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Ge Y, Janson V, Dong Z, Liu H. Role and mechanism of IL-33 in bacteria infection related gastric cancer continuum: From inflammation to tumor progression. Biochim Biophys Acta Rev Cancer 2025; 1880:189296. [PMID: 40058506 DOI: 10.1016/j.bbcan.2025.189296] [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: 09/04/2024] [Revised: 03/02/2025] [Accepted: 03/03/2025] [Indexed: 03/22/2025]
Abstract
Gastric cancer, a globally prevalent malignant tumor, is characterized by low early diagnosis rate, high metastasis rate, and poor prognosis, particularly in East Asia, Eastern Europe, and South America. Helicobacter pylori (H. pylori) is recognized as the primary risk factor for gastric cancer. However, the fact that fewer than 3 % of infected individuals develop cancer suggests that other bacteria may also influence gastric carcinogenesis. A diverse community of microorganisms may interact with H. pylori, thereby driving disease progression. Here, the role of the cytokine IL-33, a member of the IL-1 family, is scrutinized. Its production can be induced by H. pylori through the activation of specific signaling pathways, and it contributes to the inflammatory environment by promoting the release of pro-inflammatory cytokines. This article reviews the conflicting evidence regarding IL-33's role in the progression from gastritis to gastric cancer and discusses the potential therapeutic implications of targeting the IL-33/ST2 axis, with various antibodies and inhibitors in development or undergoing clinical trials for inflammatory diseases. However, the role of IL-33 in gastric cancer treatment remains to be fully elucidated, with its effects potentially dependent on the cellular context and stage of cancer progression. In summary, this review provides a comprehensive overview of the intricate relationship between gastric microbiota, IL-33, and gastritis - gastric cancer transition, offering insights into potential therapeutic targets and the development of novel treatment strategies.
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Affiliation(s)
- Yunxiao Ge
- Department of Pathophysiology, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Victor Janson
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Zigang Dong
- Department of Pathophysiology, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, Henan 450001, China; China-US (Henan) Hormel Cancer Institute, No.127, Dongming Road, Jinshui District, Zhengzhou, Henan 450008, China
| | - Hui Liu
- Department of Pathophysiology, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, Henan 450001, China; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; China-US (Henan) Hormel Cancer Institute, No.127, Dongming Road, Jinshui District, Zhengzhou, Henan 450008, China.
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Liu L, Luo H, Xie Y, Wang Y, Ren S, Sun H, Xin Z, Li D. Endogenous IL-33 inhibits apoptosis in non-small cell lung cancer cells by regulating BCL2/BAX via the ERK1/2 pathway. Sci Rep 2025; 15:6422. [PMID: 39984631 PMCID: PMC11845513 DOI: 10.1038/s41598-025-91202-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 02/18/2025] [Indexed: 02/23/2025] Open
Abstract
Lung cancer remains a leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for 85% of cases. Although targeted therapies have improved treatment outcomes, drug resistance poses a significant challenge, underscoring the need for novel therapeutic strategies. Interleukin-33 (IL-33), a member of the IL-1 superfamily, functions both as a nuclear protein and a cytokine, binding to its receptor, ST2. While IL-33 is known to promote tumour cell migration and metastasis, its role in regulating apoptosis remains incompletely understood. In this study, we focused on endogenous IL-33, employing lentiviral transfection to overexpress both the full-length and mature forms of IL-33 in lung cancer cells. We examined its effects on apoptosis in vitro and investigated the underlying molecular mechanisms. Our findings reveal that endogenous IL-33 inhibits apoptosis in lung cancer cells by modulating the expression of BCL2 and BAX via the ERK1/2 pathway in an autocrine manner. These results uncover a novel mechanism of IL-33-mediated tumour survival and provide a foundation for the development of IL-33/ST2-targeted therapies in NSCLC.
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Affiliation(s)
- Liping Liu
- Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Haoge Luo
- Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Yingdong Xie
- Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Ying Wang
- Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Shiying Ren
- Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Haiyang Sun
- Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Zhuoyuan Xin
- Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China.
| | - Dong Li
- Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China.
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China.
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Hubiernatorova A, Novak J, Vaskovicova M, Sekac D, Kropyvko S, Hodny Z. Tristetraprolin affects invasion-associated genes expression and cell motility in triple-negative breast cancer model. Cytoskeleton (Hoboken) 2024. [PMID: 39319680 DOI: 10.1002/cm.21934] [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: 04/26/2024] [Revised: 09/05/2024] [Accepted: 09/09/2024] [Indexed: 09/26/2024]
Abstract
Tristetraprolin (TTP) is an RNA-binding protein that negatively regulates its target mRNAs and has been shown to inhibit tumor progression and invasion. Tumor invasion requires precise regulation of cytoskeletal components, and dysregulation of cytoskeleton-associated genes can significantly alter cell motility and invasive capability. Several genes, including SH3PXD2A, SH3PXD2B, CTTN, WIPF1, and WASL, are crucial components of the cytoskeleton reorganization machinery and are essential for adequate cell motility. These genes are also involved in invasion processes, with SH3PXD2A, SH3PXD2B, WIPF1, and CTTN being key components of invadopodia-specialized structures that facilitate invasion. However, the regulation of these genes is not well understood. This study demonstrates that ectopic expression of TTP in MDA-MB-231 cells leads to decreased mRNA levels of CTTN and SH3PXD2A, as well as defects in cell motility and actin filament organization. Additionally, doxorubicin significantly increases TTP expression and reduces the mRNA levels of cytoskeleton-associated genes, enhancing our understanding of how doxorubicin may affect the transcriptional profile of cells. However, doxorubicin affects target mRNAs differently than TTP ectopic expression, suggesting it may not be the primary mechanism of doxorubicin in breast cancer (BC) treatment. High TTP expression is considered as a positive prognostic marker in multiple cancers, including BC. Given that doxorubicin is a commonly used drug for treating triple-negative BC, using TTP as a prognostic marker in this cohort of patients might be limited since it might be challenging to understand if high TTP expression occurred due to the favorable physiological state of the patient or as a consequence of treatment.
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Affiliation(s)
- Anastasiia Hubiernatorova
- Department of Functional Genomics, Institute of Molecular Biology and Genetics NAS of Ukraine, Kyiv, Ukraine
- Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics of the Czech Academy of Sciences, Libechov, Czech Republic
| | - Josef Novak
- Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Michaela Vaskovicova
- Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic
- Laboratory of DNA Integrity, Institute of Animal Physiology and Genetics of the Czech Academy of Sciences, Libechov, Czech Republic
| | - David Sekac
- Laboratory of Cell Regeneration and Plasticity, Institute of Animal Physiology and Genetics of the Czech Academy of Sciences, Libechov, Czech Republic
- Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Serhii Kropyvko
- Department of Functional Genomics, Institute of Molecular Biology and Genetics NAS of Ukraine, Kyiv, Ukraine
| | - Zdenek Hodny
- Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
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Chatterjee A, Azevedo-Martins JM, Stachler MD. Interleukin-33 as a Potential Therapeutic Target in Gastric Cancer Patients: Current Insights. Onco Targets Ther 2023; 16:675-687. [PMID: 37583706 PMCID: PMC10424681 DOI: 10.2147/ott.s389120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 08/06/2023] [Indexed: 08/17/2023] Open
Abstract
Gastric cancer is a significant global health problem as it is the fifth most prevalent cancer worldwide and the fourth leading cause of cancer-related mortality. While cytotoxic chemotherapy remains the primary treatment for advanced GC, response rates are limited. Recent progresses, focused on molecular signalling within gastric cancer, have ignited new hope for potential therapeutic targets that may improve survival and/or reduce the toxic effects of traditional therapies. Carcinomas are generally initiated when critical regulatory genes get mutated, but the progression to malignancy is usually supported by the non-neoplastic cells that create a conducive environment for transformation and progression to occur. Interleukin 33 (IL-33) functions as a dual activity cytokine as it is also a nuclear factor. IL-33 is usually present in the nuclei of the cells. Upon tissue damage, it is released into the extracellular space and binds to its receptor, suppression of tumorigenicity 2 (ST2) L, which is expressed on the membranes of the target cells. IL-33 signalling activates the T Helper 2 (Th2) immune response among other responses. Although the studies on the role of IL-33 in gastric cancer are still in the early stages, they have revealed potentially important (though sometimes conflicting) functions or roles in cancer development and progression. The pro-tumorigenic roles include induction and the recruitment of tumor-associated immune cells, promoting metaplasia progression, and inducing stem cell like and EMT properties in gastric cancer cells. Therapeutic interventions to disrupt these functions may provide a unique strategy for gastric cancer prevention and treatment. This review aims to provide a summary of the role of IL-33 in GC, state its multiple functions in relation to GC, and show potential avenues for promising therapeutic investigation.
