.7743] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 07/08/2020] [Indexed: 01/27/2023] Open
Abstract
Accumulating evidence has demonstrated that aberrant microRNA (miRNA) expression is involved in hepatocellular carcinoma (HCC) progression. Previous findings suggested that miRNA (miR)‑875‑5p participates in the development of various types of cancer. However, the expression and function of miR‑875‑5p in HCC remains largely unclear. The analysis of clinical samples in the present study demonstrated that miR‑875‑5p expression was downregulated in HCC tissues compared to adjacent non‑tumor tissues, which was associated with a large tumor size, venous infiltration, advanced tumor‑node‑metastasis stage and unfavorable overall survival. In vitro experiments revealed that ectopic expression of miR‑875‑5p suppressed, whereas inhibition of miR‑875‑5p promoted HCC cell proliferation, migration, invasion and epithelial‑to‑mesenchymal transition (EMT) progression. Overexpression of miR‑875‑5p restrained HCC tumor growth and metastasis in vivo. Mechanistically, eukaryotic translation initiation factor 3 subunit a (eIF3a) was identified as the downstream target of miR‑875‑5p in HCC. Further experiments demonstrated that the expression of eIF3a was upregulated and negatively correlated with that of miR‑875‑5p in HCC tissues. In addition, miR‑875‑5p negatively regulated the luciferase activity of wild‑type, but not mutant 3'‑untranslated region (3'UTR) of eIF3a mRNA. miR‑875‑5p suppressed eIF3a expression at the mRNA and protein level in HCC cells. Additionally, eIF3a exerted an oncogenic role, and knockdown of eIF3a inhibited the proliferation, motility and EMT of HCC cells. In addition, eIF3a overexpression abolished the inhibitory effects of miR‑875‑5p on the proliferation, motility and EMT in HCC cells. In conclusion, miR‑875‑5p, which was downregulated in HCC, may inhibit tumor growth and metastasis by eIF3a downregulation via targeting its 3'UTR and may be a promising prognostic and therapeutic strategy in HCC.
Collapse
Affiliation(s)
- Tianxiang Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Liankang Sun
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Bowen Yao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Liang Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yufeng Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yongshen Niu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Runkun Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Huanye Mo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Zhikui Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Kangsheng Tu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Qingguang Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| |
Collapse
|
|
17
|
Yin Y, Long J, Sun Y, Li H, Jiang E, Zeng C, Zhu W. The function and clinical significance of eIF3 in cancer. Gene 2018; 673:130-133. [PMID: 29908282 DOI: 10.1016/j.gene.2018.06.034] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 06/09/2018] [Accepted: 06/11/2018] [Indexed: 11/15/2022]
Abstract
Abnormal regulation of gene expression is essential for tumorigenesis. Several studies indicate that regulation of oncogene expression and neoplastic transformation are controlled by subunits of eukaryotic translation initiation factors (eIFs). Eukaryotic translation initiation factor 3 (eIF3) is the largest (800 kDa) and the most complex mammalian initiation factor. It is composed of 13 non-identical polypeptides designated as eIF3a-m and plays a pivotal role in protein synthesis that bridges the 43S pre-initiation complex and eIF4F-bound mRNA. However, the functional roles of individual subunits are not yet very clear. This review presents on several of aberrant expressed eIF3 subunits which are detected in various human cancers and the associated mechanisms have been acknowledged or are still not sure. Finally, identifying novel targets and biomarkers for caner is of great importance in early diagnosis and treatment of cancer. eIF3 may be a novel target molecule in drug development for cancer treatment and prevention.
Collapse
Affiliation(s)
- Yuting Yin
- Department of Pathology, School of Basic Medicine, Guangdong Medical University, Dongguan 523808, Guangdong Province, China
| | - Jiali Long
- Department of Pathology, School of Basic Medicine, Guangdong Medical University, Dongguan 523808, Guangdong Province, China
| | - Yanqin Sun
- Department of Pathology, School of Basic Medicine, Guangdong Medical University, Dongguan 523808, Guangdong Province, China
| | - Hongmei Li
- Department of Pathology, School of Basic Medicine, Guangdong Medical University, Dongguan 523808, Guangdong Province, China
| | - Enping Jiang
- Department of Pathology, School of Basic Medicine, Guangdong Medical University, Dongguan 523808, Guangdong Province, China
| | - Chao Zeng
- Department of Pathology, School of Basic Medicine, Guangdong Medical University, Dongguan 523808, Guangdong Province, China.
| | - Wei Zhu
- Department of Pathology, School of Basic Medicine, Guangdong Medical University, Dongguan 523808, Guangdong Province, China.
| |
Collapse
|
|
18
|
Cytosolic Cysteine Synthase Switch Cysteine and Mimosine Production in Leucaena leucocephala. Appl Biochem Biotechnol 2018; 186:613-632. [PMID: 29691793 DOI: 10.1007/s12010-018-2745-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2017] [Accepted: 03/21/2018] [Indexed: 10/17/2022]
Abstract
In higher plants, multiple copies of the cysteine synthase gene are present for cysteine biosynthesis. Some of these genes also have the potential to produce various kinds of β-substitute alanine. In the present study, we cloned a 1275-bp cDNA for cytosolic O-acetylserine(thiol)lyase (cysteine synthase) (Cy-OASTL) from Leucaena leucocephala. The purified protein product showed a dual function of cysteine and mimosine synthesis. Kinetics studies showed pH optima of 7.5 and 8.0, while temperature optima of 40 and 35 °C, respectively, for cysteine and mimosine synthesis. The kinetic parameters such as apparent Km, kcat were determined for both cysteine and mimosine synthesis with substrates O-acetylserine (OAS) and Na2S or 3-hydroxy-4-pyridone (3H4P). From the in vitro results with the common substrate OAS, the apparent kcat for Cys production is over sixfold higher than mimosine synthesis and the apparent Km is 3.7 times lower, suggesting Cys synthesis is the favored pathway.
Collapse
|
|
19
|
Liu HH, McClatchy DB, Schiapparelli L, Shen W, Yates JR, Cline HT. Role of the visual experience-dependent nascent proteome in neuronal plasticity. eLife 2018; 7:e33420. [PMID: 29412139 PMCID: PMC5815848 DOI: 10.7554/elife.33420] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 02/05/2018] [Indexed: 01/02/2023] Open
Abstract
Experience-dependent synaptic plasticity refines brain circuits during development. To identify novel protein synthesis-dependent mechanisms contributing to experience-dependent plasticity, we conducted a quantitative proteomic screen of the nascent proteome in response to visual experience in Xenopus optic tectum using bio-orthogonal metabolic labeling (BONCAT). We identified 83 differentially synthesized candidate plasticity proteins (CPPs). The CPPs form strongly interconnected networks and are annotated to a variety of biological functions, including RNA splicing, protein translation, and chromatin remodeling. Functional analysis of select CPPs revealed the requirement for eukaryotic initiation factor three subunit A (eIF3A), fused in sarcoma (FUS), and ribosomal protein s17 (RPS17) in experience-dependent structural plasticity in tectal neurons and behavioral plasticity in tadpoles. These results demonstrate that the nascent proteome is dynamic in response to visual experience and that de novo synthesis of machinery that regulates RNA splicing and protein translation is required for experience-dependent plasticity.
Collapse
Affiliation(s)
- Han-Hsuan Liu
- The Dorris Neuroscience CenterThe Scripps Research InstituteLa JollaUnited States
- Department of NeuroscienceThe Scripps Research InstituteLa JollaUnited States
- Kellogg School of Science and TechnologyThe Scripps Research InstituteLa JollaUnited States
| | - Daniel B McClatchy
- Department of Molecular MedicineThe Scripps Research InstituteLa JollaUnited States
| | - Lucio Schiapparelli
- The Dorris Neuroscience CenterThe Scripps Research InstituteLa JollaUnited States
- Department of NeuroscienceThe Scripps Research InstituteLa JollaUnited States
| | - Wanhua Shen
- The Dorris Neuroscience CenterThe Scripps Research InstituteLa JollaUnited States
- Department of NeuroscienceThe Scripps Research InstituteLa JollaUnited States
- Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental SciencesHangzhou Normal UniversityHangzhouChina
| | - John R Yates
- Department of NeuroscienceThe Scripps Research InstituteLa JollaUnited States
- Department of Molecular MedicineThe Scripps Research InstituteLa JollaUnited States
| | - Hollis T Cline
- The Dorris Neuroscience CenterThe Scripps Research InstituteLa JollaUnited States
- Department of NeuroscienceThe Scripps Research InstituteLa JollaUnited States
- Kellogg School of Science and TechnologyThe Scripps Research InstituteLa JollaUnited States
- Department of Molecular MedicineThe Scripps Research InstituteLa JollaUnited States
| |
Collapse
|
|
20
|
Abstract
The eukaryotic initiation factor 3 (eIF3) is one of the most complex translation initiation factors in mammalian cells, consisting of several subunits (eIF3a to eIF3m). It is crucial in translation initiation and termination, and in ribosomal recycling. Accordingly, deregulated eIF3 expression is associated with different pathological conditions, including cancer. In this manuscript, we discuss the interactome and function of each subunit of the human eIF3 complex. Furthermore, we review how altered levels of eIF3 subunits correlate with neurodegenerative disorders and cancer onset and development; in addition, we evaluate how such misregulation may also trigger infection cascades. A deep understanding of the molecular mechanisms underlying eIF3 role in human disease is essential to develop new eIF3-targeted therapeutic approaches and thus, overcome such conditions.
