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Li Z, Zheng C, Liu H, Lv J, Wang Y, Zhang K, Kong S, Chen F, Kong Y, Yang X, Cheng Y, Yang Z, Zhang C, Tian Y. A novel oxidative stress-related gene signature as an indicator of prognosis and immunotherapy responses in HNSCC. Aging (Albany NY) 2023; 15:14957-14984. [PMID: 38157249 PMCID: PMC10781479 DOI: 10.18632/aging.205323] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 11/02/2023] [Indexed: 01/03/2024]
Abstract
PURPOSE To identify molecular subtypes of oxidative stress-related genes in head and neck squamous cell carcinoma (HNSCC) and to construct a scoring model of oxidative stress-related genes. METHODS R language based scRNA-seq and bulk RNA-seq analyses were used to identify molecular isoforms of oxidative stress-related genes in HNSCC. An oxidative stress-related gene scoring (OSRS) model was constructed, which were verified through online data and immunohistochemical staining of clinical samples. RESULTS Using TCGA-HNSCC datasets, nine predictive genes for overall patient survival, rarely reported in previous similar studies, were screened. AREG and CES1 were identified as prognostic risk factors. CSTA, FDCSP, JCHAIN, IFFO2, PGLYRP4, SPOCK2 and SPINK6 were identified as prognostic factors. Collectively, all genes formed a prognostic risk signature model for oxidative stress in HNSCC, which were validated in GSE41613, GSE103322 and PRJEB23709 datasets. Immunohistochemical staining of SPINK6 in nasopharyngeal cancer samples validated the gene panel. Subsequent analysis indicated that subgroups of the oxidative stress prognostic signature played important roles during cellular communication, the immune microenvironment, the differential activation of transcription factors, oxidative stress and immunotherapeutic responses. CONCLUSIONS The risk model might predict HNSCC prognosis and immunotherapeutic responses.
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Affiliation(s)
- Zhuoqi Li
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong 250299, P.R. China
- Radiotherapy Department, Shandong Second Provincial General Hospital, Shandong University, Jinan, Shandong 250299, P.R. China
| | - Chunning Zheng
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China
| | - Hongtao Liu
- Department of Pathology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Clinical Pathology, Shandong Lung Cancer Institute, Shandong Institute of Nephrology, Jinan, Shandong 250014, P.R. China
| | - Jiling Lv
- Department of Respiratory and Critical Care Medicine, Shandong Second Provincial General Hospital, Jinan, Shandong 250299, P.R. China
| | - Yuanyuan Wang
- Department of Oncology, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250299, P.R. China
| | - Kai Zhang
- Generalsurgery Department, Wenshang County People’s Hospital, Wenshang, Shandong 272500, P.R. China
| | - Shuai Kong
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China
| | - Feng Chen
- Department of Thoracic Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China
| | - Yongmei Kong
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong 250299, P.R. China
- Radiotherapy Department, Shandong Second Provincial General Hospital, Shandong University, Jinan, Shandong 250299, P.R. China
| | - Xiaowei Yang
- Department of Hepatobiliary Intervention, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, P.R. China
| | - Yuxia Cheng
- Department of Pathology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Clinical Pathology, Shandong Lung Cancer Institute, Shandong Institute of Nephrology, Jinan, Shandong 250014, P.R. China
| | - Zhensong Yang
- Department of Gastrointestinal Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong 264000, P.R. China
| | - Chi Zhang
- Department of Cardiology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, P.R. China
| | - Yuan Tian
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Shandong University, Jinan, Shandong 250299, P.R. China
- Radiotherapy Department, Shandong Second Provincial General Hospital, Shandong University, Jinan, Shandong 250299, P.R. China
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Cole AJ, Panesso-Gómez S, Shah JS, Ebai T, Jiang Q, Gumusoglu-Acar E, Bello MG, Vlad A, Modugno F, Edwards RP, Buckanovich RJ. Quiescent Ovarian Cancer Cells Secrete Follistatin to Induce Chemotherapy Resistance in Surrounding Cells in Response to Chemotherapy. Clin Cancer Res 2023; 29:1969-1983. [PMID: 36795892 PMCID: PMC10192102 DOI: 10.1158/1078-0432.ccr-22-2254] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 12/22/2022] [Accepted: 02/14/2023] [Indexed: 02/18/2023]
Abstract
PURPOSE We recently reported that the transcription factor NFATC4, in response to chemotherapy, drives cellular quiescence to increase ovarian cancer chemoresistance. The goal of this work was to better understand the mechanisms of NFATC4-driven ovarian cancer chemoresistance. EXPERIMENTAL DESIGN We used RNA sequencing to identify NFATC4-mediated differential gene expression. CRISPR-Cas9 and FST (follistatin)-neutralizing antibodies were used to assess impact of loss of FST function on cell proliferation and chemoresistance. ELISA was used to quantify FST induction in patient samples and in vitro in response to chemotherapy. RESULTS We found that NFATC4 upregulates FST mRNA and protein expression predominantly in quiescent cells and FST is further upregulated following chemotherapy treatment. FST acts in at least a paracrine manner to induce a p-ATF2-dependent quiescent phenotype and chemoresistance in non-quiescent cells. Consistent with this, CRISPR knockout (KO) of FST in ovarian cancer cells or antibody-mediated neutralization of FST sensitizes ovarian cancer cells to chemotherapy treatment. Similarly, CRISPR KO of FST in tumors increased chemotherapy-mediated tumor eradication in an otherwise chemotherapy-resistant tumor model. Suggesting a role for FST in chemoresistance in patients, FST protein in the abdominal fluid of patients with ovarian cancer significantly increases within 24 hours of chemotherapy exposure. FST levels decline to baseline levels in patients no longer receiving chemotherapy with no evidence of disease. Furthermore, elevated FST expression in patient tumors is correlated with poor progression-free, post-progression-free, and overall survival. CONCLUSIONS FST is a novel therapeutic target to improve ovarian cancer response to chemotherapy and potentially reduce recurrence rates.