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Affiliation(s)
- Annesha Chatterjee
- University of California San Francisco, Department of Pathology, San Francisco, CA, USA
| | | | - Matthew D Stachler
- University of California San Francisco, Department of Pathology, San Francisco, CA, USA
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Guo H, Bossila EA, Ma X, Zhao C, Zhao Y. Dual Immune Regulatory Roles of Interleukin-33 in Pathological Conditions. Cells 2022; 11:cells11203237. [PMID: 36291105 PMCID: PMC9600220 DOI: 10.3390/cells11203237] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 10/07/2022] [Accepted: 10/11/2022] [Indexed: 11/20/2022] Open
Abstract
Interleukin-33 (IL-33), a member of the IL-1 cytokine family and a multifunctional cytokine, plays critical roles in maintaining host homeostasis and in pathological conditions, such as allergy, infectious diseases, and cancer, by acting on multiple types of immune cells and promoting type 1 and 2 immune responses. IL-33 is rapidly released by immune and non-immune cells upon stimulation by stress, acting as an “alarmin” by binding to its receptor, suppression of tumorigenicity 2 (ST2), to trigger downstream signaling pathways and activate inflammatory and immune responses. It has been recognized that IL-33 displays dual-functioning immune regulatory effects in many diseases and has both pro- and anti-tumorigenic effects, likely depending on its primary target cells, IL-33/sST2 expression levels, cellular context, and the cytokine microenvironment. Herein, we summarize our current understanding of the biological functions of IL-33 and its roles in the pathogenesis of various conditions, including inflammatory and autoimmune diseases, infections, cancers, and cases of organ transplantation. We emphasize the nature of context-dependent dual immune regulatory functions of IL-33 in many cells and diseases and review systemic studies to understand the distinct roles of IL-33 in different cells, which is essential to the development of more effective diagnoses and therapeutic approaches for IL-33-related diseases.
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Affiliation(s)
- Han Guo
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101499, China
| | - Elhusseny A. Bossila
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101499, China
- Biotechnology Department, Faculty of Agriculture Al-Azhar University, Cairo 11311, Egypt
| | - Xinran Ma
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101499, China
| | - Chenxu Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101499, China
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101499, China
- Beijing Institute for Stem Cell and Regeneration, Beijing 100101, China
- Correspondence: ; Tel.: +86-10-64807302; Fax: +86-10-64807313
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6
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Liu QH, Zhang JW, Xia L, Wise SG, Hambly BD, Tao K, Bao SS. Clinical implications of interleukins-31, 32, and 33 in gastric cancer. World J Gastrointest Oncol 2022; 14:1808-1822. [PMID: 36187404 PMCID: PMC9516641 DOI: 10.4251/wjgo.v14.i9.1808] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/21/2022] [Accepted: 07/31/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the most common malignancies in China with a high morbidity and mortality. AIM To determine whether interleukin (IL)-31, IL-32, and IL-33 can be used as biomarkers for the detection of GC, via evaluating the correlations between their expression and clinicopathological parameters of GC patients. METHODS Tissue array (n = 180) gastric specimens were utilised. IL-31, IL-32, and IL-33 expression in GC and non-GC tissues was detected immunohistochemically. The correlations between IL-31, IL-32, and IL-33 expression in GC and severity of clinicopathological parameters were evaluated. Survival curves were plotted using the Kaplan-Meier method/Cox regression. Circulating IL-31, IL-32, and IL-33 were detected by ELISA. RESULTS We found that the expression levels of IL-31, IL-32, and IL-33 were all lower in GC than in adjacent non-GC gastric tissues (P < 0.05). IL-33 in peripheral blood of GC patients was significantly lower than that of healthy individuals (1.50 ± 1.11 vs 9.61 ± 8.00 ng/mL, P <0.05). Decreased IL-31, IL-32, and IL-33 in GC were observed in younger patients (< 60 years), and IL-32 and IL-33 were lower in female patients (P < 0.05). Higher IL-32 correlated with a longer survival in two GC subgroups: T4 invasion depth and TNM I-II stage. Univariate/multivariate analysis revealed that IL-32 was an independent prognostic factor for GC in the T4 stage subgroup. Circulating IL-33 was significantly lower in GC patients at TNM stage IV than in healthy people (P < 0.05). CONCLUSION Our findings may provide new insights into the roles of IL-31, IL-32, and IL-33 in the carcinogenesis of GC and demonstrate their relative usefulness as prognostic markers for GC. The underlying mechanism of IL-31, IL-32, and IL-33 actions in GC should be further explored.
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Affiliation(s)
- Qing-Hua Liu
- Department of Pathology, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
| | - Ji-Wei Zhang
- Department of Surgery, The Central Hospital of Songjiang District, Shanghai Jiaotong University, Shanghai 201699, Shanghai, China
| | - Lei Xia
- Department of Pathology, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
| | - Steven G Wise
- Faculty of Medicine and Health, School of Medical Sciences, University of Sydney, Sydney 2006, NSW, Australia
| | | | - Kun Tao
- Department of Pathology,Tongren Hospital, Shanghai 200336, China
| | - Shi-San Bao
- Department of Pathology,Tongren Hospital, Shanghai 200336, China
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Lee W, Kim S, An J, Kim TK, Cha H, Chang H, Kim S, Kim S, Han M. Tristetraprolin regulates phagocytosis through interaction with CD47 in head and neck cancer. Exp Ther Med 2022; 24:541. [PMID: 35978923 PMCID: PMC9366311 DOI: 10.3892/etm.2022.11478] [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: 01/18/2022] [Accepted: 05/03/2022] [Indexed: 11/17/2022] Open
Abstract
CD47 is expressed in all human cancer cells, including head and neck cancer, and initiates a signaling cascade to inhibit macrophage phagocytosis. However, the mechanism underlying CD47 overexpression has not been elucidated in radioresistant head and neck cancer. The present study demonstrated that decreased Tristetraprolin (TTP) expression induced a sustained overexpression of CD47 using reverse transcription-quantitative PCR and western blotting, and that CD47 overexpression prevented phagocytosis using a phagocytosis assay in a radioresistant HN31R cell line. Subsequently, using TTP transfection, RNA interference, duel-luciferase assay and EMSA, it was revealed that TTP transfection enhanced phagocytosis through degradation of CD47 mRNA by directly binding to CD47 AREs within the CD47 3'UTR. Based on our previous study, methylation-specific PCR and western blotting revealed that DNMT1 was overexpressed in radioresistant HN31R cell line and TTP expression was decreased epigenetically by DMNT1 associated DNA methylation. Overall, these findings provided novel insight into the role of TTP as a biomarker of CD47-positive head and neck cancer patients.