Collapse
Affiliation(s)
- Andreia Gomes-Duarte
- a Department of Human Genetics , Instituto Nacional de Saúde Doutor Ricardo Jorge , Lisbon , Portugal.,b Gene Expression and Regulation Group, Biosystems & Integrative Sciences Institute (BioISI), Faculdade de Ciências , Universidade de Lisboa , Lisbon , Portugal
| | - Rafaela Lacerda
- a Department of Human Genetics , Instituto Nacional de Saúde Doutor Ricardo Jorge , Lisbon , Portugal.,b Gene Expression and Regulation Group, Biosystems & Integrative Sciences Institute (BioISI), Faculdade de Ciências , Universidade de Lisboa , Lisbon , Portugal
| | - Juliane Menezes
- a Department of Human Genetics , Instituto Nacional de Saúde Doutor Ricardo Jorge , Lisbon , Portugal.,b Gene Expression and Regulation Group, Biosystems & Integrative Sciences Institute (BioISI), Faculdade de Ciências , Universidade de Lisboa , Lisbon , Portugal
| | - Luísa Romão
- a Department of Human Genetics , Instituto Nacional de Saúde Doutor Ricardo Jorge , Lisbon , Portugal.,b Gene Expression and Regulation Group, Biosystems & Integrative Sciences Institute (BioISI), Faculdade de Ciências , Universidade de Lisboa , Lisbon , Portugal
| |
Collapse
|
|
21
|
He J, Wang X, Cai J, Wang W, Qin X. High expression of eIF3d is associated with poor prognosis in patients with gastric cancer. Cancer Manag Res 2017; 9:539-544. [PMID: 29123423 PMCID: PMC5661832 DOI: 10.2147/cmar.s142324] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Eukaryotic initiation factor 3 subunit d (eIF3d) is the largest subunit of eIF3, which is shown to promote protein synthesis in cancer cells. Increased expression of eIF3d has been shown in some types of cancers, but has not been previously studied in gastric cancer (GC). Thus, the aim of this study was to analyze eIF3d expression in GC. Patients and methods Expression of eIF3d was detected by immunohistochemistry in GC tissues and adjacent noncancerous (ANC) tissues. Samples were obtained from 210 patients with GC who had received curative gastrectomy. Clinicopathological features and survival rate were also analyzed. Results Expression rates of eIF3d in GC and ANC were 45.2% and 21.0%, respectively. High expression of eIF3d protein was significantly related to tumor stage, as determined by lymph node metastasis and depth of invasion (p<0.05). The Kaplan–Meier survival curves showed that patients with high eIF3d expression had a significantly poor overall survival (p=0.005). Multivariate Cox regression analyses showed that the level of eIF3d was an independent predictive factor of poor prognosis for GC (p=0.017). Conclusion Expression of eIF3d was upregulated in GC. High expression of eIF3d was determined as an independent poor prognostic factor in GC. It is suggested that eIF3d could be a good biomarker in GC.
Collapse
Affiliation(s)
- Jiaqi He
- Department of General Surgery, Huadong Hospital
| | - Xuefei Wang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Jianhua Cai
- Department of General Surgery, Huadong Hospital
| | - Wei Wang
- Department of General Surgery, Huadong Hospital
| | - Xinyu Qin
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| |
Collapse
|
|
22
|
eIF3i activity is critical for endothelial cells in tumor induced angiogenesis through regulating VEGFR and ERK translation. Oncotarget 2017; 8:19968-19979. [PMID: 28193911 PMCID: PMC5386737 DOI: 10.18632/oncotarget.15274] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Accepted: 11/30/2016] [Indexed: 02/05/2023] Open
Abstract
Translational control is a critical step in the regulation of gene expression. Accumulating evidence shows that translational control of a subgroup of mRNAs tends to be selective. However, our understanding of the function of selective translational control in endothelial cells is still incomplete. We found that a key translational regulator, eIF3i, is highly expressed in endothelial cells during embryonic and tumor angiogenesis. Knockdown of eIF3i restrained cell proliferation and migration in endothelial cells. In zebrafish angiogenesis model, eIF3i mutant endothelial cells could not respond to induction signals from tumor mass. Mechanistically, we showed that eIF3i knockdown reduced VEGFR/ERK signaling by down-regulating VEGFR2 and ERK protein expression. Gene therapy model suggested that the growth and metastasis of cancer cells were suppressed by eIF3i shRNA. Therefore, our work established a selective translational regulatory mechanism during tumor induced angiogenesis and suggested that targeting eIF3i may be applicable for anticancer therapy.
Collapse
|
|
23
|
Yin JY, Zhang JT, Zhang W, Zhou HH, Liu ZQ. eIF3a: A new anticancer drug target in the eIF family. Cancer Lett 2017; 412:81-87. [PMID: 29031564 DOI: 10.1016/j.canlet.2017.09.055] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2017] [Revised: 09/12/2017] [Accepted: 09/25/2017] [Indexed: 02/04/2023]
Abstract
eIF3a is the largest subunit of eIF3, which is a key player in all steps of translation initiation. During the past years, eIF3a is recognized as a proto-oncogene, which is an important discovery in this field. It is widely reported to be correlated with cancer occurrence, metastasis, prognosis, and therapeutic response. Recently, the mechanisms of eIF3a action in the carcinogenesis are unveiled gradually. A number of cellular, physiological, and pathological processes involving eIF3a are identified. Most importantly, it is emerging as a new potential drug target in the eIF family, and some small molecule inhibitors are being developed. Thus, we perform a critical review of recent advances in understanding eIF3a physiological and pathological functions, with specific focus on its role in cancer and anticancer drug targets.
Collapse
Affiliation(s)
- Ji-Ye Yin
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, PR China.
| | - Jian-Ting Zhang
- Department of Pharmacology & Toxicology and IU Cancer Center, Indiana University School of Medicine, Indianapolis IN 46202, USA
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, PR China
| | - Hong-Hao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, PR China
| | - Zhao-Qian Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, PR China.
| |
Collapse
|
|
24
|
Differential response to doxorubicin in breast cancer subtypes simulated by a microfluidic tumor model. J Control Release 2017; 266:129-139. [PMID: 28939108 DOI: 10.1016/j.jconrel.2017.09.024] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 09/13/2017] [Accepted: 09/15/2017] [Indexed: 02/08/2023]
Abstract
Successful drug delivery and overcoming drug resistance are the primary clinical challenges for management and treatment of cancer. The ability to rapidly screen drugs and delivery systems within physiologically relevant environments is critically important; yet is currently limited due to lack of appropriate tumor models. To address this problem, we developed the Tumor-microenvironment-on-chip (T-MOC), a new microfluidic tumor model simulating the interstitial flow, plasma clearance, and transport of the drug within the tumor. We demonstrated T-MOC's capabilities by assessing the delivery and efficacy of doxorubicin in small molecular form versus hyaluronic acid nanoparticle (NP) formulation in MCF-7 and MDA-MB-231, two cell lines representative of different molecular subtypes of breast cancer. Doxorubicin accumulated and penetrated similarly in both cell lines while the NP accumulated more in MDA-MB-231 than MCF-7 potentially due to binding of hyaluronic acid to CD44 expressed by MDA-MB-231. However, the penetration of the NP was less than the molecular drug due to its larger size. In addition, both cell lines cultured on the T-MOC showed increased resistance to the drug compared to 2D culture where MDA-MB-231 attained a drug-resistant tumor-initiating phenotype indicated by increased CD44 expression. When grown in immunocompromised mice, both cell lines exhibited cell-type-dependent resistance and phenotypic changes similar to T-MOC, confirming its predictive ability for in vivo drug response. This initial characterization of T-MOC indicates its transformative potential for in vitro testing of drug efficacy towards prediction of in vivo outcomes and investigation of drug resistance mechanisms for advancement of personalized medicine.