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Affiliation(s)
- Alexander J. Cole
- Department of Internal Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Santiago Panesso-Gómez
- Department of Internal Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jaynish S. Shah
- Australian Centre for Blood Diseases, Central Clinical School, Monash University and Alfred Health, Melbourne, VIC, Australia
| | - Tonge Ebai
- Department of Internal Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Qi Jiang
- Department of Internal Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA
- School of Medicine, Tsinghua University, Beijing, China
| | - Ece Gumusoglu-Acar
- Department of Internal Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Maya G. Bello
- Department of Internal Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Anda Vlad
- Department of Internal Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Francesmary Modugno
- Department of Internal Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Robert P. Edwards
- Department of Internal Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Ronald J. Buckanovich
- Department of Internal Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA
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ATF2 loss promotes tumor invasion in colorectal cancer cells via upregulation of cancer driver TROP2. Cell Mol Life Sci 2022; 79:423. [PMID: 35838828 PMCID: PMC9287261 DOI: 10.1007/s00018-022-04445-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 06/21/2022] [Accepted: 06/23/2022] [Indexed: 12/24/2022]
Abstract
In cancer, the activating transcription factor 2 (ATF2) has pleiotropic functions in cellular responses to growth stimuli, damage, or inflammation. Due to only limited studies, the significance of ATF2 in colorectal cancer (CRC) is not well understood. We report that low ATF2 levels correlated with worse prognosis and tumor aggressiveness in CRC patients. NanoString gene expression and ChIP analysis confirmed trophoblast cell surface antigen 2 (TROP2) as a novel inhibitory ATF2 target gene. This inverse correlation was further observed in primary human tumor tissues. Immunostainings revealed that high intratumoral heterogeneity for ATF2 and TROP2 expression was sustained also in liver metastasis. Mechanistically, our in vitro data of CRISPR/Cas9-generated ATF2 knockout (KO) clones revealed that high TROP2 levels were critical for cell de-adhesion and increased cell migration without triggering EMT. TROP2 was enriched in filopodia and displaced Paxillin from adherens junctions. In vivo imaging, micro-computer tomography, and immunostainings verified that an ATF2KO/TROP2high status triggered tumor invasiveness in in vivo mouse and chicken xenograft models. In silico analysis provided direct support that ATF2low/TROP2high expression status defined high-risk CRC patients. Finally, our data demonstrate that ATF2 acts as a tumor suppressor by inhibiting the cancer driver TROP2. Therapeutic TROP2 targeting might prevent particularly the first steps in metastasis, i.e., the de-adhesion and invasion of colon cancer cells.
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Karatas OF, Capik O, Barlak N, Aydin Karatas E. Comprehensive in silico analysis for identification of novel candidate target genes, including DHX36, OPA1, and SENP2, located on chromosome 3q in head and neck cancers. Head Neck 2020; 43:288-302. [PMID: 33006201 DOI: 10.1002/hed.26493] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 08/27/2020] [Accepted: 09/21/2020] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND Major milestones of head and neck carcinogenesis have been associated with various genetic abnormalities; however, a clear picture of the molecular networks deregulated during the carcinogenesis of head and neck squamous cell carcinoma (HNSC) has not yet completely revealed. METHODS In this study, we used in silico tools and online data sets to evaluate the underlying reasons for the expressional changes of genes residing within the chromosome 3q and to help understanding their contributions to HNSC carcinogenesis. RESULTS We found that 13 of 20 most upregulated genes in HNSC are localized to 3q. Further analysis revealed a gene signature consisting of DHX36, OPA1, and SENP2, which showed significant correlation in HNSC samples and potentially be deregulated through similar mechanisms including DNA amplification, transcriptional, and posttranscriptional regulation. CONCLUSIONS Considering our findings, we suggest DHX36, OPA1, and SENP2 genes as overexpressed in HNSC tumors and that might be concurrently involved in HNSC carcinogenesis, tumor progression, and induction of angiogenic pathways.
