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Marroquin-Muciño M, Benito-Lopez JJ, Perez-Medina M, Aguilar-Cazares D, Galicia-Velasco M, Chavez-Dominguez R, Meza-Toledo SE, Meneses-Flores M, Camarena A, Lopez-Gonzalez JS. SOCS1 Inhibits IL-6-Induced CD155 Overexpression in Lung Adenocarcinoma. Int J Mol Sci 2024; 25:12141. [PMID: 39596207 PMCID: PMC11595078 DOI: 10.3390/ijms252212141] [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: 10/02/2024] [Revised: 11/04/2024] [Accepted: 11/07/2024] [Indexed: 11/28/2024] Open
Abstract
CD155, also known as the poliovirus receptor (PVR), is a crucial molecule in the development and progression of cancer, as its overexpression favors immune evasion and resistance to immunotherapy. However, little is known about the mechanisms that regulate its overexpression. Proinflammatory factors produced by various cellular components of the tumor microenvironment (TME) have been associated with CD155 expression. We analyzed the effect of interleukin (IL)-6 on CD155 expression in lung adenocarcinoma. We found a positive relationship between mRNA and protein levels. This correlation was also observed in bioinformatics analysis and in biopsies and serum from patients with lung adenocarcinoma. Interestingly, lung adenocarcinoma cell lines expressing suppressor of cytokine signaling 1 (SOCS1) did not show increased CD155 levels upon IL-6 stimulation, and SOCS1 silencing reverted this effect. IL-6 and SOCS1 are critical regulators of CD155 expression in lung adenocarcinoma. Further basic and clinical studies are needed to define the role of these molecules during tumor development and to improve their clinical impact as biomarkers and targets for predicting the efficacy of immunotherapies. This study deepens the understanding of the intricate regulation of the immune checkpoints mediated by soluble factors and allows us to devise new ways to combine conventional treatments with the most innovative anticancer options.
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Affiliation(s)
- Mario Marroquin-Muciño
- Laboratorio de Cancer Pulmonar, Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City 14080, Mexico; (M.M.-M.); (M.P.-M.); (D.A.-C.); (M.G.-V.); (R.C.-D.); (M.M.-F.)
- Laboratorio de Quimioterapia Experimental, Departamento de Bioquimica, Escuela Nacional de Ciencias Biologicas, Instituto Politecnico Nacional, Mexico City 11340, Mexico;
| | - Jesus J. Benito-Lopez
- Laboratorio de Cancer Pulmonar, Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City 14080, Mexico; (M.M.-M.); (M.P.-M.); (D.A.-C.); (M.G.-V.); (R.C.-D.); (M.M.-F.)
- Posgrado en Ciencias Biologicas, Universidad Nacional Autonoma de Mexico, Mexico City 04510, Mexico
| | - Mario Perez-Medina
- Laboratorio de Cancer Pulmonar, Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City 14080, Mexico; (M.M.-M.); (M.P.-M.); (D.A.-C.); (M.G.-V.); (R.C.-D.); (M.M.-F.)
- Laboratorio de Quimioterapia Experimental, Departamento de Bioquimica, Escuela Nacional de Ciencias Biologicas, Instituto Politecnico Nacional, Mexico City 11340, Mexico;
| | - Dolores Aguilar-Cazares
- Laboratorio de Cancer Pulmonar, Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City 14080, Mexico; (M.M.-M.); (M.P.-M.); (D.A.-C.); (M.G.-V.); (R.C.-D.); (M.M.-F.)
| | - Miriam Galicia-Velasco
- Laboratorio de Cancer Pulmonar, Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City 14080, Mexico; (M.M.-M.); (M.P.-M.); (D.A.-C.); (M.G.-V.); (R.C.-D.); (M.M.-F.)
| | - Rodolfo Chavez-Dominguez
- Laboratorio de Cancer Pulmonar, Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City 14080, Mexico; (M.M.-M.); (M.P.-M.); (D.A.-C.); (M.G.-V.); (R.C.-D.); (M.M.-F.)
| | - Sergio E. Meza-Toledo
- Laboratorio de Quimioterapia Experimental, Departamento de Bioquimica, Escuela Nacional de Ciencias Biologicas, Instituto Politecnico Nacional, Mexico City 11340, Mexico;
| | - Manuel Meneses-Flores
- Laboratorio de Cancer Pulmonar, Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City 14080, Mexico; (M.M.-M.); (M.P.-M.); (D.A.-C.); (M.G.-V.); (R.C.-D.); (M.M.-F.)
- Departamento de Patologia, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City 14080, Mexico
| | - Angel Camarena
- Laboratorio de Inmunobiologia y Genetica, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City 14080, Mexico;
| | - Jose S. Lopez-Gonzalez
- Laboratorio de Cancer Pulmonar, Departamento de Enfermedades Cronico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City 14080, Mexico; (M.M.-M.); (M.P.-M.); (D.A.-C.); (M.G.-V.); (R.C.-D.); (M.M.-F.)
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Fatemeh S, Mahboobeh Z, Khadijeh A, Amirhossein MK, Pegah M. An in-silico study to determine susceptibility to cancer by evaluating the coding and non-coding non-synonymous single nucleotide variants in the SOCS3 gene. J Biomol Struct Dyn 2024; 42:8281-8292. [PMID: 37753777 DOI: 10.1080/07391102.2023.2256408] [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: 03/27/2023] [Accepted: 07/30/2023] [Indexed: 09/28/2023]
Abstract
Single Nucleotide Variant (SNVs) affect gene expression as well as protein structure and activity, leading to reduced signaling capabilities and ultimately, increasing cancer risk. SOCS3 (suppressor of cytokine signaling 3), a critical tumor suppressor providing a substantial part in the feedback loop of the JAK/STAT pathway, is abnormally suppressed in various cancer. This study aims to screen non-coding and potentially deleterious coding SNVs in the SOCS3 gene. We performed six programs: PredictSNP1.0 (predicting Deleterious nsSNVs), ConSurf (analyzing sequence conservation), ModPred (analyzing SNVS in PTMs sites), I-Mutant and MUpro (to analyze SNVs effecting protein stability), and molecular docking and molecular dynamics (MD) (to assess the consequences of SOCS3 genetic variations on JAK interactions) for coding regions and three programs (UTRSite, SNP2TFBS, miRNA SNP) (to analyze SNVs effecting the gene expression) in non-coding regions, respectively. After screening 2786 SOCS3 SNVs, we found 10 SNVs, as well as 49 SNPs that change the function of non-coding areas. Out of 10 selected nsSNVs, 3 SNVs (W48R, R71C, N198S) predicted to be the most damaging by all the software programs, as well as one nsSNV (R194W) could be highly deleterious from Molecular Docking analysis combined with MD Simulations. Our findings propose a procedure for studying the structure-related consequences of SNVs on protein function in the future.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Sadri Fatemeh
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Zarei Mahboobeh
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Ahmadi Khadijeh
- Infectious and Tropical Diseases Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | | | - Mousavi Pegah
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
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Morelli M, Madonna S, Albanesi C. SOCS1 and SOCS3 as key checkpoint molecules in the immune responses associated to skin inflammation and malignant transformation. Front Immunol 2024; 15:1393799. [PMID: 38975347 PMCID: PMC11224294 DOI: 10.3389/fimmu.2024.1393799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 06/07/2024] [Indexed: 07/09/2024] Open
Abstract
SOCS are a family of negative inhibitors of the molecular cascades induced by cytokines, growth factors and hormones. At molecular level, SOCS proteins inhibit the kinase activity of specific sets of receptor-associated Janus Activated Kinases (JAKs), thereby suppressing the propagation of intracellular signals. Of the eight known members, SOCS1 and SOCS3 inhibit activity of JAKs mainly induced by cytokines and can play key roles in regulation of inflammatory and immune responses. SOCS1 and SOCS3 are the most well-characterized SOCS members in skin inflammatory diseases, where their inhibitory activity on cytokine activated JAKs and consequent anti-inflammatory action has been widely investigated in epidermal keratinocytes. Structurally, SOCS1 and SOCS3 share the presence of a N-terminal domain containing a kinase inhibitory region (KIR) motif able to act as a pseudo-substrate for JAK and to inhibit its activity. During the last decades, the design and employment of SOCS1 and SOCS3-derived peptides mimicking KIR domains in experimental models of dermatoses definitively established a strong anti-inflammatory and ameliorative impact of JAK inhibition on skin inflammatory responses. Herein, we discuss the importance of the findings collected in the past on SOCS1 and SOCS3 function in the inflammatory responses associated to skin immune-mediated diseases and malignancies, for the development of the JAK inhibitor drugs. Among them, different JAK inhibitors have been introduced in the clinical practice for treatment of atopic dermatitis and psoriasis, and others are being investigated for skin diseases like alopecia areata and vitiligo.