Collapse
|
|
25
|
Zang Y, Zhang X, Yan L, Gu G, Li D, Zhang Y, Fang L, Fu S, Ren J, Xu Z. Eukaryotic Translation Initiation Factor 3b is both a Promising Prognostic Biomarker and a Potential Therapeutic Target for Patients with Clear Cell Renal Cell Carcinoma. J Cancer 2017; 8:3049-3061. [PMID: 28928896 PMCID: PMC5604456 DOI: 10.7150/jca.19594] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 08/06/2017] [Indexed: 12/24/2022] Open
Abstract
Eukaryotic translation initiation factors (eIFs) constitute a new class of therapeutic cancer targets. EIF3b is the major scaffold protein of eIF3 (the largest core of eIFs). We sought to define the role played by and the mechanism of action of eIF3b in patients with clear cell renal cell carcinoma (ccRCC). We found that high-level eIF3b expression in tumors was not only associated with an aggressive tumor phenotype, but was also independently prognostic for patients with ccRCC. Knockdown of eIF3b impaired the action of the Akt pathway, thus inhibiting cell proliferation by disrupting the cell cycle and triggering apoptosis. Furthermore, the epithelial-to-mesenchymal transition was impaired after eIF3b depletion, via suppression of cell migration and invasion. Additionally, eIF3b knockdown significantly inhibited the growth of subcutaneous xenografts in mice. Together, these data show that eIF3b is both a promising prognostic biomarker and a potential therapeutic target for patients with ccRCC.
Collapse
Affiliation(s)
- Yuanwei Zang
- Department of Urology, Qilu Hospital, Shandong University, 107 Wenhua West Road, Jinan 250012, China
| | - Xiang Zhang
- Department of Urology, Qilu Hospital, Shandong University, 107 Wenhua West Road, Jinan 250012, China
| | - Lei Yan
- Department of Urology, Qilu Hospital, Shandong University, 107 Wenhua West Road, Jinan 250012, China
| | - Gangli Gu
- Department of Urology, Qilu Hospital, Shandong University, 107 Wenhua West Road, Jinan 250012, China
| | - Dawei Li
- Department of Urology, Qilu Hospital, Shandong University, 107 Wenhua West Road, Jinan 250012, China
| | - Yongzhen Zhang
- Department of Urology, Qilu Hospital, Shandong University, 107 Wenhua West Road, Jinan 250012, China
| | - Liang Fang
- Department of Urology, Qilu Hospital, Shandong University, 107 Wenhua West Road, Jinan 250012, China
| | - Shanshan Fu
- Department of Gastroenterology, Shandong Provincial Qianfoshan Hospital, 16766 Jingshi Road, Jinan 250014, China
| | - Juchao Ren
- Department of Urology, Qilu Hospital, Shandong University, 107 Wenhua West Road, Jinan 250012, China
| | - Zhonghua Xu
- Department of Urology, Qilu Hospital, Shandong University, 107 Wenhua West Road, Jinan 250012, China
| |
Collapse
|
|
26
|
Xu JZ, Wen F, Wang XR. The eIF3a Arg803Lys genetic polymorphism is associated with susceptibility to and chemoradiotherapy efficacy in cervical carcinoma. Kaohsiung J Med Sci 2017; 33:187-194. [DOI: 10.1016/j.kjms.2017.01.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Revised: 12/20/2016] [Accepted: 12/26/2016] [Indexed: 10/20/2022] Open
|
|
27
|
Li K, Zhou S, Guo Q, Chen X, Lai DH, Lun ZR, Guo X. The eIF3 complex of Trypanosoma brucei: composition conservation does not imply the conservation of structural assembly and subunits function. RNA (NEW YORK, N.Y.) 2017; 23:333-345. [PMID: 27932584 PMCID: PMC5311491 DOI: 10.1261/rna.058651.116] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2016] [Accepted: 11/24/2016] [Indexed: 05/03/2023]
Abstract
The multisubunit eukaryotic initiation factor 3 (eIF3) plays multiple roles in translation but is poorly understood in trypanosomes. The putative subunits eIF3a and eIF3f of Trypanosoma brucei (TbIF3a and TbIF3f) were overexpressed and purified, and 11 subunits were identified, TbIF3a through l minus j, which form a tight complex. Both TbIF3a and TbIF3f are essential for the viability of T. brucei RNAi knockdown of either of them severely reduced total translation and the ratio of the polysome/80S peak area. TbIF3f and TbIF3a RNAi cell lines were modified to express tagged-TbIF3a and -TbIF3f, respectively. RNAi in combination with affinity purification assays indicated that both subunits are variably required for TbIF3 stability and integrity. The relative abundance of other subunits in the TbIF3f-tag complex changed little upon TbIF3a depletion; while only subunits TbIF3b, i, and e copurified comparably with TbIF3a-tag upon TbIF3f depletion. A genome-wide UV-crosslinking assay showed that several TbIF3 subunits have direct RNA-binding activity, with TbIF3c showing the strongest signal. In addition, CrPV IRES, but neither EMCV IRES nor HCV IRES, was found to mediate translation in T. brucei These results together imply that the structure of TbIF3 and the subunits function have trypanosome-specific features, although the composition is evolutionarily conserved.
Collapse
Affiliation(s)
- Kunrao Li
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
- Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou 510080, China
| | - Shuru Zhou
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
- Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou 510080, China
| | - Qixuan Guo
- Chengde Nursing Vocational College, Chengde 067000, China
| | - Xin Chen
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
- Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou 510080, China
| | - De-Hua Lai
- Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou 510080, China
- Center for Parasitic Organisms, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China
| | - Zhao-Rong Lun
- Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou 510080, China
- Center for Parasitic Organisms, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China
| | - Xuemin Guo
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
- Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou 510080, China
| |
Collapse
|
|
28
|
Fang C, Chen YX, Wu NY, Yin JY, Li XP, Huang HS, Zhang W, Zhou HH, Liu ZQ. MiR-488 inhibits proliferation and cisplatin sensibility in non-small-cell lung cancer (NSCLC) cells by activating the eIF3a-mediated NER signaling pathway. Sci Rep 2017; 7:40384. [PMID: 28074905 PMCID: PMC5225486 DOI: 10.1038/srep40384] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Accepted: 12/06/2016] [Indexed: 12/11/2022] Open
Abstract
Our previous studied indicated that eukaryotic translation initiation factor 3a (eIF3a) increases the sensitive of platinum-based chemotherapy in lung cancer. MiRNAs play an important role in lung carcinogenesis and drug response. In this study, we aimed to identify potential endogenous miRNAs that inhibit eIF3a expression and determine their influence of this inhibition on cisplatin resistance. Using bioinformatics analysis prediction and confirmation with dual-luciferase reporter assays, we found that miRNA-488 inhibited eIF3a expression by directly binding to the 3’UTR of eIF3a. In addition, the overexpression of miRNA-488 inhibited cell migration and invasion in A549 cells, and also inhibited cell proliferation, cell cycle progression by elevated P27 expression. Compared to the parental cell line, A549/cisplatin (DDP) resistant cells exhibited a higher level of miRNA-488. Moreover, we found that miRNA-488 was associated with cisplatin resistance in three NSCLC cells (A549, H1299 and SK-MES-1). The mechanism of miRNA-488 induced cisplatin resistance was that miRNA-488 activated nucleotide excision repair (NER) by increasing the expression of Replication Protein A (RPA) 14 and Xeroderma pigmentosum group C (XPC). In conclusion, our results demonstrated that miRNA-488 is a tumor suppressor miRNA that acts by targeting eIF3a. Moreover, miRNA-488 also participates in eIF3a mediated cisplatin resistance in NSCLC cells.
Collapse
Affiliation(s)
- Chao Fang
- Departments of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China.,Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, P. R. China
| | - Yi-Xin Chen
- Departments of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China.,Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, P. R. China
| | - Na-Yiyuan Wu
- Departments of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China.,Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, P. R. China
| | - Ji-Ye Yin
- Departments of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China.,Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, P. R. China
| | - Xiang-Ping Li
- Departments of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, P. R. China
| | - Hsuan-Shun Huang
- Department of Research, Cervical Cancer Prevention Center, Tzu Chi University, Hualien 970, Taiwan, Republic of China
| | - Wei Zhang
- Departments of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China.,Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, P. R. China
| | - Hong-Hao Zhou
- Departments of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China.,Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, P. R. China.,Hunan Province Cooperation Innovation Center for Molecular Target New Drug Study, Hengyang 421001, P. R. China
| | - Zhao-Qian Liu
- Departments of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China.,Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, P. R. China.,Hunan Province Cooperation Innovation Center for Molecular Target New Drug Study, Hengyang 421001, P. R. China
| |
Collapse
|
|
29
|
Yin JY, Dong Z, Zhang JT. eIF3 Regulation of Protein Synthesis, Tumorigenesis, and Therapeutic Response. Methods Mol Biol 2017; 1507:113-127. [PMID: 27832536 DOI: 10.1007/978-1-4939-6518-2_9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Translation initiation is the rate-limiting step of protein synthesis and highly regulated. Eukaryotic initiation factor 3 (eIF3) is the largest and most complex initiation factor consisting of 13 putative subunits. A growing number of studies suggest that eIF3 and its subunits may represent a new group of proto-oncogenes and associates with prognosis. They regulate translation of a subset of mRNAs involved in many cellular processes including proliferation, apoptosis, DNA repair, and cell cycle. Therefore, unveiling the mechanisms of eIF3 action in tumorigenesis may help identify attractive targets for cancer therapy. Here, we describe a series of methods used in the study of eIF3 function in regulating protein synthesis, tumorigenesis, and cellular response to therapeutic treatments.