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Affiliation(s)
- Omer Faruk Karatas
- Molecular Biology and Genetics Department, Erzurum Technical University, Erzurum, Turkey.,Molecular Cancer Biology Laboratory, High Technology Application and Research Center, Erzurum Technical University, Erzurum, Turkey
| | - Ozel Capik
- Molecular Biology and Genetics Department, Erzurum Technical University, Erzurum, Turkey.,Molecular Cancer Biology Laboratory, High Technology Application and Research Center, Erzurum Technical University, Erzurum, Turkey
| | - Neslisah Barlak
- Molecular Biology and Genetics Department, Erzurum Technical University, Erzurum, Turkey.,Molecular Cancer Biology Laboratory, High Technology Application and Research Center, Erzurum Technical University, Erzurum, Turkey
| | - Elanur Aydin Karatas
- Molecular Biology and Genetics Department, Erzurum Technical University, Erzurum, Turkey.,Molecular Cancer Biology Laboratory, High Technology Application and Research Center, Erzurum Technical University, Erzurum, Turkey
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Yang Q, Sun Z, Zhou Y, Tran NT, Zhang X, Lin Q, Zhou C, Zhang Y, Li S. SpATF2 participates in maintaining the homeostasis of hemolymph microbiota by regulating dual oxidase expression in mud crab. FISH & SHELLFISH IMMUNOLOGY 2020; 104:252-261. [PMID: 32497727 DOI: 10.1016/j.fsi.2020.05.049] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Revised: 05/17/2020] [Accepted: 05/19/2020] [Indexed: 06/11/2023]
Abstract
Activating transcription factors 2 (ATF2) is a transcription factor of the members of ATF/CREB family that is phosphorylated and activated by the mitogen-activated protein kinase (MAPK) in responding to the stimulation of stimuli. In present study, SpATF2 from mud crab (Scylla paramamosain) was identified and studied. The open reading frame of SpATF2 with 2136 bp in length encodes a protein with 711 amino acids. The SpATF2 protein includes the putative zinc finger domain in the N-terminus and bZIP type DNA-binding domain in the C-terminal. Tissue distribution of SpATF2 transcripts showed that SpATF2 was ubiquitously expressed in all examined tissues of the untreated mud crabs, with the highest expression levels in muscle and hepatopancreas. The transcriptional level of SpATF2 was up-regulated in the hemocytes after Vibrio parahemolyticus or WSSV infection. Reporter gene assays indicated that SpATF2 could activate the expression of dual oxidase (SpDuox1) in S. paramamosain. The RNA interference (RNAi) of SpATF2 significantly decreased the expression of SpDuox1, and consequently reduced reactive oxygen species production thereby significantly increased the bacterial load in the hemolymph of mud crabs. Similarly, significant reduction in bacterial clearance of hemolymph was observed after the V. parahemolyticus infection in SpATF2 knockdown mud crabs. This study showed that SpATF2 played a vital role in maintaining homeostasis of the hemolymph microbiota through regulating the expression of dual oxidase of mud crab.
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Affiliation(s)
- Qiuhua Yang
- Institute of Marine Sciences, Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, 515063, China; Key Laboratory of Cultivation and High-value Utilization of Marine Organisms, Fisheries Research Institute of Fujian, Xiamen, 361021, China
| | - Zaiqiao Sun
- Institute of Marine Sciences, Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, 515063, China
| | - Yanlian Zhou
- Institute of Marine Sciences, Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, 515063, China
| | - Ngoc Tuan Tran
- Institute of Marine Sciences, Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou, 515063, China
| | - Xusheng Zhang
- Institute of Marine Sciences, Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, 515063, China
| | - Qi Lin
- Key Laboratory of Cultivation and High-value Utilization of Marine Organisms, Fisheries Research Institute of Fujian, Xiamen, 361021, China
| | - Chen Zhou
- Key Laboratory of Cultivation and High-value Utilization of Marine Organisms, Fisheries Research Institute of Fujian, Xiamen, 361021, China
| | - Yueling Zhang
- Institute of Marine Sciences, Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou, 515063, China
| | - Shengkang Li
- Institute of Marine Sciences, Guangdong Provincial Key Laboratory of Marine Biotechnology, Shantou University, Shantou, 515063, China; STU-UMT Joint Shellfish Research Laboratory, Shantou University, Shantou, 515063, China.
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Huebner K, Procházka J, Monteiro AC, Mahadevan V, Schneider-Stock R. The activating transcription factor 2: an influencer of cancer progression. Mutagenesis 2020; 34:375-389. [PMID: 31799611 PMCID: PMC6923166 DOI: 10.1093/mutage/gez041] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 11/18/2019] [Indexed: 12/26/2022] Open
Abstract
In contrast to the continuous increase in survival rates for many cancer entities, colorectal cancer (CRC) and pancreatic cancer are predicted to be ranked among the top 3 cancer-related deaths in the European Union by 2025. Especially, fighting metastasis still constitutes an obstacle to be overcome in CRC and pancreatic cancer. As described by Fearon and Vogelstein, the development of CRC is based on sequential mutations leading to the activation of proto-oncogenes and the inactivation of tumour suppressor genes. In pancreatic cancer, genetic alterations also attribute to tumour development and progression. Recent findings have identified new potentially important transcription factors in CRC, among those the activating transcription factor 2 (ATF2). ATF2 is a basic leucine zipper protein and is involved in physiological and developmental processes, as well as in tumorigenesis. The mutation burden of ATF2 in CRC and pancreatic cancer is rather negligible; however, previous studies in other tumours indicated that ATF2 expression level and subcellular localisation impact tumour progression and patient prognosis. In a tissue- and stimulus-dependent manner, ATF2 is activated by upstream kinases, dimerises and induces target gene expression. Dependent on its dimerisation partner, ATF2 homodimers or heterodimers bind to cAMP-response elements or activator protein 1 consensus motifs. Pioneering work has been performed in melanoma in which the dual role of ATF2 is best understood. Even though there is increasing interest in ATF2 recently, only little is known about its involvement in CRC and pancreatic cancer. In this review, we summarise the current understanding of the underestimated ‘cancer gene chameleon’ ATF2 in apoptosis, epithelial-to-mesenchymal transition and microRNA regulation and highlight its functions in CRC and pancreatic cancer. We further provide a novel ATF2 3D structure with key phosphorylation sites and an updated overview of all so-far available mouse models to study ATF2 in vivo.
