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1
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Xu DG, Tan J. Interplay of genetic and clinical factors in cancer-associated thrombosis: Deciphering the prothrombotic landscape of colorectal cancer. World J Gastroenterol 2025; 31:103901. [PMID: 40248375 PMCID: PMC12001197 DOI: 10.3748/wjg.v31.i14.103901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 03/03/2025] [Accepted: 03/25/2025] [Indexed: 04/11/2025] Open
Abstract
Colorectal cancer (CRC), the third most prevalent cancer globally, exhibits a notable association with venous thromboembolism (VTE), significantly impacting patient morbidity and mortality. We delve into the complex pathogenesis of cancer-associated thrombosis (CAT) in CRC, highlighting the interplay of clinical risk factors and tumor-specific mechanisms. Our comprehensive review synthesizes the current understanding of CRC's pro-thrombotic tendencies, examining both general clinical factors (e.g., age, gender, obesity, prior VTE history) and tumor-specific aspects (e.g., tumor location, stage, targeted therapies). Key findings illustrate how CRC cells themselves actively contribute to coagulation cascade activation through various procoagulant elements such as tissue factor, cancer procoagulant, and extracellular vesicles. We also explore how CRC influences host cells to adopt a procoagulant phenotype, thereby exacerbating thrombotic risks. This review underscores the role of genetic mutations in CRC (e.g., KRAS, p53) in modulating coagulation-related protein expression and thrombosis risks. An in-depth understanding of the genetic landscape specific to CRC subtypes is essential for developing targeted anticoagulation strategies and could significantly advance thrombosis prevention while improving the overall management of patients with CRC. This highlights the urgent need for precision in addressing CAT within clinical settings.
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Affiliation(s)
- Duo-Gang Xu
- Department of General Surgery, Yan'an Hospital Affiliated to Kunming Medical University, Kunming 650051, Yunnan Province, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan Province, China
| | - Jing Tan
- Department of General Surgery, Yan'an Hospital Affiliated to Kunming Medical University, Kunming 650051, Yunnan Province, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan Province, China
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Lian J, Zhuang H, Li F, Pei R, Chen D, Ye P, Li S, Wang T, Cao J, Yuan J, Yu Z, Lu Y. High expression of EBP is an adverse prognostic factor for de novo acute myeloid leukemia. Hematology 2024; 29:2381171. [PMID: 39087796 DOI: 10.1080/16078454.2024.2381171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 07/10/2024] [Indexed: 08/02/2024] Open
Abstract
BACKGROUND Acute myeloid leukemia (AML) is a heterogeneous disease, for which identifying reliable prognostic markers is critical for accurate clinical prognosis and treatment optimization. The inhibition of emopamil-binding protein gene (EBP) expression has been demonstrated to induce cancer cell death via depleting downstream sterols. Nevertheless, no comprehensive studies have been conducted specifically in tumors, including AML. METHOD Herein, survival analyses were performed on the dataset obtained from The Cancer Genome Atlas (TCGA). Besides, the EBP levels were quantified using real-time qPCR in a cohort of 120 AML patients, and the value of EBP was further assessed using our clinical data. RESULTS Patients with high EBP expression had worse overall survival (OS) and event-free survival (EFS) than patients with low EBP expression, both in the TCGA dataset and our clinical data. Additionally, white blood cell (WBC) counts were higher in patients with high EBP expression (P = 0.032). Moreover, in patients with intermediate-risk AML, it was discovered that elevated EBP expression was linked to a worse EFS (P = 0.038). Multivariate analysis demonstrated that high EBP expression was an independent prognostic factor in AML patients and was associated with a shorter OS and EFS (OS: P = 0.041; EFS: P = 0.017). Furthermore, the data revealed that transplantation in the high-EBP group led to an improvement in survival (OS: P = 0.001; EFS: P = 0.001). The same benefit was also observed in intermediate-risk AML patients (OS: P = 0.026; EFS: P = 0.026). CONCLUSION Collectively, our findings indicated that high expression of EBP in AML patients was an adverse prognostic factor, but transplantation had the otential to alleviate its negative effects.
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MESH Headings
- Humans
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/therapy
- Leukemia, Myeloid, Acute/mortality
- Leukemia, Myeloid, Acute/diagnosis
- Female
- Male
- Middle Aged
- Prognosis
- Adult
- Aged
- Biomarkers, Tumor
- Young Adult
- RNA-Binding Proteins
- Adaptor Proteins, Signal Transducing
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Affiliation(s)
- Jiaying Lian
- Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, People's Republic of China
- Institute of Hematology, Ningbo University, Ningbo, People's Republic of China
| | - Haihui Zhuang
- Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, People's Republic of China
- Institute of Hematology, Ningbo University, Ningbo, People's Republic of China
| | - Fenglin Li
- Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, People's Republic of China
- Institute of Hematology, Ningbo University, Ningbo, People's Republic of China
| | - Renzhi Pei
- Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, People's Republic of China
- Institute of Hematology, Ningbo University, Ningbo, People's Republic of China
| | - Dong Chen
- Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, People's Republic of China
- Institute of Hematology, Ningbo University, Ningbo, People's Republic of China
| | - Peipei Ye
- Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, People's Republic of China
- Institute of Hematology, Ningbo University, Ningbo, People's Republic of China
| | - Shuangyue Li
- Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, People's Republic of China
- Institute of Hematology, Ningbo University, Ningbo, People's Republic of China
| | - Tiantian Wang
- Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, People's Republic of China
- Institute of Hematology, Ningbo University, Ningbo, People's Republic of China
| | - Junjie Cao
- Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, People's Republic of China
- Institute of Hematology, Ningbo University, Ningbo, People's Republic of China
| | - Jiaojiao Yuan
- Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, People's Republic of China
- Institute of Hematology, Ningbo University, Ningbo, People's Republic of China
| | - Zhuruohan Yu
- Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, People's Republic of China
- Institute of Hematology, Ningbo University, Ningbo, People's Republic of China
| | - Ying Lu
- Department of Hematology, The Affiliated People's Hospital of Ningbo University, Ningbo, People's Republic of China
- Institute of Hematology, Ningbo University, Ningbo, People's Republic of China
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Yamaguchi N, Sakaguchi T, Wei JJ, Tazoe Y, Inamine T, Fukuda D, Ohnita K, Hirayama T, Isomoto H, Matsushima K, Tsukamoto K. The C/C Genotype of rs1231760 in RGS2 Is a Risk Factor for the Progression of H. pylori-Positive Atrophic Gastritis by Increasing RGS2 Expression. Diagnostics (Basel) 2024; 14:2563. [PMID: 39594230 PMCID: PMC11592620 DOI: 10.3390/diagnostics14222563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 10/26/2024] [Accepted: 11/06/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND Chronic gastritis caused by Helicobacter pylori (H. pylori) infection can progress to gastric cancer through atrophic gastritis (AG). The risk of gastric cancer increases with the progression of AG. Therefore, investigating the risk factors for the progression of AG is important. METHODS Using the GTEx and GEO databases, we extracted thirty-four candidate genes involved in the progression of AG. Then, with in silico analysis using HaploReg v4.1 and JASPAR (Matrix ID: MA0113.3), we extracted rs1231760 of RGS2 as a key single-nucleotide polymorphism (SNP) that could be involved in the functional change in the candidate gene. A correlation analysis between the selected SNP and AG in 200 H. pylori-positive and 302 H. pylori-negative participants was conducted. For functional analysis of the SNP, a dual-luciferase assay using reporter plasmids with a major or minor allele sequence was carried out. RESULTS The frequency of the C/C genotype of rs1231760 was higher in the AG group than in the non-AG group (p = 0.0471). Functional analysis showed that the transcriptional activities were higher at the dexamethasone-stimulating C allele than at the others (p < 0.05). CONCLUSIONS The C/C genotype of rs1231760 in RGS2 could be a biomarker of high-risk H. pylori-positive AG because of an increase in RGS2 expression.
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Affiliation(s)
- Naoyuki Yamaguchi
- Department of Gastroenterology and Hepatology, Graduate School of Biological Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Takuki Sakaguchi
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-Cho, Yonago 683-8504, Japan
| | - Jing-Jing Wei
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-Cho, Yonago 683-8504, Japan
- Department of Endoscopy, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350004, China
| | - Yuna Tazoe
- Department of Pharmacotherapeutics, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Tatsuo Inamine
- Department of Pharmacotherapeutics, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Daisuke Fukuda
- Department of Gastroenterology and Hepatology, Graduate School of Biological Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
- Department of Surgical Oncology, Graduate School of Biological Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
- Fukuda Yutaka Surgical Clinic, 3-5 Hamaguchi-machi, Nagasaki 852-8107, Japan
| | - Ken Ohnita
- Department of Gastroenterology and Hepatology, Graduate School of Biological Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
- Shunkaikai Inoue Hospital, 6-12 Takara-machi, Nagasaki 850-0045, Japan
| | - Tatsuro Hirayama
- Department of Pharmacotherapeutics, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Hajime Isomoto
- Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, 36-1 Nishi-Cho, Yonago 683-8504, Japan
| | - Kayoko Matsushima
- Department of Gastroenterology and Hepatology, Graduate School of Biological Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
| | - Kazuhiro Tsukamoto
- Department of Pharmacotherapeutics, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
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Wang Y, Qin J, Sharma A, Dakal TC, Wang J, Pan T, Bhushan R, Chen P, Setiawan MF, Schmidt-Wolf IGH, Li F. Exploring the promise of regulator of G Protein Signaling 20: insights into potential mechanisms and prospects across solid cancers and hematological malignancies. Cancer Cell Int 2024; 24:305. [PMID: 39227952 PMCID: PMC11373255 DOI: 10.1186/s12935-024-03487-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 08/18/2024] [Indexed: 09/05/2024] Open
Abstract
RGS (Regulator of G protein signaling) proteins have long captured the fascination of researchers due to their intricate involvement across a wide array of signaling pathways within cellular systems. Their diverse and nuanced functions have positioned them as continual subjects of scientific inquiry, especially given the implications of certain family members in various cancer types. Of particular note in this context is RGS20, whose clinical relevance and molecular significance in hepatocellular carcinoma we have recently investigated. These investigations have prompted questions into the prevalence of pathogenic mutations within the RGS20 gene and the intricate network of interacting proteins that could contribute to the complex landscape of cancer biology. In our study, we aim to unravel the mutations within the RGS20 gene and the multifaceted interplay between RGS20 and other proteins within the context of cancer. Expanding on this line of inquiry, our research is dedicated to uncovering the intricate mechanisms of RGS20 in various cancers. In particular, we have redirected our attention to examining the role of RGS20 within hematological malignancies, with a specific focus on multiple myeloma and follicular lymphoma. These hematological cancers hold significant promise for further investigation, as understanding the involvement of RGS20 in their pathogenesis could unveil novel therapeutic strategies and treatment avenues. Furthermore, our exploration has extended to encompass the latest discoveries concerning the potential involvement of RGS20 in diseases affecting the central nervous system, thereby broadening the scope of its implications beyond oncology to encompass neurobiology and related fields.
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Affiliation(s)
- Yulu Wang
- Jiangxi Provincial Key Laboratory of Hematological Diseases, Department of Hematology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Jiading Qin
- Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Amit Sharma
- Department of Integrated Oncology, Center for Integrated Oncology (CIO), University Hospital of Bonn, Bonn, Germany
- Department of Neurosurgery, University Hospital of Bonn, Bonn, Germany
| | - Tikam Chand Dakal
- Department of Biotechnology, Mohanlal Sukhadia University, Udaipur, Rajasthan, India
| | - Jieyu Wang
- Jiangxi Provincial Key Laboratory of Hematological Diseases, Department of Hematology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Tiantian Pan
- Jiangxi Provincial Key Laboratory of Hematological Diseases, Department of Hematology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Ravi Bhushan
- Department of Zoology, M.S. College, Motihari, Bihar, India
| | - Peng Chen
- Department of Integrated Oncology, Center for Integrated Oncology (CIO), University Hospital of Bonn, Bonn, Germany
| | - Maria F Setiawan
- Department of Integrated Oncology, Center for Integrated Oncology (CIO), University Hospital of Bonn, Bonn, Germany
| | - Ingo G H Schmidt-Wolf
- Department of Integrated Oncology, Center for Integrated Oncology (CIO), University Hospital of Bonn, Bonn, Germany
| | - Fei Li
- Jiangxi Provincial Key Laboratory of Hematological Diseases, Department of Hematology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
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Xu H, Xu B, Hu J, Xia J, Tong L, Zhang P, Yang L, Tang L, Chen S, Du J, Wang Y, Li Y. Development of a novel autophagy-related gene model for gastric cancer prognostic prediction. Front Oncol 2022; 12:1006278. [PMID: 36276067 PMCID: PMC9585256 DOI: 10.3389/fonc.2022.1006278] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 09/23/2022] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is a major global health issue and one of the leading causes of tumor-associated mortality worldwide. Autophagy is thought to play a critical role in the development and progression of GC, and this process is controlled by a set of conserved regulators termed autophagy-related genes (ATGs). However, the complex contribution of autophagy to cancers is not completely understood. Accordingly, we aimed to develop a prognostic model based on the specific role of ATGs in GC to improve the prediction of GC outcomes. First, we screened 148 differentially expressed ATGs between GC and normal tissues in The Cancer Genome Atlas (TCGA) cohort. Consensus clustering in these ATGs was performed, and based on that, 343 patients were grouped into two clusters. According to Kaplan–Meier survival analysis, cluster C2 had a worse prognosis than cluster C1. Then, a disease risk model incorporating nine differentially expressed ATGs was constructed based on the least absolute shrinkage and selection operator (LASSO) regression analysis, and the ability of this model to stratify patients into high- and low-risk groups was verified. The predictive value of the model was confirmed using both training and validation cohorts. In addition, the results of functional enrichment analysis suggested that GC risk is correlated with immune status. Moreover, autophagy inhibition increased sensitivity to cisplatin and exacerbated reactive oxygen species accumulation in GC cell lines. Collectively, the results indicated that this novel constructed risk model is an effective and reliable tool for predicting GC outcomes and could help with individual treatment through ATG targeting.