Collapse
Affiliation(s)
- Ji-Ye Yin
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 110 Xiang Ya Road, Changsha, Hunan, 410078, China.
| | - Zizheng Dong
- Department of Pharmacology and Toxicology and IU Simon Cancer Center, Indiana University School of Medicine, 980 W. Walnut Street, Indianapolis, IN, 46202, USA
| | - Jian-Ting Zhang
- Department of Pharmacology and Toxicology and IU Simon Cancer Center, Indiana University School of Medicine, 980 W. Walnut Street, Indianapolis, IN, 46202, USA.
| |
Collapse
|
|
30
|
Role of Eukaryotic Initiation Factors during Cellular Stress and Cancer Progression. J Nucleic Acids 2016; 2016:8235121. [PMID: 28083147 PMCID: PMC5204094 DOI: 10.1155/2016/8235121] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Accepted: 11/14/2016] [Indexed: 12/12/2022] Open
Abstract
Protein synthesis can be segmented into distinct phases comprising mRNA translation initiation, elongation, and termination. Translation initiation is a highly regulated and rate-limiting step of protein synthesis that requires more than 12 eukaryotic initiation factors (eIFs). Extensive evidence shows that the transcriptome and corresponding proteome do not invariably correlate with each other in a variety of contexts. In particular, translation of mRNAs specific to angiogenesis, tumor development, and apoptosis is altered during physiological and pathophysiological stress conditions. In cancer cells, the expression and functions of eIFs are hampered, resulting in the inhibition of global translation and enhancement of translation of subsets of mRNAs by alternative mechanisms. A precise understanding of mechanisms involving eukaryotic initiation factors leading to differential protein expression can help us to design better strategies to diagnose and treat cancer. The high spatial and temporal resolution of translation control can have an immediate effect on the microenvironment of the cell in comparison with changes in transcription. The dysregulation of mRNA translation mechanisms is increasingly being exploited as a target to treat cancer. In this review, we will focus on this context by describing both canonical and noncanonical roles of eIFs, which alter mRNA translation.
Collapse
|
|
31
|
Highly expressed ribosomal protein L34 indicates poor prognosis in osteosarcoma and its knockdown suppresses osteosarcoma proliferation probably through translational control. Sci Rep 2016; 6:37690. [PMID: 27883047 PMCID: PMC5121591 DOI: 10.1038/srep37690] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 11/01/2016] [Indexed: 01/25/2023] Open
Abstract
Osteosarcoma has devastating health implications on children and adolescents. However, due to its low incidence and high tumor heterogeneity, it is hard to achieve any further improvements in therapy and overall survival. Ribosomal protein L34 (RPL34) has been increasingly recognized to promote the proliferation of malignant cells, but its role in osteosarcoma has not been investigated. In this study, real-time quantitative PCR (RT-qPCR) and immunohistochemistry revealed that RPL34 was highly expressed in osteosarcoma tissues when compared to adjacent tissues and normal bone tissues. Survival analysis showed that high expression of RPL34 predicted a poor prognosis for osteosarcoma patients. Knockdown of RPL34 in Saos-2 cells via lentivirus-mediated small interfering RNA (siRNA) significantly inhibited cell proliferation, induced cell apoptosis and G2/M phase arrest. Moreover, screening of transcription factors using University of California Santa Cruz (UCSC) Genome Browser, protein-protein interaction (PPI) network analysis, Gene Ontology (GO) and pathway enrichment analysis revealed that MYC participates in the transcriptional regulation of RPL34, which interacts with the subunits of eukaryotic translation initiation factor 3 (eIF3) and probably involves the translational control of growth-promoting proteins. Our findings suggest that RPL34 plays an important role in the proliferation of osteosarcoma cells.
Collapse
|
|
32
|
Abstract
The eukaryotic translation initiation factor 3a (eIF3a) is one of the core subunits of the translation initiation complex eIF3, responsible for ribosomal subunit joining and mRNA recruitment to the ribosome. Our previous study identified that it was correlated with platinum response in lung cancer. The current study aims to test the hypothesis that eIF3a may affect the drug response and prognosis of ovarian cancer patients receiving platinum-based chemotherapy by regulating xeroderma pigmentosum complementation group C (XPC) and p27Kip1. Immunohistochemistry and western blot was used to determine the expression of eIF3a in 126 human ovarian cancer tissues followed by association analysis of eIF3a expression with patient's response and survival. Ectopic over-expression and RNA interference knockdown of eIF3a were carried out in A2780/cisplatin (DDP) and its parental A2780 cells, respectively, to determine the effect of altered eIF3a expression on cellular response to cisplatin by employing MTT assay. Western Blot analyses were also carried out to determine the regulation of eIF3a on XPC and p27Kip1. eIF3a expression was associated with response of ovarian cancer patients to DDP-based chemotherapy and their survival. Overexpression and knockdown of eIF3a increased and decreased the cellular response to cisplatin in A2780/DDP and A2780 cells, respectively. In addition, XPC and p27Kip1 were down regulated by eIF3a. eIF3a improves ovarian cancer patients' response to DDP-based chemotherapy via down regulating XPC and p27Kip1.
Collapse
|
|
33
|
Nguyen BCQ, Tawata S. The Chemistry and Biological Activities of Mimosine: A Review. Phytother Res 2016; 30:1230-42. [PMID: 27213712 DOI: 10.1002/ptr.5636] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Revised: 04/05/2016] [Accepted: 04/12/2016] [Indexed: 12/14/2022]
Abstract
Mimosine [β-[N-(3-hydroxy-4-oxypyridyl)]-α-aminopropionic acid] is a non-protein amino acid found in the members of Mimosoideae family. There are a considerable number of reports available on the chemistry, methods for estimation, biosynthesis, regulation, and degradation of this secondary metabolite. On the other hand, over the past years of active research, mimosine has been found to have various biological activities such as anti-cancer, antiinflammation, anti-fibrosis, anti-influenza, anti-virus, herbicidal and insecticidal activities, and others. Mimosine is a leading compound of interest for use in the development of RAC/CDC42-activated kinase 1 (PAK1)-specific inhibitors for the treatment of various diseases/disorders, because PAK1 is not essential for the growth of normal cells. Interestingly, the new roles of mimosine in malignant glioma treatment, regenerative dentistry, and phytoremediation are being emerged. These identified properties indicate an exciting future for this amino acid. The present review is focused on the chemistry and recognized biological activities of mimosine in an attempt to draw a link between these two characteristics. Copyright © 2016 John Wiley & Sons, Ltd.
Collapse
Affiliation(s)
- Binh Cao Quan Nguyen
- Department of Bioscience and Biotechnology, The United Graduate School of Agricultural Sciences, Kagoshima University, Kagoshima, 890-0065, Japan.,PAK Research Center, Okinawa, 903-0213, Japan
| | - Shinkichi Tawata
- PAK Research Center, Okinawa, 903-0213, Japan.,Department of Bioscience and Biotechnology, Faculty of Agriculture, University of the Ryukyus, Senbaru 1, Nishihara-cho, Okinawa, 903-0213, Japan
| |
Collapse
|
|
34
|
Li XW, Li XH, Du J, Li D, Li YJ, Hu CP. Calcitonin gene-related peptide down-regulates bleomycin-induced pulmonary fibrosis. Can J Physiol Pharmacol 2016; 94:1315-1324. [PMID: 27556497 DOI: 10.1139/cjpp-2015-0602] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We have found that eIF3a plays an important role in bleomycin-induced pulmonary fibrosis, and up-regulation of eIF3a induced by TGF-β1 is mediated via the ERK1/2 pathway. Whether ERK1/2 - eIF3a signal pathway is involved in calcitonin gene-related peptide (CGRP)-mediated pathogenesis of bleomycin-induced pulmonary fibrosis remains unknown. Pulmonary fibrosis was induced by intratracheal instillation of bleomycin (5 mg/kg) in rats. Primary pulmonary fibroblasts were cultured to investigate the proliferation by BrdU incorporation method and flow cytometry. Sensory CGRP depletion by capsaicin exacerbated bleomycin-induced pulmonary fibrosis in rats, as shown by a significant disturbed alveolar structure, marked thickening of the interalveolar septa and dense interstitial infiltration by inflammatory cells and fibroblasts, accompanied with increased expression of TGF-β1, eIF3a, phosphorylated ERK1/2, α-SMA, collagen I, and collagen III. Exogenous application of CGRP significantly inhibited TGF-β1-induced proliferation and differentiation of pulmonary fibroblasts concomitantly with decreased expression of eIF3a, phosphorylated ERK1/2, α-SMA, collagen I, and collagen III. These effects of CGRP were abolished in the presence of CGRP8-37. These results suggest that endogenous CGRP is related to the development of pulmonary fibrosis induced by bleomycin, and the inhibitory effect of CGRP on proliferation of lung fibroblasts involves the ERK1/2 - eIF3a signaling pathway.