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Affiliation(s)
- Kerstin Huebner
- Experimental Tumorpathology, Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Jan Procházka
- Czech Centre for Phenogenomics, Institute of Molecular Genetics of the ASCR, Prague, Czech Republic
| | - Ana C Monteiro
- Experimental Tumorpathology, Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Vijayalakshmi Mahadevan
- Institute of Bioinformatics and Applied Biotechnology, Biotech Park, Electronic City Phase I, Bangalore, India
| | - Regine Schneider-Stock
- Experimental Tumorpathology, Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
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Liu Y, Chang Y, Cai Y. circTNFRSF21, a newly identified circular RNA promotes endometrial carcinoma pathogenesis through regulating miR-1227-MAPK13/ATF2 axis. Aging (Albany NY) 2020; 12:6774-6792. [PMID: 32299063 PMCID: PMC7202486 DOI: 10.18632/aging.103037] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 02/20/2020] [Indexed: 12/22/2022]
Abstract
Background: Circular RNA is a type of non-coding RNA with great potential in regulating gene expression and associated with disease progression. However, the role of circular RNA in endometrial carcinoma (EC) remains largely unknown. Results: In this study, we found that circTNFRSF21 was highly expressed in EC cells and tumor tissues. In vitro and in vivo results showed that circTNFRSF21 was linked to increased EC cell growth and EC xenografts formation in nude mice. Mechanically, we showed that circTNFRSF21 acts as a sponge of miR-1227 in EC cells to rescue MAPK13/ATF2 signaling pathway activity. Conclusions: Our studies suggested that in the EC, circTNFRSF21 promotes EC formation through downregulating miR-1227 expression and activating MAPK13/ATF2 signaling pathway. These findings provide strong evidence that circTNFRSF21-miR-1227-MAPK13/ATF2 axis is a promising target for EC treatment. Methods: qRT-PCR was used to detect circTNFRSF21expression in EC patients and EC cell lines. Cell growth, cell colony formation, cell apoptosis, cell cycle progression, and in vivo tumor formation assays were used to evaluate the roles of circTNFRSF21 in EC. Western blot, luciferase assay, RNA pull-down, siRNA knockdown, and CRISPR gene knock out assays were applied to study the mechanisms through which circTNFRSF21 regulates EC formation.
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Affiliation(s)
- Yun Liu
- Department of Obstetrics and Gynecology, Beijing Friendship Hospital Affiliated to Capital Medical University, Beijing, China
| | - Yue Chang
- Department of Obstetrics and Gynecology, Beijing Friendship Hospital Affiliated to Capital Medical University, Beijing, China
| | - Yixuan Cai
- Department of Obstetrics and Gynecology, Beijing Friendship Hospital Affiliated to Capital Medical University, Beijing, China
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Inoue S, Mizushima T, Ide H, Jiang G, Goto T, Nagata Y, Netto GJ, Miyamoto H. ATF2 promotes urothelial cancer outgrowth via cooperation with androgen receptor signaling. Endocr Connect 2018; 7:1397-1408. [PMID: 30521479 PMCID: PMC6280600 DOI: 10.1530/ec-18-0364] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 11/09/2018] [Indexed: 11/09/2022]
Abstract
We investigated the functional role of ATF2, a transcription factor normally activated via its phosphorylation in response to phospho-ERK/MAPK signals, in the outgrowth of urothelial cancer. In both neoplastic and non-neoplastic urothelial cells, the expression levels of androgen receptor (AR) correlated with those of phospho-ATF2. Dihydrotestosterone treatment in AR-positive bladder cancer cells also induced the expression of phospho-ATF2 and phospho-ERK as well as nuclear translocation and transcriptional activity of ATF2. Meanwhile, ATF2 knockdown via shRNA resulted in significant decreases in cell viability, migration and invasion of AR-positive bladder cancer lines, but not AR-negative lines, as well as significant increases and decreases in apoptosis or G0/G1 cell cycle phase and S or G2/M phase, respectively. Additionally, the growth of AR-positive tumors expressing ATF2-shRNA in xenograft-bearing mice was retarded, compared with that of control tumors. ATF2 knockdown also resulted in significant inhibition of neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene, as well as the expression of Bcl-2/cyclin-A2/cyclin-D1/JUN/MMP-2, in immortalized human normal urothelial SVHUC cells stably expressing AR, but not AR-negative SVHUC cells. Finally, immunohistochemistry in surgical specimens demonstrated significant elevation of ATF2/phospho-ATF2/phospho-ERK expression in bladder tumors, compared with non-neoplastic urothelial tissues. Multivariate analysis further showed that moderate/strong ATF2 expression and phospho-ATF2 positivity were independent predictors for recurrence of low-grade tumors (hazard ratio (HR) = 2.956, P = 0.045) and cancer-specific mortality of muscle-invasive tumors (HR = 5.317, P = 0.012), respectively. Thus, ATF2 appears to be activated in urothelial cells through the AR pathway and promotes the development and progression of urothelial cancer.