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Affiliation(s)
| | - Stefania Madonna
- Laboratory of Experimental Immunology, Istituto Dermopatico dell'Immacolata - Istituto di Ricovero e Cura a Carattere Scientifico (IDI-IRCCS), Rome, Italy
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Jeong IH, Yun JK, Jin JO, Hong JH, Lee JY, Lee GD, Lee PCW. E3 ligase SOCS3 regulates NOD2 expression by ubiquitin proteasome system in lung cancer progression. Cell Oncol (Dordr) 2024; 47:819-832. [PMID: 37910276 DOI: 10.1007/s13402-023-00896-5] [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] [Accepted: 10/24/2023] [Indexed: 11/03/2023] Open
Abstract
PURPOSE Despite lung cancer is one of the leading causes of cancer-related deaths, it remains hard to discover effective diagnostic and therapeutic approaches. Moreover, the five-year survival rate is relatively lower than other tumors. So urgent needs for finding a new theranostic target to treat lung cancer effectively. This study aims to present SOCS3 and NOD2 proteins as novel targets for diagnosis and therapy. METHODS We first confirmed SOCS3 expression level in patients' tissues. Then, we applied knockdown and overexpression of SOCS3 on lung cancer cell lines and performed proliferation, migration, and invasion assay. After that, we found NOD2 is a target of SOCS3 and introduced overexpression of NOD2 to A549 for verifying reduced tumorigenicity of lung cancer cells. RESULTS We identified protein expression level of SOCS3 was frequently higher in tumor tissues than adjacent normal tissues. Truly, overexpression of SOCS3 promoted proliferation, migration, and invasion capacity of lung cancer cells. We found that SOCS3 interacts with NOD2 and SOCS3 ubiquitinates NOD2 directly. Furthermore, lung cancer tissues with higher SOCS3 expression showed lower NOD2 expression. We confirmed overexpression of NOD2 leads to suppressed tumorigenicity of lung cancer cells, and these effects occurred through MAPK pathway. CONCLUSION Collectively, our work reveals novel roles of SOCS3 in lung tumorigenesis and proposes SOCS3 as a promising biomarker candidate for therapeutic and diagnostic target for lung cancer.
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Affiliation(s)
- In-Ho Jeong
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea
| | - Jae Kwang Yun
- Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea
| | - Jun-O Jin
- Department of Microbiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea
| | - Jeong Hee Hong
- Department of Physiology, College of Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 21999, Korea
| | - Ji Yeon Lee
- Division of Rheumatology, Department of Medicine, Seoul St. Mary's Hospital, Catholic University, Seoul, 06591, Korea.
| | - Geun Dong Lee
- Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.
- Lung Cancer Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.
| | - Peter Chang-Whan Lee
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.
- Lung Cancer Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.
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Ivanova E, Hue-Beauvais C, Castille J, Laubier J, Le Guillou S, Aujean E, Lecardonnel J, Lebrun L, Jaffrezic F, Rousseau-Ralliard D, Péchoux C, Letheule M, Foucras G, Charlier M, Le Provost F. Mutation of SOCS2 induces structural and functional changes in mammary development. Development 2024; 151:dev202332. [PMID: 38391249 DOI: 10.1242/dev.202332] [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: 09/04/2023] [Accepted: 02/15/2024] [Indexed: 02/24/2024]
Abstract
Lactation is an essential process for mammals. In sheep, the R96C mutation in suppressor of cytokine signaling 2 (SOCS2) protein is associated with greater milk production and increased mastitis sensitivity. To shed light on the involvement of R96C mutation in mammary gland development and lactation, we developed a mouse model carrying this mutation (SOCS2KI/KI). Mammary glands from virgin adult SOCS2KI/KI mice presented a branching defect and less epithelial tissue, which were not compensated for in later stages of mammary development. Mammary epithelial cell (MEC) subpopulations were modified, with mutated mice having three times as many basal cells, accompanied by a decrease in luminal cells. The SOCS2KI/KI mammary gland remained functional; however, MECs contained more lipid droplets versus fat globules, and milk lipid composition was modified. Moreover, the gene expression dynamic from virgin to pregnancy state resulted in the identification of about 3000 differentially expressed genes specific to SOCS2KI/KI or control mice. Our results show that SOCS2 is important for mammary gland development and milk production. In the long term, this finding raises the possibility of ensuring adequate milk production without compromising animal health and welfare.
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Affiliation(s)
- Elitsa Ivanova
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, Jouy-en-Josas 78350, France
| | - Cathy Hue-Beauvais
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, Jouy-en-Josas 78350, France
| | - Johan Castille
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, Jouy-en-Josas 78350, France
| | - Johann Laubier
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, Jouy-en-Josas 78350, France
| | - Sandrine Le Guillou
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, Jouy-en-Josas 78350, France
| | - Etienne Aujean
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, Jouy-en-Josas 78350, France
| | - Jerome Lecardonnel
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, Jouy-en-Josas 78350, France
| | - Laura Lebrun
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, Jouy-en-Josas 78350, France
| | - Florence Jaffrezic
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, Jouy-en-Josas 78350, France
| | - Delphine Rousseau-Ralliard
- Université Paris-Saclay, UVSQ, INRAE, BREED, Jouy-en-Josas 78350, France
- Ecole Nationale Vétérinaire d'Alfort, BREED, Maisons-Alfort 94700, France
| | - Christine Péchoux
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, Jouy-en-Josas 78350, France
| | - Martine Letheule
- Université Paris-Saclay, UVSQ, INRAE, BREED, Jouy-en-Josas 78350, France
- Ecole Nationale Vétérinaire d'Alfort, BREED, Maisons-Alfort 94700, France
| | - Gilles Foucras
- IHAP, Université de Toulouse, INRAE, ENVT, Toulouse 31076, France
| | - Madia Charlier
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, Jouy-en-Josas 78350, France
| | - Fabienne Le Provost
- Université Paris-Saclay, INRAE, AgroParisTech, GABI, Jouy-en-Josas 78350, France
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Ilangumaran S, Gui Y, Shukla A, Ramanathan S. SOCS1 expression in cancer cells: potential roles in promoting antitumor immunity. Front Immunol 2024; 15:1362224. [PMID: 38415248 PMCID: PMC10897024 DOI: 10.3389/fimmu.2024.1362224] [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: 12/27/2023] [Accepted: 01/31/2024] [Indexed: 02/29/2024] Open
Abstract
Suppressor of cytokine signaling 1 (SOCS1) is a potent regulator immune cell responses and a proven tumor suppressor. Inhibition of SOCS1 in T cells can boost antitumor immunity, whereas its loss in tumor cells increases tumor aggressivity. Investigations into the tumor suppression mechanisms so far focused on tumor cell-intrinsic functions of SOCS1. However, it is possible that SOCS1 expression in tumor cells also regulate antitumor immune responses in a cell-extrinsic manner via direct and indirect mechanisms. Here, we discuss the evidence supporting the latter, and its implications for antitumor immunity.
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Affiliation(s)
- Subburaj Ilangumaran
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
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Shukla A, Khan MGM, Cayarga AA, Namvarpour M, Chowdhury MMH, Levesque D, Lucier JF, Boisvert FM, Ramanathan S, Ilangumaran S. The Tumor Suppressor SOCS1 Diminishes Tolerance to Oxidative Stress in Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:292. [PMID: 38254783 PMCID: PMC10814246 DOI: 10.3390/cancers16020292] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/05/2024] [Accepted: 01/08/2024] [Indexed: 01/24/2024] Open
Abstract
SOCS1 is a tumor suppressor in hepatocellular carcinoma (HCC). Recently, we showed that a loss of SOCS1 in hepatocytes promotes NRF2 activation. Here, we investigated how SOCS1 expression in HCC cells affected oxidative stress response and modulated the cellular proteome. Murine Hepa1-6 cells expressing SOCS1 (Hepa-SOCS1) or control vector (Hepa-Vector) were treated with cisplatin or tert-butyl hydroperoxide (t-BHP). The induction of NRF2 and its target genes, oxidative stress, lipid peroxidation, cell survival and cellular proteome profiles were evaluated. NRF2 induction was significantly reduced in Hepa-SOCS1 cells. The gene and protein expression of NRF2 targets were differentially induced in Hepa-Vector cells but markedly suppressed in Hepa-SOCS1 cells. Hepa-SOCS1 cells displayed an increased induction of reactive oxygen species but reduced lipid peroxidation. Nonetheless, Hepa-SOCS1 cells treated with cisplatin or t-BHP showed reduced survival. GCLC, poorly induced in Hepa-SOCS1 cells, showed a strong positive correlation with NFE2L2 and an inverse correlation with SOCS1 in the TCGA-LIHC transcriptomic data. A proteomic analysis of Hepa-Vector and Hepa-SOCS1 cells revealed that SOCS1 differentially modulated many proteins involved in diverse molecular pathways, including mitochondrial ROS generation and ROS detoxification, through peroxiredoxin and thioredoxin systems. Our findings indicate that maintaining sensitivity to oxidative stress is an important tumor suppression mechanism of SOCS1 in HCC.
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Affiliation(s)
- Akhil Shukla
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (A.S.); (M.G.M.K.); (A.A.C.); (M.N.); (M.M.H.C.); (D.L.); (F.-M.B.); (S.R.)
| | - Md Gulam Musawwir Khan
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (A.S.); (M.G.M.K.); (A.A.C.); (M.N.); (M.M.H.C.); (D.L.); (F.-M.B.); (S.R.)
| | - Anny Armas Cayarga
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (A.S.); (M.G.M.K.); (A.A.C.); (M.N.); (M.M.H.C.); (D.L.); (F.-M.B.); (S.R.)
| | - Mozhdeh Namvarpour
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (A.S.); (M.G.M.K.); (A.A.C.); (M.N.); (M.M.H.C.); (D.L.); (F.-M.B.); (S.R.)
| | - Mohammad Mobarak H. Chowdhury
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (A.S.); (M.G.M.K.); (A.A.C.); (M.N.); (M.M.H.C.); (D.L.); (F.-M.B.); (S.R.)
| | - Dominique Levesque
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (A.S.); (M.G.M.K.); (A.A.C.); (M.N.); (M.M.H.C.); (D.L.); (F.-M.B.); (S.R.)
| | - Jean-François Lucier
- Department of Biology, Université de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada;
| | - François-Michel Boisvert
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (A.S.); (M.G.M.K.); (A.A.C.); (M.N.); (M.M.H.C.); (D.L.); (F.-M.B.); (S.R.)
| | - Sheela Ramanathan
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (A.S.); (M.G.M.K.); (A.A.C.); (M.N.); (M.M.H.C.); (D.L.); (F.-M.B.); (S.R.)