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Affiliation(s)
- Haifeng Xu
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
- School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China
| | - Bing Xu
- Department of Clinical Laboratory, Hangzhou Women’s Hospital, Hangzhou, China
| | - Jiayu Hu
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Jun Xia
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Le Tong
- College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Ping Zhang
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Lei Yang
- School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China
| | - Lusheng Tang
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Sufeng Chen
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Jing Du
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
- *Correspondence: Jing Du, ; Ying Wang, ; Yanchun Li,
| | - Ying Wang
- Department of Central Laboratory, Affiliated Hangzhou first people’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- *Correspondence: Jing Du, ; Ying Wang, ; Yanchun Li,
| | - Yanchun Li
- Department of Central Laboratory, Affiliated Hangzhou first people’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- *Correspondence: Jing Du, ; Ying Wang, ; Yanchun Li,
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Abstract
BACKGROUND Ulcerative colitis is a chronic and progressive inflammatory disorder. The regulator of the G-protein signaling (RGS) is involved in the pathogenesis of several immune system disorders. RGS16, a member of the RGS protein superfamily, has been shown to play critical roles in several immune system-related diseases. However, the roles of RGS16 in ulcerative colitis remain to be elucidated. METHODS We analyzed the expression of RGS16 in peripheral blood mononuclear cells (PBMCs) and inflamed mucosa of ulcerative colitis patients using quantitative reverse transcription-PCR, western blotting and immunohistochemistry. We performed Spearman's correlation to analyze the correlation between RGS16 expression and the ulcerative colitis endoscopic index of severity (UCEIS), Mayo index, erythrocyte sedimentation rate (ESR) and serum tumor necrosis factor alpha (TNF-a) and IL-17A levels. Further, PBMCs were stimulated with inflammatory cytokines in vitro . RESULTS RGS16 expression significantly increased in the colonic mucosa and PBMCs from patients with ulcerative colitis and significantly correlated with the Mayo index, UCEIS, ESR and serum TNF-α and IL-17A levels. TNF-α upregulated RGS16 expression in PBMCs in a dose- and time-dependent manner via the nuclear factor kappa beta (NF-kB) signaling pathway. Moreover, anti-TNF treatment with infliximab significantly decreased RGS16 expression in PBMCs and intestinal mucosa of patients with ulcerative colitis. CONCLUSION Our study revealed a novel mechanism by which RGS16 expression in ulcerative colitis is positively correlated with disease activity. Thus, RGS16 might serve as a potential therapeutic marker for the treatment of ulcerative colitis.
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Ihlow J, Monjé N, Hoffmann I, Bischoff P, Sinn BV, Schmitt WD, Kunze CA, Darb-Esfahani S, Kulbe H, Braicu EI, Sehouli J, Denkert C, Horst D, Taube ET. Low Expression of RGS2 Promotes Poor Prognosis in High-Grade Serous Ovarian Cancer. Cancers (Basel) 2022; 14:cancers14194620. [PMID: 36230542 PMCID: PMC9561967 DOI: 10.3390/cancers14194620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/03/2022] [Accepted: 09/19/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Recent advances in molecular medicine have indicated G-protein coupled receptors (GPCRs) as possible therapeutic targets in ovarian cancer. The cellular effects of GPCRs are determined by regulator of G protein signaling (RGS) proteins. Especially RGS2 has currently moved into focus of cancer therapy. Therefore, we retrospectively analyzed RGS2 and its association with the prognosis of high-grade serous ovarian cancer (HGSOC). Here, we provide in situ and in silico analyses regarding the expression patterns and prognostic value of RGS2. In silico we found that RGS2 is barely detectable in tumor cells on the mRNA level in bulk and single-cell data. Applying immunohistochemistry in 519 HGSOC patients, we detected moderate to strong protein expression of RGS2 in situ in approximately half of the cohort, suggesting regulation by post translational modification. Furthermore, low protein expression of RGS2 was associated with an inferior overall- and progression-free survival. These results warrant further research of its role and related new therapeutic implications in HGSOC. Abstract RGS2 regulates G-protein signaling by accelerating hydrolysis of GTP and has been identified as a potentially druggable target in carcinomas. Since the prognosis of patients with high-grade serous ovarian carcinoma (HGSOC) remains utterly poor, new therapeutic options are urgently needed. Previous in vitro studies have linked RGS2 suppression to chemoresistance in HGSOC, but in situ data are still missing. In this study, we characterized the expression of RGS2 and its relation to prognosis in HGSOC on the protein level by immunohistochemistry in 519 patients treated at Charité, on the mRNA level in 299 cases from TCGA and on the single-cell level in 19 cases from publicly available datasets. We found that RGS2 is barely detectable on the mRNA level in both bulk tissue (median 8.2. normalized mRNA reads) and single-cell data (median 0 normalized counts), but variably present on the protein level (median 34.5% positive tumor cells, moderate/strong expression in approximately 50% of samples). Interestingly, low expression of RGS2 had a negative impact on overall survival (p = 0.037) and progression-free survival (p = 0.058) on the protein level in lower FIGO stages and in the absence of residual tumor burden. A similar trend was detected on the mRNA level. Our results indicated a significant prognostic impact of RGS2 protein suppression in HGSOC. Due to diverging expression patterns of RGS2 on mRNA and protein levels, posttranslational modification of RGS2 is likely. Our findings warrant further research to unravel the functional role of RGS2 in HGSOC, especially in the light of new drug discovery.
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Affiliation(s)
- Jana Ihlow
- Institute of Pathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Nanna Monjé
- Institute of Pathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Inga Hoffmann
- Institute of Pathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Philip Bischoff
- Institute of Pathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
- German Cancer Consortium (DKTK), Partner Site Berlin, and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Bruno Valentin Sinn
- Institute of Pathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Wolfgang Daniel Schmitt
- Institute of Pathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Catarina Alisa Kunze
- Institute of Pathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Sylvia Darb-Esfahani
- Institute of Pathology, Berlin-Spandau, Stadtrandstraße 555, 13589 Berlin, Germany
| | - Hagen Kulbe
- Department of Obstetrics and Gynecology with Center of Oncological Surgery, European Competence Center for Ovarian Cancer, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Virchow-Clinic, Augustenburger Platz 1, 13353 Berlin, Germany
- Tumorbank Ovarian Cancer Network, Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Virchow-Clinic, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Elena Ioana Braicu
- Department of Obstetrics and Gynecology with Center of Oncological Surgery, European Competence Center for Ovarian Cancer, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Virchow-Clinic, Augustenburger Platz 1, 13353 Berlin, Germany
- Tumorbank Ovarian Cancer Network, Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Virchow-Clinic, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Jalid Sehouli
- Department of Obstetrics and Gynecology with Center of Oncological Surgery, European Competence Center for Ovarian Cancer, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Virchow-Clinic, Augustenburger Platz 1, 13353 Berlin, Germany
- Tumorbank Ovarian Cancer Network, Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Virchow-Clinic, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Carsten Denkert
- Institute of Pathology, Philipps-University Marburg, Baldingerstraße, 35043 Marburg, Germany
| | - David Horst
- Institute of Pathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Eliane Tabea Taube
- Institute of Pathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany
- Correspondence: ; Tel.: +49-30-450-536-033; Fax: +49-30-450-536-900
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Chan KYY, Chung PY, Zhang C, Poon ENY, Leung AWK, Leung KT. R4 RGS proteins as fine tuners of immature and mature hematopoietic cell trafficking. J Leukoc Biol 2022; 112:785-797. [PMID: 35694792 DOI: 10.1002/jlb.1mr0422-475r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 04/28/2022] [Indexed: 11/08/2022] Open
Abstract
G-protein-coupled receptors (GPCRs) are the largest and most diverse group of membrane receptors. They are involved in almost every physiologic process and consequently have a pivotal role in an extensive number of pathologies, including genetic, neurologic, and immune system disorders. Indeed, the vast array of GPCRs mechanisms have led to the development of a tremendous number of drug therapies and already account for about a third of marketed drugs. These receptors mediate their downstream signals primarily via G proteins. The regulators of G-protein signaling (RGS) proteins are now in the spotlight as the critical modulatory factors of active GTP-bound Gα subunits of heterotrimeric G proteins to fine-tune the biologic responses driven by the GPCRs. Also, they possess noncanonical functions by multiple mechanisms, such as protein-protein interactions. Essential roles and impacts of these RGS proteins have been revealed in physiology, including hematopoiesis and immunity, and pathologies, including asthma, cancers, and neurologic disorders. This review focuses on the largest subfamily of R4 RGS proteins and provides a brief overview of their structures and G-proteins selectivity. With particular interest, we explore and highlight, their expression in the hematopoietic system and the regulation in the engraftment of hematopoietic stem/progenitor cells (HSPCs). Distinct expression patterns of R4 RGS proteins in the hematopoietic system and their pivotal roles in stem cell trafficking pave the way for realizing new strategies for enhancing the clinical performance of hematopoietic stem cell transplantation. Finally, we discuss the exciting future trends in drug development by targeting RGS activity and expression with small molecules inhibitors and miRNA approaches.
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Affiliation(s)
- Kathy Yuen Yee Chan
- Department of Paediatrics, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Po Yee Chung
- Department of Paediatrics, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Chi Zhang
- Department of Paediatrics, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Ellen Ngar Yun Poon
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Alex Wing Kwan Leung
- Department of Paediatrics, The Chinese University of Hong Kong, Shatin, Hong Kong, China.,Department of Paediatrics & Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong SAR, China
| | - Kam Tong Leung
- Department of Paediatrics, The Chinese University of Hong Kong, Shatin, Hong Kong, China.,Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Shatin, Hong Kong, China
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9
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Singh RP, Hahn BH, Bischoff DS. Cellular and Molecular Phenotypes of pConsensus Peptide (pCons) Induced CD8 + and CD4 + Regulatory T Cells in Lupus. Front Immunol 2021; 12:718359. [PMID: 34867947 PMCID: PMC8640085 DOI: 10.3389/fimmu.2021.718359] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 10/26/2021] [Indexed: 11/16/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with widespread inflammation, immune dysregulation, and is associated with the generation of destructive anti-DNA autoantibodies. We have shown previously the immune modulatory properties of pCons peptide in the induction of both CD4+ and CD8+ regulatory T cells which can in turn suppress development of the autoimmune disease in (NZB/NZW) F1 (BWF1) mice, an established model of lupus. In the present study, we add novel protein information and further demonstrate the molecular and cellular phenotypes of pCons-induced CD4+ and CD8+ Treg subsets. Flow cytometry analyses revealed that pCons induced CD8+ Treg cells with the following cell surface molecules: CD25highCD28high and low subsets (shown earlier), CD62Lhigh, CD122low, PD1low, CTLA4low, CCR7low and 41BBhigh. Quantitative real-time PCR (qRT-PCR) gene expression analyses revealed that pCons-induced CD8+ Treg cells downregulated the following several genes: Regulator of G protein signaling (RGS2), RGS16, RGS17, BAX, GPT2, PDE3b, GADD45β and programmed cell death 1 (PD1). Further, we confirmed the down regulation of these genes by Western blot analyses at the protein level. To our translational significance, we showed herein that pCons significantly increased the percentage of CD8+FoxP3+ T cells and further increased the mean fluorescence intensity (MFI) of FoxP3 when healthy peripheral blood mononuclear cells (PBMCs) are treated with pCons (10 μg/ml, for 24-48 hours). In addition, we found that pCons reduced apoptosis in CD4+ and CD8+ T cells and B220+ B cells of BWF1 lupus mice. These data suggest that pCons stimulates cellular, immunological, and molecular changes in regulatory T cells which in turn protect against SLE autoimmunity.
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Affiliation(s)
- Ram P Singh
- Research Service, Veteran Administration Greater Los Angeles Healthcare System, Los Angeles, CA, United States.,Division of Rheumatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Bevra H Hahn
- Division of Rheumatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.,Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - David S Bischoff
- Research Service, Veteran Administration Greater Los Angeles Healthcare System, Los Angeles, CA, United States.,Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
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10
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Transcriptional drug repositioning and cheminformatics approach for differentiation therapy of leukaemia cells. Sci Rep 2021; 11:12537. [PMID: 34131166 PMCID: PMC8206077 DOI: 10.1038/s41598-021-91629-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 05/21/2021] [Indexed: 02/05/2023] Open
Abstract
Differentiation therapy is attracting increasing interest in cancer as it can be more specific than conventional chemotherapy approaches, and it has offered new treatment options for some cancer types, such as treating acute promyelocytic leukaemia (APL) by retinoic acid. However, there is a pressing need to identify additional molecules which act in this way, both in leukaemia and other cancer types. In this work, we hence developed a novel transcriptional drug repositioning approach, based on both bioinformatics and cheminformatics components, that enables selecting such compounds in a more informed manner. We have validated the approach for leukaemia cells, and retrospectively retinoic acid was successfully identified using our method. Prospectively, the anti-parasitic compound fenbendazole was tested in leukaemia cells, and we were able to show that it can induce the differentiation of leukaemia cells to granulocytes in low concentrations of 0.1 μM and within as short a time period as 3 days. This work hence provides a systematic and validated approach for identifying small molecules for differentiation therapy in cancer.