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Affiliation(s)
- Satoshi Inoue
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Taichi Mizushima
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Hiroki Ide
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Guiyang Jiang
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
| | - Takuro Goto
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
| | - Yujiro Nagata
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
| | - George J Netto
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Hiroshi Miyamoto
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Urology, University of Rochester Medical Center, Rochester, New York, USA
- Correspondence should be addressed to H Miyamoto:
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9
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p38 Expression and Modulation of STAT3 Signaling in Oral Cancer. Pathol Oncol Res 2018; 26:183-192. [DOI: 10.1007/s12253-018-0405-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 03/07/2018] [Indexed: 12/19/2022]
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10
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Liu S, Wang F, Liu J, Jin P, Wang X, Yang L, Xi S. ATF2 partly mediated the expressions of proliferative factors and inhibited pro-inflammatory factors' secretion in arsenite-treated human uroepithelial cells. Toxicol Res (Camb) 2017; 6:468-476. [PMID: 30090515 PMCID: PMC6062379 DOI: 10.1039/c6tx00407e] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 03/28/2017] [Indexed: 11/21/2022] Open
Abstract
Inorganic arsenic (iAs) could induce the expression of activating transcription factor-2 (ATF2) in the human urinary bladder epithelial cell line (SV-HUC-1 cells). ATF2, as a member of the bZIP transcription factor family, has been implicated in a transcriptional response leading to cell growth, migration and malignant tumor progression. However, little is known about the effects of ATF2 on proliferative factors in iAs treated human urothelial cells. In this study, ATF2 siRNA was employed to investigate the relationship between ATF2 activation and the expressions of proliferative factors, such as BCL2, cyclin D1, COX-2, MMP1 and PCNA, and pro-inflammatory factors (TNFα, TGFα and IL-8) in SV-HUC-1 cells. The results showed that low concentration arsenite increased the expressions of proliferative factors BCL2, cyclin D1, COX-2, MMP1 and PCNA in SV-HUC-1 cells, and ATF2 siRNA partly decreased the expressions of BCL2, cyclin D1, and COX-2. A neutralizing antibody of IL-8 was used for attenuating the levels of IL-8 and neutralizing antibody of IL-8 did not relieve the expressions of ATF2 and proliferative factors induced by arsenite in SV-HUC-1 cells. In addition, ATF2 knockdown did not decrease the expressions of pro-inflammatory cytokines induced by arsenite in SV-HUC-1 cells, but dramatically increased mRNA expressions of TNFα, TGFα and IL-8 under arsenite and non-arsenite conditions. In conclusion, our present study indicated that ATF2, but not IL-8, played a partial role in the expressions of proliferative factors induced by arsenite in human uroepithelial cells.
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Affiliation(s)
- Shengnan Liu
- Department of Environmental and Occupational Health , School of Public Health , China Medical University , No. 77 Puhe Road , Shenyang North New Area , Shenyang , Liaoning Province 110122 , People's Republic of China .
| | - Fei Wang
- Department of Environmental and Occupational Health , School of Public Health , China Medical University , No. 77 Puhe Road , Shenyang North New Area , Shenyang , Liaoning Province 110122 , People's Republic of China .
| | - Jieyu Liu
- Department of Environmental and Occupational Health , School of Public Health , China Medical University , No. 77 Puhe Road , Shenyang North New Area , Shenyang , Liaoning Province 110122 , People's Republic of China .
| | - Peiyu Jin
- Department of Environmental and Occupational Health , School of Public Health , China Medical University , No. 77 Puhe Road , Shenyang North New Area , Shenyang , Liaoning Province 110122 , People's Republic of China .
| | - Xiaoyan Wang
- Department of Environmental and Occupational Health , School of Public Health , China Medical University , No. 77 Puhe Road , Shenyang North New Area , Shenyang , Liaoning Province 110122 , People's Republic of China .
| | - Li Yang
- Department of Environmental and Occupational Health , School of Public Health , China Medical University , No. 77 Puhe Road , Shenyang North New Area , Shenyang , Liaoning Province 110122 , People's Republic of China .
| | - Shuhua Xi
- Department of Environmental and Occupational Health , School of Public Health , China Medical University , No. 77 Puhe Road , Shenyang North New Area , Shenyang , Liaoning Province 110122 , People's Republic of China .