- Centre de Recherche, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
| | - Subburaj Ilangumaran
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; (A.S.); (M.G.M.K.); (A.A.C.); (M.N.); (M.M.H.C.); (D.L.); (F.-M.B.); (S.R.)
- Centre de Recherche, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
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Liu Z, Li SS, Zhang GY, Lv S, Wang S, Li FQ. Whole transcriptome sequencing for revealing the pathogenesis of sporotrichosis caused by Sporothrix globosa. Sci Rep 2024; 14:359. [PMID: 38172590 PMCID: PMC10764346 DOI: 10.1038/s41598-023-50728-7] [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: 07/20/2023] [Accepted: 12/23/2023] [Indexed: 01/05/2024] Open
Abstract
This study aimed to investigate the molecular mechanism of sporotrichosis and identify possible novel therapeutic targets. Total RNA was extracted from skin lesion samples from sporotrichosis patients and used to construct a long-chain RNA transcriptome library and miRNA transcriptome library for whole transcriptome sequencing. The differentially expressed genes (DEGs) between the groups were identified, and then Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis enrichment analyses were performed based on the DEGs. An lncRNA-miRNA-mRNA ceRNA network was constructed. The expressions of JAK/STAT pathway-related proteins were detected in the patient and control tissues using RT-qPCR and Western blot analysis. Enrichment analysis showed that the DEGs were mainly enriched in various infectious diseases and immune response-related signaling pathways. Competing endogenous RNA network analysis was performed and identified the hub lncRNAs, miRNAs, and mRNAs. Compared with the control group, the mRNA expressions of SOCS3, IL-6, and JAK3 were significantly upregulated, while the expression of STAT3 did not change significantly. Also, the protein expressions of SOCS3, IL-6, JAK3, and STAT3, as well as phosphorylated JAK3 and STAT3, were significantly upregulated. We identified 671 lncRNA DEGs, 3281 mRNA DEGs, and 214 miRNA DEGs to be involved in Sporothrix globosa infection. The study findings suggest that the JAK/STAT pathway may be a therapeutic target for sporotrichosis.
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Affiliation(s)
- Zhe Liu
- Department of Dermatology, The Second Hospital of Jilin University, No. 218 Ziqiang Road, Nanguan District, Changchun, 130041, Jilin Province, China
| | - Su-Shan Li
- Department of Dermatology, The Second Hospital of Jilin University, No. 218 Ziqiang Road, Nanguan District, Changchun, 130041, Jilin Province, China
| | - Gui-Yun Zhang
- Department of Dermatology, The Second Hospital of Jilin University, No. 218 Ziqiang Road, Nanguan District, Changchun, 130041, Jilin Province, China
| | - Sha Lv
- Department of Dermatology, The Second Hospital of Jilin University, No. 218 Ziqiang Road, Nanguan District, Changchun, 130041, Jilin Province, China
| | - Shuang Wang
- Department of Dermatology, The Second Hospital of Jilin University, No. 218 Ziqiang Road, Nanguan District, Changchun, 130041, Jilin Province, China.
| | - Fu-Qiu Li
- Department of Dermatology, The Second Hospital of Jilin University, No. 218 Ziqiang Road, Nanguan District, Changchun, 130041, Jilin Province, China.
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Paeiz H, Salehi Z, Mashayekhi F, Saeidi Saedi H, Mirzanejad L. The importance of SOCS1 - 1478 CA/del polymorphism and expression in breast cancer: a case-control study in the north of Iran. Breast Cancer Res Treat 2023; 202:389-395. [PMID: 37526791 DOI: 10.1007/s10549-023-07070-3] [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: 05/11/2023] [Accepted: 07/20/2023] [Indexed: 08/02/2023]
Abstract
PURPOSE This project aimed to evaluate the relationship between the suppressor of cytokine signaling-1 (SOCS1) - 1478 CA > del genetic variation and breast cancer susceptibility. Moreover, we investigated the SOCS1 mRNA expression level in cancerous tissues. METHODS A total of 100 patients with breast cancer and 120 healthy individuals were selected. Genomic DNA was extracted from blood. SOCS1 genotyping and relative gene expression were performed using ARMS-PCR (Amplification-Refractory Mutation System-Polymerase Chain Reaction) and real-time PCR, respectively. RESULTS In breast cancer patients, the prevalence of genotype frequencies of SOCS1 (- 1478 CA > del) CA/CA, CA/del, and del/del was 52, 31, and 17%, respectively. Among controls, the distribution of CA/CA, CA/del, and del/del was 63, 15, and 22%, respectively. The chi-square test reported that a significant difference was observed in the genotypic distribution of SOCS1 (- 1478 CA > del) polymorphism between cases and controls (χ2 = 8.08, P = 0.01). In addition, the presence of the CA/del genotype was associated with an elevated risk of breast cancer (in the codominant model: OR 2.51; 95% CI 1.27-4.96, P = 0.007 and in the over dominant model: OR 2.54; 95% CI 1.32-4.90, P = 0.005). However, there was no significant difference in allelic distributions between the groups (P > 0.05). There was no significant difference in the breast cancer risk associated with the dominant and recessive genetic models when the reference was CA/CA and CA/CA + CA/del genotype, respectively (P = 0.09 and P = 0.38). Moreover, the expression of SOCS1 decreased in cancerous tissues as compared to the adjacent non-cancerous tissues (P < 0.0001). CONCLUSION In conclusion, a functional SOCS1 promoter polymorphism (- 1478 CA > del) may affect breast cancer susceptibility.
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Affiliation(s)
- Habibbullah Paeiz
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran
| | - Zivar Salehi
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran.
| | - Farhad Mashayekhi
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran
| | - Hamid Saeidi Saedi
- Department of Radiation Oncology, Cancer Research Center, Guilan University of Medical Sciences (GUMS), Rasht, Iran
| | - Laleh Mirzanejad
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran
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10
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Luo Y, Vermeer MH, de Haan S, Kinderman P, de Gruijl FR, van Hall T, Tensen CP. Socs1-knockout in skin-resident CD4 + T cells in a protracted contact-allergic reaction results in an autonomous skin inflammation with features of early-stage mycosis fungoides. Biochem Biophys Rep 2023; 35:101535. [PMID: 37664523 PMCID: PMC10470183 DOI: 10.1016/j.bbrep.2023.101535] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 08/18/2023] [Accepted: 08/18/2023] [Indexed: 09/05/2023] Open
Abstract
Recent detailed genomic analysis of mycosis fungoides (MF) identified suppressor of cytokine signaling 1 (SOCS1), an inhibitor of JAK/STAT signaling, as one of the frequently deleted tumor suppressors in MF, and one-copy deletion of SOCS1 was confirmed in early-stage MF lesions. To better understand the functional role of SOCS1 in the genesis of MF, we used a genetically engineered mouse model emulating heterozygous SOCS1 loss in skin resident CD4+ T cells. In these mice an experimentally induced contact-allergic reaction was maintained for 20 weeks. Ten weeks after discontinuing contact-allergic challenges, only the skin with locally one-copy deletion of Socs1 in CD4+ T cells still showed high numbers of CD3+/CD4+ Socs1 k.o. cells in the dermis (p ＜ 0.0001) with prevalent Stat3 activation (p ＜0.001). And in one out of 9 mice, this had progressed to far more dramatic increases, including the thickened epidermis, and with an explosive growth of Socs1 k.o. T cells in circulation; indicative of cutaneous lymphoma. Hence, we show that Socs1 mono-allelic loss in CD4+ T cells locally in protractedly inflamed skin results in autonomous skin inflammation with features of early-stage MF.
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Affiliation(s)
- Yixin Luo
- Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Maarten H. Vermeer
- Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Sanne de Haan
- Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Priscilla Kinderman
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Frank R. de Gruijl
- Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Thorbald van Hall
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | - Cornelis P. Tensen
- Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands
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11
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Gu J, Yang S, Wang X, Wu Y, Wei J, Xu J. Hypoxic lung adenocarcinoma-derived exosomal miR-1290 induces M2 macrophage polarization by targeting SOCS3. Cancer Med 2023. [PMID: 37081748 DOI: 10.1002/cam4.5954] [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: 01/30/2023] [Revised: 03/09/2023] [Accepted: 03/31/2023] [Indexed: 04/22/2023] Open
Abstract
BACKGROUND Exosomes are critical mediators of tumor cell-microenvironment cross talk. However, the mechanisms by which hypoxic Lung adenocarcinoma (LUAD)-derived exosomes modulate macrophage polarization remain largely unknown. The aim of this study was to investigate the effects of hypoxic LUAD-derived exosome on macrophage polarization and explore the underlying molecular mechanism. MATERIALS AND METHODS LUAD-derived exosomes were isolated, and then confirmed by transmission electron microscopy, nanoparticle tracking analysis, and Western blot. Internalization of exosomes in macrophages was detected by confocal microscope. Gain- and loss-of-function experiments, rescue experiments, and xenograft models were performed to uncover the underlying mechanisms of exosomal miR-1290 induced macrophage polarization in vitro and in vivo. RESULTS miR-1290 was enriched in hypoxic LUAD cancer cell-derived exosomes and could be transferred to macrophages. Overexpression of miR-1290 in macrophages-induced polarization of M2 phenotype. Luciferase assay verified SOCS3 was the target of miR-1290. Hypoxic LUAD cell-derived exosomal miR-1290 activated the STAT3 signaling pathway by targeting SOCS3 to promote M2 macrophage polarization. CONCLUSION Hypoxic LUAD cells generate miR-1290-rich exosomes that promote M2 polarization of macrophages. Targeting exosomal miR-1290 may provide a potential immunotherapeutic strategy for LUAD.