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11
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Lin CZ, Liu ZQ, Zhou WK, Ji T, Cao W. Effect of the regulator of G-protein signaling 2 on the proliferation and invasion of oral squamous cell carcinoma cells and its molecular mechanism. HUA XI KOU QIANG YI XUE ZA ZHI = HUAXI KOUQIANG YIXUE ZAZHI = WEST CHINA JOURNAL OF STOMATOLOGY 2021; 39:320-327. [PMID: 34041882 PMCID: PMC8218255 DOI: 10.7518/hxkq.2021.03.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 02/15/2021] [Indexed: 02/08/2023]
Abstract
OBJECTIVES This study aims to investigate the effect of the regulator of G-protein signaling 2 (RGS2) on the proliferation and invasion of oral squamous cell carcinoma (OSCC) cells and its potential molecular mechanism. Metho⁃ds The expression status and clinical significance of RGS2 in head and neck squamous cell carcinomas and matched adjacent normal tissues were evaluated using TCGA database. Three OSCC cell lines (i.e., SCC-9, Cal27, and Fadu) were overexpressed with RGS2, and the effect of RGS2 on cell proliferation and invasion was determined using the Transwell, clone formation, and cell counting kit (CCK)-8 assays. Moreover, the yeast two-hybrid scree-ning and co-immunoprecipitation (Co-IP) assays were conducted to detect the correlation of RGS2, four and a half LIM domains protein 1 (FHL1), and damage DNA-binding protein 1 (DDB1). RESULTS The expression level of RGS2 in OSCC was significantly lower than that in matched adjacent normal tissues (P=0.023). The high RGS2 expression level was negatively correlated with lymphovascular invasion (P<0.001). After transfection with lentiv-RGS2, the expression of RGS2 was increased, and the invasion and proliferation abilities of OSCC cell lines were evidently inhibited. FHL1 could competitively bind with RGS2, which decreased the integration of DDB1 and RGS2, inhibited the ubiquitination process of RGS2, and maintained the stability of the RGS2 protein. CONCLUSIONS RGS2 plays an important role in the inhibition of OSCC proliferation and invasion. The structure stability of RGS2 is competitively regulated by FHL1 and DDB1.
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Affiliation(s)
- Cheng-Zhong Lin
- The 2nd Dental Center, Ninth People,s Hospital, Shanghai Jiao Tong University School of Medicine; National Clinical Research Center for Oral Disease; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, China
| | - Zhe-Qi Liu
- Dept. of Oral and Maxillofacial-Head and Neck Oncology, Ninth People,s Hospital, Shanghai Jiao Tong University, School of Medicine; National Clinical Research Center for Oral Disease; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, China
| | - Wen-Kai Zhou
- Dept. of Oral and Maxillofacial-Head and Neck Oncology, Ninth People,s Hospital, Shanghai Jiao Tong University, School of Medicine; National Clinical Research Center for Oral Disease; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, China
| | - Tong Ji
- Dept. of Oral and Maxillofacial-Head and Neck Oncology, Ninth People,s Hospital, Shanghai Jiao Tong University, School of Medicine; National Clinical Research Center for Oral Disease; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, China
| | - Wei Cao
- Dept. of Oral and Maxillofacial-Head and Neck Oncology, Ninth People,s Hospital, Shanghai Jiao Tong University, School of Medicine; National Clinical Research Center for Oral Disease; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, China
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12
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McNabb HJ, Zhang Q, Sjögren B. Emerging Roles for Regulator of G Protein Signaling 2 in (Patho)physiology. Mol Pharmacol 2020; 98:751-760. [PMID: 32973086 DOI: 10.1124/molpharm.120.000111] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 09/08/2020] [Indexed: 12/11/2022] Open
Abstract
Since their discovery in the mid-1990s, regulator of G protein signaling (RGS) proteins have emerged as key regulators of signaling through G protein-coupled receptors. Among the over 20 known RGS proteins, RGS2 has received increasing interest as a potential therapeutic drug target with broad clinical implications. RGS2 is a member of the R4 subfamily of RGS proteins and is unique in that it is selective for Gα q Despite only having an RGS domain, responsible for the canonical GTPase activating protein activity, RGS2 can regulate additional processes, such as protein synthesis and adenylate cyclase activity, through protein-protein interactions. Here we provide an update of the current knowledge of RGS2 function as it relates to molecular mechanisms of regulation as well as its potential role in regulating a number of physiologic systems and pathologies, including cardiovascular disease and central nervous system disorders, as well as various forms of cancer. SIGNIFICANCE STATEMENT: Regulator of G protein signaling (RGS) proteins represent an exciting class of novel drug targets. RGS2, in particular, could have broad clinical importance. As more details are emerging on the regulation of RGS2 in various physiological systems, the potential utility of this small protein in therapeutic development is increasing.
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Affiliation(s)
- Harrison J McNabb
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana
| | - Qian Zhang
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana
| | - Benita Sjögren
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana
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13
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Molecular Mechanisms of Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia: Ongoing Challenges and Future Treatments. Cells 2020; 9:cells9112493. [PMID: 33212779 PMCID: PMC7697863 DOI: 10.3390/cells9112493] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 11/07/2020] [Accepted: 11/13/2020] [Indexed: 12/17/2022] Open
Abstract
Treatment of FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD)-positive acute myeloid leukemia (AML) remains a challenge despite the development of novel FLT3-directed tyrosine kinase inhibitors (TKI); the relapse rate is still high even after allogeneic stem cell transplantation. In the era of next-generation FLT3-inhibitors, such as midostaurin and gilteritinib, we still observe primary and secondary resistance to TKI both in monotherapy and in combination with chemotherapy. Moreover, remissions are frequently short-lived even in the presence of continuous treatment with next-generation FLT3 inhibitors. In this comprehensive review, we focus on molecular mechanisms underlying the development of resistance to relevant FLT3 inhibitors and elucidate how this knowledge might help to develop new concepts for improving the response to FLT3-inhibitors and reducing the development of resistance in AML. Tailored treatment approaches that address additional molecular targets beyond FLT3 could overcome resistance and facilitate molecular responses in AML.
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14
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Huang R, Li G, Zhao Z, Zeng F, Zhang K, Liu Y, Wang K, Hu H. RGS16 promotes glioma progression and serves as a prognostic factor. CNS Neurosci Ther 2020; 26:791-803. [PMID: 32319728 PMCID: PMC7366748 DOI: 10.1111/cns.13382] [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: 01/21/2020] [Revised: 03/27/2020] [Accepted: 03/31/2020] [Indexed: 12/13/2022] Open
Abstract
Background RGS protein family members have recently became new potentially promising therapeutic targets in many cancers. However, as a key member of RGS family, RGS16 has seldom been studied in glioma. The present study was designed to investigate the prognostic value and biological function of RGS16 based on large‐scale databases and functional assays in vitro. Methods Here, we performed comprehensive analysis for the expression characteristic of RGS16 in Chinese Glioma Genome Atlas (CGGA) microarray database with 301 patients and validated in The Cancer Genome Atlas (TCGA) microarray and RNA sequencing database. Student's t‐test, one‐way ANOVA test and long‐rank test were used to assess differences between groups. Kaplan‐Meier survival, univariate and multivariate Cox analysis and ROC curve were used to estimate the survival distributions. Biological implication of abnormal expression of RGS16 in glioma was also explored. Functional analysis of RGS16 was performed in several glioblastoma (GBM) cell lines. R language and SPSS were used for statistical analysis and graphical work. Results We found that the expression of RGS16 was positively related to the grade of glioma. High level of RGS16 commonly gathered in glioma of mesenchymal subtype and wild‐type IDH1. Moreover, higher expression level of RGS16 was found to be significantly correlated with poor prognosis. The univariate and multivariate Cox regression analysis and ROC curve showed that RGS16 was an independent prognostic factor for glioma patients. Gene ontology analysis, gene set enrichment analysis, and gene set variation analysis suggested that the overexpression of RGS16 tightly related to cell proliferation, migration, epithelial‐mesenchymal transition (EMT), immune and inflammatory response of glioma. Knockdown of RGS16 in glioma cell lines also showed that RGS16 promoted the malignant progress of glioma cell lines. Conclusions RGS16 plays an important role in glioma progression and serves as an independent prognostic factor, especially in GBM patients.
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Affiliation(s)
- Ruoyu Huang
- Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.,Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,Chinese Glioma Cooperative Group (CGCG), Beijing, China
| | - Guanzhang Li
- Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.,Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,Chinese Glioma Cooperative Group (CGCG), Beijing, China
| | - Zheng Zhao
- Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.,Chinese Glioma Cooperative Group (CGCG), Beijing, China
| | - Fan Zeng
- Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.,Chinese Glioma Cooperative Group (CGCG), Beijing, China
| | - Kenan Zhang
- Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.,Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,Chinese Glioma Cooperative Group (CGCG), Beijing, China
| | - Yanwei Liu
- Chinese Glioma Cooperative Group (CGCG), Beijing, China.,Department of Radiotherapy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Kuanyu Wang
- Chinese Glioma Cooperative Group (CGCG), Beijing, China.,Department of Gamma Knife Center, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Huimin Hu
- Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.,Chinese Glioma Cooperative Group (CGCG), Beijing, China
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15
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Gschwandtner M, Derler R, Midwood KS. More Than Just Attractive: How CCL2 Influences Myeloid Cell Behavior Beyond Chemotaxis. Front Immunol 2019; 10:2759. [PMID: 31921102 PMCID: PMC6923224 DOI: 10.3389/fimmu.2019.02759] [Citation(s) in RCA: 434] [Impact Index Per Article: 72.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 11/11/2019] [Indexed: 12/15/2022] Open
Abstract
Monocyte chemoattractant protein-1 (MCP-1/CCL2) is renowned for its ability to drive the chemotaxis of myeloid and lymphoid cells. It orchestrates the migration of these cell types both during physiological immune defense and in pathological circumstances, such as autoimmune diseases including rheumatoid arthritis and multiple sclerosis, inflammatory diseases including atherosclerosis, as well as infectious diseases, obesity, diabetes, and various types of cancer. However, new data suggest that the scope of CCL2's functions may extend beyond its original characterization as a chemoattractant. Emerging evidence shows that it can impact leukocyte behavior, influencing adhesion, polarization, effector molecule secretion, autophagy, killing, and survival. The direction of these CCL2-induced responses is context dependent and, in some cases, synergistic with other inflammatory stimuli. The involvement of CCL2 signaling in multiple diseases renders it an interesting therapeutic target, although current targeting strategies have not met early expectations in the clinic. A better understanding of how CCL2 affects immune cells will be pivotal to the improvement of existing therapeutic approaches and the development of new drugs. Here, we provide an overview of the pleiotropic effects of CCL2 signaling on cells of the myeloid lineage, beyond chemotaxis, and highlight how these actions might help to shape immune cell behavior and tumor immunity.
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Affiliation(s)
- Martha Gschwandtner
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Rupert Derler
- Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria
| | - Kim S. Midwood
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
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16
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Selheim F, Aasebø E, Ribas C, Aragay AM. An Overview on G Protein-coupled Receptor-induced Signal Transduction in Acute Myeloid Leukemia. Curr Med Chem 2019; 26:5293-5316. [PMID: 31032748 DOI: 10.2174/0929867326666190429153247] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 03/22/2019] [Accepted: 04/05/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Acute Myeloid Leukemia (AML) is a genetically heterogeneous disease characterized by uncontrolled proliferation of precursor myeloid-lineage cells in the bone marrow. AML is also characterized by patients with poor long-term survival outcomes due to relapse. Many efforts have been made to understand the biological heterogeneity of AML and the challenges to develop new therapies are therefore enormous. G Protein-coupled Receptors (GPCRs) are a large attractive drug-targeted family of transmembrane proteins, and aberrant GPCR expression and GPCR-mediated signaling have been implicated in leukemogenesis of AML. This review aims to identify the molecular players of GPCR signaling, focusing on the hematopoietic system, which are involved in AML to help developing novel drug targets and therapeutic strategies. METHODS We undertook an exhaustive and structured search of bibliographic databases for research focusing on GPCR, GPCR signaling and expression in AML. RESULTS AND CONCLUSION Many scientific reports were found with compelling evidence for the involvement of aberrant GPCR expression and perturbed GPCR-mediated signaling in the development of AML. The comprehensive analysis of GPCR in AML provides potential clinical biomarkers for prognostication, disease monitoring and therapeutic guidance. It will also help to provide marker panels for monitoring in AML. We conclude that GPCR-mediated signaling is contributing to leukemogenesis of AML, and postulate that mass spectrometrybased protein profiling of primary AML cells will accelerate the discovery of potential GPCR related biomarkers for AML.