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Affiliation(s)
- Won Lee
- Department of Otolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Republic of Korea
| | - Song Kim
- Department of Otolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Republic of Korea
| | - Jae An
- Department of Otolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Republic of Korea
| | - Tae-Koon Kim
- Department of Otolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Republic of Korea
| | - Hee Cha
- Department of Pathology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Republic of Korea
| | - Hyo Chang
- Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Sang Kim
- Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Seong Kim
- Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Myung Han
- Department of Otolaryngology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan 44033, Republic of Korea
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Hikichi Y, Motomura Y, Takeuchi O, Moro K. Posttranscriptional regulation of ILC2 homeostatic function via tristetraprolin. J Exp Med 2021; 218:e20210181. [PMID: 34709349 PMCID: PMC8558840 DOI: 10.1084/jem.20210181] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 08/05/2021] [Accepted: 10/08/2021] [Indexed: 12/28/2022] Open
Abstract
Group 2 innate lymphoid cells (ILC2s) are unique in their ability to produce low levels of type 2 cytokines at steady state, and their production capacity is dramatically increased upon stimulation with IL-33. However, it is unknown how constitutive cytokine production is regulated in the steady state. Here, we found that tristetraprolin (TTP/Zfp36), an RNA-binding protein that induces mRNA degradation, was highly expressed in naive ILC2s and was downregulated following IL-33 stimulation. In ILC2s from Zfp36-/- mice, constitutive IL-5 production was elevated owing to the stabilization of its mRNA and resulted in an increased number of eosinophils in the intestine. Luciferase assay demonstrated that TTP directly regulates Il5 mRNA stability, and overexpression of TTP markedly suppressed IL-5 production by ILC2s, even under IL-33 stimulation. Collectively, TTP-mediated posttranscriptional regulation acts as a deterrent of excessive cytokine production in steady-state ILC2s to maintain body homeostasis, and downregulation of TTP may contribute to massive cytokine production under IL-33 stimulation.
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Affiliation(s)
- Yuki Hikichi
- Laboratory for Innate Immune Systems, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan
- Division of Immunobiology, Department of Medical Life Science, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Kanagawa, Japan
| | - Yasutaka Motomura
- Laboratory for Innate Immune Systems, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan
- Laboratory for Innate Immune Systems, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- Laboratory for Innate Immune Systems, Osaka University Immunology Frontier Research Center, Suita, Osaka, Japan
| | - Osamu Takeuchi
- Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan
| | - Kazuyo Moro
- Laboratory for Innate Immune Systems, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan
- Division of Immunobiology, Department of Medical Life Science, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Kanagawa, Japan
- Laboratory for Innate Immune Systems, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- Laboratory for Innate Immune Systems, Osaka University Immunology Frontier Research Center, Suita, Osaka, Japan
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Busada JT, Khadka S, Peterson KN, Druffner SR, Stumpo DJ, Zhou L, Oakley RH, Cidlowski JA, Blackshear PJ. Tristetraprolin Prevents Gastric Metaplasia in Mice by Suppressing Pathogenic Inflammation. Cell Mol Gastroenterol Hepatol 2021; 12:1831-1845. [PMID: 34358715 PMCID: PMC8554534 DOI: 10.1016/j.jcmgh.2021.07.015] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 07/27/2021] [Accepted: 07/27/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Aberrant immune activation is associated with numerous inflammatory and autoimmune diseases and contributes to cancer development and progression. Within the stomach, inflammation drives a well-established sequence from gastritis to metaplasia, eventually resulting in adenocarcinoma. Unfortunately, the processes that regulate gastric inflammation and prevent carcinogenesis remain unknown. Tristetraprolin (TTP) is an RNA-binding protein that promotes the turnover of numerous proinflammatory and oncogenic messenger RNAs. Here, we assess the role of TTP in regulating gastric inflammation and spasmolytic polypeptide-expressing metaplasia (SPEM) development. METHODS We used a TTP-overexpressing model, the TTPΔadenylate-uridylate rich element mouse, to examine whether TTP can protect the stomach from adrenalectomy (ADX)-induced gastric inflammation and SPEM. RESULTS We found that TTPΔadenylate-uridylate rich element mice were completely protected from ADX-induced gastric inflammation and SPEM. RNA sequencing 5 days after ADX showed that TTP overexpression suppressed the expression of genes associated with the innate immune response. Importantly, TTP overexpression did not protect from high-dose-tamoxifen-induced SPEM development, suggesting that protection in the ADX model is achieved primarily by suppressing inflammation. Finally, we show that protection from gastric inflammation was only partially due to the suppression of Tnf, a well-known TTP target. CONCLUSIONS Our results show that TTP exerts broad anti-inflammatory effects in the stomach and suggest that therapies that increase TTP expression may be effective treatments of proneoplastic gastric inflammation. Transcript profiling: GSE164349.
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Affiliation(s)
- Jonathan T. Busada
- Molecular Endocrinology Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina,Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia,Correspondence Address correspondence to: Jonathan T. Busada, PhD, Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, 64 Medical Center Drive, PO Box 9177, Morgantown, West Virginia 26506.
| | - Stuti Khadka
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia
| | - Kylie N. Peterson
- Molecular Endocrinology Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
| | - Sara R. Druffner
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia
| | - Deborah J. Stumpo
- Post-Transcriptional Gene Expression Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
| | - Lecong Zhou
- Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
| | - Robert H. Oakley
- Molecular Endocrinology Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
| | - John A. Cidlowski
- Molecular Endocrinology Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
| | - Perry J. Blackshear
- Post-Transcriptional Gene Expression Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
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10
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Zhang D, Zhou Z, Yang R, Zhang S, Zhang B, Tan Y, Chen L, Li T, Tu J. Tristetraprolin, a Potential Safeguard Against Carcinoma: Role in the Tumor Microenvironment. Front Oncol 2021; 11:632189. [PMID: 34026612 PMCID: PMC8138596 DOI: 10.3389/fonc.2021.632189] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 04/14/2021] [Indexed: 12/15/2022] Open
Abstract
Tristetraprolin (TTP), a well-known RNA-binding protein, primarily affects the expression of inflammation-related proteins by binding to the targeted AU-rich element in the 3' untranslated region after transcription and subsequently mediates messenger RNA decay. Recent studies have focused on the role of TTP in tumors and their related microenvironments, most of which have referred to TTP as a potential tumor suppressor involved in regulating cell proliferation, apoptosis, and metastasis of various cancers, as well as tumor immunity, inflammation, and metabolism of the microenvironment. Elevated TTP expression levels could aid the diagnosis and treatment of different cancers, improving the prognosis of patients. The aim of this review is to describe the role of TTP as a potential safeguard against carcinoma.
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Affiliation(s)
- Diwen Zhang
- Institute of Pharmacy and Pharmacology, University of South China, Hengyang, China.,Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
| | - Zhigang Zhou
- The Second Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Ruixia Yang
- Institute of Pharmacy and Pharmacology, University of South China, Hengyang, China
| | - Sujun Zhang
- Department of Experimental Animals, University of South China, Hengyang, China
| | - Bin Zhang
- Institute of Pharmacy and Pharmacology, University of South China, Hengyang, China
| | - Yanxuan Tan
- Institute of Pharmacy and Pharmacology, University of South China, Hengyang, China
| | - Lingyao Chen
- Pharmacy School of Guilin Medical University, Guilin, China
| | - Tao Li
- Shanghai Veterinary Research Institute, Chinese Academy of Agriculture Science, Shanghai, China
| | - Jian Tu
- Institute of Pharmacy and Pharmacology, University of South China, Hengyang, China.,Pharmacy School of Guilin Medical University, Guilin, China
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11
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Jiang W, Zhu D, Wang C, Zhu Y. Tumor suppressing effects of tristetraprolin and its small double-stranded RNAs in bladder cancer. Cancer Med 2021; 10:269-285. [PMID: 33259133 PMCID: PMC7826468 DOI: 10.1002/cam4.3622] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 10/20/2020] [Accepted: 10/25/2020] [Indexed: 12/23/2022] Open
Abstract
Bladder cancer (BCa) is a common malignant tumor of urinary system with few treatments, so more useful therapeutic targets are still needed. Antitumor effects of tristetraprolin (TTP) have been explored in many type tumors, but its roles in bladder cancer are still unknown until now. In this study, public expression profiles and tissue microarray analysis showed that TTP mRNA and protein levels decreased in BCa relative to the normal bladder tissue. To explore biological functions of TTP in BCa, 488 TTP target genes, which could be both suppressed and bound by TTP, were identified by comprehensively analyzing publicly available high-throughput data obtained from Gene Expression Omnibus (GEO). Gene enrichment analysis showed that these genes were enriched in pathways such as cell cycle, epithelial to mesenchymal transition (EMT), and Wnt signaling. Clustering analysis and gene set variation analysis indicated that patients with high expression of TTP target genes had poorer prognosis and stronger tumor proliferation ability relative to the BCa patients with low expression of TTP target genes. In vitro experiments validated that TTP could suppress proliferation, migration, and invasiveness of BCa cells. And TTP could suppress mRNA expression of cyclin-dependent kinase 1 (CDK1) in BCa cells by target its 3' UTR. Then, we identified a new small double-stranded RNA (dsRNA) named dsTTP-973 which could increase TTP expression in BCa cells, in vivo and in vitro experiments revealed that dsTTP-973 could suppress aggressiveness of BCa. In conclusion, TTP played a role of tumor suppressor gene in BCa like other tumors, and its dsRNA named dsTTP-973 could induce TTP expression in BCa and suppress aggressiveness of BCa. With the help of materials science, dsTTP-973 may become a potential treatment for BCa in the future.