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Affiliation(s)
- Jiahui Gu
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shengrui Yang
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xueying Wang
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yining Wu
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jia Wei
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jian Xu
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, China
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12
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Brandstoetter T, Schmoellerl J, Grausenburger R, Kollmann S, Doma E, Huuhtanen J, Klampfl T, Eder T, Grebien F, Hoermann G, Zuber J, Mustjoki S, Maurer B, Sexl V. SBNO2 is a critical mediator of STAT3-driven hematological malignancies. Blood 2023; 141:1831-1845. [PMID: 36630607 PMCID: PMC10646773 DOI: 10.1182/blood.2022018494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/12/2022] [Accepted: 01/07/2023] [Indexed: 01/13/2023] Open
Abstract
Gain-of-function mutations in the signal transducer and activator of transcription 3 (STAT3) gene are recurrently identified in patients with large granular lymphocytic leukemia (LGLL) and in some cases of natural killer (NK)/T-cell and adult T-cell leukemia/lymphoma. To understand the consequences and molecular mechanisms contributing to disease development and oncogenic transformation, we developed murine hematopoietic stem and progenitor cell models that express mutated STAT3Y640F. These cells show accelerated proliferation and enhanced self-renewal potential. We integrated gene expression analyses and chromatin occupancy profiling of STAT3Y640F-transformed cells with data from patients with T-LGLL. This approach uncovered a conserved set of direct transcriptional targets of STAT3Y640F. Among these, strawberry notch homolog 2 (SBNO2) represents an essential transcriptional target, which was identified by a comparative genome-wide CRISPR/Cas9-based loss-of-function screen. The STAT3-SBNO2 axis is also present in NK-cell leukemia, T-cell non-Hodgkin lymphoma, and NPM-ALK-rearranged T-cell anaplastic large cell lymphoma (T-ALCL), which are driven by STAT3-hyperactivation/mutation. In patients with NPM-ALK+ T-ALCL, high SBNO2 expression correlates with shorter relapse-free and overall survival. Our findings identify SBNO2 as a potential therapeutic intervention site for STAT3-driven hematopoietic malignancies.
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Affiliation(s)
- Tania Brandstoetter
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
| | | | - Reinhard Grausenburger
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Sebastian Kollmann
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Eszter Doma
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Jani Huuhtanen
- Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
- Department of Computer Science, Aalto University, Espoo, Finland
| | - Thorsten Klampfl
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Thomas Eder
- Institute for Medical Biochemistry, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Florian Grebien
- Institute for Medical Biochemistry, University of Veterinary Medicine Vienna, Vienna, Austria
| | | | - Johannes Zuber
- Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria
| | - Satu Mustjoki
- Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
- Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
- ICAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland
- Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland
| | - Barbara Maurer
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Veronika Sexl
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria
- University of Innsbruck, Innsbruck, Austria
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13
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SOCS2 regulates alveolar bone loss in Aggregatibacter actinomycetemcomitans-induced periodontal disease. Inflamm Res 2023; 72:859-873. [PMID: 36912916 DOI: 10.1007/s00011-023-01711-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 12/19/2022] [Accepted: 02/16/2023] [Indexed: 03/14/2023] Open
Abstract
INTRODUCTION The role of suppressor of cytokine signaling 2 (SOCS2) in Aggregatibacter actinomycetemcomitans (Aa)-induced alveolar bone loss is unknown; thus, it was investigated in this study. METHODS Alveolar bone loss was induced by infecting C57BL/6 wild-type (WT) and Socs2-knockout (Socs2-/-) mice with Aa. Bone parameters, bone loss, bone cell counts, the expression of bone remodeling markers, and cytokine profile were evaluated by microtomography, histology, qPCR, and/or ELISA. Bone marrow cells (BMC) from WT and Socs2-/- mice were differentiated in osteoblasts or osteoclasts for analysis of the expression of specific markers. RESULTS Socs2-/- mice intrinsically exhibited irregular phenotypes in the maxillary bone and an increased number of osteoclasts. Upon Aa infection, SOCS2 deficiency resulted in the increased alveolar bone loss, despite decreased proinflammatory cytokine production, in comparison to the WT mice. In vitro, SOCS2 deficiency resulted in the increased osteoclasts formation, decreased expression of bone remodeling markers, and proinflammatory cytokines after Aa-LPS stimulus. CONCLUSIONS Collectively, data suggest that SOCS2 is a regulator of Aa-induced alveolar bone loss by controlling the differentiation and activity of bone cells, and proinflammatory cytokines availability in the periodontal microenvironment and an important target for new therapeutic strategies. Thus, it can be helpful in preventing alveolar bone loss in periodontal inflammatory conditions.
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14
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SOCS2 regulation of growth hormone signaling requires a canonical interaction with phosphotyrosine. Biosci Rep 2022; 42:232115. [PMID: 36398696 DOI: 10.1042/bsr20221683] [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: 08/03/2022] [Revised: 10/21/2022] [Accepted: 10/26/2022] [Indexed: 11/19/2022] Open
Abstract
Suppressor of cytokine signaling (SOCS) 2 is the critical negative regulator of growth hormone (GH) and prolactin signaling. Mice lacking SOCS2 display gigantism with increased body weight and length, and an enhanced response to GH treatment. Here, we characterized mice carrying a germ-line R96C mutation within the SOCS2-SH2 domain, which disrupts the ability of SOCS2 to interact with tyrosine-phosphorylated targets. Socs2R96C/R96C mice displayed a similar increase in growth as previously observed in SOCS2 null (Socs2-/-) mice, with a proportional increase in body and organ weight, and bone length. Embryonic fibroblasts isolated from Socs2R96C/R96C and Socs2-/- mice also showed a comparable increase in phosphorylation of STAT5 following GH stimulation, indicating the critical role of phosphotyrosine binding in SOCS2 function.
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15
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Song M, Cui X, Zhang J, Li Y, Li J, Zang Y, Li Q, Yang Q, Chen Y, Cai W, Weng X, Wang Y, Zhu X. Shenlian extract attenuates myocardial ischaemia-reperfusion injury via inhibiting M1 macrophage polarization by silencing miR-155. PHARMACEUTICAL BIOLOGY 2022; 60:2011-2024. [PMID: 36239618 PMCID: PMC9578494 DOI: 10.1080/13880209.2022.2117828] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 08/11/2022] [Accepted: 08/19/2022] [Indexed: 06/16/2023]
Abstract
CONTEXT Shenlian extract (SL) is a combination of Salvia miltiorrhiza Bge. (Labiatae) and Andrographis paniculata (Burm. F.) Wall. Ex Nees (Acanthaceae) extracts, which promote blood circulation and clear endogenous heat toxins. Myocardial ischaemia-reperfusion injury (MI/RI) is aggravated myocardial tissue damage induced by reperfusion therapy after myocardial infarction. OBJECTIVES This study explores the effect of SL on MI/RI and the underlying mechanism. MATERIALS AND METHODS Primary peritoneal macrophages (pMACs) were treated with LPS and SL (5, 10 or 20 μg/mL) for 24 h. The myocardial ischaemia-reperfusion (MI/R) model was established after administration of different doses of SL (90, 180 or 360 mg/kg). Myocardial tissue injury was assessed by methylthiazolyl tetrazolium (TTC) staining and levels of creatine kinase (CK), lactate dehydrogenase (LDH) and superoxide dismutase (SOD) in mice. The double immunofluorescence staining of iNOS/F4/80 and CD86/F4/80 was used to detect macrophage M1 polarization. The levels of miR-155, inflammatory factors and chemokines were detected by qRT-PCR or ELISA. CD86, iNOS, SOCS3, JAK2, p-JAK2, STAT3 and p-STAT3 proteins expressions in macrophages were analyzed by western blotting. Conditioned medium transfer systems were designed to unite M1 macrophages with H/R cardiomyocytes, and cell apoptosis was detected by TUNEL staining, western blotting or immunohistochemistry. RESULTS SL reduced apoptosis, diminished CK and LDH levels, raised SOD concentration and decreased infarct size in the MI/R model. Meanwhile, SL decreased miR-155 level, inhibited M1 macrophage polarization and inflammation. Furthermore, SL promoted SOCS3 expression and blocked JAK2/STAT3 pathway in vitro. CONCLUSIONS SL may be a promising TCM candidate for MI/RI. The underlying mechanisms could be associated with inhibition of M1 macrophage polarization via down-regulating miR-155.