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Affiliation(s)
- Frode Selheim
- The Proteomics Unit at the University of Bergen, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway
| | - Elise Aasebø
- The Proteomics Unit at the University of Bergen, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway.,Department of Clinical Science, University of Bergen, Jonas Lies vei 87, 5021 Bergen, Norway
| | - Catalina Ribas
- Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), 28049 Madrid, Spain.,Instituto de Investigación Sanitaria La Princesa, 28006 Madrid, Spain.,CIBER de Enfermedades Cardiovasculares, ISCIII (CIBERCV), 28029 Madrid, Spain
| | - Anna M Aragay
- Departamento de Biologia Celular. Instituto de Biología Molecular de Barcelona (IBMB-CSIC), Spanish National Research Council (CSIC), Baldiri i Reixac, 15, 08028 Barcelona, Spain
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17
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Zjablovskaja P, Danek P, Kardosova M, Alberich-Jorda M. Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells. J Vis Exp 2018. [PMID: 29553501 DOI: 10.3791/57033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
Understanding of the hematopoietic stem and progenitor cell biology has important implications for regenerative medicine and the treatment of hematological pathologies. Despite the most relevant data that can be acquired using in vivo models or primary cultures, the low abundance of hematopoietic stem and progenitor cells considerably restricts the pool of suitable techniques for their investigation. Therefore, the use of cell lines allows sufficient production of biological material for the performance of screenings or assays that require large cell numbers. Here we present a detailed description, readout, and interpretation of proliferation and differentiation assays which are used for the investigation of processes involved in myelopoiesis and neutrophilic differentiation. These experiments employ the 32D/G-CSF-R cytokine dependent murine myeloid cell line, which possesses the ability to proliferate in the presence of IL-3 and differentiate in G-CSF. We provide optimized protocols for handling 32D/G-CSF-R cells and discuss major pitfalls and drawbacks that might compromise the described assays and expected results. Additionally, this article contains protocols for lentiviral and retroviral production, titration, and transduction of 32D/G-CSF-R cells. We demonstrate that genetic manipulation of these cells can be employed to successfully perform functional and molecular studies, which can complement results obtained with primary hematopoietic stem and progenitor cells or in vivo models.
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Affiliation(s)
- Polina Zjablovskaja
- Department of Hemato-Oncology, Institute of Molecular Genetics of the ASCR; Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University
| | - Petr Danek
- Department of Hemato-Oncology, Institute of Molecular Genetics of the ASCR
| | | | - Meritxell Alberich-Jorda
- Department of Hemato-Oncology, Institute of Molecular Genetics of the ASCR; Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University;
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18
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Wang C, Ye Q, Cao Y, Tan J, Wang F, Jiang J, Cao Y. Downregulation of regulator of G protein signaling 2 expression in breast invasive carcinoma of no special type: Clinicopathological associations and prognostic relevance. Oncol Lett 2018; 15:213-220. [PMID: 29391880 PMCID: PMC5769397 DOI: 10.3892/ol.2017.7351] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2016] [Accepted: 09/28/2017] [Indexed: 12/29/2022] Open
Abstract
Changes in the expression of regulator of G protein signaling 2 (RGS2) are involved in the genesis and development of a number of malignancies. However, the association between changes in the expression of RGS2 and breast invasive carcinoma of no special type (BIC-NST) remains unknown. The present study found that, in comparison to normal breast tissue, BIC-NST exhibited low expression of RGS2 mRNA and protein, as detected using data mining and immunohistochemical analysis. The low expression of RGS2 was associated with the positive status of hormone receptor expression in BIC-NST. Kaplan-Meier analysis revealed that patients with low RGS2 expression had a significantly poorer overall survival rate. Furthermore, multivariate Cox regression analysis demonstrated that the RGS2 low expression was an independent high-risk factor. Gene set enrichment analysis using data from The Cancer Genome Atlas supported these results. In summary, the results of the current study indicate that RGS2 acts as a suppressor gene in the progression of BIC-NST. To the best of our knowledge, the present study is the first concerning the association between RGS2 and hormone receptors in BIC-NST, as well as that between RGS2 expression and the prognosis of patients with BIC-NST. However, the effect of RGS2 in breast cancer requires further investigation.
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Affiliation(s)
- Chenglong Wang
- Department of Pathology, Chongqing Traditional Chinese Medicine Hospital, Chongqing 400021, P.R. China
| | - Qian Ye
- Department of Pathology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Yijia Cao
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Juan Tan
- Department of Pathology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Fei Wang
- Department of Pathology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Jin Jiang
- Department of Pathology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Youde Cao
- Department of Pathology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
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19
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Ruvolo PP. GSK-3 as a novel prognostic indicator in leukemia. Adv Biol Regul 2017; 65:26-35. [PMID: 28499784 DOI: 10.1016/j.jbior.2017.05.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 05/05/2017] [Accepted: 05/07/2017] [Indexed: 06/07/2023]
Abstract
While leukemias represent a diverse set of diseases with malignant cells derived from myeloid or lymphoid origin, a common feature is the dysregulation of signal transduction pathways that influence leukemogeneisis, promote drug resistance, and favor leukemia stem cells. Mutations in PI3K, PTEN, RAS, or other upstream regulators can activate the AKT kinase which has central roles in supporting cell proliferation and survival. A major target of AKT is Glycogen Synthase Kinase 3 (GSK3). GSK3 has two isoforms (alpha and beta) that were studied as regulators of metabolism but emerged as central players in cancer in the early 1990s. GSK3 is unique in that the isoforms are constitutively active. Active GSK3 promotes destruction of oncogenic proteins such as beta Catenin, c-MYC, and MCL-1 and thus has tumor suppressor properties. In AML, inactivation of GSK3 is associated with poor overall survival. Interestingly in some leukemias GSK3 targets a tumor suppressor and thus the kinases can act as tumor promoters in those instances. An example is GSK3 targeting p27Kip1 in AML with MLL translocation. This review will cover the role of GSK3 in various leukemias both as tumor suppressor and tumor promoter. We will also briefly cover current state of GSK3 inhibitors for leukemia therapy.
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Affiliation(s)
- Peter P Ruvolo
- Department of Leukemia, Unit 448, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States.
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20
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Hospital MA, Green AS, Maciel TT, Moura IC, Leung AY, Bouscary D, Tamburini J. FLT3 inhibitors: clinical potential in acute myeloid leukemia. Onco Targets Ther 2017; 10:607-615. [PMID: 28223820 PMCID: PMC5304990 DOI: 10.2147/ott.s103790] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy that is cured in as few as 15%–40% of cases. Tremendous improvements in AML prognostication arose from a comprehensive analysis of leukemia cell genomes. Among normal karyotype AML cases, mutations in the FLT3 gene are the ones most commonly detected as having a deleterious prognostic impact. FLT3 is a transmembrane tyrosine kinase receptor, and alterations of the FLT3 gene such as internal tandem duplications (FLT3-ITD) deregulate FLT3 downstream signaling pathways in favor of increased cell proliferation and survival. FLT3 tyrosine kinase inhibitors (TKI) emerged as a new therapeutic option in FLT3-ITD AML, and clinical trials are ongoing with a variety of TKI either alone, combined with chemotherapy, or even as maintenance after allogenic stem cell transplantation. However, a wide range of molecular resistance mechanisms are activated upon TKI therapy, thus limiting their clinical impact. Massive research efforts are now ongoing to develop more efficient FLT3 TKI and/or new therapies targeting these resistance mechanisms to improve the prognosis of FLT3-ITD AML patients in the future.
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Affiliation(s)
- Marie-Anne Hospital
- Département Développement, Reproduction, Cancer, Institut Cochin, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8104, Institut National de la Santé et de la Recherche Médicale (INSERM) U1016; Faculté de Médecine Sorbonne Paris Cité, Université Paris Descartes; Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC)
| | - Alexa S Green
- Département Développement, Reproduction, Cancer, Institut Cochin, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8104, Institut National de la Santé et de la Recherche Médicale (INSERM) U1016; Faculté de Médecine Sorbonne Paris Cité, Université Paris Descartes; Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC)
| | - Thiago T Maciel
- INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications; Paris Descartes - Sorbonne Paris Cité University; CNRS ERL 8254, Imagine Institute; Laboratory of Excellence GR-Ex, Paris, France
| | - Ivan C Moura
- INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications; Paris Descartes - Sorbonne Paris Cité University; CNRS ERL 8254, Imagine Institute; Laboratory of Excellence GR-Ex, Paris, France
| | - Anskar Y Leung
- Department of Medicine, Division of Hematology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, People's Republic of China
| | - Didier Bouscary
- Département Développement, Reproduction, Cancer, Institut Cochin, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8104, Institut National de la Santé et de la Recherche Médicale (INSERM) U1016; Faculté de Médecine Sorbonne Paris Cité, Université Paris Descartes; Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC)
| | - Jerome Tamburini
- Département Développement, Reproduction, Cancer, Institut Cochin, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8104, Institut National de la Santé et de la Recherche Médicale (INSERM) U1016; Faculté de Médecine Sorbonne Paris Cité, Université Paris Descartes; Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC)
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21
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Alachkar H, Mutonga M, Malnassy G, Park JH, Fulton N, Woods A, Meng L, Kline J, Raca G, Odenike O, Takamatsu N, Miyamoto T, Matsuo Y, Stock W, Nakamura Y. T-LAK cell-originated protein kinase presents a novel therapeutic target in FLT3-ITD mutated acute myeloid leukemia. Oncotarget 2016; 6:33410-25. [PMID: 26450903 PMCID: PMC4741775 DOI: 10.18632/oncotarget.5418] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 09/22/2015] [Indexed: 11/25/2022] Open
Abstract
Gain-of-function mutations of FLT3 (FLT3-ITD), comprises up to 30% of normal karyotype acute myeloid leukemia (AML) and is associated with an adverse prognosis. Current FLT3 kinase inhibitors have been tested extensively, but have not yet resulted in a survival benefit and novel therapies are awaited. Here we show that T-LAK cell-originated protein kinase (TOPK), a mitotic kinase highly expressed in and correlated with more aggressive phenotype in several types of cancer, is expressed in AML but not in normal CD34+ cells and that TOPK knockdown decreased cell viability and induced apoptosis. Treatment of AML cells with TOPK inhibitor (OTS514) resulted in a dose-dependent decrease in cell viability with lower IC50 in FLT3-mutated cells, including blasts obtained from patients relapsed after FLT3-inhibitor treatment. Using a MV4-11-engrafted mouse model, we found that mice treated with 7.5 mg/kg IV daily for 3 weeks survived significantly longer than vehicle treated mice (median survival 46 vs 29 days, P < 0.001). Importantly, we identified TOPK as a FLT3-ITD and CEBPA regulated kinase, and that modulating TOPK expression or activity resulted in significant decrease of FLT3 expression and CEBPA phosphorylation. Thus, targeting TOPK in FLT3-ITD AML represents a novel therapeutic approach for this adverse risk subset of AML.
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Affiliation(s)
- Houda Alachkar
- Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA
| | - Martin Mutonga
- Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA
| | - Gregory Malnassy
- Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA
| | - Jae-Hyun Park
- Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA
| | - Noreen Fulton
- Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA
| | - Alex Woods
- Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA
| | - Liping Meng
- Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA
| | - Justin Kline
- Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA
| | - Gordana Raca
- Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA
| | - Olatoyosi Odenike
- Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA
| | | | | | - Yo Matsuo
- OncoTherapy Science, Inc., Kanagawa, Japan
| | - Wendy Stock
- Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA
| | - Yusuke Nakamura
- Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA
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22
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Lynch JR, Yi H, Casolari DA, Voli F, Gonzales-Aloy E, Fung TK, Liu B, Brown A, Liu T, Haber M, Norris MD, Lewis ID, So CWE, D'Andrea RJ, Wang JY. Gaq signaling is required for the maintenance of MLL-AF9-induced acute myeloid leukemia. Leukemia 2016; 30:1745-8. [PMID: 26859074 DOI: 10.1038/leu.2016.24] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Affiliation(s)
- J R Lynch
- Cancer and Stem Cell Biology Group, Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
| | - H Yi
- Cancer and Stem Cell Biology Group, Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
| | - D A Casolari
- Acute Leukemia Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia
- Department of Haematology, SA Pathology and Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - F Voli
- Cancer and Stem Cell Biology Group, Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
| | - E Gonzales-Aloy
- Cancer and Stem Cell Biology Group, Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
| | - T K Fung
- Leukaemia and Stem Cell Biology Group, Department of Haematological Medicine, King's College London, Denmark Hill, London, UK
| | - B Liu
- Kids Cancer Alliance, Translational Cancer Research Centre for Kids, Cancer Institute New South Wales, Sydney, NSW, Australia
| | - A Brown
- Acute Leukemia Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia
- Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, South Australia, Australia
| | - T Liu
- Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
- Centre for Childhood Cancer Research, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - M Haber
- Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
| | - M D Norris
- Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
- Centre for Childhood Cancer Research, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - I D Lewis
- Acute Leukemia Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia
- Department of Haematology, SA Pathology and Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - C W E So
- Leukaemia and Stem Cell Biology Group, Department of Haematological Medicine, King's College London, Denmark Hill, London, UK
| | - R J D'Andrea
- Acute Leukemia Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia
- Department of Haematology, SA Pathology and Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - J Y Wang
- Cancer and Stem Cell Biology Group, Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
- Centre for Childhood Cancer Research, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
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23
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Yang SH, Li CF, Chu PY, Ko HH, Chen LT, Chen WW, Han CH, Lung JH, Shih NY. Overexpression of regulator of G protein signaling 11 promotes cell migration and associates with advanced stages and aggressiveness of lung adenocarcinoma. Oncotarget 2016; 7:31122-31136. [PMID: 27105500 PMCID: PMC5058744 DOI: 10.18632/oncotarget.8860] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Accepted: 04/01/2016] [Indexed: 11/25/2022] Open
Abstract
Regulator of G protein signaling 11 (RGS11), a member of the R7 subfamily of RGS proteins, is a well-characterized GTPase-accelerating protein that is involved in the heterotrimeric G protein regulation of the amplitude and kinetics of receptor-promoted signaling in retinal bipolar and nerve cells. However, the role of RGS11 in cancer is completely unclear. Using subtractive hybridization analysis, we found that RGS11 was highly expressed in the lymph-node metastatic tissues and bone-metastatic tumors obtained from patients with lung adenocarcinoma. Characterization of the clinicopathological features of 91 patients showed that around 57.1% of the tumor samples displayed RGS11 overexpression that was associated with primary tumor status, nodal metastasis and increased disease stages. Its high expression was an independent predictive factor for poor prognosis of these patients. Cotransfection of guanine nucleotide-binding protein beta-5 (GNB5) markedly increased RGS11 expression. Enhancement or attenuation of RGS11 expression pinpointed its specific role in cell migration, but not in cell invasion and proliferation. Signaling events initiated by the RGS11-GNB5 coexpression activated the c-Raf/ERK/FAK-mediated pathway through upregulation of the Rac1 activity. Consistently, increasing the cell invasiveness of the transfectants by additional cotransfection of the exogenous urokinase-plasminogen activator gene caused a significant promotion in cell invasion in vitro and in vivo, confirming that RGS11 functions in cell migration, but requires additional proteolytic activity for cell and tissue invasion. Collectively, overexpression of RGS11 promotes cell migration, participates in tumor metastasis, and correlates the clinicopathological conditions of patients with lung adenocarcinoma.