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Affiliation(s)
- Wen Jiang
- Department of UrologyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Dandan Zhu
- Department of UrologyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Chenghe Wang
- Department of UrologyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yu Zhu
- Department of UrologyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
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12
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Zhang X, Chen W, Zeng P, Xu J, Diao H. The Contradictory Role of Interleukin-33 in Immune Cells and Tumor Immunity. Cancer Manag Res 2020; 12:7527-7537. [PMID: 32904627 PMCID: PMC7457384 DOI: 10.2147/cmar.s262745] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 08/02/2020] [Indexed: 12/29/2022] Open
Abstract
Interleukin (IL)-33 is a member of the IL-1 superfamily and is a crucial cytokine playing the role of a dual-function molecule. IL-33 mediates its function by interacting with its receptor suppression of tumorigenicity 2 (ST2), which is constitutively expressed on T helper (Th)1 cells, Th2 cells, and other immune cells. Previously, we summarized findings on IL-33 and performed an intensive study of the correlation between IL-33 and tumor. IL-33 enables anti-tumor immune responses through Th1 cells and natural killer (NK) cells and plays a role in tumor immune escape in cancers via Th2 cells and regulatory T cells. Herein, we discuss the contradictory role of IL-33 in immune cells in different cancer, and our summaries may be helpful for better understanding of the development of research on IL-33 and tumor immunity.
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Affiliation(s)
- Xujun Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, People's Republic of China
| | - Wenbiao Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, People's Republic of China
| | - Ping Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, People's Republic of China
| | - Jia Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, People's Republic of China
| | - Hongyan Diao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, People's Republic of China
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13
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Wang LY, Zhao S, Lv GJ, Ma XJ, Zhang JB. Mechanisms of resveratrol in the prevention and treatment of gastrointestinal cancer. World J Clin Cases 2020; 8:2425-2437. [PMID: 32607320 PMCID: PMC7322414 DOI: 10.12998/wjcc.v8.i12.2425] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 05/20/2020] [Accepted: 05/23/2020] [Indexed: 02/05/2023] Open
Abstract
Gastrointestinal (GI) cancer is one of the leading causes of cancer-related deaths worldwide. According to the Global Cancer Statistics, colorectal cancer is the second leading cause of cancer-related mortality, closely followed by gastric cancer (GC). Environmental, dietary, and lifestyle factors including cigarette smoking, alcohol intake, and genetics are the most important risk factors for GI cancer. Furthermore, infections caused by Helicobacter pylori are a major cause of GC initiation. Despite improvements in conventional therapies, including surgery, chemotherapy, and radiotherapy, the length or quality of life of patients with advanced GI cancer is still poor because of delayed diagnosis, recurrence and side effect. Resveratrol (3, 4, 5-trihydroxy-trans-stilbene; Res), a natural polyphenolic compound, reportedly has various pharmacologic functions including anti-oxidant, anti-inflammatory, anti-cancer, and cardioprotective functions. Many studies have demonstrated that Res also exerts a chemopreventive effect on GI cancer. Research investigating the anti-cancer mechanism of Res for the prevention and treatment of GI cancer has implicated multiple pathways including oxidative stress, cell proliferation, and apoptosis. Therefore, this paper provides a review of the function and molecular mechanisms of Res in the prevention and treatment of GI cancer.
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Affiliation(s)
- Li-Yan Wang
- Department of Pharmacy, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
| | - Shan Zhao
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, Liaoning Province, China
| | - Guo-Jun Lv
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, Liaoning Province, China
| | - Xiao-Jun Ma
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, Liaoning Province, China
| | - Jian-Bin Zhang
- College of Pharmacy, Dalian Medical University, Dalian 116044, Liaoning Province, China
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14
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Saaoud F, Wang J, Iwanowycz S, Wang Y, Altomare D, Shao Y, Liu J, Blackshear PJ, Lessner SM, Murphy EA, Wang H, Yang X, Fan D. Bone marrow deficiency of mRNA decaying protein Tristetraprolin increases inflammation and mitochondrial ROS but reduces hepatic lipoprotein production in LDLR knockout mice. Redox Biol 2020; 37:101609. [PMID: 32591281 PMCID: PMC7767740 DOI: 10.1016/j.redox.2020.101609] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 05/30/2020] [Accepted: 06/14/2020] [Indexed: 12/11/2022] Open
Abstract
Tristetraprolin (TTP), an mRNA binding and decaying protein, plays a significant role in controlling inflammation by decaying mRNAs encoding inflammatory cytokines such as TNFalpha. We aimed to test a hypothesis that TTP in bone marrow (BM) cells regulates atherogenesis by modulating inflammation and lipid metabolism through the modulation of oxidative stress pathways by TTP target genes. In a BM transplantation study, lethally irradiated atherogenic LDLR-/- mice were reconstituted with BM cells from either wild type (TTP+/+) or TTP knockout (TTP-/-) mice, and fed a Western diet for 12 weeks. We made the following observations: (1) TTP-/- BM recipients display a significantly higher systemic and multi-organ inflammation than TTP+/+ BM recipients; (2) BM TTP deficiency modulates hepatic expression of genes, detected by microarray, involved in lipid metabolism, inflammatory responses, and oxidative stress; (3) TTP-/- BM derived macrophages increase production of mitochondrial reactive oxygen species (mtROS); (4) BM-TTP-/- mice display a significant reduction in serum VLDL/LDL levels, and attenuated hepatic steatosis compared to controls; and (5) Reduction of serum VLDL/LDL levels offsets the increased inflammation, resulting in no changes in atherosclerosis. These findings provide a novel mechanistic insight into the roles of TTP-mediated mRNA decay in bone marrow-derived cells in regulating systemic inflammation, oxidative stress, and liver VLDL/LDL biogenesis.
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Affiliation(s)
- Fatma Saaoud
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, 29209, USA; Centers for Inflammation, Translational & Clinical Lung Research, Departments of Microbiology and Immunology and Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 14190, USA
| | - Junfeng Wang
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, 29209, USA
| | - Stephen Iwanowycz
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, 29209, USA
| | - Yuzhen Wang
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, 29209, USA
| | - Diego Altomare
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, 29208, USA
| | - Ying Shao
- Centers for Inflammation, Translational & Clinical Lung Research, Departments of Microbiology and Immunology and Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 14190, USA
| | - Jianguo Liu
- Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA
| | - Perry J Blackshear
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, 27709, USA
| | - Susan M Lessner
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, 29209, USA
| | - E Angela Murphy
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, 29209, USA
| | - Hong Wang
- Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Departments of Microbiology and Immunology, and Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 14190, USA
| | - Xiaofeng Yang
- Centers for Inflammation, Translational & Clinical Lung Research, Departments of Microbiology and Immunology and Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 14190, USA; Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Departments of Microbiology and Immunology, and Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 14190, USA.
| | - Daping Fan
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, 29209, USA.