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Affiliation(s)
- Min Song
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, Beijing, China
| | - Xihe Cui
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, Beijing, China
| | - Jing Zhang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, Beijing, China
| | - Yujie Li
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, Beijing, China
| | - Jingjing Li
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, Beijing, China
| | - Yuanlong Zang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, Beijing, China
| | - Qi Li
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, Beijing, China
| | - Qing Yang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, Beijing, China
| | - Ying Chen
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, Beijing, China
| | - Weiyan Cai
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, Beijing, China
| | - Xiaogang Weng
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, Beijing, China
| | - Yajie Wang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, Beijing, China
| | - Xiaoxin Zhu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Science, Beijing, China
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16
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Luo Y, Vermeer MH, de Gruijl FR, Zoutman WH, Sluijter M, van Hall T, Tensen CP. In vivo modelling of cutaneous T-cell lymphoma: The role of SOCS1. Front Oncol 2022; 12:1031052. [PMID: 36505769 PMCID: PMC9730277 DOI: 10.3389/fonc.2022.1031052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 11/03/2022] [Indexed: 11/25/2022] Open
Abstract
Introduction Mycosis fungoides (MF), the most common type of Cutaneous T cell Lymphoma (CTCL), is characterized by an inflamed skin intermixed with proliferating malignant mature skin-homing CD4+ T cells. Detailed genomic analyses of MF skin biopsies revealed several candidate genes possibly involved in genesis of these tumors and/or potential targets for therapy. These studies showed, in addition to common loss of cell cycle regulator CDKN2A, activation of several oncogenic pathways, most prominently and consistently involving JAK/STAT signaling. SOCS1, an endogenous inhibitor of the JAK/STAT signaling pathway, was identified as a recurrently deleted gene in MF, already occurring in the earliest stages of the disease. Methods To explore the mechanisms of MF, we create in vivo mouse models of autochthonous CTCLs and these genetically engineered mouse models (GEMMS) can also serve as valid experimental models for targeted therapy. We describe the impact of allelic deletion of Socs1 in CD4 T cells of the skin. To achieve this, we crossed inducible Cre-transgenic mice in the CD4 lineage with transgenic mice carrying floxed genes of Socs1. We first determined optimal conditions for Socs1 ablation with limited effects on circulating CD4 T-cells in blood. Next, we started time-course experiments mimicking sustained inflammation, typical in CTCL. FACS analysis of the blood was done every week. Skin biopsies were analyzed by immunocytochemical staining at the end of the experiment. Results We found that the Socs1 knockout transgenic group had thicker epidermis of treated skin compared with the control group and had more CD3 and CD4 in the skin of the transgenic group compared to the control group. We also noted more activation of Stat3 by staining for P-Stat3 in Socs1 knockout compared to wt CD4+T cells in the skin. The results also indicated that single copy loss of Socs1 in combination with sustained inflammation is insufficient to start a phenotype resembling early stage mycosis fungoides within eight weeks in these mice. Conclusion In sum, we developed and optimized an autochthonous murine model permitting selective knockout of Socs1 in skin infiltrating CD4 T-cells. This paves the way for more elaborate experiments to gain insight in the oncogenesis of CTCL.
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Affiliation(s)
- Yixin Luo
- Department of Dermatology, Leiden University Medical Center, Leiden, Netherlands
| | - Maarten H. Vermeer
- Department of Dermatology, Leiden University Medical Center, Leiden, Netherlands
| | - Frank R. de Gruijl
- Department of Dermatology, Leiden University Medical Center, Leiden, Netherlands
| | - Willem H. Zoutman
- Department of Dermatology, Leiden University Medical Center, Leiden, Netherlands
| | - Marjolein Sluijter
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, Netherlands
| | - Thorbald van Hall
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, Netherlands
| | - Cornelis P. Tensen
- Department of Dermatology, Leiden University Medical Center, Leiden, Netherlands,*Correspondence: Cornelis P. Tensen,
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17
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Zhou RW, Xu J, Martin TC, Zachem AL, He J, Ozturk S, Demircioglu D, Bansal A, Trotta AP, Giotti B, Gryder B, Shen Y, Wu X, Carcamo S, Bosch K, Hopkins B, Tsankov A, Steinhagen R, Jones DR, Asara J, Chipuk JE, Brody R, Itzkowitz S, Chio IIC, Hasson D, Bernstein E, Parsons RE. A local tumor microenvironment acquired super-enhancer induces an oncogenic driver in colorectal carcinoma. Nat Commun 2022; 13:6041. [PMID: 36253360 PMCID: PMC9576746 DOI: 10.1038/s41467-022-33377-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 09/15/2022] [Indexed: 12/24/2022] Open
Abstract
Tumors exhibit enhancer reprogramming compared to normal tissue. The etiology is largely attributed to cell-intrinsic genomic alterations. Here, using freshly resected primary CRC tumors and patient-matched adjacent normal colon, we find divergent epigenetic landscapes between CRC tumors and cell lines. Intriguingly, this phenomenon extends to highly recurrent aberrant super-enhancers gained in CRC over normal. We find one such super-enhancer activated in epithelial cancer cells due to surrounding inflammation in the tumor microenvironment. We restore this super-enhancer and its expressed gene, PDZK1IP1, following treatment with cytokines or xenotransplantation into nude mice, thus demonstrating cell-extrinsic etiology. We demonstrate mechanistically that PDZK1IP1 enhances the reductive capacity CRC cancer cells via the pentose phosphate pathway. We show this activation enables efficient growth under oxidative conditions, challenging the previous notion that PDZK1IP1 acts as a tumor suppressor in CRC. Collectively, these observations highlight the significance of epigenomic profiling on primary specimens.
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Affiliation(s)
- Royce W Zhou
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Medical Scientist Training Program, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Jia Xu
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Tiphaine C Martin
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Alexis L Zachem
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - John He
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Sait Ozturk
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Deniz Demircioglu
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Ankita Bansal
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Andrew P Trotta
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Bruno Giotti
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Berkley Gryder
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Yao Shen
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Xuewei Wu
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Saul Carcamo
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Kaitlyn Bosch
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Benjamin Hopkins
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Alexander Tsankov
- Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Randolph Steinhagen
- Division of Colon and Rectal Surgery, Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Drew R Jones
- Metabolomics Core Resource Laboratory, NYU Langone Health, New York, NY, 10016, USA
| | - John Asara
- Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA
| | - Jerry E Chipuk
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Rachel Brody
- Mount Sinai Biorepository, Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Steven Itzkowitz
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Iok In Christine Chio
- Institute for Cancer Genetics, Department of Genetics and Development, Columbia University Medical Center, New York, NY, 10032, USA
| | - Dan Hasson
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Emily Bernstein
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Ramon E Parsons
- Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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18
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Kausar S, Gul I, Liu R, Ke XX, Dong Z, Abbas MN, Cui H. Antheraea pernyi Suppressor of Cytokine Signaling 2 Negatively Modulates the JAK/STAT Pathway to Attenuate Microbial Infection. Int J Mol Sci 2022; 23:ijms231810389. [PMID: 36142300 PMCID: PMC9499667 DOI: 10.3390/ijms231810389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 08/29/2022] [Accepted: 08/30/2022] [Indexed: 11/16/2022] Open
Abstract
The Janus kinase (JAK) signal transducer and activator of transcription (STAT) pathway has been shown to govern various physiological processes, including immune responses, hematopoiesis, cell growth, and differentiation. Recent studies show that suppressors of cytokine signaling (SOCS) proteins attenuate JAK-STAT signaling in mammals; however, their functions are less clear in lepidopteran insects. Here, we report a full-length sequence of SOCS-2 from the Chinese oak silkworm Antheraea pernyi (designated as ApSOCS-2) and study its biological role in immune responses via the JAK-STAT pathway. ApSOCS-2 expression was high in the fat bodies and hemocytes of A. pernyi fifth instar larvae. After pathogen infection with nucleopolyhedrovirus, Beauveria bassiana, Escherichia coli, and Microccus luteus, ApSOCS-2 mRNA was strongly increased compared to the control group. To elucidate the possible involvement in innate immunity, we measured antimicrobial peptide genes expression profiles in the fat body of A. pernyi. In contrast, recombinant ApSOCS-2 protein administration significantly reduced the AMPs transcription, while the depletion of ApSOCS-2 by RNAi increased their expression. Furthermore, we observed higher antibacterial activity and lower bacterial replication in dsApSOCS-2-treated larvae. The ApSOCS-2 transcription level was reduced in STAT depleted A. pernyi larvae challenged by M. luteus. The ApSOCS-2 RNAi data sets were also subjected to transcriptomic analysis, which suggests that ApSOCS-2 is a key regulator of immune function. Taken together, our data suggest that ApSOCS-2 is required for the negative regulation of AMPs transcripts via the JAK-STAT pathway in the insect.
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Affiliation(s)
- Saima Kausar
- State Key Laboratory of Silkworm Genome Biology, Key Laboratory of Sericultural Biology and Genetic Breeding, Ministry of Agriculture, Southwest University, Chongqing 400716, China
- Affiliation Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China
| | - Isma Gul
- State Key Laboratory of Silkworm Genome Biology, Key Laboratory of Sericultural Biology and Genetic Breeding, Ministry of Agriculture, Southwest University, Chongqing 400716, China
- Affiliation Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China
| | - Ruochen Liu
- State Key Laboratory of Silkworm Genome Biology, Key Laboratory of Sericultural Biology and Genetic Breeding, Ministry of Agriculture, Southwest University, Chongqing 400716, China
- Affiliation Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China
| | - Xiao-Xue Ke
- State Key Laboratory of Silkworm Genome Biology, Key Laboratory of Sericultural Biology and Genetic Breeding, Ministry of Agriculture, Southwest University, Chongqing 400716, China
- Affiliation Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China
| | - Zhen Dong
- State Key Laboratory of Silkworm Genome Biology, Key Laboratory of Sericultural Biology and Genetic Breeding, Ministry of Agriculture, Southwest University, Chongqing 400716, China
- Affiliation Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China
| | - Muhammad Nadeem Abbas
- State Key Laboratory of Silkworm Genome Biology, Key Laboratory of Sericultural Biology and Genetic Breeding, Ministry of Agriculture, Southwest University, Chongqing 400716, China
- Affiliation Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China
- Correspondence: (M.N.A.); (H.C.); Tel.: +86-23-68251712 (H.C.)