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Affiliation(s)
- Sheng-Huei Yang
- Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
| | - Chien-Feng Li
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
- Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan
| | - Pei-Yi Chu
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
- Department of Pathology, Show Chwan Memorial Hospital, Changhua City, Taiwan
| | - Hsiu-Hsing Ko
- Division of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Tri-Service General Hospital, Taipei, Taiwan
| | - Li-Tzong Chen
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
| | - Wan-Wen Chen
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
| | - Chia-Hung Han
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
| | - Jr-Hau Lung
- Division of Pulmonary and Critical care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Neng-Yao Shih
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaoshiung Medical University, Kaoshiung, Taiwan
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24
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Jiang X, Hu C, Arnovitz S, Bugno J, Yu M, Zuo Z, Chen P, Huang H, Ulrich B, Gurbuxani S, Weng H, Strong J, Wang Y, Li Y, Salat J, Li S, Elkahloun AG, Yang Y, Neilly MB, Larson RA, Le Beau MM, Herold T, Bohlander SK, Liu PP, Zhang J, Li Z, He C, Jin J, Hong S, Chen J. miR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia. Nat Commun 2016; 7:11452. [PMID: 27116251 PMCID: PMC5477496 DOI: 10.1038/ncomms11452] [Citation(s) in RCA: 108] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Accepted: 03/23/2016] [Indexed: 01/07/2023] Open
Abstract
MicroRNAs are subject to precise regulation and have key roles in tumorigenesis. In contrast to the oncogenic role of miR-22 reported in myelodysplastic syndrome (MDS) and breast cancer, here we show that miR-22 is an essential anti-tumour gatekeeper in de novo acute myeloid leukaemia (AML) where it is significantly downregulated. Forced expression of miR-22 significantly suppresses leukaemic cell viability and growth in vitro, and substantially inhibits leukaemia development and maintenance in vivo. Mechanistically, miR-22 targets multiple oncogenes, including CRTC1, FLT3 and MYCBP, and thus represses the CREB and MYC pathways. The downregulation of miR-22 in AML is caused by TET1/GFI1/EZH2/SIN3A-mediated epigenetic repression and/or DNA copy-number loss. Furthermore, nanoparticles carrying miR-22 oligos significantly inhibit leukaemia progression in vivo. Together, our study uncovers a TET1/GFI1/EZH2/SIN3A/miR-22/CREB-MYC signalling circuit and thereby provides insights into epigenetic/genetic mechanisms underlying the pathogenesis of AML, and also highlights the clinical potential of miR-22-based AML therapy.
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Affiliation(s)
- Xi Jiang
- Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio 45219, USA.,Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA
| | - Chao Hu
- Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio 45219, USA.,Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.,Department of Hematology, The First Affiliated Hospital Zhejiang University, Hangzhou, 310003 Zhejiang, China
| | - Stephen Arnovitz
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA
| | - Jason Bugno
- Department of Biopharmaceutical Sciences College of Pharmacy, The University of Illinois, Chicago, Illinois 60612, USA
| | - Miao Yu
- Department of Chemistry and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois 60637, USA
| | - Zhixiang Zuo
- Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio 45219, USA.,Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060 Guangzhou, China
| | - Ping Chen
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA
| | - Hao Huang
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA
| | - Bryan Ulrich
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA
| | - Sandeep Gurbuxani
- Department of Pathology, University of Chicago, Chicago, Illinois 60637, USA
| | - Hengyou Weng
- Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio 45219, USA.,Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA
| | - Jennifer Strong
- Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio 45219, USA
| | - Yungui Wang
- Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio 45219, USA.,Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.,Department of Hematology, The First Affiliated Hospital Zhejiang University, Hangzhou, 310003 Zhejiang, China
| | - Yuanyuan Li
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA
| | - Justin Salat
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA
| | - Shenglai Li
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA
| | - Abdel G Elkahloun
- Division of Intramural Research, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA
| | - Yang Yang
- Department of Biopharmaceutical Sciences College of Pharmacy, The University of Illinois, Chicago, Illinois 60612, USA
| | - Mary Beth Neilly
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA
| | - Richard A Larson
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA
| | - Michelle M Le Beau
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA
| | - Tobias Herold
- Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität, 81377 Munich, Germany
| | - Stefan K Bohlander
- Department of Molecular Medicine and Pathology, University of Auckland, Auckland 1142, New Zealand
| | - Paul P Liu
- Division of Intramural Research, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA
| | - Jiwang Zhang
- Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, Illinois 60153, USA
| | - Zejuan Li
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.,Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA
| | - Chuan He
- Department of Chemistry and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois 60637, USA
| | - Jie Jin
- Department of Hematology, The First Affiliated Hospital Zhejiang University, Hangzhou, 310003 Zhejiang, China
| | - Seungpyo Hong
- Department of Biopharmaceutical Sciences College of Pharmacy, The University of Illinois, Chicago, Illinois 60612, USA.,Integrated Science and Engineering Division, Underwood International College, Yonsei University, Incheon 406-840, Korea
| | - Jianjun Chen
- Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio 45219, USA.,Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA
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25
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Wang J, Li T, Zhou M, Hu Z, Zhou X, Zhou S, Wang N, Huang L, Zhao L, Cao Y, Xiao M, Ma D, Zhou P, Shang Z, Zhou J. TALENs-mediated gene disruption of FLT3 in leukemia cells: Using genome-editing approach for exploring the molecular basis of gene abnormality. Sci Rep 2015; 5:18454. [PMID: 26669855 PMCID: PMC4680874 DOI: 10.1038/srep18454] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 11/17/2015] [Indexed: 12/11/2022] Open
Abstract
Novel analytic tools are needed to elucidate the molecular basis of leukemia-relevant gene mutations in the post-genome era. We generated isogenic leukemia cell clones in which the FLT3 gene was disrupted in a single allele using TALENs. Isogenic clones with mono-allelic disrupted FLT3 were compared to an isogenic wild-type control clone and parental leukemia cells for transcriptional expression, downstream FLT3 signaling and proliferation capacity. The global gene expression profiles of mutant K562 clones and corresponding wild-type controls were compared using RNA-seq. The transcriptional levels and the ligand-dependent autophosphorylation of FLT3 were decreased in the mutant clones. TALENs-mediated FLT3 haplo-insufficiency impaired cell proliferation and colony formation in vitro. These inhibitory effects were maintained in vivo, improving the survival of NOD/SCID mice transplanted with mutant K562 clones. Cluster analysis revealed that the gene expression pattern of isogenic clones was determined by the FLT3 mutant status rather than the deviation among individual isogenic clones. Differentially expressed genes between the mutant and wild-type clones revealed an activation of nonsense-mediated decay pathway in mutant K562 clones as well as an inhibited FLT3 signaling. Our data support that this genome-editing approach is a robust and generally applicable platform to explore the molecular bases of gene mutations.
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Affiliation(s)
- Jue Wang
- Department of hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Tongjuan Li
- Department of hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Mi Zhou
- Department of hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zheng Hu
- Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaoxi Zhou
- Department of hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shiqiu Zhou
- Department of hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Na Wang
- Department of hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Liang Huang
- Department of hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lei Zhao
- Department of hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yang Cao
- Department of hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Min Xiao
- Department of hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ding Ma
- Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Pengfei Zhou
- Wuhan YZY Bio-Pharma Co., Ltd., Wuhan, Hubei, China
| | - Zhen Shang
- Department of hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jianfeng Zhou
- Department of hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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26
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Wen WW, Sun X, Zhuang HF, Lin XJ, Zheng ZY, Gao RL, Yin LM. Effects of panaxadiol saponins component as a new Chinese patent medicine on proliferation, differentiation and corresponding gene expression profile of megakaryocytes. Chin J Integr Med 2015; 22:28-35. [DOI: 10.1007/s11655-015-1970-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Indexed: 12/14/2022]
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27
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van der Linden MH, Seslija L, Schneider P, Driessen EMC, Castro PG, Stumpel DJPM, van Roon E, de Boer J, Williams O, Pieters R, Stam RW. Identification of genes transcriptionally responsive to the loss of MLL fusions in MLL-rearranged acute lymphoblastic leukemia. PLoS One 2015; 10:e0120326. [PMID: 25793396 PMCID: PMC4368425 DOI: 10.1371/journal.pone.0120326] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2014] [Accepted: 01/20/2015] [Indexed: 01/08/2023] Open
Abstract
INTRODUCTION MLL-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year) is characterized by high relapse rates and a dismal prognosis. To facilitate the discovery of novel therapeutic targets, we here searched for genes directly influenced by the repression of various MLL fusions. METHODS For this, we performed gene expression profiling after siRNA-mediated repression of MLL-AF4, MLL-ENL, and AF4-MLL in MLL-rearranged ALL cell line models. The obtained results were compared with various already established gene signatures including those consisting of known MLL-AF4 target genes, or those associated with primary MLL-rearranged infant ALL samples. RESULTS Genes that were down-regulated in response to the repression of MLL-AF4 and MLL-ENL appeared characteristically expressed in primary MLL-rearranged infant ALL samples, and often represented known MLL-AF4 targets genes. Genes that were up-regulated in response to the repression of MLL-AF4 and MLL-ENL often represented genes typically silenced by promoter hypermethylation in MLL-rearranged infant ALL. Genes that were affected in response to the repression of AF4-MLL showed significant enrichment in gene expression profiles associated with AF4-MLL expressing t(4;11)+ infant ALL patient samples. CONCLUSION We conclude that the here identified genes readily responsive to the loss of MLL fusion expression potentially represent attractive therapeutic targets and may provide additional insights in MLL-rearranged acute leukemias.
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Affiliation(s)
- Marieke H. van der Linden
- Department of Pediatric Oncology/Hematology, Erasmus MC—Sophia Children’s Hospital, Rotterdam, The Netherlands
| | - Lidija Seslija
- Department of Pediatric Oncology/Hematology, Erasmus MC—Sophia Children’s Hospital, Rotterdam, The Netherlands
| | - Pauline Schneider
- Department of Pediatric Oncology/Hematology, Erasmus MC—Sophia Children’s Hospital, Rotterdam, The Netherlands
| | - Emma M. C. Driessen
- Department of Pediatric Oncology/Hematology, Erasmus MC—Sophia Children’s Hospital, Rotterdam, The Netherlands
| | - Patricia Garrido Castro
- Department of Pediatric Oncology/Hematology, Erasmus MC—Sophia Children’s Hospital, Rotterdam, The Netherlands
| | - Dominique J. P. M. Stumpel
- Department of Pediatric Oncology/Hematology, Erasmus MC—Sophia Children’s Hospital, Rotterdam, The Netherlands
| | - Eddy van Roon
- Department of Pediatric Oncology/Hematology, Erasmus MC—Sophia Children’s Hospital, Rotterdam, The Netherlands
| | - Jasper de Boer
- Molecular Haematology and Cancer Biology Unit, University College London Institute of Child Health and Great Ormond Street Hospital for Children, London, United Kingdom
| | - Owen Williams
- Molecular Haematology and Cancer Biology Unit, University College London Institute of Child Health and Great Ormond Street Hospital for Children, London, United Kingdom
| | - Rob Pieters
- Department of Pediatric Oncology/Hematology, Erasmus MC—Sophia Children’s Hospital, Rotterdam, The Netherlands
- Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Ronald W. Stam
- Department of Pediatric Oncology/Hematology, Erasmus MC—Sophia Children’s Hospital, Rotterdam, The Netherlands
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28
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Saied MH, Marzec J, Khalid S, Smith P, Molloy G, Young BD. Trisomy 8 Acute Myeloid Leukemia Analysis Reveals New Insights of DNA Methylome with Identification of HHEX as Potential Diagnostic Marker. BIOMARKERS IN CANCER 2015; 7:1-6. [PMID: 25674022 PMCID: PMC4315123 DOI: 10.4137/bic.s19614] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 11/09/2014] [Accepted: 11/13/2014] [Indexed: 01/17/2023]
Abstract
Trisomy 8 acute myeloid leukemia (AML) is the commonest numerical aberration in AML. Here we present a global analysis of trisomy 8 AML using methylated DNA immunoprecipitation-sequencing (MeDIP-seq). The study is based on three diagnostic trisomy 8 AML and their parallel relapse status in addition to nine non-trisomic AML and four normal bone marrows (NBMs). In contrast to non-trisomic DNA samples, trisomy 8 AML showed a characteristic DNA methylation distribution pattern because an increase in the frequency of the hypermethylation signals in chromosome 8 was associated with an increase in the hypomethylation signals in the rest of the chromosomes. Chromosome 8 hypermethylation signals were found mainly in the CpG island (CGI) shores and interspersed repeats. Validating the most significant differentially methylated CGI (P = 7.88 × 10(-11)) identified in trisomy 8 AML demonstrated a specific core region within the gene body of HHEX, which was significantly correlated with HHEX expression in both diagnostic and relapse trisomy 8 AMLs. Overall, the existence of extra chromosome 8 was associated with a global impact on the DNA methylation distribution with identification of HHEX gene methylation as a potential diagnostic marker for trisomy 8 AML.