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15
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The Tristetraprolin Family of RNA-Binding Proteins in Cancer: Progress and Future Prospects. Cancers (Basel) 2020; 12:cancers12061539. [PMID: 32545247 PMCID: PMC7352335 DOI: 10.3390/cancers12061539] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 06/07/2020] [Accepted: 06/09/2020] [Indexed: 12/12/2022] Open
Abstract
Post-transcriptional regulation of gene expression plays a key role in cellular proliferation, differentiation, migration, and apoptosis. Increasing evidence suggests dysregulated post-transcriptional gene expression as an important mechanism in the pathogenesis of cancer. The tristetraprolin family of RNA-binding proteins (RBPs), which include Zinc Finger Protein 36 (ZFP36; commonly referred to as tristetraprolin (TTP)), Zinc Finger Protein 36 like 1 (ZFP36L1), and Zinc Finger Protein 36 like 2 (ZFP36L2), play key roles in the post-transcriptional regulation of gene expression. Mechanistically, these proteins function by binding to the AU-rich elements within the 3′-untranslated regions of their target mRNAs and, in turn, increasing mRNA turnover. The TTP family RBPs are emerging as key regulators of multiple biological processes relevant to cancer and are aberrantly expressed in numerous human cancers. The TTP family RBPs have tumor-suppressive properties and are also associated with cancer prognosis, metastasis, and resistance to chemotherapy. Herein, we summarize the various hallmark molecular traits of cancers that are reported to be regulated by the TTP family RBPs. We emphasize the role of the TTP family RBPs in the regulation of trait-associated mRNA targets in relevant cancer types/cell lines. Finally, we highlight the potential of the TTP family RBPs as prognostic indicators and discuss the possibility of targeting these TTP family RBPs for therapeutic benefits.
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16
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Zeng X, Li J, Kang LN, Xi MR, Liao GD. Potential clinical value of interleukin-31 and interleukin-33 with their receptors expression as diagnostic and predictive factors in endometrial cancer: a case-control study. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2020; 13:1324-1332. [PMID: 32661468 PMCID: PMC7344009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 04/17/2020] [Indexed: 06/11/2023]
Abstract
Aims: To evaluate the potential role of interleukin-31 and interleukin-33 in diagnosis and prognosis from endometrial cancer. Methods: Tissue samples and clinical data were collected from 260 patients with endometrial cancer and 150 control patients with benign uterine diseases. Immunohistochemistry and ELISA testing quantified the expressions of interleukin-31 and interleukin-33 and their receptors. After surgery, all patients were followed up for an average of 56.3 months. Surgical effects were evaluated based on the patients' symptoms and signs. A two-sided P value <0.05 was considered significant. Results: IL-31, IL-33 and their receptors were significantly accumulated with the progression of endometrial cancer, in comparison to the controls. Moreover, the expressions were correlated with clinical characteristics, including tumor stage, differentiation, and associated with patients' disease-free survival. Conclusions: Limited data was available between the expressions of IL-31 and IL-33 and the receptors in patients with endometrial cancer. Our study findings suggested that the expressions of IL-31 and IL-33 might become possible biomarkers for the diagnosis and prediction in endometrial cancer.
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Affiliation(s)
- Xi Zeng
- Department of Gynecology and Obstetrics, The West China Second University Hospital, Sichuan UniversityChengdu 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of EducationChengdu 610041, China
| | - Jing Li
- Department of Environmental and Occupational Health, West China School of Public Health, Sichuan UniversityChengdu, Sichuan, China
| | - Le-Ni Kang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of EducationChengdu 610041, China
- National Office for Maternal and Child Health Surveillance of China, West China Second University Hospital, Sichuan UniversityChengdu, Sichuan, China
| | - Ming-Rong Xi
- Department of Gynecology and Obstetrics, The West China Second University Hospital, Sichuan UniversityChengdu 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of EducationChengdu 610041, China
| | - Guang-Dong Liao
- Department of Gynecology and Obstetrics, The West China Second University Hospital, Sichuan UniversityChengdu 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of EducationChengdu 610041, China
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17
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Miliotis CN, Slack FJ. Multi-layered control of PD-L1 expression in Epstein-Barr virus-associated gastric cancer. ACTA ACUST UNITED AC 2020; 6. [PMID: 34212113 PMCID: PMC8244904 DOI: 10.20517/2394-4722.2020.12] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Gastric cancer (GC) is the fifth most common cancer worldwide. In approximately 10% of GC cases, cancer cells show ubiquitous and monoclonal Epstein-Barr virus (EBV) infection. A significant feature of EBV-associated GC (EBVaGC) is high lymphocytic infiltration and high expression of immune checkpoint proteins, including programmed death-ligand 1 (PD-L1). This highlights EBVaGC as a strong candidate for immune checkpoint blockade therapy. Indeed, several recent studies have shown that EBV positivity in GC correlates with positive response to programmed cell death protein 1 (PD-1)/PD-L1 blockade therapy. Understanding the mechanisms that control PD-L1 expression in EBVaGC can indicate new predictive biomarkers for immunotherapy, as well as therapeutic targets for combination therapy. Various mechanisms have been implicated in PD-L1 expression regulation, including structural variations, post-transcriptional control, oncogenic activation of intrinsic signaling pathways, and increased sensitivity to extrinsic signals. This review provides the most recent updates on the multilayered control of PD-L1 expression in EBVaGC.
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Affiliation(s)
- Christos N Miliotis
- HMS Initiative for RNA Medicine, Department of Pathology, Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
| | - Frank J Slack
- HMS Initiative for RNA Medicine, Department of Pathology, Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
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18
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Wang S, Zhao G, Zhao S, Qiao Y, Yang H. The Effects of Interleukin-33 (IL-33) on Osteosarcoma Cell Viability, Apoptosis, and Epithelial-Mesenchymal Transition are Mediated Through the PI3K/AKT Pathway. Med Sci Monit 2020; 26:e920766. [PMID: 32312946 PMCID: PMC7191962 DOI: 10.12659/msm.920766] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background Osteosarcoma is the most common primary tumor of bone. Interleukin-33 (IL-33) is a pro-inflammatory cytokine that also participates in tumor progression. This study aimed to investigate the role of IL-33 in human osteosarcoma cell viability, proliferation, apoptosis, and epithelial-mesenchymal transition (EMT) in vitro and the molecular mechanisms involved. Material/Methods The normal osteoblast cell line, hFOB 1.19, and the human osteosarcoma cell lines SOSP-9607, SAOS2, MG63, and U2OS were studied. The expression of IL-33 mRNA and protein in human osteosarcoma cell lines were detected using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot, respectively. The effects of IL-33 on human osteosarcoma cell viability, apoptosis, EMT, and the signaling pathways were studied using the MTT assay, flow cytometry, qRT-PCR, and Western blot. Results IL-33 was upregulated in human osteosarcoma cell lines, including U2OS cells. The use of an IL-33 gene plasmid promoted osteosarcoma cell viability, inhibited cell apoptosis, increased the expression of Bcl-2, and reduced the expression of Bax. IL-33 reduced the level of E-cadherin and increased the levels of N-cadherin and matrix metalloproteinase-9 (MMP-9) in osteosarcoma cells at the mRNA and protein level. The use of the IL-33 plasmid increased the protein expression levels of p-AKT and the p-AKT/AKT ratio in osteosarcoma cells, and IL-33 siRNA reversed these findings. Conclusions IL-33 was highly expressed in human osteosarcoma cells. Down-regulation of IL-33 reduced cell viability and EMT of osteosarcoma cells, and induced cell apoptosis through activation of the PI3K/AKT signaling pathway.