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Watson G, Ronai ZA, Lau E. ATF2, a paradigm of the multifaceted regulation of transcription factors in biology and disease. Pharmacol Res 2017; 119:347-357. [PMID: 28212892 PMCID: PMC5457671 DOI: 10.1016/j.phrs.2017.02.004] [Citation(s) in RCA: 93] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 02/01/2017] [Accepted: 02/02/2017] [Indexed: 01/16/2023]
Abstract
Stringent transcriptional regulation is crucial for normal cellular biology and organismal development. Perturbations in the proper regulation of transcription factors can result in numerous pathologies, including cancer. Thus, understanding how transcription factors are regulated and how they are dysregulated in disease states is key to the therapeutic targeting of these factors and/or the pathways that they regulate. Activating transcription factor 2 (ATF2) has been studied in a number of developmental and pathological conditions. Recent findings have shed light on the transcriptional, post-transcriptional, and post-translational regulatory mechanisms that influence ATF2 function, and thus, the transcriptional programs coordinated by ATF2. Given our current knowledge of its multiple levels of regulation and function, ATF2 represents a paradigm for the mechanistic complexity that can regulate transcription factor function. Thus, increasing our understanding of the regulation and function of ATF2 will provide insights into fundamental regulatory mechanisms that influence how cells integrate extracellular and intracellular signals into a genomic response through transcription factors. Characterization of ATF2 dysfunction in the context of pathological conditions, particularly in cancer biology and response to therapy, will be important in understanding how pathways controlled by ATF2 or other transcription factors might be therapeutically exploited. In this review, we provide an overview of the currently known upstream regulators and downstream targets of ATF2.
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Affiliation(s)
- Gregory Watson
- Department of Tumor Biology and Program in Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Ze'ev A Ronai
- Tumor Initiation and Maintenance Program, Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA; Technion Integrated Cancer Center, Rappaport Faculty of Medicine, Technion, Haifa, 3109601, Israel
| | - Eric Lau
- Department of Tumor Biology and Program in Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
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Li M, Wu X, Liu N, Li X, Meng F, Song S. Silencing of ATF2 inhibits growth of pancreatic cancer cells and enhances sensitivity to chemotherapy. Cell Biol Int 2017; 41:599-610. [PMID: 28318081 DOI: 10.1002/cbin.10760] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 03/04/2017] [Indexed: 01/03/2023]
Affiliation(s)
- Mu Li
- Department of General Surgery; Pancreatic Surgery; The First Affiliated Hospital of China Medical University; Shenyang 110001 People's Republic of China
| | - Xingda Wu
- Department of General Surgery; Pancreatic Surgery; The First Affiliated Hospital of China Medical University; Shenyang 110001 People's Republic of China
| | - Ning Liu
- Department of General Surgery; Pancreatic Surgery; The First Affiliated Hospital of China Medical University; Shenyang 110001 People's Republic of China
| | - Xiaoying Li
- Department of General Surgery; Pancreatic Surgery; The First Affiliated Hospital of China Medical University; Shenyang 110001 People's Republic of China
| | - Fanbin Meng
- Department of General Surgery; Pancreatic Surgery; The First Affiliated Hospital of China Medical University; Shenyang 110001 People's Republic of China
| | - Shaowei Song
- Department of General Surgery; Pancreatic Surgery; The First Affiliated Hospital of China Medical University; Shenyang 110001 People's Republic of China
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The role of Nrf2 and ATF2 in resistance to platinum-based chemotherapy. Cancer Chemother Pharmacol 2017; 79:369-380. [DOI: 10.1007/s00280-016-3225-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 12/12/2016] [Indexed: 10/20/2022]
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Mitochondrial ATF2 translocation contributes to apoptosis induction and BRAF inhibitor resistance in melanoma through the interaction of Bim with VDAC1. Oncotarget 2016; 6:36338-53. [PMID: 26462148 PMCID: PMC4742181 DOI: 10.18632/oncotarget.5537] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Accepted: 09/29/2015] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND The mitochondrial accumulation of ATF2 is involved in tumor suppressor activities via cytochrome c release in melanoma cells. However, the signaling pathways that connect mitochondrial ATF2 accumulation and cytochrome c release are not well documented. METHODS Several melanoma cell lines, B16F10, K1735M2, A375 and A375-R1, were treated with paclitaxel and vemurafenib to test the function of mitochondrial ATF2 and its connection to Bim and voltage-dependent anion channel 1 (VDAC1). Immunoprecipitation analysis was performed to investigate the functional interaction between the involved proteins. VDAC1 oligomerization was evaluated using an EGS-based crosslinking assay. RESULTS The expression and migration of ATF2 to the mitochondria accounted for paclitaxel stimuli and acquired resistance to BRAF inhibitors. Mitochondrial ATF2 facilitated Bim stabilization through the inhibition of its degradation by the proteasome, thereby promoting cytochrome c release and inducing apoptosis in B16F10 and A375 cells. Studies using B16F10 and A375 cells genetically modified for ATF2 indicated that mitochondrial ATF2 was able to dissociate Bim from the Mcl-1/Bim complex to trigger VDAC1 oligomerization. Immunoprecipitation analysis revealed that Bim interacts with VDAC1, and this interaction was remarkably enhanced during apoptosis. CONCLUSION These results reveal that mitochondrial ATF2 is associated with the induction of apoptosis and BRAF inhibitor resistance through Bim activation, which might suggest potential novel therapies for the targeted induction of apoptosis in melanoma therapy.