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, Key Laboratory of Sericultural Biology and Genetic Breeding, Ministry of Agriculture, Southwest University, Chongqing 400716, China
- Affiliation Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China
- Correspondence: (M.N.A.); (H.C.); Tel.: +86-23-68251712 (H.C.)
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19
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You X, Lei Y, Zhang P, Xu D, Ahmed Z, Yang Y. Role of transcription factors in porcine reproductive and respiratory syndrome virus infection: A review. Front Microbiol 2022; 13:924004. [PMID: 35928151 PMCID: PMC9344050 DOI: 10.3389/fmicb.2022.924004] [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: 05/03/2022] [Accepted: 06/28/2022] [Indexed: 11/13/2022] Open
Abstract
Porcine reproductive and respiratory syndrome (PRRS) is an infectious disease caused by the PRRS virus that leads to reproductive disorders and severe dyspnoea in pigs, which has serious economic impacts. One of the reasons PRRSV cannot be effectively controlled is that it has developed countermeasures against the host immune response, allowing it to survive and replicate for long periods. Transcription Factors acts as a bridge in the interactions between the host and PRRSV. PRRSV can create an environment conducive to PRRSV replication through transcription factors acting on miRNAs, inflammatory factors, and immune cells. Conversely, some transcription factors also inhibit PRRSV proliferation in the host. In this review, we systematically described how PRRSV uses host transcription factors such as SP1, CEBPB, STATs, and AP-1 to escape the host immune system. Determining the role of transcription factors in immune evasion and understanding the pathogenesis of PRRSV will help to develop new treatments for PRRSV.
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Affiliation(s)
- Xiangbin You
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, China
- Luoyang Key Laboratory of Animal Genetics and Breeding, Luoyang, China
| | - Ying Lei
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, China
- Luoyang Key Laboratory of Animal Genetics and Breeding, Luoyang, China
| | - Ping Zhang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, China
| | - Dequan Xu
- College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Zulfiqar Ahmed
- Faculty of Veterinary and Animal Sciences, University of Poonch Rawalakot, Rawalakot, Pakistan
| | - Youbing Yang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, China
- Luoyang Key Laboratory of Animal Genetics and Breeding, Luoyang, China
- *Correspondence: Youbing Yang
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20
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Ni Y, Low JT, Silke J, O’Reilly LA. Digesting the Role of JAK-STAT and Cytokine Signaling in Oral and Gastric Cancers. Front Immunol 2022; 13:835997. [PMID: 35844493 PMCID: PMC9277720 DOI: 10.3389/fimmu.2022.835997] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 05/16/2022] [Indexed: 12/12/2022] Open
Abstract
When small proteins such as cytokines bind to their associated receptors on the plasma membrane, they can activate multiple internal signaling cascades allowing information from one cell to affect another. Frequently the signaling cascade leads to a change in gene expression that can affect cell functions such as proliferation, differentiation and homeostasis. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) and the tumor necrosis factor receptor (TNFR) are the pivotal mechanisms employed for such communication. When deregulated, the JAK-STAT and the TNF receptor signaling pathways can induce chronic inflammatory phenotypes by promoting more cytokine production. Furthermore, these signaling pathways can promote replication, survival and metastasis of cancer cells. This review will summarize the essentials of the JAK/STAT and TNF signaling pathways and their regulation and the molecular mechanisms that lead to the dysregulation of the JAK-STAT pathway. The consequences of dysregulation, as ascertained from founding work in haematopoietic malignancies to more recent research in solid oral-gastrointestinal cancers, will also be discussed. Finally, this review will highlight the development and future of therapeutic applications which modulate the JAK-STAT or the TNF signaling pathways in cancers.
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Affiliation(s)
- Yanhong Ni
- Central Laboratory, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jun T. Low
- Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - John Silke
- Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Lorraine A. O’Reilly
- Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
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21
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SOCS3 gene silencing does not occur through methylation and mutations in gastric cancer. Hum Cell 2022; 35:1114-1125. [PMID: 35596898 DOI: 10.1007/s13577-022-00715-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 05/04/2022] [Indexed: 11/04/2022]
Abstract
Gastric cancer (GC) is ranked the third leading cause of cancer-related deaths worldwide. Mutations and epigenetic alterations in several essential genes, including p53, KRAS, PIK3CA, FAT4 and ARID1A, are often reported. Furthermore, loss of SOCS3 expression was reported in GC, suggesting its tumor suppressor role. To assess the mutational and methylation status of SOCS3, we performed gene panel exome sequencing on 47 human GC samples. The SOCS3 gene was rarely mutated, suggesting alternative regulation mechanisms, such as promoter hypermethylation and/or long non-coding RNAs (lncRNAs). We first explored SOCS3 promoter methylation status in 44 human GC samples by methylation-specific PCR (MS-PCR). Thirteen out of forty-four patients (29.5%) displayed a methylation pattern. Then, to see whether SOCS3 expression is silenced by CpG methylation, we examined publicly available databases (cbioportal and The Cancer Genome Atlas (TCGA)). The analysis revealed β values lower than 0.1, indicating hypo-methylation in healthy and GC samples. Moreover, moderate methylation (β < 0.4) and high methylation (β > 0.4) did not affect the free survival, suggesting that methylation is unlikely to be the mechanism ruling SOCS3 silencing in GC. Next, to assess the regulatory effects of lncRNAs on SOCS3, we silenced the AC125807.2-lncRNA and quantified the SOCS3 gene expression in AGS and NCI-N87 gastric cancer cell line. SOCS3 was found to be downregulated following AC125807.2-lncRNA silencing in AGS cells, suggesting the potential implication of lncRNA AC125807.2 in SOCS3 regulation. However, in NCI-N87 cells, there was no significant change in SOCS3 expression. In conclusion, neither mutations nor hypermethylation was associated with the SOCS3 downregulation in GC, and alternative mechanisms, including non-coding RNAs-mediated gene silencing, may be proposed.
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22
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The ubiquitin ligase Cul5 regulates CD4 + T cell fate choice and allergic inflammation. Nat Commun 2022; 13:2786. [PMID: 35589717 PMCID: PMC9120070 DOI: 10.1038/s41467-022-30437-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 04/21/2022] [Indexed: 12/24/2022] Open
Abstract
Antigen encounter directs CD4+ T cells to differentiate into T helper or regulatory cells. This process focuses the immune response on the invading pathogen and limits tissue damage. Mechanisms that govern T helper cell versus T regulatory cell fate remain poorly understood. Here, we show that the E3 ubiquitin ligase Cul5 determines fate selection in CD4+ T cells by regulating IL-4 receptor signaling. Mice lacking Cul5 in T cells develop Th2 and Th9 inflammation and show pathophysiological features of atopic asthma. Following T cell activation, Cul5 forms a complex with CIS and pJak1. Cul5 deletion reduces ubiquitination and subsequent degradation of pJak1, leading to an increase in pJak1 and pSTAT6 levels and reducing the threshold of IL-4 receptor signaling. As a consequence, Cul5 deficient CD4+ T cells deviate from Treg to Th9 differentiation in low IL-4 conditions. These data support the notion that Cul5 promotes a tolerogenic T cell fate choice and reduces susceptibility to allergic asthma. Cytokine signaling influences the differentiation of CD4+ T cells into varying functional subsets. Here the authors show that an E3 ubiquitin ligase Cul5 alters TH2 and TH9 development and absence of Cul5 in T cells results in higher levels of allergy-associated IL-4 and IL-9 secreting T cells.
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23
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Li L, Zhang J, Peng H, Jiang X, Liu Z, Tian H, Hou S, Xie X, Peng Q, Zhou T. Knockdown of miR-92a suppresses the stemness of colorectal cancer cells via mediating SOCS3. Bioengineered 2022; 13:5613-5624. [PMID: 35184640 PMCID: PMC8974062 DOI: 10.1080/21655979.2021.2022267] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
MiRNAs (microRNAs) participate in colorectal cancer (CRC) progression and act as potential biomarkers for CRC prognosis. In this study, we investigated the mechanisms of microRNA-92a (miR-92a) in CRC. Expressions of miR-92a and SOCS3 (Suppressor Of Cytokine Signaling 3) were investigated by qRT-PCR in CRC cell lines and 30 cases of CRC. The self-renewal capacity and proliferation of CRC stem cells were estimated by the sphere formation assay, EdU staining, and Flow cytometry analysis. Moreover, the interplay between miR-92a and SOCS3 in CRC cells was validated by luciferase reporter experiments. MiR-92a was found to be remarkably increased while SOCS3 was significantly downregulated in CRC tissues. Inhibition of miR-92a or SOCS3 attenuated the sphere formation capacity, decreased expressions of stemness-related proteins, and inhibited the proliferation of cancer stem-like cells. Knockdown of SOCS3 reversed the repressive impacts of miR-92a inhibitors on self-renewal and growth of CRC cancer stem cells. This study suggested that miR-92a functions as an oncogene of CRC through mediating the stemness of colorectal cancer cells by directly binding and repressing SOCS3.