Collapse
Affiliation(s)
- Xian-Wei Li
- a Department of Pharmacology, Wannan Medical College, Wen-Chang West Road #22, Wuhu, Anhui 241002, China
| | - Xiao-Hui Li
- b Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Xiang-Ya Road #110, Changsha, Hunan 410078, China
| | - Jie Du
- b Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Xiang-Ya Road #110, Changsha, Hunan 410078, China
| | - Dai Li
- b Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Xiang-Ya Road #110, Changsha, Hunan 410078, China
| | - Yuan-Jian Li
- b Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Xiang-Ya Road #110, Changsha, Hunan 410078, China
| | - Chang-Ping Hu
- b Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Xiang-Ya Road #110, Changsha, Hunan 410078, China
| |
Collapse
|
|
35
|
Toompuu M, Kärblane K, Pata P, Truve E, Sarmiento C. ABCE1 is essential for S phase progression in human cells. Cell Cycle 2016; 15:1234-47. [PMID: 26985706 DOI: 10.1080/15384101.2016.1160972] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
ABCE1 is a highly conserved protein universally present in eukaryotes and archaea, which is crucial for the viability of different organisms. First identified as RNase L inhibitor, ABCE1 is currently recognized as an essential translation factor involved in several stages of eukaryotic translation and ribosome biogenesis. The nature of vital functions of ABCE1, however, remains unexplained. Here, we study the role of ABCE1 in human cell proliferation and its possible connection to translation. We show that ABCE1 depletion by siRNA results in a decreased rate of cell growth due to accumulation of cells in S phase, which is accompanied by inefficient DNA synthesis and reduced histone mRNA and protein levels. We infer that in addition to the role in general translation, ABCE1 is involved in histone biosynthesis and DNA replication and therefore is essential for normal S phase progression. In addition, we analyze whether ABCE1 is implicated in transcript-specific translation via its association with the eIF3 complex subunits known to control the synthesis of cell proliferation-related proteins. The expression levels of a few such targets regulated by eIF3A, however, were not consistently affected by ABCE1 depletion.
Collapse
Affiliation(s)
- Marina Toompuu
- a Department of Gene Technology , Tallinn University of Technology , Tallinn , Estonia
| | - Kairi Kärblane
- a Department of Gene Technology , Tallinn University of Technology , Tallinn , Estonia
| | - Pille Pata
- a Department of Gene Technology , Tallinn University of Technology , Tallinn , Estonia
| | - Erkki Truve
- a Department of Gene Technology , Tallinn University of Technology , Tallinn , Estonia
| | - Cecilia Sarmiento
- a Department of Gene Technology , Tallinn University of Technology , Tallinn , Estonia
| |
Collapse
|
|
36
|
Wu YH, Li XW, Li WQ, Li XH, Li YJ, Hu GY, Liu ZQ, Li D. Fluorofenidone attenuates bleomycin-induced pulmonary fibrosis by inhibiting eukaryotic translation initiation factor 3a (eIF3a) in rats. Eur J Pharmacol 2016; 773:42-50. [PMID: 26821114 DOI: 10.1016/j.ejphar.2016.01.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Revised: 01/14/2016] [Accepted: 01/24/2016] [Indexed: 12/15/2022]
Abstract
Fluorofenidone is a novel derivative of l-mimosine. It has remarkable anti-fibrotic properties. In this study, we established that fluorofenidone ameliorates pulmonary fibrosis (PF) both in vivo and in vitro by specifically inhibiting the expression of eukaryotic translation initiation factor 3a (eIF3a). eIF3a plays an important role in the development and progression of PF. An animal model of PF was induced by intratracheal instillation of bleomycin (5mg/kg) in rats. Rats were orally administered with fluorofenidone (250, 500 mg/kg/d·[i.g.]) and pirfenidone (500 mg/kg/d·[i.g.]) for 28 days. Primary pulmonary fibroblasts were cultured to determine the effect of fluorofenidone on TGF-β1-induced (5 ng/ml) proliferation and differentiation of fibroblasts. The expression/level of eIF3a, TGF-β1, α-SMA, collagen I, and collagen III were analyzed by ELISA, real-time PCR, and western blot. The cell proliferation rate was determined by MTS assay. The results indicate that fluorofenidone significantly improves the pathological changes in lung tissues and reduces the deposition of collagen by inhibiting eIF3a in rats with bleomycin-induced PF. Moreover, in a culture of pulmonary fibroblasts, fluorofenidone decreased the up-regulation of TGF-β1-induced eIF3a by inhibiting the proliferation of cells and reducing the expression of α-SMA, collagen I, and collagen III. These findings suggest that eIF3a is a new and special target of fluorofenidone, which could be potentially used in the development of a drug that treats PF.
Collapse
Affiliation(s)
- Yue-Han Wu
- Hunan Provincial Key Laboratory of Cardiovascular Research, School of Pharmaceutical Sciences, Central South University, Changsha, China
| | - Xian-Wei Li
- Department of Pharmacology, Wannan Medical College, Wuhu, Anhui Province, China
| | - Wen-Qun Li
- Hunan Provincial Key Laboratory of Cardiovascular Research, School of Pharmaceutical Sciences, Central South University, Changsha, China
| | - Xiao-Hui Li
- Hunan Provincial Key Laboratory of Cardiovascular Research, School of Pharmaceutical Sciences, Central South University, Changsha, China
| | - Yuan-Jian Li
- Hunan Provincial Key Laboratory of Cardiovascular Research, School of Pharmaceutical Sciences, Central South University, Changsha, China
| | - Gao-Yun Hu
- Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Central South University, Changsha, China
| | - Zhao-Qian Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
| | - Dai Li
- National Institution of Drug Clinical Trial, Xiangya Hospital, Central South University, Changsha, China.
| |
Collapse
|
|
37
|
Liu K, Lei Z, Yao H, Lei S, Zhao H. Impact of a Eukaryotic Translation Initiation Factor 3a Polymorphism on Susceptibility to Gastric Cancer. Med Princ Pract 2016; 25:461-5. [PMID: 27333287 PMCID: PMC5588499 DOI: 10.1159/000447741] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Accepted: 06/21/2016] [Indexed: 01/17/2023] Open
Abstract
OBJECTIVE To investigate single nucleotide polymorphisms in the eukaryotic translation initiation factor 3a (eIF3a) gene and the risk for gastric cancer within the Chinese population. SUBJECTS AND METHODS A total of 322 patients with gastric cancer were selected as the patient group and 340 non-gastric cancer patients were selected as the control group using the case-control method. Polymerase chain reaction-sequence-specific primer technology was leveraged to genotype the rs77382849 single nucleotide polymorphism in the eIF3a gene. The demographic characteristics of the study population and other exposures to risk factors were collected. Unconditional logistic regression analysis was performed to determine the association between the risk factors and gastric cancer. RESULTS A higher frequency of the eIF3a rs77382849 GG homozygote genotype was observed in the gastric cancer patients compared with the controls (63.98 vs. 54.41%, p < 0.05). After adjustment of exposure risks, such as age, gender, smoking, and drinking, the rs77382849 single nucleotide polymorphism was still associated with susceptibility to gastric cancer. When the eIF3a rs77382849 GG homozygote genotype was used as the reference group, the GA genotype (GA vs. GG: OR = 0.545, 95% CI: 0.386-0.769, p = 0.001) and AA genotype (AA vs. GG: OR = 0.245, 95% CI: 0.072-0.836, p = 0.025) were both correlated with a significantly decreased risk for gastric cancer development. CONCLUSION An association between eIF3a rs77382849 polymorphism and susceptibility to gastric cancer was observed in these Chinese patients.
Collapse
Affiliation(s)
| | | | | | | | - Hua Zhao
- *Dr. Hua Zhao, Department of General Surgery, The Second Xiangya Hospital, Central South University, 139, Middle Renmin road, Changsha, Hunan 410000 (PR China), E-Mail
| |
Collapse
|
|
38
|
Li WQ, Li XH, Wu YH, Du J, Wang AP, Li D, Li YJ. Role of eukaryotic translation initiation factors 3a in hypoxia-induced right ventricular remodeling of rats. Life Sci 2015; 144:61-8. [PMID: 26612348 DOI: 10.1016/j.lfs.2015.11.020] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Revised: 10/14/2015] [Accepted: 11/19/2015] [Indexed: 11/25/2022]
Abstract
AIM Eukaryotic translation initiation factors 3a (eIF3a) is involved in regulating cell cycle, cell division, growth and differentiation. Previous studies suggest a role of eIF3a on fibrosis disease and cellular proliferation and differentiation of fibroblasts. The present study aims to investigate the role of eIF3a on hypoxia-induced right ventricular (RV) remodeling and underlying mechanism. MAIN METHODS RV remodeling was induced by hypoxia (10% O2, 3 weeks) in rats. Primary cardiac fibroblasts were cultured in vitro and their proliferation was investigated by MTS and EdU incorporation method. eIF3a knockdown was conducted by eIF3a siRNA. The expression/level of TGF-β1, eIF3a, p27 and α-SMA, collagen-I, collagen-III, ANP and BNP were analyzed by ELISA, real-time PCR or Western blot. KEY FINDINGS The expression of eIF3a was obviously increased in right ventricle of RV remodeling rats accompanied by up-regulation of α-SMA and collagens. In cultured cardiac fibroblasts, application of exogenous TGF-β1-induced cellular proliferation and differentiation concomitantly with up-regulation of eIF3a expression and down-regulation of p27 expression. The effects of TGF-β1-induced proliferation and up-regulation of α-SMA and collagen in cardiac fibroblasts were abolished by eIF3a siRNA. eIF3a siRNA reversed TGF-β1 induced down-regulation of p27 expression. SIGNIFICANCE The eIF3a plays a crucial role in hypoxia-induced RV remodeling by regulating TGF-β1-induced proliferation and differentiation of cardiac fibroblasts, which is mediated via eIF3a/p27 pathway.