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You Z, Zhou Y, Guo Y, Chen W, Chen S, Wang X. Activating transcription factor 2 expression mediates cell proliferation and is associated with poor prognosis in human non-small cell lung carcinoma. Oncol Lett 2015; 11:760-766. [PMID: 26870280 DOI: 10.3892/ol.2015.3922] [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: 10/01/2014] [Accepted: 08/20/2015] [Indexed: 12/22/2022] Open
Abstract
Activating transcription factor 2 (ATF2) is a member of the cAMP response element binding protein family that heterodimerizes and activates other transcription factors involved in stress and DNA damage responses, growth, differentiation and apoptosis. ATF2 has been investigated as a potential carcinogenic biomarker in certain types of cancer, such as melanoma. However, its function and clinical significance in non-small cell lung cancer (NSCLC) has not been well studied. Therefore, the present study aimed to analyze the association between ATF2/phosphorylated (p)-ATF2 expression and NSCLC malignant behavior, and discuss its clinical significance. Reverse transcription-quantitative polymerase chain reaction and western blotting were used to detect the expression of ATF2 in NSCLC cell lines and fresh NSCLC tissue samples. In addition, immunohistochemistry (IHC) was performed to identify the location and expression of ATF2 and p-ATF2 (threonine 71) in paraffin-embedded sections of NSCLC and adjacent normal tissue. The results demonstrated that ATF2 was markedly overexpressed in the NSCLC cells and significantly overexpressed in the fresh NSCLC tissues compared with the control cells and samples (86 paraffin-embedded tissue sections), respectively (P<0.01). Further data demonstrated that ATF2 expression levels were significantly increased in tumor tissues compared to normal tissues and ATF2 was located in the cytoplasm and nucleus. ATF2 expression was closely associated with adverse clinical characteristics such as TNM stage (P=0.002), tumor size (P=0.018) and metastasis (P=0.027). In addition, nuclear p-ATF2 staining was positive in 65/86 samples of NSCLC. Furthermore, the Kaplan-Meier analysis indicated that patients with high levels of ATF2 and p-ATF2 expression had a significantly shorter overall survival compared with patients exhibiting a low expression (P<0.01 and P<0.05, respectively). Subsequent in vitro experiments revealed that cell growth decreased following knockdown of ATF2 expression using RNA interference, indicating that ATF2 may suppress cell proliferation. Taken together, the results of the present study demonstrated that ATF2 and p-ATF2 were significantly overexpressed in NSCLC tissues, and ATF2 and p-ATF2 overexpression predicted significantly worse outcomes for patients with NSCLC.
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Affiliation(s)
- Zhenyu You
- Department of Oncology, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yong Zhou
- Department of Pharmacy, Peking University, Beijing 100083, P.R. China
| | - Yuling Guo
- Department of Oncology, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Wenyan Chen
- Department of Oncology, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Shaoqing Chen
- Department of Oncology, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Xiaolang Wang
- Department of Oncology, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Liu Z, Luo Q, Guo C. Bim and VDAC1 are hierarchically essential for mitochondrial ATF2 mediated cell death. Cancer Cell Int 2015; 15:34. [PMID: 25852302 PMCID: PMC4387661 DOI: 10.1186/s12935-015-0188-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2015] [Accepted: 03/20/2015] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND ATF2 mediated cytochrome c release is the formation of a channel with some unknown factors larger than that of the individual proteins. BHS-only proteins (BH3s), such as Bim, could induce BAX and VDAC, forming a new channel. According to this facts, we can speculated that there is possible signal relationship with BH3s and ATF2, which is associated with mitochondrial-based death programs. METHODS The growth inhibitory effects of mitochondrial ATF2 were tested in cancer cell lines B16F10, A549, EG7, and LL2. Apoptosis was measured by flow cytometry. The effects of ATF2 and levels of apoptosis regulatory proteins were measured by Western blotting. The interaction of proteins were evaluated by immunoprecipitation analysis. The in vivo antitumor activity of mitochondrial ATF2 were tested in xenograft B16F10 models. RESULTS Genotoxic stress enabled mitochondrial ATF2 accumulation, perturbing the HK1-VDAC1 complex, increasing mitochondrial permeability, and promoting apoptosis. ATF2 inhibition strongly reduced the conformational activation of Bim, suggesting that Bim acts downstream of ATF2. Although Bim downregulation had no effect on ATF2 activation, Bim knockdown abolished VDAC1 activation; the failure of VDAC1 activation in Bim-depleted cells could be reversed by the BH3-only protein mimic ABT-737. We also demonstrate that silencing of ATF2 in B16F10 cells increases both the incidence and prevalence of tumor xenografts in vivo, whereas stably mitochondrial ATF2 transfection inhibited B16F10 tumor xenografts growth. CONCLUSIONS Altogether, these results show that ATF2 is a component of the apoptosis machinery that involves a hierarchical contribution of ATF2, Bim, and VDAC1. Our data offer new insight into the mechanism of mitochondrial ATF2 in mitochondrial apoptosis.