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Affiliation(s)
- Shenyu Wang
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China (mainland)
| | - Gongyin Zhao
- Department of Orthopedics, The Affiliated Hospital of Nanjing Medical University, Changzhou No. 2 People's Hospital, Changzhou, Jiangsu, China (mainland)
| | - Shujie Zhao
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China (mainland)
| | - Yusen Qiao
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China (mainland)
| | - Huilin Yang
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China (mainland)
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19
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Nader CP, Cidem A, Verrills NM, Ammit AJ. Protein phosphatase 2A (PP2A): a key phosphatase in the progression of chronic obstructive pulmonary disease (COPD) to lung cancer. Respir Res 2019; 20:222. [PMID: 31623614 PMCID: PMC6798356 DOI: 10.1186/s12931-019-1192-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Accepted: 09/20/2019] [Indexed: 02/06/2023] Open
Abstract
Lung cancer (LC) has the highest relative risk of development as a comorbidity of chronic obstructive pulmonary disease (COPD). The molecular mechanisms that mediate chronic inflammation and lung function impairment in COPD have been identified in LC. This suggests the two diseases are more linked than once thought. Emerging data in relation to a key phosphatase, protein phosphatase 2A (PP2A), and its regulatory role in inflammatory and tumour suppression in both disease settings suggests that it may be critical in the progression of COPD to LC. In this review, we uncover the importance of the functional and active PP2A holoenzyme in the context of both diseases. We describe PP2A inactivation via direct and indirect means and explore the actions of two key PP2A endogenous inhibitors, cancerous inhibitor of PP2A (CIP2A) and inhibitor 2 of PP2A (SET), and the role they play in COPD and LC. We explain how dysregulation of PP2A in COPD creates a favourable inflammatory micro-environment and promotes the initiation and progression of tumour pathogenesis. Finally, we highlight PP2A as a druggable target in the treatment of COPD and LC and demonstrate the potential of PP2A re-activation as a strategy to halt COPD disease progression to LC. Although further studies are required to elucidate if PP2A activity in COPD is a causal link for LC progression, studies focused on the potential of PP2A reactivating agents to reduce the risk of LC formation in COPD patients will be pivotal in improving clinical outcomes for both COPD and LC patients in the future.
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Affiliation(s)
- Cassandra P Nader
- Woolcock Emphysema Centre, Woolcock Institute of Medical Research, University of Sydney, Sydney, NSW, Australia
| | - Aylin Cidem
- Woolcock Emphysema Centre, Woolcock Institute of Medical Research, University of Sydney, Sydney, NSW, Australia
| | - Nicole M Verrills
- School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, 2308, Australia
- Priority Research Centre for Cancer Research, Innovation & Translation, Faculty of Health & Medicine, Hunter Medical Research Institute, New Lambton Heights, NSW, 2305, Australia
| | - Alaina J Ammit
- Woolcock Emphysema Centre, Woolcock Institute of Medical Research, University of Sydney, Sydney, NSW, Australia.
- School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia.
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20
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Masuda K, Kuwano Y. Diverse roles of RNA-binding proteins in cancer traits and their implications in gastrointestinal cancers. WILEY INTERDISCIPLINARY REVIEWS-RNA 2018; 10:e1520. [PMID: 30479000 DOI: 10.1002/wrna.1520] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 10/31/2018] [Accepted: 11/01/2018] [Indexed: 02/06/2023]
Abstract
Gene expression patterns in cancer cells are strongly influenced by posttranscriptional mechanisms. RNA-binding proteins (RBPs) play key roles in posttranscriptional gene regulation; they can interact with target mRNAs in a sequence- and structure-dependent manner, and determine cellular behavior by manipulating the processing of these mRNAs. Numerous RBPs are aberrantly deregulated in many human cancers and hence, affect the functioning of mRNAs that encode proteins, implicated in carcinogenesis. Here, we summarize the key roles of RBPs in posttranscriptional gene regulation, describe RBPs disrupted in cancer, and lastly focus on RBPs that are responsible for implementing cancer traits in the digestive tract. These evidences may reveal a potential link between changes in expression/function of RBPs and malignant transformation, and a framework for new insights and potential therapeutic applications. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.
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Affiliation(s)
- Kiyoshi Masuda
- Kawasaki Medical School at Kurashiki-City, Okayama, Japan
| | - Yuki Kuwano
- Department of Pathophysiology, Institute of Biomedical Sciences, Tokushima University Graduate School at Tokushima-City, Tokushima, Japan
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21
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Guo J, Qu H, Shan T, Chen Y, Chen Y, Xia J. Tristetraprolin Overexpression in Gastric Cancer Cells Suppresses PD-L1 Expression and Inhibits Tumor Progression by Enhancing Antitumor Immunity. Mol Cells 2018; 41:653-664. [PMID: 29936792 PMCID: PMC6078856 DOI: 10.14348/molcells.2018.0040] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 04/06/2018] [Accepted: 05/23/2018] [Indexed: 12/17/2022] Open
Abstract
The RNA-binding protein tristetraprolin (TTP) binds to adenosine-uridine AU-rich elements in the 3'-untranslated region of messenger RNAs and facilitates rapid degradation of the target mRNAs. Therefore, it regulates the expression of multiple cancer and immunity-associated transcripts. Furthermore, a lack of TTP in cancer cells influences cancer progression and predicts poor survival. Although the functions of TTP on cancer cells have previously been researched, the mechanism of TTP on the interaction between cancer cells with their microenvironment remains undiscovered. In this study, we admed to determine the role of cancer cell TTP during the interaction between tumor and immune cells, specifically regulatory T cells (Tregs). We evaluate the capability of TTP to modulate the antitumor immunity of GC and explored the underlying mechanism. The overexpression of TTP in GC cells dramatically increased peripheral blood mononuclear lymphocyte (PBML) -mediated cytotoxicity against GC cells. Increased cytotoxicity against TTP-overexpressed GC cells by PBMLs was determined by Treg development and infiltration. Surprisingly, we found the stabilization of programmed death-ligand 1 (PD-L1) mRNA was declining while TTP was elevated. The PD-L1 protein level was reduced in TTP-abundant GC cells. PD-L1 gas been found to play a pivotal role in Treg development and functional maintenance in immune system. Taken together, our results suggest the overexpression of TTP in GC cells not only affects cell survival and apoptosis but also increases PBMLs -mediated cytotoxicity against GC cells to decelerate tumor progression. Moreover, we identified PD-L1 as a critical TTP-regulated factor that contributes to inhibiting antitumor immunity.
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Affiliation(s)
- Jian Guo
- Department of General Surgery and Center of Translational Medicine, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical University,
China
| | - Huiheng Qu
- Department of General Surgery and Center of Translational Medicine, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical University,
China
| | - Ting Shan
- Department of General Surgery and Center of Translational Medicine, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical University,
China
| | - Yigang Chen
- Department of General Surgery and Center of Translational Medicine, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical University,
China
| | - Ye Chen
- Department of General Surgery and Center of Translational Medicine, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical University,
China
| | - Jiazeng Xia
- Department of General Surgery and Center of Translational Medicine, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical University,
China
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22
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Lee SR, Jin H, Kim WT, Kim WJ, Kim SZ, Leem SH, Kim SM. Tristetraprolin activation by resveratrol inhibits the proliferation and metastasis of colorectal cancer cells. Int J Oncol 2018; 53:1269-1278. [PMID: 29956753 DOI: 10.3892/ijo.2018.4453] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Accepted: 05/25/2018] [Indexed: 12/22/2022] Open
Abstract
Resveratrol (RSV) is a polyphenolic compound that naturally occurs in grapes, peanuts and berries. Considerable research has been conducted to determine the benefits of RSV against various human cancer types. Tristetraprolin (TTP) is an AU-rich element-binding protein that regulates mRNA stability and has decreased expression in human cancer. The present study investigated the biological effect of RSV on TTP gene regulation in colon cancer cells. RSV inhibited the proliferation and invasion/metastasis of HCT116 and SNU81 colon cancer cells. Furthermore, RSV induced a dose-dependent increase in TTP expression in HCT116 and SNU81 cells. The microarray experiment revealed that RSV significantly increased TTP expression by downregulating E2F transcription factor 1 (E2F1), a downstream target gene of TTP and regulated genes associated with inflammation, cell proliferation, cell death, angiogenesis and metastasis. Although TTP silencing inhibited TTP mRNA expression, the expression was subsequently restored by RSV. Small interfering RNA-induced TTP inhibition attenuated the effects of RSV on cell growth. In addition, RSV induced the mRNA-decaying activity of TTP and inhibited the relative luciferase activity of baculoviral IAP repeat containing 3 (cIAP2), large tumor suppressor kinase 2 (LATS2), E2F1, and lin‑28 homolog A (Lin28) in HCT116 and SNU81 cells. Therefore, RSV enhanced the inhibitory activity of TTP in HCT116 and SNU81 cells by negatively regulating cIAP2, E2F1, LATS2, and Lin28 expression. In conclusion, RSV suppressed the proliferation and invasion/metastasis of colon cancer cells by activating TTP.