Collapse
Affiliation(s)
- Wen-Qun Li
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
| | - Xiao-Hui Li
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
| | - Yue-Han Wu
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
| | - Jie Du
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
| | - Ai-Ping Wang
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China; Department of Anatomy, School of Medicine, University of South China, Hengyang 421001, China
| | - Dai Li
- National Institution of Drug Clinical Trial, Xiangya Hospital, Central South University, Changsha 410078, China
| | - Yuan-Jian Li
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China.
| |
Collapse
|
|
39
|
Gao Y, Teng J, Hong Y, Qu F, Ren J, Li L, Pan X, Chen L, Yin L, Xu D, Cui X. The oncogenic role of EIF3D is associated with increased cell cycle progression and motility in prostate cancer. Med Oncol 2015; 32:518. [PMID: 26036682 DOI: 10.1007/s12032-015-0518-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Accepted: 02/13/2015] [Indexed: 11/24/2022]
Abstract
EIF3 is the largest multi-protein complex, and several studies have revealed the oncogenic roles of its subunits in many human cancers. However, the roles of EIF3D in the development and progression of PCa remain uncovered. In the present study, the expression of EIF3D in prostate cancer and paracarcinoma tissues, as well as PCa cell lines, was examined. In PCa tissues, the expression of EIF3D was up-regulated compared to that in paracarcinoma tissues. In order to investigate whether EIF3D could serve as potential therapeutic target for prostate cancer, EIF3D was knocked down to verify its functional role in prostate cancer cells. After EIF3D knockdown in PC-3 and DU145 cells, cell proliferation, invasion and colony formation were significantly inhibited; meanwhile, cell cycle analysis revealed cell cycle arrest at G2/M phase. EIF3D is associated with PCa, and silencing EIF3D will result in decreased proliferation, and migration, as well as G2/M arrest in DU145 and PC-3 cells. These results suggest that EIF3D plays an oncogenic role in PCa development and progression.
Collapse
Affiliation(s)
- Yi Gao
- Department of Urinary Surgery of Changzheng Hospital, Second Military Medical University, No.415, Fengyang Road, Shanghai, 200003, China
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Lin Z, Xiong L, Lin Q. Knockdown of eIF3d inhibits cell proliferation through G2/M phase arrest in non-small cell lung cancer. Med Oncol 2015; 32:183. [PMID: 26008152 DOI: 10.1007/s12032-015-0625-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Accepted: 04/21/2015] [Indexed: 12/15/2022]
Abstract
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and remains the leading cause of cancer-related death worldwide. Eukaryotic translation initiation factor 3, subunit d (eIF3d) has been recognized recently in several human cancers. In this paper, we attempt to evaluate the functional role of eIF3d in NSCLC cells. Lentivirus-mediated RNA interference (RNAi) was applied to silence eIF3d in the human NSCLC cell lines A549 and 95D. Cell viability was measured by MTT. Cell colony-forming ability was measured by colony formation. Cell cycle progression was determined by propidium iodide staining and flow cytometry. Intracellular signaling molecules were detected using a PathScan(®) intracellular signaling array kit. In this study, we firstly proved that lentivirus-mediated RNAi specifically suppressed the expression of eIF3d both at the mRNA and protein levels in A549 and 95D cell lines. Further investigations revealed that eIF3d knockdown significantly inhibited cell proliferation and colony formation. Moreover, the cell cycle of A549 cells was arrested at G2/M phase after eIF3d knockdown. Furthermore, the activations of AKT, HSP27 and SAPK/JNK were suppressed by eIF3d knockdown. This study highlights the crucial role of eIF3d in promoting NSCLC cell proliferation, and provides a foundation for further study into the clinical potential of lentiviral-mediated delivery of eIF3d RNAi therapy for treatment of NSCLC.
Collapse
Affiliation(s)
- Zhifeng Lin
- Department of Thoracic Surgery, Shanghai First People's Hospital, Shanghai Jiaotong University, No. 100 HaiNing Road, Shanghai, 200080, China
| | | | | |
Collapse
|
|
41
|
Li XW, Hu CP, Li YJ, Gao YX, Wang XM, Yang JR. Inhibitory effect of l-mimosine on bleomycin-induced pulmonary fibrosis in rats: Role of eIF3a and p27. Int Immunopharmacol 2015; 27:53-64. [PMID: 25957199 DOI: 10.1016/j.intimp.2015.04.048] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2014] [Revised: 04/08/2015] [Accepted: 04/24/2015] [Indexed: 10/23/2022]
Abstract
It has also been shown that the decreased expression of eukaryotic translation initiation factor 3a (eIF3a) by L-mimosine caused cell cycle arrest. Our previous study has found that eIF3a is involved in bleomycin-induced pulmonary fibrosis. Whether the eIF3a/p27 signal pathway is involved in the inhibitory effect of L-mimosine on bleomycin-induced pulmonary fibrosis remains unknown. Pulmonary fibrosis was induced by intratracheal instillation of bleomycin (5 mg/kg) in rats. Primary pulmonary fibroblasts were cultured to investigate the proliferation by BrdU incorporation method and flow cytometry. The expression of eIF3a, p27, α-SMA, collagen I and collagen III was analyzed by qPCR and Western blot. In vivo, L-mimosine treatment significantly ameliorated the bleomycin-mediated histological fibrosis alterations and blocked collagen deposition concomitantly with reversing bleomycin-induced expression up-regulation of eIF3a, α-SMA, collagen I and collagen III (both mRNA and protein) and expression down- regulation of p27. In vitro, L-mimosine remarkably attenuated proliferation of pulmonary fibroblasts and expression of α-SMA, collagen I and collagen III induced by TGF-β1, and this inhibitory effect of L-mimosine was accompanied by inhibiting eIF3a expression and increasing p27 expression. Knockdown of eIF3a gene expression reversed TGF-β1-induced proliferation of fibroblasts, down-regulation of p27 expression and up-regulation of α-SMA, collagen I, and collagen III expression. These results suggest that L-mimosine inhibited the progression of bleomycin-induced pulmonary fibrosis in rats via the eIF3a/p27 pathway.
Collapse
Affiliation(s)
- Xian-Wei Li
- Department of Pharmacology, Wannan Medical College, Wuhu 241002, Anhui, China
| | - Chang-Ping Hu
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078 China.
| | - Yuan-Jian Li
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078 China
| | - Yuan-Xing Gao
- Department of Immunology, Wannan Medical College, Wuhu 241002, China
| | - Xiang-Ming Wang
- Department of Pathology, Wannan Medical College, Wuhu 241002, China
| | - Jie-Ren Yang
- Department of Pharmacology, Wannan Medical College, Wuhu 241002, Anhui, China
| |
Collapse
|
|
42
|
Wang J, Betancourt A, Jenkins S, Biro F, Pinney SM, Chen D, Russo J, Lamartiniere CA. Altered blood proteome in girls with high urine concentrations of bisphenol a, genistein, mono-ethyl hexylphthalate and mono-benzyl phthalate. ACTA ACUST UNITED AC 2015; 2:44-57. [PMID: 31360934 DOI: 10.15406/mojpb.2015.02.00040] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Children exposed to endocrine disruptors are hypothesized to be susceptible for cancer development later in life. Identifying functional biomarkers of specific exposures may indicate predisposition for this disease. The objectives of this study were to identify protein biomarkers of 1) effect and 2) susceptibility for cancer from the blood of girls exposed to select environmental chemicals. In prepubertal girls, urine concentrations of bisphenol A (BPA), genistein, mono-ethyl hexylphthalate (MEHP) and mono-benzyl phthalate (MBzP) were used to identify girls in the top quintile of exposure for each of these environmental chemicals, and age-matched prepubertal girls with urine analyte concentrations below the median. Blood samples of these girls were depleted of the seven most abundant proteins using human-specific affinity spin columns. Using isobaric Tandem Mass Tags and quantitative mass spectrometry (TMT-MS), 51, 34, 57 and 47 differentially expressed proteins were identified from the blood of prepubertal girls with high urine concentrations of BPA, genistein, MEHP and MBzP, respectively, compared to controls. The data demonstrates the potential of proteomic technology to not only provide biomarkers of effect from aminimally invasive source of biological material, blood, but to identify protein molecules that are intimately involved in the pathobiology of cancer. The differentially regulated cancer associated proteins in girls with high concentrations of BPA and genistein are consistent with reported roles of BPA in carcinogenesis and of genistein in mammary cancer prevention, respectively.