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Affiliation(s)
- Lifa Li
- Department of Gastrointestinal Surgery II, Hepatobiliary and Pancreatic Research, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Jingxiao Zhang
- Department of Medica, The Second Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Hong Peng
- Department of Anorectal Surgery, Nanchong Central Hospital, the Second Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Xianhong Jiang
- Department of Gastrointestinal Surgery II, Hepatobiliary and Pancreatic Research, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Zuoliang Liu
- Department of Gastrointestinal Surgery II, Hepatobiliary and Pancreatic Research, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Hongpeng Tian
- Department of Gastrointestinal Surgery II, Hepatobiliary and Pancreatic Research, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Songlin Hou
- Department of Gastrointestinal Surgery II, Hepatobiliary and Pancreatic Research, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Xingjiang Xie
- Department of Gastrointestinal Surgery II, Hepatobiliary and Pancreatic Research, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Qiang Peng
- Department of Gastrointestinal Surgery II, Hepatobiliary and Pancreatic Research, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Tong Zhou
- Department of Gastrointestinal Surgery II, The Second Affiliated Hospital of North Sichuan Medical College, Sichuan, China
- Department of Gastrointestinal Surgery II, Affiliated Hospital of North Sichuan Medical College, Sichuan, China
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24
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Pan J, Tong R, Deng Q, Tian Y, Wang N, Peng Y, Fei S, Zhang W, Cui J, Guo C, Yao J, Wei C, Xu J. The Effect of SOCS2 Polymorphisms on Type 2 Diabetes Mellitus Susceptibility and Diabetic Complications in the Chinese Han Population. Pharmgenomics Pers Med 2022; 15:65-79. [PMID: 35125882 PMCID: PMC8809519 DOI: 10.2147/pgpm.s347018] [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: 10/30/2021] [Accepted: 12/23/2021] [Indexed: 12/07/2022] Open
Abstract
BACKGROUND SOCS2 is downregulated in diabetes, which might be related to diabetes. We explored the effect of SOCS2 polymorphisms on the development of type 2 diabetes mellitus (T2DM) and diabetic complications. METHODS The subjects consisted of 500 patients with T2DM and 501 healthy controls. Five variants in SOCS2 were genotyped by Agena MassARRAY system. RT-qPCR profiling was performed to detect the expression of SOCS2 mRNA. Logistic regression analysis was utilized to calculate odds ratio (OR) and 95% confidence intervals (95% CIs). RESULTS Rs3825199 (OR = 1.44, p = 0.007), rs11107116 (OR = 1.39, p = 0.014) and rs10492321 (OR = 1.48, p = 0.004) had an increased T2DM risk of T2DM. Moreover, the contribution of SOCS2 polymorphisms to T2DM risk was associated with age, gender, smoking, drinking, and BMI. SOCS2 variants also had a reduced risk for T2DM patients with diabetic nephropathy, diabetic retinopathy and coronary heart disease. SOCS2 rs10492321 was the best single locus model. SOCS2 mRNA was downregulated in patients with T2DM compared to healthy controls (p = 0.029). CONCLUSION This study firstly reported that rs3825199, rs11107116 and rs10492321 in SOCS2 conferred to an increased risk for the occurrence of T2DM in the Chinese Han population. Moreover, SOCS2 mRNA was downregulated in patients with T2DM, suggesting that SOCS2 might have an important role in the occurrence of T2DM.
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Affiliation(s)
- Juan Pan
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, Shaanxi, People’s Republic of China
- Department of Endocrinology, Xianyang Central Hospital, Xianyang, 712000, Shaanxi, People’s Republic of China
| | - Rui Tong
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, Shaanxi, People’s Republic of China
| | - Qing Deng
- Department of Endocrinology, No. 215 Hospital of Shaanxi Nuclear Industry, Xianyang, 712000, Shaanxi, People’s Republic of China
| | - Yanni Tian
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, Shaanxi, People’s Republic of China
| | - Ning Wang
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, Shaanxi, People’s Republic of China
| | - Yanqi Peng
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, Shaanxi, People’s Republic of China
| | - Sijia Fei
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, Shaanxi, People’s Republic of China
| | - Wei Zhang
- Department of Breast Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, Shaanxi, People’s Republic of China
| | - Jiaqi Cui
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, Shaanxi, People’s Republic of China
| | - Chaoying Guo
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, Shaanxi, People’s Republic of China
| | - Juanchuan Yao
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, Shaanxi, People’s Republic of China
| | - Cui Wei
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, Shaanxi, People’s Republic of China
| | - Jing Xu
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, Shaanxi, People’s Republic of China
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25
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Xu J, Lin H, Wu G, Zhu M, Li M. IL-6/STAT3 Is a Promising Therapeutic Target for Hepatocellular Carcinoma. Front Oncol 2021; 11:760971. [PMID: 34976809 PMCID: PMC8714735 DOI: 10.3389/fonc.2021.760971] [Citation(s) in RCA: 109] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 11/29/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a common malignant tumor of which the occurrence and development, the tumorigenicity of HCC is involving in multistep and multifactor interactions. Interleukin-6 (IL-6), a multifunctional inflammatory cytokine, has increased expression in HCC patients and is closely related to the occurrence of HCC and prognosis. IL-6 plays a role by binding to the IL-6 receptor (IL-6R) and then triggering the Janus kinase (JAK) associated with the receptor, stimulating phosphorylation and activating signal transducer and activator of transcription 3 (STAT3) to initiate downstream signals, participating in the processes of anti-apoptosis, angiogenesis, proliferation, invasion, metastasis, and drug resistance of cancer cells. IL-6/STAT3 signal axes elicit an immunosuppressive in tumor microenvironment, it is important to therapy HCC by blocking the IL-6/STAT3 signaling pathway. Recent, some inhibitors of IL-6/STAT3 have been development, such as S31-201 or IL-6 neutralizing monoclonal antibody (IL-6 mAb), Madindoline A (Inhibits the dimerization of IL-6/IL-6R/gpl30 trimeric complexes), C188-9 and Curcumin (Inhibits STAT3 phosphorylation), etc. for treatment of cancers. Overall, consideration of the IL-6/STAT3 signaling pathway, and its role in the carcinogenesis and progression of HCC will contribute to the development of potential drugs for targeting treatment of liver cancer.
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Affiliation(s)
- Junnv Xu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, China
- Department of Medical Oncology, Second Affiliated Hospital, Hainan Medical College, Haikou, China
| | - Haifeng Lin
- Department of Medical Oncology, Second Affiliated Hospital, Hainan Medical College, Haikou, China
| | - Gang Wu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, China
| | - Mingyue Zhu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, China
| | - Mengsen Li
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, China
- Department of Medical Oncology, Second Affiliated Hospital, Hainan Medical College, Haikou, China
- Institution of Tumour, Hainan Medical College, Haikou, China
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26
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Dai L, Li Z, Liang W, Hu W, Zhou S, Yang Z, Tao Y, Hou X, Xing Z, Mao J, Shi Z, Wang X. SOCS proteins and their roles in the development of glioblastoma. Oncol Lett 2021; 23:5. [PMID: 34820004 PMCID: PMC8607235 DOI: 10.3892/ol.2021.13123] [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: 07/29/2021] [Accepted: 10/11/2021] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most common type of primary brain tumor in adults. GBM is characterized by a high degree of malignancy and aggressiveness, as well as high morbidity and mortality rates. GBM is currently treatable via surgical resection, chemotherapy and radiotherapy, but the prognosis of patients with GBM is poor. The suppressor of cytokine signaling (SOCS) protein family comprises eight members, including SOCS1-SOCS7 and cytokine-inducible SH2-containing protein. SOCS proteins regulate the biogenesis of GBM via the JAK/STAT and NF-κB signaling pathways. Driven by NF-κB, the expression of SOCS proteins can serve as a negative regulator of the JAK/STAT signaling pathway and exerts a potential inhibitory effect on GBM. In GBM, E3 ubiquitin ligase is involved in the regulation of cellular functions, such as the receptor tyrosine kinase (RTK) survival signal, in which SOCS proteins negatively regulate RTK signaling, and kinase overexpression or mutation can lead to the development of malignancies. Moreover, SOCS proteins affect the proliferation and differentiation of GBM cells by regulating the tumor microenvironment. SOCS proteins also serve specific roles in GBM of different grades and different isocitrate dehydrogenase mutation status. The aim of the present review was to describe the biogenesis and function of the SOCS protein family, the roles of SOCS proteins in the microenvironment of GBM, as well as the role of this protein family and E3 ubiquitin ligases in GBM. Furthermore, the role of SOCS proteins as diagnostic and prognostic markers in GBM and their potential role as GBM therapeutics were explored.