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Affiliation(s)
- Se-Ra Lee
- Department of Biological Science, Dong-A University, Busan 49315, Republic of Korea
| | - Hua Jin
- Department of Physiology, Institute of Medical Science, Chonbuk National University Medical School, Jeonju, Jeonbuk 54907, Republic of Korea
| | - Won-Tae Kim
- Department of Biological Science, Dong-A University, Busan 49315, Republic of Korea
| | - Won-Jung Kim
- Department of Biological Science, Dong-A University, Busan 49315, Republic of Korea
| | - Sung Zoo Kim
- Department of Physiology, Institute of Medical Science, Chonbuk National University Medical School, Jeonju, Jeonbuk 54907, Republic of Korea
| | - Sun-Hee Leem
- Department of Biological Science, Dong-A University, Busan 49315, Republic of Korea
| | - Soo Mi Kim
- Department of Physiology, Institute of Medical Science, Chonbuk National University Medical School, Jeonju, Jeonbuk 54907, Republic of Korea
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23
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Wang H, Chen Y, Guo J, Shan T, Deng K, Chen J, Cai L, Zhou H, Zhao Q, Jin S, Xia J. Dysregulation of tristetraprolin and human antigen R promotes gastric cancer progressions partly by upregulation of the high-mobility group box 1. Sci Rep 2018; 8:7080. [PMID: 29728635 PMCID: PMC5935726 DOI: 10.1038/s41598-018-25443-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 04/16/2018] [Indexed: 12/13/2022] Open
Abstract
Aberrant expression of ARE-binding proteins (ARE-BPs) plays an important role in several diseases, including cancer. Both tristetraprolin (TTP) and human antigen R (HuR) are important ARE-BPs and always play opposite roles in regulating target mRNAs. Our previous work has demonstrated that TTP expression is decreased in gastric cancer (GC). In this study, we reported that HuR was elevated in GC cell lines and gastric cancer patients and that decreased TTP expression partly contributed to the elevated HuR levels by regulating its mRNA turnover. We also observed that dysregulation of TTP and HuR elevated the high-mobility group box 1 (HMGB1) expression in different ways. HuR promoted HMGB1 expression at translational level, while TTP regulated HMGB1 mRNA turnover by destabilizing its mRNA. Increased HuR promoted cancer cell proliferation and the metastasis potential partly by HMGB1. Using immunohistochemistry, we observed that both positive cytoplasmic and high-expression of nuclear HuR were associated with poor pathologic features and survival of GC patients. In conclusion, this study demonstrated that dysregulation of the TTP and HuR plays an important role in GC. Moreover, high HuR nuclear expression or aberrant cytoplasmic distribution may serve as a predictor of poor survival.
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Affiliation(s)
- Hao Wang
- Department of General Surgery and Translational Medicine Center, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, 214002, China
| | - Yigang Chen
- Department of General Surgery and Translational Medicine Center, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, 214002, China
| | - Jian Guo
- Department of General Surgery and Translational Medicine Center, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, 214002, China
| | - Ting Shan
- Department of General Surgery and Translational Medicine Center, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, 214002, China
| | - Kaiyuan Deng
- Department of General Surgery and Translational Medicine Center, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, 214002, China
| | - Jialin Chen
- Department of General Surgery and Translational Medicine Center, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, 214002, China
| | - Liping Cai
- Department of General Surgery and Translational Medicine Center, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, 214002, China
| | - Hong Zhou
- Department of General Surgery and Translational Medicine Center, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, 214002, China
| | - Qin Zhao
- Department of General Surgery and Translational Medicine Center, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, 214002, China
| | - Shimao Jin
- Department of General Surgery and Translational Medicine Center, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, 214002, China
| | - Jiazeng Xia
- Department of General Surgery and Translational Medicine Center, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, 214002, China.
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24
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Wei S, Li Q, Li Z, Wang L, Zhang L, Xu Z. miR-424-5p promotes proliferation of gastric cancer by targeting Smad3 through TGF-β signaling pathway. Oncotarget 2018; 7:75185-75196. [PMID: 27655675 PMCID: PMC5342733 DOI: 10.18632/oncotarget.12092] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 09/10/2016] [Indexed: 02/07/2023] Open
Abstract
MiRNAs have been reported to regulate gene expression and be associated with cancer progression. Recently, miR-424-5p was reported to play important role in a variety of tumors. However, the role and molecular mechanisms of miR-424-5p in GC (gastric cancer) remains largely unknown. In this study, we aimed to explore the role of miR-424-5p in GC. QRT-PCR was used to determine the expression levels of miR-424-5p and Smad3. CCK8 assay, plate clone assay and cell cycle assay were used to measure the effects of miR-424-5p on GC cell proliferation. Luciferase reporter assay and western blotting were used to prove that Smad3 was one of the direct targets of miR-424-5p. Tumorigenesis assay was used to investigate the role of miR-424-5p in tumor growth of GC cells in vivo. We found that miR-424-5p was up-regulated in GC tissues and cells. Over-expression of miR-424-5p could promote the proliferation of GC cells. In addition, luciferase reporter assay and western blotting assay revealed that Smad3 was a direct target of miR-424-5p. Over-expression of Smad3 could partially reverse the effects of miR-424-5p on GC cell proliferation. Our study further revealed that miR-424-5p could inhibit TGF-β signaling pathway by Smad3.
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Affiliation(s)
- Song Wei
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qing Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zheng Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Linjun Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lei Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zekuan Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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25
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Bisogno LS, Keene JD. RNA regulons in cancer and inflammation. Curr Opin Genet Dev 2017; 48:97-103. [PMID: 29175729 DOI: 10.1016/j.gde.2017.11.004] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Revised: 11/07/2017] [Accepted: 11/10/2017] [Indexed: 01/05/2023]
Abstract
Gene expression is the fundamental driving force that coordinates normal cellular processes and adapts to dysfunctional conditions such as oncogenic development and progression. While transcription is the basal process of gene expression, RNA transcripts are both the templates that encode proteins as well as perform functions that directly regulate diverse cellular processes. All levels of gene expression require coordination to optimize available resources, but how global gene expression drives cancers or responds to disrupting oncogenic mutations is not understood. Post-transcriptional coordination is controlled by RNA regulons that are governed by RNA-binding proteins (RBPs) and noncoding RNAs (ncRNAs) that bind and regulate multiple overlapping groups of functionally related RNAs. RNA regulons have been demonstrated to affect many biological functions and diseases, and many examples are known to regulate protein production in cancer and immune cells. In this review, we discuss RNA regulons demonstrated to coordinate global post-transcriptional mechanisms in carcinogenesis and inflammation.