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Affiliation(s)
- Marwa H Saied
- Centre for Haemato-Oncology, Barts Cancer Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom
- Clinical Pathology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Jacek Marzec
- Centre for Haemato-Oncology, Barts Cancer Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom
- Centre for Molecular Oncology, Barts Cancer Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom
| | - Sabah Khalid
- Centre for Haemato-Oncology, Barts Cancer Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom
| | - Paul Smith
- Centre for Haemato-Oncology, Barts Cancer Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom
| | - Gael Molloy
- Centre for Haemato-Oncology, Barts Cancer Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom
| | - Bryan D Young
- Centre for Haemato-Oncology, Barts Cancer Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom
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29
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Physiology of RGS10 in Neurons and Immune Cells. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2015; 133:153-67. [DOI: 10.1016/bs.pmbts.2015.01.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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30
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Ying L, Lin J, Qiu F, Cao M, Chen H, Liu Z, Huang Y. Epigenetic repression of regulator of G-protein signaling 2 by ubiquitin-like with PHD and ring-finger domain 1 promotes bladder cancer progression. FEBS J 2014; 282:174-82. [PMID: 25323766 DOI: 10.1111/febs.13116] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Revised: 09/12/2014] [Accepted: 10/15/2014] [Indexed: 12/18/2022]
Abstract
Ubiquitin-like with PHD and ring-finger domain 1 (UHRF1) binds to methylated promoters of tumor-suppressor genes and suppresses gene expression by forming complexes with DNA methyltransferases. Recent studies have shown that repression of regulator of G-protein signaling (RGS) 2 increases cancer cell growth. However, little is known about whether UHRF1 promotes bladder cancer progression by epigenetic silencing of RGS2. Here, we show that UHRF1 expression is increased in bladder cancer cell lines and in most bladder cancer tissues as compared with normal controls. UHRF1 overexpression increases bladder cancer cell proliferation, whereas inhibition of UHRF1 suppresses cell proliferation. In bladder cancer cells, UHRF1 inhibits RGS2 expression by increasing the methylation of CpG nucleotides of the RGS2 promoter. DNA methylation analysis showed tumor-specific TGS2 promoter methylation in 73% (38/52) of bladder tumors. High UHRF1 expression of correlated with aberrant TGS2 promoter methylation in bladder tumors, which results in the loss of TGS2 expression, as confirmed by demethylation analysis in cell lines. Functionally, re-expression of RGS2 partly abrogates UHRF1-induced bladder cell proliferation. Furthermore, Kaplan-Meier analysis showed that low TGS2 expression is significantly correlated with reduced overall survival in patients with bladder cancer. These results demonstrate that epigenetic repression of RGS2 by UHRF1 contributes to bladder cancer progression.
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Affiliation(s)
- Liang Ying
- Department of Urology, Renji Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, China
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31
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Yang S, Hao L, McConnell M, Zhou X, Wang M, Zhang Y, Mountz JD, Reddy M, Eleazer PD, Li YP, Chen W. Inhibition of Rgs10 Expression Prevents Immune Cell Infiltration in Bacteria-induced Inflammatory Lesions and Osteoclast-mediated Bone Destruction. Bone Res 2013; 1:267-281. [PMID: 24761229 DOI: 10.4248/br201303005] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Regulator of G-protein Signaling 10 (Rgs10) plays an important function in osteoclast differentiation. However, the role of Rgs10 in immune cells and inflammatory responses, which activate osteoclasts in inflammatory lesions, such as bacteria-induced periodontal disease lesions, remains largely unknown. In this study, we used an adeno-associated virus (AAV-) mediated RNAi (AAV-shRNA-Rgs10) knockdown approach to study Rgs10's function in immune cells and osteoclasts in bacteria-induced inflammatory lesions in a mouse model of periodontal disease. We found that AAV-shRNA-Rgs10 mediated Rgs10 knockdown impaired osteoclastogenesis and osteoclast-mediated bone resorption, in vitro and in vivo. Interestingly, local injection of AAV-shRNA-Rgs10 into the periodontal tissues in the bacteria-induced inflammatory lesion greatly decreased the number of dendritic cells, T-cells and osteoclasts, and protected the periodontal tissues from local inflammatory damage and bone destruction. Importantly, AAV-mediated Rgs10 knockdown also reduced local expression of osteoclast markers and pro-inflammatory cytokines. Our results demonstrate that AAV-shRNA-Rgs10 knockdown in periodontal disease tissues can prevent bone resorption and inflammation simultaneously. Our data indicate that Rgs10 may regulate dendritic cell proliferation and maturation, as well as the subsequent stimulation of T-cell proliferation and maturation, and osteoclast differentiation and activation. Our study suggests that AAV-shRNA-Rgs10 can be useful as a therapeutic treatment of periodontal disease.
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Affiliation(s)
- Sen Yang
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Liang Hao
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Matthew McConnell
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Xuedong Zhou
- The State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Sichuan, P. R. China
| | - Min Wang
- The State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Sichuan, P. R. China
| | - Yan Zhang
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - John D Mountz
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Michael Reddy
- Department of Periodontology, University of Alabama at Birmingham School of Dentistry, Birmingham, Alabama, USA
| | - Paul D Eleazer
- Department of Endodontics, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Yi-Ping Li
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Wei Chen
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA
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32
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The Impact of FLT3 Mutations on the Development of Acute Myeloid Leukemias. LEUKEMIA RESEARCH AND TREATMENT 2013; 2013:275760. [PMID: 23936658 PMCID: PMC3725705 DOI: 10.1155/2013/275760] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/01/2013] [Revised: 04/30/2013] [Accepted: 05/14/2013] [Indexed: 11/17/2022]
Abstract
The development of the genetic studies on acute myeloid leukemias (AMLs) has led to the identification of some recurrent genetic abnormalities. Their discovery was of fundamental importance not only for a better understanding of the molecular pathogenesis of AMLs, but also for the identification of new therapeutic targets. In this context, it is essential to identify AML-associated “driver” mutations, which have a causative role in leukemogenesis. Evidences accumulated during the last years indicate that activating internal tandem duplication mutations in FLT3 (FLT3-ITD), detected in about 20% of AMLs, represents driver mutations and valid therapeutic targets in AMLs. Furthermore, the screening of FLT3-ITD mutations has also considerably helped to improve the identification of more accurate prognostic criteria and of the therapeutic selection of patients.
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33
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Volpe G, Walton DS, Del Pozzo W, Garcia P, Dassé E, O’Neill LP, Griffiths M, Frampton J, Dumon S. C/EBPα and MYB regulate FLT3 expression in AML. Leukemia 2013; 27:1487-96. [PMID: 23340802 PMCID: PMC4214120 DOI: 10.1038/leu.2013.23] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2012] [Revised: 12/22/2012] [Accepted: 01/09/2013] [Indexed: 11/09/2022]
Abstract
The interaction between the receptor FLT3 (FMS-like tyrosine kinase-3) and its ligand FL leads to crucial signalling during the early stages of the commitment of haematopoietic stem cells. Mutation or over-expression of the FLT3 gene, leading to constitutive signalling, enhances the survival and expansion of a variety of leukaemias and is associated with an unfavourable clinical outcome for acute myeloid leukaemia (AML) patients. In this study, we used a murine cellular model for AML and primary leukaemic cells from AML patients to investigate the molecular mechanisms underlying the regulation of FLT3 gene expression and identify its key cis- and trans-regulators. By assessing DNA accessibility and epigenetic markings, we defined regulatory domains in the FLT3 promoter and first intron. These elements permit in vivo binding of several AML-related transcription factors, including the proto-oncogene MYB and the CCAAT/enhancer binding protein C/EBPα, which are recruited to the FLT3 promoter and intronic module, respectively. Substantiating their relevance to the human disease, our analysis of gene expression profiling arrays from AML patients uncovered significant correlations between FLT3 expression level and that of MYB and CEBPA. The latter relationship permits discrimination between patients with CEBPA mono- and bi-allelic mutations, and thus connects two major prognostic factors for AML.
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MESH Headings
- Animals
- Base Sequence
- CCAAT-Enhancer-Binding Proteins/genetics
- CCAAT-Enhancer-Binding Proteins/metabolism
- Cell Line, Tumor
- Disease Models, Animal
- Epigenesis, Genetic/physiology
- Gene Expression Regulation, Leukemic/physiology
- Genetic Complementation Test
- Homeodomain Proteins/genetics
- Humans
- Introns/genetics
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/metabolism
- Mice
- Molecular Sequence Data
- Myeloid Ecotropic Viral Integration Site 1 Protein
- Neoplasm Proteins/genetics
- Promoter Regions, Genetic/genetics
- Proto-Oncogene Mas
- Proto-Oncogene Proteins c-myb/genetics
- Proto-Oncogene Proteins c-myb/metabolism
- Tumor Cells, Cultured
- fms-Like Tyrosine Kinase 3/genetics
- fms-Like Tyrosine Kinase 3/metabolism
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Affiliation(s)
- G Volpe
- Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - DS Walton
- Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - W Del Pozzo
- Nikhef, Science Park, Amsterdam, XG, The Netherlands
| | - P Garcia
- Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - E Dassé
- Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - LP O’Neill
- Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - M Griffiths
- West Midlands Regional Genetics Laboratory, Birmingham Women’s NHS Foundation Trust, Birmingham, UK
| | - J Frampton
- Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - S Dumon
- Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
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34
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Smrcka AV. Molecular targeting of Gα and Gβγ subunits: a potential approach for cancer therapeutics. Trends Pharmacol Sci 2013; 34:290-8. [PMID: 23557963 DOI: 10.1016/j.tips.2013.02.006] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2012] [Revised: 02/21/2013] [Accepted: 02/26/2013] [Indexed: 11/26/2022]
Abstract
G-Protein-coupled receptors (GPCRs) signal through G protein α and βγ subunit families to regulate a wide range of physiological and pathophysiological processes. As such, GPCRs are major targets for therapeutic drugs. Downstream targets of GPCRs have also gained interest as a therapeutic approach to complex pathologies involving multiple GPCRs. One such approach involves targeting of the G proteins themselves. Several small molecule Gα and Gβγ modulators have been developed and been tested in various animal models of disease. Here we will discuss the requirements for targeting Gα and Gβγ subunits, the mechanisms of action of currently identified inhibitors, and focus on the potential utility of Gα and Gβγ inhibitors in the treatment of various cancers.
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Affiliation(s)
- Alan V Smrcka
- Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
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35
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Bulk E, Yu J, Hascher A, Koschmieder S, Wiewrodt R, Krug U, Timmermann B, Marra A, Hillejan L, Wiebe K, Berdel WE, Schwab A, Müller-Tidow C. Mutations of the EPHB6 receptor tyrosine kinase induce a pro-metastatic phenotype in non-small cell lung cancer. PLoS One 2012; 7:e44591. [PMID: 23226491 PMCID: PMC3514309 DOI: 10.1371/journal.pone.0044591] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2012] [Accepted: 08/03/2012] [Indexed: 12/16/2022] Open
Abstract
Alterations of Eph receptor tyrosine kinases are frequent events in human cancers. Genetic variations of EPHB6 have been described but the functional outcome of these alterations is unknown. The current study was conducted to screen for the occurrence and to identify functional consequences of EPHB6 mutations in non-small cell lung cancer. Here, we sequenced the entire coding region of EPHB6 in 80 non-small cell lung cancer patients and 3 tumor cell lines. Three potentially relevant mutations were identified in primary patient samples of NSCLC patients (3.8%). Two point mutations led to instable proteins. An in frame deletion mutation (del915-917) showed enhanced migration and accelerated wound healing in vitro. Furthermore, the del915-917 mutation increased the metastatic capability of NSCLC cells in an in vivo mouse model. Our results suggest that EPHB6 mutations promote metastasis in a subset of patients with non-small cell lung cancer.