Collapse
Affiliation(s)
- Jun Wang
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham, USA
| | - Angela Betancourt
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham, USA
| | - Sarah Jenkins
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham, USA
| | - Frank Biro
- Division of Adolescent Medicine, Children's Hospital Medical Center, USA
| | - Susan M Pinney
- Department of Environmental Health, University of Cincinnati College of Medicine, USA
| | - Dongquan Chen
- Division of Preventive Medicine, UAB.,UAB Comprehensive Cancer Center, University of Alabama at Birmingham, USA
| | - Jose Russo
- The Irma Russo Breast Cancer Research Laboratory, Fox Chase Cancer Center-Temple University Health System, USA
| | - Coral A Lamartiniere
- Department of Pharmacology and Toxicology, University of Alabama at Birmingham, USA.,UAB Comprehensive Cancer Center, University of Alabama at Birmingham, USA
| |
Collapse
|
|
43
|
Li XW, Wu YH, Li XH, Li D, Du J, Hu CP, Li YJ. Role of eukaryotic translation initiation factor 3a in bleomycin-induced pulmonary fibrosis. Eur J Pharmacol 2015; 749:89-97. [PMID: 25592322 DOI: 10.1016/j.ejphar.2015.01.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Revised: 01/04/2015] [Accepted: 01/06/2015] [Indexed: 11/25/2022]
Abstract
Eukaryotic translation initiation factor 3a (eIF3a) is a multifunctional protein and plays an important role in regulation of cellular function including proliferation and differentiation. In the present study, we tested the function of eIF3a in pulmonary fibrosis. Pulmonary fibrosis was induced by intratracheal instillation of bleomycin (5mg/kg) in rats. Primary pulmonary fibroblasts were cultured for proliferation investigation by BrdU incorporation method and flow cytometry. The expression/level of eIF3a, TGF-β1, ERK1/2 and α-SMA were analyzed by ELISA, real-time PCR or western blot. Results showed that the expression of eIF3a was obviously increased in lungs of pulmonary fibrosis rats accompanied by up-regulation of α-SMA and collagens. In cultured pulmonary fibroblasts, application of exogenous TGF-β1 induced cell proliferation and differentiation concomitantly with up-regulation of eIF3a expression and ERK1/2 phosphorylation. The effects of TGF-β1-induced proliferation of fibroblasts and up-regulation of α-SMA were abolished by eIF3a siRNA. TGF-β1-induced eIF3a expression was reversed in the presence of PD98059, an inhibitor of ERK1/2. These findings suggest that eIF3a plays an important role in bleomycin-induced pulmonary fibrosis by regulating pulmonary fibroblasts׳ function, and up-regulation of eIF3a induced by TGF-β1 is mediated via the ERK1/2 pathway.
Collapse
Affiliation(s)
- Xian-Wei Li
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China; Department of Pharmacology, Wannan Medical College, Wuhu 241002, China
| | - Yue-Han Wu
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
| | - Xiao-Hui Li
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
| | - Dai Li
- National Institution of Drug Clinical Trial, Xiangya Hospital, Central South University, Changsha 410078, China
| | - Jie Du
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
| | - Chang-Ping Hu
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
| | - Yuan-Jian Li
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China.
| |
Collapse
|
|
44
|
Hershey JWB. The role of eIF3 and its individual subunits in cancer. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2014; 1849:792-800. [PMID: 25450521 DOI: 10.1016/j.bbagrm.2014.10.005] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Revised: 10/28/2014] [Accepted: 10/28/2014] [Indexed: 12/15/2022]
Abstract
Specific individual subunits of eIF3 are elevated or reduced in numerous human tumors, and their ectopic overexpression in immortal cells can result in malignant transformation. The structure and assembly of eIF3 and its role in promoting mRNA and methionyl-tRNAi binding to the ribosome during the initiation phase of protein synthesis are described. Methods employed to detect altered levels of eIF3 subunits in cancers are critically evaluated in order to conclude rigorously that such subunits may cause malignant transformation. Strong evidence is presented that the individual overexpression of eIF3 subunits 3a, 3b, 3c, 3h, 3i and 3m may cause malignant transformation, whereas underexpression of subunits 3e and 3f may cause a similar outcome. Possible mechanisms to explain the malignant phenotypes are examined. The involvement of eIF3 in cancer reinforces the view that translational control plays an important role in the regulation of cell proliferation, and provides new targets for the development of therapeutic agents. This article is part of a Special Issue entitled: Translation and Cancer.
Collapse
Affiliation(s)
- John W B Hershey
- Department of Biochemistry and Molecular Medicine, University of California, Davis, CA 95616, United States.
| |
Collapse
|
|
45
|
Qi J, Dong Z, Liu J, Zhang JT. EIF3i promotes colon oncogenesis by regulating COX-2 protein synthesis and β-catenin activation. Oncogene 2014; 33:4156-63. [PMID: 24056964 PMCID: PMC3962800 DOI: 10.1038/onc.2013.397] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Revised: 08/02/2013] [Accepted: 08/05/2013] [Indexed: 12/21/2022]
Abstract
Translational control of gene expression has recently been recognized as an important mechanism controlling cell proliferation and oncogenesis, and it mainly occurs in the initiation step of protein synthesis that involves multiple eukaryotic initiation factors (eIFs). Many eIFs have been found to have aberrant expression in human tumors and the aberrant expression may contribute to oncogenesis. However, how these previously considered house-keeping proteins are potentially oncogenic remains elusive. In this study, we investigated the expression of eIF3i in human colon cancers, tested its contribution to colon oncogenesis and determined the mechanism of eIF3i action in colon oncogenesis. We found that eIF3i expression was upregulated in both human colon adenocarcinoma and adenoma polyps as well as in model inducible colon tumorigenic cell lines. Overexpression of ectopic eIF3i in intestinal epithelial cells causes oncogenesis by directly upregulating the synthesis of cyclooxygenase-2 (COX-2) protein and activates the β-catenin/T-cell factor 4 signaling pathway that mediates the oncogenic function of eIF3i. Together, we conclude that eIF3i is a proto-oncogene that drives colon oncogenesis by translationally upregulating COX-2 and activating the β-catenin signaling pathway. These findings imply that proto-oncogenic eIFs likely exert their tumorigenic function by regulating/altering the synthesis level of downstream tumor suppressor or oncogenes.
Collapse
Affiliation(s)
- J Qi
- Department of Pharmacology and Toxicology and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Z Dong
- Department of Pharmacology and Toxicology and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
| | - J Liu
- Department of Pharmacology and Toxicology and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
| | - J-T Zhang
- Department of Pharmacology and Toxicology and IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
| |
Collapse
|
|
46
|
Wagner S, Herrmannová A, Malík R, Peclinovská L, Valášek LS. Functional and biochemical characterization of human eukaryotic translation initiation factor 3 in living cells. Mol Cell Biol 2014; 34:3041-52. [PMID: 24912683 PMCID: PMC4135593 DOI: 10.1128/mcb.00663-14] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Accepted: 06/04/2014] [Indexed: 11/20/2022] Open
Abstract
The main role of the translation initiation factor 3 (eIF3) is to orchestrate formation of 43S-48S preinitiation complexes (PICs). Until now, most of our knowledge on eIF3 functional contribution to regulation of gene expression comes from yeast studies. Hence, here we developed several novel in vivo assays to monitor the integrity of the 13-subunit human eIF3 complex, defects in assembly of 43S PICs, efficiency of mRNA recruitment, and postassembly events such as AUG recognition. We knocked down expression of the PCI domain-containing eIF3c and eIF3a subunits and of eIF3j in human HeLa and HEK293 cells and analyzed the functional consequences. Whereas eIF3j downregulation had barely any effect and eIF3a knockdown disintegrated the entire eIF3 complex, eIF3c knockdown produced a separate assembly of the a, b, g, and i subunits (closely resembling the yeast evolutionary conserved eIF3 core), which preserved relatively high 40S binding affinity and an ability to promote mRNA recruitment to 40S subunits and displayed defects in AUG recognition. Both eIF3c and eIF3a knockdowns also severely reduced protein but not mRNA levels of many other eIF3 subunits and indeed shut off translation. We propose that eIF3a and eIF3c control abundance and assembly of the entire eIF3 and thus represent its crucial scaffolding elements critically required for formation of PICs.