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Affiliation(s)
- Laura Simone Bisogno
- Department of Molecular Genetics & Microbiology, Duke University Medical Center, Durham, NC 27710, United States
| | - Jack Donald Keene
- Department of Molecular Genetics & Microbiology, Duke University Medical Center, Durham, NC 27710, United States.
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26
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Guo J, Qu H, Chen Y, Xia J. The role of RNA-binding protein tristetraprolin in cancer and immunity. Med Oncol 2017; 34:196. [DOI: 10.1007/s12032-017-1055-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 11/06/2017] [Indexed: 12/20/2022]
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27
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Wang K, Shan S, Yang Z, Gu X, Wang Y, Wang C, Ren T. IL-33 blockade suppresses tumor growth of human lung cancer through direct and indirect pathways in a preclinical model. Oncotarget 2017; 8:68571-68582. [PMID: 28978138 PMCID: PMC5620278 DOI: 10.18632/oncotarget.19786] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2017] [Accepted: 06/18/2017] [Indexed: 02/07/2023] Open
Abstract
Non-small-cell lung cancer (NSCLC) is the most common type in lung cancer, a leading cause of cancer-related death worldwide. Our previous study unraveled a pro-cancer function of IL-33 in fueling outgrowth and metastasis of human NSCLC cells. Herein, we determined that interfere with IL-33 activity was an effective strategy for limiting NSCLC tumor growth using a preclinical model with human NSCLC xenografts. IL-33 blockade efficiently inhibited tumor growth of NSCLC xenografts in immune-deficient mice. Mechanistically, IL-33 blockade suppressed outgrowth capacity of human NSCLC cells. Meanwhile, IL-33 blockade abrogated polarization of M2 tumor-associated macrophages (TAMs) and reduced accumulation of regulatory T cells (Tregs) in tumor microenvironments, shaping functional immune surveillance. In NSCLC patients, IL-33 expressions were positively correlated with Ki-67 proliferation index and expressions of M2 TAM- and Teg-related genes. These findings identify IL-33 as a dual-functional factor in NSCLC pathogenesis and suggest IL-33 blockade as a promising therapeutic for NSCLC patients.
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Affiliation(s)
- Kailing Wang
- Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Shan Shan
- Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.,Department of Respiratory Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Zongjun Yang
- Department of Clinical Laboratory, Qingdao Women & Children Hospital, Qingdao 266034, China
| | - Xia Gu
- Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Yuanyuan Wang
- Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Chunhong Wang
- Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Tao Ren
- Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.,Department of Respiratory Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
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28
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Bagheri V, Memar B, Momtazi AA, Sahebkar A, Gholamin M, Abbaszadegan MR. Cytokine networks and their association with Helicobacter pylori infection in gastric carcinoma. J Cell Physiol 2017; 233:2791-2803. [PMID: 28121015 DOI: 10.1002/jcp.25822] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Accepted: 12/16/2016] [Indexed: 12/20/2022]
Abstract
Cytokine networks as dynamic networks are pivotal aspects of tumor immunology, especially in gastric cancer (GC), in which infection, inflammation, and antitumor immunity are key elements of disease progression. In this review, we describe functional roles of well-known GC-modulatory cytokines, highlight the functions of cytokines with more recently described roles in GC, and emphasize the therapeutic potential of targeting the complex cytokine milieu. We also focus on the role of Helicobacter pylori (HP)-induced inflammation in GC and discuss how HP-induced chronic inflammation can lead to the induction of stem cell hyperplasia, morphological changes in gastric mucosa and GC development.
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Affiliation(s)
- Vahid Bagheri
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Human Genetic Division, Immunology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Bahram Memar
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pathology, Faculty of Medicine, Emam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Abbas Momtazi
- Department of Medical Biotechnology, Student Research Committee, Nanotechnology Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehran Gholamin
- Human Genetic Division, Immunology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Laboratory Sciences, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Reza Abbaszadegan
- Human Genetic Division, Immunology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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29
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Interleukin-33 Expression does not Correlate with Survival of Gastric Cancer Patients. Pathol Oncol Res 2016; 23:615-619. [PMID: 28000059 DOI: 10.1007/s12253-016-0167-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2016] [Accepted: 12/14/2016] [Indexed: 12/15/2022]
Abstract
The aim of the study was to investigate IL-33 expression in gastric cancer (GC) and its association with the clinical characteristics and the prognosis. IL-33 protein in tumor and corresponding adjacent tissues were detected by immunohistochemistry in 179 GC patients and clinical features plus prognostic value were analyzed via Pearson's chi-square test and Kaplan-Meier test in Cox proportional hazards model, respectively. IL-33 protein levels were significantly lower in tumor tissues than adjacent tissues (29.05% vs. 78.77%, χ 2 = 89.05, P < 0.001). The positive rate of IL-33 in the ulcerative type group was the lowest among all groups (P < 0.05). IL-33 levels were correlated with age (P = 0.025) and invasion depth (P = 0.030) while not significantly associated with the overall survival of GC patients. IL-33 expression is associated with age and invasive depth of GC patients but not an independent risk factor of prognosis.
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30
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Dysregulation of TTP and HuR plays an important role in cancers. Tumour Biol 2016; 37:14451-14461. [DOI: 10.1007/s13277-016-5397-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Accepted: 09/09/2016] [Indexed: 12/16/2022] Open
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31
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IL-33 signaling fuels outgrowth and metastasis of human lung cancer. Biochem Biophys Res Commun 2016; 479:461-468. [PMID: 27644880 DOI: 10.1016/j.bbrc.2016.09.081] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Accepted: 09/16/2016] [Indexed: 12/21/2022]
Abstract
IL-33 is a member of IL-1 superfamily that drives production of Th2-related cytokines. Recently, accumulating evidence suggest an involvement of IL-33 in carcinogenesis. Herein, we determine a close correlation of IL-33 expression and cancer progress in patients with non-small-cell lung cancer (NSCLC). Overexpression of IL-33 by transfection with IL-33 expression vector enhances NSCLC outgrowth and metastasis, while genetic knockdown of IL-33 by transfection with IL-33 shRNA limits NSCLC progression. In consistent, IL-33 stimulation of NSCLC cells leads to robust NSCLC outgrowth and metastasis in vitro and in vivo. Mechanically, IL-33-triggered NSCLC progression relies on ST2 receptor and could be abrogated by ST2 blockade. IL-33/ST2 pathway up-regulates membrane glucose transporter 1 (GLUT1) on NSCLC cells, enhancing their glucose uptake and glycolysis. Accordingly, interfering GLUT1 expression dampens IL-33-enhanced glucose uptake and glycolysis in NSCLC cells, thereby abrogates IL-33-induced NSCLC outgrowth and metastasis. In essence, these findings derived from patients' NSCLC cells uncover a new function of IL-33 in NSCLC pathogenesis and identify GLUT1 as a novel target of IL-33 signaling. Block IL-33 is a promising therapeutic strategy to limit NSCLC glycolysis and tumor progression in clinical practice.
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32
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Khabar KSA. Hallmarks of cancer and AU-rich elements. WILEY INTERDISCIPLINARY REVIEWS-RNA 2016; 8. [PMID: 27251431 PMCID: PMC5215528 DOI: 10.1002/wrna.1368] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 05/05/2016] [Accepted: 05/09/2016] [Indexed: 12/14/2022]
Abstract
Post‐transcriptional control of gene expression is aberrant in cancer cells. Sustained stabilization and enhanced translation of specific mRNAs are features of tumor cells. AU‐rich elements (AREs), cis‐acting mRNA decay determinants, play a major role in the posttranscriptional regulation of many genes involved in cancer processes. This review discusses the role of aberrant ARE‐mediated posttranscriptional processes in each of the hallmarks of cancer, including sustained cellular growth, resistance to apoptosis, angiogenesis, invasion, and metastasis. WIREs RNA 2017, 8:e1368. doi: 10.1002/wrna.1368 For further resources related to this article, please visit the WIREs website.
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Affiliation(s)
- Khalid S A Khabar
- King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
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