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Affiliation(s)
- Etmar Bulk
- Department of Medicine A – Hematology, Oncology, Pneumology, University of Muenster, Muenster, Germany
- Institute of Physiology II, University of Muenster, Muenster, Germany
| | - Jun Yu
- Department of Medicine A – Hematology, Oncology, Pneumology, University of Muenster, Muenster, Germany
- Center of Teaching Experiment, School of Basic Medical Science, Fourth Military Medical University, Xi’an, Shaanxi, People’s Republic of China
| | - Antje Hascher
- Department of Medicine A – Hematology, Oncology, Pneumology, University of Muenster, Muenster, Germany
| | - Steffen Koschmieder
- Department of Medicine A – Hematology, Oncology, Pneumology, University of Muenster, Muenster, Germany
| | - Rainer Wiewrodt
- Department of Medicine A – Hematology, Oncology, Pneumology, University of Muenster, Muenster, Germany
| | - Utz Krug
- Department of Medicine A – Hematology, Oncology, Pneumology, University of Muenster, Muenster, Germany
| | | | - Alessandro Marra
- Department of Thoracic Surgery, Niels-Stensen-Hospital Ostercappeln, Ostercappeln, Germany
| | - Ludger Hillejan
- Department of Thoracic Surgery, Niels-Stensen-Hospital Ostercappeln, Ostercappeln, Germany
| | - Karsten Wiebe
- Department of Thoracic Surgery, University of Muenster, Muenster, Germany
| | - Wolfgang E. Berdel
- Department of Medicine A – Hematology, Oncology, Pneumology, University of Muenster, Muenster, Germany
| | - Albrecht Schwab
- Institute of Physiology II, University of Muenster, Muenster, Germany
| | - Carsten Müller-Tidow
- Department of Medicine A – Hematology, Oncology, Pneumology, University of Muenster, Muenster, Germany
- * E-mail:
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36
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SOCS1 cooperates with FLT3-ITD in the development of myeloproliferative disease by promoting the escape from external cytokine control. Blood 2012; 120:1691-702. [DOI: 10.1182/blood-2010-08-301416] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Abstract
Activating mutations in the receptor tyrosine kinase FLT3 are frequently found in acute myelogenous leukemia patients and confer poor clinical prognosis. It is unclear how leukemic blasts escape cytokine control that regulates normal hematopoiesis. We have recently demonstrated that FLT3-internal tandem duplication (ITD), when localized to the biosynthetic compartment, aberrantly activates STAT5. Here, we show that one of the target genes induced by STAT5 is suppressor of cytokine signaling (SOCS)1—a surprising finding for a known tumor suppressor. Although SOCS1 expression in murine bone marrow severely impaired cytokine-induced colony growth, it failed to inhibit FLT3-ITD–supported colony growth, indicating resistance of FLT3-ITD to SOCS1. In addition, SOCS1 coexpression did not affect FLT3-ITD–mediated signaling or proliferation. Importantly, SOCS1 coexpression inhibited interferon-α and interferon-γ signaling and protected FLT3-ITD hematopoietic cells from interferon-mediated growth inhibitory effects. In a murine bone marrow transplantation model, the coexpression of SOCS1 and FLT3-ITD significantly shortened the latency of a myeloproliferative disease compared with FLT3-ITD alone (P < .01). Mechanistically, SOCS proteins shield FLT3-ITD from external cytokine control, thereby promoting leukemogenesis. The data demonstrate that SOCS1 acts as a conditional oncogene, providing novel molecular insights into cytokine resistance in oncogenic transformation. Restoring cytokine control may provide a new way of therapeutic intervention.
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37
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Wolff DW, Xie Y, Deng C, Gatalica Z, Yang M, Wang B, Wang J, Lin MF, Abel PW, Tu Y. Epigenetic repression of regulator of G-protein signaling 2 promotes androgen-independent prostate cancer cell growth. Int J Cancer 2012; 130:1521-31. [PMID: 21500190 PMCID: PMC3155664 DOI: 10.1002/ijc.26138] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2011] [Accepted: 04/01/2011] [Indexed: 12/28/2022]
Abstract
G-protein-coupled receptor (GPCR)-stimulated androgen-independent activation of androgen receptor (AR) contributes to acquisition of a hormone-refractory phenotype by prostate cancer. We previously reported that regulator of G-protein signaling (RGS) 2, an inhibitor of GPCRs, inhibits androgen-independent AR activation (Cao et al., Oncogene 2006;25:3719-34). Here, we show reduced RGS2 protein expression in human prostate cancer specimens compared to adjacent normal or hyperplastic tissue. Methylation-specific PCR analysis and bisulfite sequencing indicated that methylation of the CpG island in the RGS2 gene promoter correlated with RGS2 downregulation in prostate cancer. In vitro methylation of this promoter suppressed reporter gene expression in transient transfection studies, whereas reversal of this promoter methylation with 5-aza-2'-deoxycytidine (5-Aza-dC) induced RGS2 reexpression in androgen-independent prostate cancer cells and inhibited their growth under androgen-deficient conditions. Interestingly, the inhibitory effect of 5-Aza-dC was significantly reduced by an RGS2-targeted short hairpin RNA, indicating that reexpressed RGS2 contributed to this growth inhibition. Restoration of RGS2 levels by ectopic expression in androgen-independent prostate cancer cells suppressed growth of xenografts in castrated mice. Thus, RGS2 promoter hypermethylation represses its expression and unmasks a latent pathway for AR transactivation in prostate cancer cells. Targeting this reversible process may provide a new strategy for suppressing prostate cancer progression by reestablishing its androgen sensitivity.
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Affiliation(s)
- Dennis W. Wolff
- Department of Pharmacology, Creighton University School of Medicine, Omaha, NE 68178, USA
| | - Yan Xie
- Department of Pharmacology, Creighton University School of Medicine, Omaha, NE 68178, USA
| | - Caishu Deng
- Department of Pathology, Creighton University School of Medicine, Omaha, NE 68178, USA
| | - Zoran Gatalica
- Department of Pathology, Creighton University School of Medicine, Omaha, NE 68178, USA
| | - Mingjie Yang
- Department of Pharmacology, Creighton University School of Medicine, Omaha, NE 68178, USA
| | - Bo Wang
- Department of Pathology, Creighton University School of Medicine, Omaha, NE 68178, USA
| | - Jincheng Wang
- Department of Pharmacology, Creighton University School of Medicine, Omaha, NE 68178, USA
- National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Ming-Fong Lin
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Peter W. Abel
- Department of Pharmacology, Creighton University School of Medicine, Omaha, NE 68178, USA
| | - Yaping Tu
- Department of Pharmacology, Creighton University School of Medicine, Omaha, NE 68178, USA
- National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
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38
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Sorafenib treatment of FLT3-ITD(+) acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a D835 mutation. Blood 2012; 119:5133-43. [PMID: 22368270 DOI: 10.1182/blood-2011-06-363960] [Citation(s) in RCA: 238] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 (FLT3) gene occurs in 30% of acute myeloid leukemias (AMLs) and confers a poor prognosis. Thirteen relapsed or chemo-refractory FLT3-ITD(+) AML patients were treated with sorafenib (200-400 mg twice daily). Twelve patients showed clearance or near clearance of bone marrow myeloblasts after 27 (range 21-84) days with evidence of differentiation of leukemia cells. The sorafenib response was lost in most patients after 72 (range 54-287) days but the FLT3 and downstream effectors remained suppressed. Gene expression profiling showed that leukemia cells that have become sorafenib resistant expressed several genes including ALDH1A1, JAK3, and MMP15, whose functions were unknown in AML. Nonobese diabetic/severe combined immunodeficiency mice transplanted with leukemia cells from patients before and during sorafenib resistance recapitulated the clinical results. Both ITD and tyrosine kinase domain mutations at D835 were identified in leukemia initiating cells (LICs) from samples before sorafenib treatment. LICs bearing the D835 mutant have expanded during sorafenib treatment and dominated during the subsequent clinical resistance. These results suggest that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations, and might provide important leads to further improvement of treatment outcome with FLT3 inhibitors.
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39
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Abstract
The characterization of functional CD8(+) inhibitory or regulatory T cells and their gene regulation remains a critical challenge in the field of tolerance and autoimmunity. Investigating the genes induced in regulatory cells and the regulatory networks and pathways that underlie mechanisms of immune resistance and prevent apoptosis in the CD8(+) T cell compartment are crucial to understanding tolerance mechanisms in systemic autoimmunity. Little is currently known about the genetic control that governs the ability of CD8(+) Ti or regulatory cells to suppress anti-DNA Ab production in B cells. Silencing genes with siRNA or shRNA and overexpression of genes with lentiviral cDNA transduction are established approaches to identifying and understanding the function of candidate genes in tolerance and immunity. Elucidation of interactions between genes and proteins, and their synergistic effects in establishing cell-cell cross talk, including receptor modulation/antagonism, are essential for delineating the roles of these cells. In this review, we will examine recent reports which describe the modulation of cells from lupus prone mice or lupus patients to confer anti-inflammatory and protective gene expression and novel associated phenotypes. We will highlight recent findings on the role of selected genes induced by peptide tolerance in CD8(+) Ti.
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40
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Kühnl A, Kaiser M, Neumann M, Fransecky L, Heesch S, Radmacher M, Marcucci G, Bloomfield CD, Hofmann WK, Thiel E, Baldus CD. High expression of IGFBP2 is associated with chemoresistance in adult acute myeloid leukemia. Leuk Res 2011; 35:1585-90. [PMID: 21899885 DOI: 10.1016/j.leukres.2011.08.006] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2011] [Revised: 08/08/2011] [Accepted: 08/09/2011] [Indexed: 12/22/2022]
Abstract
Insulin-like growth factor (IGF) signaling plays an important role in many tumors and overexpression of IGF Binding Protein (IGFBP) 2 has been associated with adverse outcome in childhood leukemia. Here, we evaluated IGFBP2 mRNA expression and its prognostic implications in 99 adult acute myeloid leukemia (AML) patients by quantitative real-time RT-PCR. High IGFBP2 was associated with a high incidence of primary resistant disease (IGFBP2 high 65%, IGFBP2 low 32%; P=0.02) and was independently predictive for therapy resistance [OR 3.6 (95% CI 1.2-11); P=0.02] in multivariate analyses. Gene-expression profiling revealed an up-regulation of genes implicated in leukemogenesis (MYB, MEIS1, HOXB3, HOXA9) and genes associated with adverse outcome (ERG, WT1) in patients with high IGFBP2 expression. Thus, our data suggest a role of IGFBP2 and IGF signaling in chemoresistance of AML. Patients with high IGFBP2 expression might benefit from molecular therapies targeting the IGF pathway.
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Affiliation(s)
- Andrea Kühnl
- Department of Hematology and Oncology, Charité University Hospital, Campus Benjamin Franklin, Berlin, Germany.
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41
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Dai J, Gu J, Lu C, Lin J, Stewart D, Chang D, Roth JA, Wu X. Genetic variations in the regulator of G-protein signaling genes are associated with survival in late-stage non-small cell lung cancer. PLoS One 2011; 6:e21120. [PMID: 21698121 PMCID: PMC3117866 DOI: 10.1371/journal.pone.0021120] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2011] [Accepted: 05/19/2011] [Indexed: 01/08/2023] Open
Abstract
The regulator of G-protein signaling (RGS) pathway plays an important role in signaling transduction, cellular activities, and carcinogenesis. We hypothesized that genetic variations in RGS gene family may be associated with the response of late-stage non-small cell lung cancer (NSCLC) patients to chemotherapy or chemoradiotherapy. We selected 95 tagging single nucleotide polymorphisms (SNPs) in 17 RGS genes and genotyped them in 598 late-stage NSCLC patients. Thirteen SNPs were significantly associated with overall survival. Among them, rs2749786 of RGS12 was most significant. Stratified analysis by chemotherapy or chemoradiation further identified SNPs that were associated with overall survival in subgroups. Rs2816312 of RGS1 and rs6689169 of RGS7 were most significant in chemotherapy group and chemoradiotherapy group, respectively. A significant cumulative effect was observed when these SNPs were combined. Survival tree analyses identified potential interactions between rs944343, rs2816312, and rs1122794 in affecting survival time in patients treated with chemotherapy, while the genotype of rs6429264 affected survival in chemoradiation-treated patients. To our knowledge, this is the first study to reveal the importance of RGS gene family in the survival of late-stage NSCLC patients.
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Affiliation(s)
- Jingyao Dai
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Jian Gu
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Charles Lu
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Jie Lin
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - David Stewart
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - David Chang
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Jack A. Roth
- Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Xifeng Wu
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
- * E-mail:
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Heltemes-Harris LM, Willette MJL, Ramsey LB, Qiu YH, Neeley ES, Zhang N, Thomas DA, Koeuth T, Baechler EC, Kornblau SM, Farrar MA. Ebf1 or Pax5 haploinsufficiency synergizes with STAT5 activation to initiate acute lymphoblastic leukemia. ACTA ACUST UNITED AC 2011; 208:1135-49. [PMID: 21606506 PMCID: PMC3173246 DOI: 10.1084/jem.20101947] [Citation(s) in RCA: 132] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
As STAT5 is critical for the differentiation, proliferation, and survival of progenitor B cells, this transcription factor may play a role in acute lymphoblastic leukemia (ALL). Here, we show increased expression of activated signal transducer and activator of transcription 5 (STAT5), which is correlated with poor prognosis, in ALL patient cells. Mutations in EBF1 and PAX5, genes critical for B cell development have also been identified in human ALL. To determine whether mutations in Ebf1 or Pax5 synergize with STAT5 activation to induce ALL, we crossed mice expressing a constitutively active form of STAT5 (Stat5b-CA) with mice heterozygous for Ebf1 or Pax5. Haploinsufficiency of either Pax5 or Ebf1 synergized with Stat5b-CA to rapidly induce ALL in 100% of the mice. The leukemic cells displayed reduced expression of both Pax5 and Ebf1, but this had little effect on most EBF1 or PAX5 target genes. Only a subset of target genes was deregulated; this subset included a large percentage of potential tumor suppressor genes and oncogenes. Further, most of these genes appear to be jointly regulated by both EBF1 and PAX5. Our findings suggest a model whereby small perturbations in a self-reinforcing network of transcription factors critical for B cell development, specifically PAX5 and EBF1, cooperate with STAT5 activation to initiate ALL.