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Affiliation(s)
- Zhaoyun Liu
- Laboratory of Surgery, Children's Hospital of Chongqing Medical University, 136 Zhongshan 2nd Rd, Chongqing, 400014 P. R. China
| | - Qianfu Luo
- Laboratory of Surgery, Children's Hospital of Chongqing Medical University, 136 Zhongshan 2nd Rd, Chongqing, 400014 P. R. China
| | - Chunbao Guo
- Laboratory of Surgery, Children's Hospital of Chongqing Medical University, 136 Zhongshan 2nd Rd, Chongqing, 400014 P. R. China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, P. R. China
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Chen J, Solomides C, Simpkins H. Sensitization of mesothelioma cells to platinum-based chemotherapy by GSTπ knockdown. Biochem Biophys Res Commun 2014; 447:77-82. [PMID: 24690178 DOI: 10.1016/j.bbrc.2014.03.100] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Accepted: 03/20/2014] [Indexed: 01/13/2023]
Abstract
It is predicted that the incidence of mesothelioma will increase and thus it is important to find new ways to treat this chemoresistant tumor. Glutathione-S-Transferase π (GSTπ) is found at significant levels in mesotheliomas and thus attenuating its intracellular levels may provide a means of sensitizing mesothelioma cells to chemotherapy. GSTπ knockdowns were therefore prepared with shRNA (less off-target effects) employing two cell lines (211H, H2452) that were typed by immunohistochemistry to be of mesothelial origin. The knockdowns exhibited a decrease in both total GST enzyme activity and GSTπ protein levels as well as an increase in both glutathione levels and sensitivity to cis and oxaliplatin. Cisplatin treatment of the knockdowns increased ROS levels significantly (as compared to the parental cells) and produced activation of the JNK/p38 pathways and activating transcription factor (ATF2). The degree of activation and increase in ROS appeared to correlate with the cell line's sensitivity to cisplatin. Treatment with N-Acetyl Cysteine decreased ROS production and JNK/p38 phosphorylation but had minimal affect on ATF2 suggesting a direct interaction of GTPπ with this transcription factor. Oxaliplatin treatment produced only minimal changes in ROS levels and activation of the JNK/p38 pathway. Recently, new methods of siRNA delivery (nanoparticles) have been shown to be effective in decreasing the levels of target proteins in humans including candidate genes involved in drug resistance - thus this approach may have promise in sensitizing cisplatin-resistant tumors to chemotherapy.
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Affiliation(s)
- Jianli Chen
- The Feinstein Institute for Medical Research, NS-LIJ Health System, 350 Community Drive, Manhasset, NY 11030, USA; Department of Pathology and Laboratory Medicine at Staten Island University Hospital, 475 Seaview Avenue, Staten Island, NY 10305, USA.
| | - Charalambos Solomides
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Jefferson Medical College, 132 S. 10th Street, 260E Main, Philadelphia, PA 19107, USA.
| | - Henry Simpkins
- The Feinstein Institute for Medical Research, NS-LIJ Health System, 350 Community Drive, Manhasset, NY 11030, USA; Department of Pathology and Laboratory Medicine at Staten Island University Hospital, 475 Seaview Avenue, Staten Island, NY 10305, USA.
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Feng FL, Yu Y, Liu C, Zhang BH, Cheng QB, Li B, Tan WF, Luo XJ, Jiang XQ. KAT5 silencing induces apoptosis of GBC-SD cells through p38MAPK-mediated upregulation of cleaved Casp9. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2013; 7:80-91. [PMID: 24427328 PMCID: PMC3885462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 11/10/2013] [Accepted: 12/05/2013] [Indexed: 06/03/2023]
Abstract
The poor overall prognosis of Gallbladder carcinoma (GBC) patients and the limited therapeutic regimens for these patients demonstrates the need for better therapeutic modalities, while the growing evidences have indicated that those genes contributed to epigenetic regulation may serve as therapeutic targets. The function of histone acetylation on growth and survival of GBC cells remains unknown. In present study, an RNAi screening of 16 genes involving histone acetyltransferases (HATs) was applied to GBC-SD cells and we found that KAT5 knockdown specifically inhibits the proliferation of GBC-SD cells by casp9-mediated apoptosis. Microarray data analysis showed that KAT5 RNAi may result in cleaved casp9 upregulation through p38MAPK activation in GBC-SD cells. The mRNA expression level of KAT5 was significantly upregulated in GBC tissues than in the adjacent normal tissues. In consistence with the mRNA level, the protein expression of KAT5 was markedly increased in tissues from patients with poor prognosis than those with good prognosis. These findings strongly indicated that KAT5 was implicated in GBC tumorigenesis and that its expression level was associated with the prognosis. Our work may also provide a potential therapeutic target for treatment of GBC patients.
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Affiliation(s)
- Fei-Ling Feng
- Department of Biliary I, Third Affiliated Hospital of PLA Second Military Medical University Shanghai, China
| | - Yong Yu
- Department of Biliary I, Third Affiliated Hospital of PLA Second Military Medical University Shanghai, China
| | - Chen Liu
- Department of Biliary I, Third Affiliated Hospital of PLA Second Military Medical University Shanghai, China
| | - Bai-He Zhang
- Department of Biliary I, Third Affiliated Hospital of PLA Second Military Medical University Shanghai, China
| | - Qing-Bao Cheng
- Department of Biliary I, Third Affiliated Hospital of PLA Second Military Medical University Shanghai, China
| | - Bin Li
- Department of Biliary I, Third Affiliated Hospital of PLA Second Military Medical University Shanghai, China
| | - Wei-Feng Tan
- Department of Biliary I, Third Affiliated Hospital of PLA Second Military Medical University Shanghai, China
| | - Xiang-Ji Luo
- Department of Biliary I, Third Affiliated Hospital of PLA Second Military Medical University Shanghai, China
| | - Xiao-Qing Jiang
- Department of Biliary I, Third Affiliated Hospital of PLA Second Military Medical University Shanghai, China
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