Collapse
Affiliation(s)
- Susan Wagner
- Laboratory of Regulation of Gene Expression, Institute of Microbiology ASCR, Videnska, Prague, Czech Republic
| | - Anna Herrmannová
- Laboratory of Regulation of Gene Expression, Institute of Microbiology ASCR, Videnska, Prague, Czech Republic
| | - Radek Malík
- Laboratory of Epigenetic Regulations, Institute of Molecular Genetics ASCR, Videnska, Prague, Czech Republic
| | - Lucie Peclinovská
- Laboratory of Regulation of Gene Expression, Institute of Microbiology ASCR, Videnska, Prague, Czech Republic
| | - Leoš Shivaya Valášek
- Laboratory of Regulation of Gene Expression, Institute of Microbiology ASCR, Videnska, Prague, Czech Republic
| |
Collapse
|
|
47
|
Shen J, Yin JY, Li XP, Liu ZQ, Wang Y, Chen J, Qu J, Xu XJ, McLeod HL, He YJ, Xia K, Jia YW, Zhou HH. The prognostic value of altered eIF3a and its association with p27 in non-small cell lung cancers. PLoS One 2014; 9:e96008. [PMID: 24789280 PMCID: PMC4005749 DOI: 10.1371/journal.pone.0096008] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Accepted: 04/01/2014] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Over-expressed eukaryotic initiation factor 3a (eIF3a) in non-small cell lung cancer (NSCLC) contributed to cisplatin sensitivity. However, the role of eIF3a in oncogenesis was still controversial. This study was designed to investigate the prognostic impact of eIF3a and p27 in radically resected NSCLC patients. METHODS The expression levels of subcellular eIF3a and p27 were evaluated immunohistochemically in 537 radically resected NSCLC samples, and another cohort of 210 stage II NSCLC patients. Disease specific survival (DSS) and disease free survival (DFS) were analyzed by Kaplan-Meier method and Cox regression model. RESULTS The subcellular expression of eIF3a was strongly correlated with status of p27 (Spearman rank coefficient correlation for cytoplasmic eIF3a and p27=0.653, for nuclear staining=0.716). Moreover, survival analysis revealed favorable prognostic impact of nuclear eIF3a, p27, and the combination high nuclear staining on NSCLC (Hazards Ratio=0.360, 95%CI=0.109-0.782, P=0.028). In addition, interaction research between biomarkers and chemotherapy status disclosed cisplatin-based regimen trend to prolong DSS of stage II NSCLC patients with high eIF3a-C (P=0.036)and low p27-N (P=0.031). CONCLUSIONS Our findings suggested altered eIF3a expression closely correlated with p27 status, and the association was of prognostic value for resected NSCLC. Altered expression of eIF3a and p27 predicted prognosis of NSCLC independently.
Collapse
Affiliation(s)
- Jie Shen
- Institute of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan 8, P. R. China
- Department of Clinical Pharmacy, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, P. R. China
| | - Ji-Ye Yin
- Institute of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan 8, P. R. China
| | - Xiang-Ping Li
- Institute of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan 8, P. R. China
| | - Zhao-Qian Liu
- Institute of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan 8, P. R. China
- * E-mail:
| | - Ying Wang
- Institute of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan 8, P. R. China
| | - Juan Chen
- Institute of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan 8, P. R. China
| | - Jian Qu
- Institute of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan 8, P. R. China
| | - Xiao-Jing Xu
- Institute of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan 8, P. R. China
| | - Howard Lewis McLeod
- Personalized Medicine Institute, Moffitt Cancer Center, Tampa, Florida, United States of America
| | - Yi-Jing He
- Institute of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan 8, P. R. China
| | - Kun Xia
- State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, P. R. China
| | - Yuan-Wei Jia
- Department of Clinical Pharmacy, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, P. R. China
| | - Hong-Hao Zhou
- Institute of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, P. R. China
- Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan 8, P. R. China
| |
Collapse
|
|
48
|
Akcakanat A, Hong DS, Meric-Bernstam F. Targeting translation initiation in breast cancer. ACTA ACUST UNITED AC 2014; 2:e28968. [PMID: 26779407 PMCID: PMC4705830 DOI: 10.4161/trla.28968] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Revised: 04/09/2014] [Accepted: 04/22/2014] [Indexed: 12/23/2022]
Abstract
Over the past 20 years, a better understanding of cancer biology, screening for early detection, improved adjuvant treatment, and targeted therapies have decreased the rate of breast cancer deaths. However, resistance to treatment is common, and new approaches are needed. Deregulation of translation initiation is associated with the commencement and progression of cancer. Often, translation initiation factors are overexpressed and the related signaling pathways activated in human tumors. Recently, a significant number of inhibitors that target translation factors and pathways have become available. These inhibitors are being tested alone or in combination with chemotherapeutic agents in clinical trials. The results are varied, and it is not yet clear which drug treatments most effectively inhibit tumor growth. This review highlights the pathways and downstream effects of the activation of translation and discusses targeting the control of translation initiation as a therapeutic approach in cancer, focusing on breast cancer clinical trials.
Collapse
Affiliation(s)
- Argun Akcakanat
- Department of Investigational Cancer Therapeutics; Houston, TX USA
| | - David S Hong
- Department of Investigational Cancer Therapeutics; Houston, TX USA
| | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics; Houston, TX USA; Department of Surgical Oncology; The University of Texas MD Anderson Cancer Center; Houston, TX USA
| |
Collapse
|
|
49
|
Lian M, Fang J, Han D, Ma H, Feng L, Wang R, Yang F. Microarray gene expression analysis of tumorigenesis and regional lymph node metastasis in laryngeal squamous cell carcinoma. PLoS One 2013; 8:e84854. [PMID: 24386425 PMCID: PMC3873425 DOI: 10.1371/journal.pone.0084854] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2013] [Accepted: 11/19/2013] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Laryngeal squamous cell carcinoma (LSCC) is the most common type in head and neck squamous cell carcinoma (HNSCC), and the development and progression of LSCC are multistep processes accompanied by changes of molecular biology. OBJECTIVE The purpose of this study was to investigate the molecular basis of tumorigenesis and regional lymph node metastasis in LSCC, and provide a set of genes that may be useful for the development of novel diagnostic markers and/or more effective therapeutic strategies. METHODS A total number of 10 patients who underwent surgery for primary laryngeal squamous cell carcinoma were recruited for microarray analysis. LSCC tissues compared with corresponding adjacent non-neoplastic tissues were analysed by Illumina mRNA microarrays, and LSCC tissues with regional lymph node metastasis and LSCC tissues without regional lymph node metastasis were analyzed in the same manner. The most frequently differently expressed genes screened by microarrays were also validated by qRT-PCR in another 42 patients diagnosed for LSCC. RESULTS Analysed by Illumina mRNA microarrays, there were 361 genes significantly related to tumorigenesis while 246 genes significantly related to regional lymph node metastasis in LSCC. We found that the six genes (CDK1, CDK2, CDK4, MCM2, MCM3, MCM4) were most frequently differently expressed functional genes related to tumorigenesis while eIF3a and RPN2 were most frequently differently expressed functional genes related to regional lymph node metastasis in LSCC. The expressions of these genes were also validated by qRT-PCR. CONCLUSIONS The research revealed a gene expression signature of tumorigenesis and regional lymph node metastasis in laryngeal squamous cell carcinoma. Of the total, the deregulation of several genes (CDK1, CDK2, CDK4, MCM2, MCM3, MCM4, EIF3a and RPN2) were potentially associated with disease development and progression. The result will contribute to the understanding of the molecular basis of LSCC and help to improve diagnosis and treatment.
Collapse
Affiliation(s)
- Meng Lian
- Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Jugao Fang
- Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
- * E-mail: (JF); (DH)
| | - Demin Han
- Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
- Key Laboratory of Otorhinolaryngology Head and Neck Surgery, Ministry of Education, Beijing Institute of Otorhinolaryngology, Beijing, China
- * E-mail: (JF); (DH)
| | - Hongzhi Ma
- Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Ling Feng
- Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Ru Wang
- Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Fan Yang
- Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| |
Collapse
|
|
50
|
Zhu W, Shen J, Li Q, Pei Q, Chen J, Chen Z, Liu Z, Hu G. Synthesis, pharmacophores, and mechanism study of pyridin-2(1H)-one derivatives as regulators of translation initiation factor 3A. Arch Pharm (Weinheim) 2013; 346:654-66. [PMID: 23959654 DOI: 10.1002/ardp.201300138] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2013] [Revised: 06/19/2013] [Accepted: 06/28/2013] [Indexed: 11/07/2022]
Abstract
Twenty-seven 1,5-disubstituted-pyridin-2(1H)-one derivatives were synthesized and evaluated for their anti-cancer and anti-fibrosis activity by A549 and NIH3T3 cell viability assays, respectively. To study the selectivity between the cancer and fibrosis cell lines, pharmacophore models (F1-F4) were built in advance for compounds with pyridin-2(1H)-one scaffold, which revealed the relationship between the occupation of the aromatic sub-site F4 and potent anti-cancer activity. The relationship between structure and anti-cancer activity for all target compounds is also reported herein: 1-Phenyl-5-((m-tolylamino)methyl)pyridine-2(1H)-one (22) displayed both potency and selectivity (IC50=0.13 mM) toward the A549 cell line through the inhibition of translation initiation, especially by eIF3a suppression, and can be treated as a lead for the design of novel eIF3a regulators and anti-lung cancer agents.
Collapse
Affiliation(s)
- Weixing Zhu
- Chemistry Section, Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
| | | | | | | | | | | | | | | |
Collapse
|