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Affiliation(s)
- Lynn M Heltemes-Harris
- Department of Laboratory Medicine and Pathology, The Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
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Boelte KC, Gordy LE, Joyce S, Thompson MA, Yang L, Lin PC. Rgs2 mediates pro-angiogenic function of myeloid derived suppressor cells in the tumor microenvironment via upregulation of MCP-1. PLoS One 2011; 6:e18534. [PMID: 21494556 PMCID: PMC3073977 DOI: 10.1371/journal.pone.0018534] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2011] [Accepted: 03/02/2011] [Indexed: 11/22/2022] Open
Abstract
Background Tumor growth is intimately linked with stromal interactions. Myeloid derived suppressor cells (MDSCs) are dramatically elevated in cancer patients and tumor bearing mice. MDSCs modulate the tumor microenvironment through attenuating host immune response and increasing vascularization. Methodology/Principal Findings In searching for molecular mediators responsible for pro-tumor functions, we found that regulator of G protein signaling-2 (Rgs2) is highly increased in tumor-derived MDSCs compared to control MDSCs. We further demonstrate that hypoxia, a common feature associated with solid tumors, upregulates the gene expression. Genetic deletion of Rgs2 in mice resulted in a significant retardation of tumor growth, and the tumors exhibit decreased vascular density and increased cell death. Interestingly, deletion of Rgs2 in MDSCs completely abolished their tumor promoting function, suggesting that Rgs2 signaling in MDSCs is responsible for the tumor promoting function. Cytokine array profiling identified that Rgs2−/− tumor MDSCs produce less MCP-1, leading to decreased angiogenesis, which could be restored with addition of recombinant MCP-1. Conclusion Our data reveal Rgs2 as a critical regulator of the pro-angiogenic function of MDSCs in the tumor microenvironment, through regulating MCP-1 production.
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Affiliation(s)
- Kimberly C. Boelte
- Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Laura E. Gordy
- Department of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Sebastian Joyce
- Department of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Mary Ann Thompson
- Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Li Yang
- Center for Cancer Research, National Institutes of Health, Bethesda, Maryland, United States of America
| | - P. Charles Lin
- Center for Cancer Research, National Institutes of Health, Bethesda, Maryland, United States of America
- * E-mail:
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Nunn C, Zhao P, Zou MX, Summers K, Guglielmo CG, Chidiac P. Resistance to age-related, normal body weight gain in RGS2 deficient mice. Cell Signal 2011; 23:1375-86. [PMID: 21447383 DOI: 10.1016/j.cellsig.2011.03.020] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2010] [Revised: 03/01/2011] [Accepted: 03/21/2011] [Indexed: 01/09/2023]
Abstract
RGS2 (regulator of G protein signaling 2) is known to limit signals mediated via Gq- and Gs-coupled GPCRs (G protein coupled receptors), and it has been implicated in the differentiation of several cells types. The physiology of RGS2 knockout mice (rgs2(-/-)) has been studied in some detail, however, a metabolic phenotype has not previously been reported. We observed that old (21-24month) rgs2(-/-) mice weigh much less than wild-type C57BL/6 controls, and exhibit greatly reduced fat deposits, decreased serum lipids, and low leptin levels. Lower weight was evident as early as four weeks and continued throughout life. Younger adult male rgs2(-/-) mice (4-8months) were found to show similar strain-related differences as the aged animals, as well improved glucose clearance and insulin sensitivity, and enhanced beta-adrenergic and glucagon signaling in isolated hepatocytes. In addition, rgs2(-/-) pre-adipocytes had reduced levels of differentiation markers (Peroxisome proliferator-activated receptor γ (PPARγ); lipoprotein lipase (Lpl); CCAAT/enhancer binding protein α (CEBPα)) and also rgs2(-/-) white adipocytes were small relative to controls, suggesting altered adipogenesis. In wild-type animals, RGS2 mRNA was decreased in brown adipose tissue after cold exposure (7 h at 4 °C) but increased in white adipose tissue in response to a high fat diet, also suggesting a role in lipid storage. No differences between strains were detected with respect to food intake, energy expenditure, GPCR-stimulated lipolysis, or adaptive thermogenesis. In conclusion this study points to RGS2 as being an important regulatory factor in controlling body weight and adipose function.
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Affiliation(s)
- Caroline Nunn
- Department of Physiology and Pharmacology, University of Western Ontario, London, Canada
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Analysis of RGS2 expression and prognostic significance in stage II and III colorectal cancer. Biosci Rep 2010; 30:383-90. [PMID: 20001967 DOI: 10.1042/bsr20090129] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The role of RGS2 (regulator of G-protein signalling 2) has been studied in several tumours. The purpose of the present study is to investigate the correlations between clinicopathological factors and patients' survival time and RGS2 expression in stage II and III CRC (colorectal cancer) patients. Real-time quantitative PCR was performed in 36 CRC tissues with recurrence and 28 without recurrence, and in three CRC-metastasis-derived cell lines (SW620, LoVo and Colo205) and 3 primary-CRC-derived ones (SW480, Caco-2 and HCT116) to examine RGS2 mRNA expression. In addition, to provide visualized evidence for RGS2 mRNA expression, random CRC samples were also performed with RT–PCR (reverse transcription–PCR). RGS2 protein was detected by immunostaining in 118 paraffin-embedded specimens, and the correlations between clinicopathological factors and survival time and RGS2 expression were analysed. We found that RGS2 mRNA was down-regulated both in CRC tissues with recurrence and metastasis-derived cell lines, and the expression level of RGS2 was unrelated to gender, age, tumour grade, or lymphovascular or perineural invasion. However, it was positively related to disease-free survival time (P<0.05). Furthermore, low RGS2 expression indicated a poorer survival rate (P<0.05, log-rank test). Multivariate analysis also showed that weak RGS2 protein expression was an independent adverse prognosticator in CRC (P<0.05). Taken together, we suggested that down-regulation of RGS2 might play an important role in CRC metastasis and predict poor prognosis in stage II and III CRC patients.
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RGS19 enhances cell proliferation through its C-terminal PDZ motif. Cell Signal 2010; 22:1700-7. [PMID: 20599498 DOI: 10.1016/j.cellsig.2010.06.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2010] [Accepted: 06/24/2010] [Indexed: 01/18/2023]
Abstract
Regulator of G protein signaling 19 (RGS19), also known as Galpha-interacting protein (GAIP), is a GTPase activating protein (GAP) for Galpha(i) subunits. Apart from its GAP function, RGS19 has been implicated in growth factor signaling through binding to GAIP-interacting protein C-terminus (GIPC) via its C-terminal PDZ-binding motif. To gain additional insight on its function, we have stably expressed RGS19 in a number of mammalian cell lines and examined its effect on cell proliferation. Interestingly, overexpression of RGS19 stimulated the growth of HEK293, PC12, Caco2, and NIH3T3 cells. This growth promoting effect was not shared by other RGS proteins including RGS4, RGS10 and RGS20. Despite its ability to stimulate cell proliferation, RGS19 failed to induce neoplastic transformation in NIH3T3 cells as determined by focus formation and soft-agar assays, and it did not induce tumor growth in athymic nude mice. Deletion mutants of RGS19 lacking the PDZ-binding motif failed to complex with GIPC and did not exhibit any growth promoting effect. Overexpression of GIPC alone in HEK293 cells stimulated cell proliferation whereas its knockdown in H1299 non-small cell lung carcinomas suppressed cell proliferation. This study demonstrates that RGS19, in addition to acting as a GAP, is able to stimulate cell proliferation in a GIPC-dependent manner.
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High BAALC expression predicts chemoresistance in adult B-precursor acute lymphoblastic leukemia. Blood 2010; 115:3737-44. [DOI: 10.1182/blood-2009-09-241943] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
AbstractOverexpression of BAALC is an adverse prognostic factor in adults with cytogenetically normal acute myeloid leukemia and T-cell acute lymphoblastic leukemia (ALL). Here, we analyzed the prognostic significance of BAALC in B-precursor ALL. BAALC MRNA expression was determined in 368 primary adult B-precursor ALL patients enrolled on the 06/99 and 07/03 GMALL trials. Patients were grouped into tertiles according to BAALC expression (T1-T3). Higher BAALC expression (T3 vs T2 vs T1) was associated with higher age (P < .001), a higher white blood cell count (P = .008), CD34 (P = .001), BCR-ABL (P < .001), and MLL-AF4 (P < .001). Higher BAALC expression predicted primary therapy resistance in the overall cohort (P = .002) and in the BCR-ABL− and MLL-AF4− subgroup (P = .01). In BCR-ABL− and MLL-AF4− patients, higher BAALC expression was associated with a shorter overall survival (OS; 5-year OS: T3, 38%; T2, 52%; T1, 70%; P = .004) and independently predicted OS in multivariate models (P = .03). Gene-expression profiling revealed an up-regulation of stem cell markers and genes involved in chemoresistance (TSPAN7 and LYN) in the high BAALC group. Thus, high BAALC expression is associated with an immature, chemoresistant leukemic phenotype and identifies patients with inferior OS. Determination of BAALC might contribute to risk assessment of molecularly undefined adult B-precursor ALL.
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Gene expression classifiers for relapse-free survival and minimal residual disease improve risk classification and outcome prediction in pediatric B-precursor acute lymphoblastic leukemia. Blood 2009; 115:1394-405. [PMID: 19880498 DOI: 10.1182/blood-2009-05-218560] [Citation(s) in RCA: 155] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
To determine whether gene expression profiling could improve outcome prediction in children with acute lymphoblastic leukemia (ALL) at high risk for relapse, we profiled pretreatment leukemic cells in 207 uniformly treated children with high-risk B-precursor ALL. A 38-gene expression classifier predictive of relapse-free survival (RFS) could distinguish 2 groups with differing relapse risks: low (4-year RFS, 81%, n = 109) versus high (4-year RFS, 50%, n = 98; P < .001). In multivariate analysis, the gene expression classifier (P = .001) and flow cytometric measures of minimal residual disease (MRD; P = .001) each provided independent prognostic information. Together, they could be used to classify children with high-risk ALL into low- (87% RFS), intermediate- (62% RFS), or high- (29% RFS) risk groups (P < .001). A 21-gene expression classifier predictive of end-induction MRD effectively substituted for flow MRD, yielding a combined classifier that could distinguish these 3 risk groups at diagnosis (P < .001). These classifiers were further validated on an independent high-risk ALL cohort (P = .006) and retainedindependent prognostic significance (P < .001) in the presence of other recently described poor prognostic factors (IKAROS/IKZF1 deletions, JAK mutations, and kinase expression signatures). Thus, gene expression classifiers improve ALL risk classification and allow prospective identification of children who respond or fail current treatment regimens. These trials were registered at http://clinicaltrials.gov under NCT00005603.
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Abstract
FLT3 is a member of the class III receptor tyrosine kinase family and is primarily expressed on hematopoietic stem/progenitor cells. Somatic mutations of FLT3 involving internal tandem duplication (ITD) of the juxtamembrane domain or point mutations in the activation loop have been identified in approximately 17 - 34% and 7 - 9% of acute myeloid leukemia (AML) patients, respectively. The ITD mutations appear to activate the tyrosine kinase domain through receptor dimerization in a FLT3 ligand-independent manner. Constitutively activated FLT3 provides cells with proliferative and anti-apoptotic advantages and portends an especially poor prognosis for patients with this mutation. FLT3/ITD mutations also contribute to a block of myeloid differentiation. FLT3 tyrosine kinase inhibitors suppress the growth and induce apoptosis and differentiation of leukemia cells expressing FLT3/ITD mutants. Therefore, FLT3 is a therapeutic target and inhibition of FLT3 tyrosine kinase activity may provide a new approach in the treatment of leukemia carrying these mutations.
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Affiliation(s)
- Rui Zheng
- Department of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
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Hurst JH, Hooks SB. Regulator of G-protein signaling (RGS) proteins in cancer biology. Biochem Pharmacol 2009; 78:1289-97. [PMID: 19559677 DOI: 10.1016/j.bcp.2009.06.028] [Citation(s) in RCA: 125] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2009] [Revised: 06/16/2009] [Accepted: 06/18/2009] [Indexed: 01/09/2023]
Abstract
The regulator of G-protein signaling (RGS) family is a diverse group of multifunctional proteins that regulate cellular signaling events downstream of G-protein coupled receptors (GPCRs). In recent years, GPCRs have been linked to the initiation and progression of multiple cancers; thus, regulators of GPCR signaling are also likely to be important to the pathophysiology of cancer. This review highlights recent studies detailing changes in RGS transcript expression during oncogenesis, single nucleotide polymorphisms in RGS proteins linked to lung and bladder cancers, and specific roles for RGS proteins in multiple cancer types.
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Affiliation(s)
- Jillian H Hurst
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA
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