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Affiliation(s)
- Lirui Dai
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Department of Science and Technology of Henan Province, Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan 450052, P.R. China
| | - Zian Li
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Department of Science and Technology of Henan Province, Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan 450052, P.R. China
| | - Wulong Liang
- Department of Science and Technology of Henan Province, Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan 450052, P.R. China
| | - Weihua Hu
- Department of Science and Technology of Henan Province, Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan 450052, P.R. China
| | - Shaolong Zhou
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Department of Science and Technology of Henan Province, Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan 450052, P.R. China
| | - Zhuo Yang
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Department of Science and Technology of Henan Province, Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan 450052, P.R. China
| | - Yiran Tao
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Department of Science and Technology of Henan Province, Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan 450052, P.R. China
| | - Xuelei Hou
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Department of Science and Technology of Henan Province, Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan 450052, P.R. China
| | - Zhe Xing
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Department of Science and Technology of Henan Province, Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan 450052, P.R. China
| | - Jianchao Mao
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Department of Science and Technology of Henan Province, Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan 450052, P.R. China
| | - Zimin Shi
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Department of Science and Technology of Henan Province, Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan 450052, P.R. China
| | - Xinjun Wang
- Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.,Department of Science and Technology of Henan Province, Henan International Joint Laboratory of Glioma Metabolism and Microenvironment Research, Zhengzhou, Henan 450052, P.R. China
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Tirone NR, Campos CG, Ferreira KJA, Stark LM, Vieira JF, Murta EFC, Michelin MA. Pathways of IFN-alpha Activation in Patients with Cervical Intraepithelial Neoplasia (CIN). REVISTA BRASILEIRA DE GINECOLOGIA E OBSTETRÍCIA 2021; 43:682-689. [PMID: 34670303 PMCID: PMC10183884 DOI: 10.1055/s-0041-1735301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
OBJECTIVE The aim of the present study was to compare the local and systemic expression of the factors linked to the interferon alpha (IFN-α) activation pathway in different degrees of cervical intraepithelial neoplasia (CIN) and cervical cancer. METHODS A total of 128 patients with CIN I, CIN II, CIN III and cervical cancer was evaluated. The real-time polymerase chain reaction (RT-PCR) technique was used to evaluate the gene expression of IFNR1, IFNR2, IFN-α, oligoadenylate synthase (2'5'OAS), cytokine signal suppressor 1 (SOCS) 1, SOCS3, signal transducer and transcription activator 1 (STAT1), and IRF9 from 128 biopsies. A total of 46 out of 128 samples were evaluated by flow cytometry for IFNAR1, IFNAR2, STAT1, IRF7 and IFN-α in peripheral blood cells. RESULTS Patients with CIN II and III (63 samples) had a low local expression of IFNR1, but not IFNR2. Patients with some degree of injury showed high expression of SOCS1 and SOCS3. Systemically, patients with CIN II and III (20 samples) had a significant increase in IFNR1, IFNR2, STAT1, IRF7, and IFN-α in helper, cytotoxic T lymphocytes, and in monocytes. CONCLUSION Patients with high-grade lesions have increased systemic expression of IFN-α and its activation pathways in helper and cytotoxic T lymphocytes, as well as in monocytes due to an exacerbation of the immune response in these patients. This phenomenon is not accompanied by resolution of the lesion due to a defect in the IFN-α activation pathway that revealed by low local IFNAR1 expression and high local expression of SOCS1 and SOCS3.
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Affiliation(s)
- Nelson Ranieri Tirone
- Instituto de Pesquisa em Oncologia, Universidade Federal do Triângulo Mineiro, Uberaba, MG, Brazil
| | - Carolina Guissoni Campos
- Instituto de Pesquisa em Oncologia, Universidade Federal do Triângulo Mineiro, Uberaba, MG, Brazil
| | | | - Léticia Montes Stark
- Instituto de Pesquisa em Oncologia, Universidade Federal do Triângulo Mineiro, Uberaba, MG, Brazil
| | - Jéssica Ferreira Vieira
- Instituto de Pesquisa em Oncologia, Universidade Federal do Triângulo Mineiro, Uberaba, MG, Brazil
| | - Eddie Fernando Cândido Murta
- Instituto de Pesquisa em Oncologia, Universidade Federal do Triângulo Mineiro, Uberaba, MG, Brazil.,Department of Gynecology and Obstetrics, Universidade Federal do Triângulo Mineiro, Uberaba, MG, Brazil
| | - Márcia Antoniazi Michelin
- Instituto de Pesquisa em Oncologia, Universidade Federal do Triângulo Mineiro, Uberaba, MG, Brazil.,Discipline of Immunology, Universidade Federal do Triângulo Mineiro, Uberaba, MG, Brazil
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Ghafouri-Fard S, Honarmand Tamizkar K, Sayad A, Taheri M, Samadian M. Expression Analysis of SOCS Genes in Migraine. Front Mol Neurosci 2021; 14:725048. [PMID: 34646121 PMCID: PMC8502924 DOI: 10.3389/fnmol.2021.725048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 09/03/2021] [Indexed: 11/13/2022] Open
Abstract
Migraine is a complex neurological condition affecting a large proportion of persons. Dysregulation of several immune-related transcripts has been noted in migraineurs suggesting an immune-based background for this condition. We measured expression levels suppressor of cytokine signaling (SOCS) genes in the venous blood of migraineurs compared with controls. SOCS1 was down-regulated in patients without aura compared with controls [Ratio of mean expression (RME) = 0.08, P value < 0.001]. This pattern was also detected among female subgroups (RME = 0.06, P value = 0.010), but not among male subgroups (RME = 0.22, P value = 0.114). Expression of SOCS1 was significantly higher in patients with aura compared with those without aura (RME = 5.89, P value = 0.037). Meanwhile, expression of SOCS2 was lower in migraineurs with aura compared with controls (RME = 0.03, P value < 0.001). In addition, this gene was under-expressed in patients without aura compared with controls and in both sex-based subgroups of this group of patients (RME = 0.01, P value < 0.001 for all comparisons). However, its expression was higher in male patients with aura compared with those without aura (P value < 0.001). For SOCS3, we detected a lower level of expression in patients without aura compared with controls (RME = 0.07, P value < 0.001). However, the expression of SOCS3 was higher in patients with aura compared with those without aura (RME = 7.46, P value = 0.001). SOCS5 was down-regulated in patients without aura compared with controls (RME = 0.10, P value < 0.001). Expression of this gene was also lower in patients with aura compared with controls (RME = 0.03, P value < 0.001), and in male patients of this group compared with controls (RME = 0.03, P value = 0.004). On the other hand, expression of SOCS5 was higher in male patients with aura compared with sex-matched patients without aura (RME = 6.67, P value = 0.001). SOCS2 levels could appropriately differentiate migraineurs from healthy subjects. The current study suggests the role of SOCS genes in the pathoetiology of migraine.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kasra Honarmand Tamizkar
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arezou Sayad
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Samadian
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Kandikattu HK, Venkateshaiah SU, Mishra A. Chronic Pancreatitis and the Development of Pancreatic Cancer. Endocr Metab Immune Disord Drug Targets 2021; 20:1182-1210. [PMID: 32324526 DOI: 10.2174/1871530320666200423095700] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 12/31/2019] [Accepted: 01/20/2020] [Indexed: 02/07/2023]
Abstract
Pancreatitis is a fibro-inflammatory disorder of the pancreas that can occur acutely or chronically as a result of the activation of digestive enzymes that damage pancreatic cells, which promotes inflammation. Chronic pancreatitis with persistent fibro-inflammation of the pancreas progresses to pancreatic cancer, which is the fourth leading cause of cancer deaths across the globe. Pancreatic cancer involves cross-talk of inflammatory, proliferative, migratory, and fibrotic mechanisms. In this review, we discuss the role of cytokines in the inflammatory cell storm in pancreatitis and pancreatic cancer and their role in the activation of SDF1α/CXCR4, SOCS3, inflammasome, and NF-κB signaling. The aberrant immune reactions contribute to pathological damage of acinar and ductal cells, and the activation of pancreatic stellate cells to a myofibroblast-like phenotype. We summarize several aspects involved in the promotion of pancreatic cancer by inflammation and include a number of regulatory molecules that inhibit that process.
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Affiliation(s)
- Hemanth K Kandikattu
- Department of Medicine, Tulane Eosinophilic Disorders Centre (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA 70112, United States
| | - Sathisha U Venkateshaiah
- Department of Medicine, Tulane Eosinophilic Disorders Centre (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA 70112, United States
| | - Anil Mishra
- Department of Medicine, Tulane Eosinophilic Disorders Centre (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA 70112, United States
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30
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Sun M, Tang C, Liu J, Jiang W, Yu H, Dong F, Huang C, Rixiati Y. Comprehensive analysis of suppressor of cytokine signaling proteins in human breast Cancer. BMC Cancer 2021; 21:696. [PMID: 34120621 PMCID: PMC8201682 DOI: 10.1186/s12885-021-08434-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 06/03/2021] [Indexed: 12/24/2022] Open
Abstract
Background Abnormal expression of suppressor of cytokine signaling (SOCS) proteins regulates tumor angiogenesis and development in cancers. In this study, we aimed to perform a comprehensive bioinformatic analysis of SOCS proteins in breast invasive carcinoma (BRCA). Methods The gene expression, methylation level, copy number, protein expression and patient survival data related to SOCS family members in BRCA patients were obtained from the following databases: Oncomine, The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Human Protein Atlas (HPA), Gene Expression Profiling Interactive Analysis (GEPIA), PCViz, cBioPortal and Kaplan-Meier plotter. Correlation analyses, identification of interacting genes and construction of regulatory networks were performed by functional and pathway enrichment analyses, weighted gene coexpression network analysis (WGCNA) and gene set enrichment analysis (GSEA). Results Data related to 1109 BRCA tissues and 113 normal breast tissue samples were extracted from the TCGA database. SOCS2 and SOCS3 exhibited significantly lower mRNA expression levels in BRCA tissues than in normal tissues. BRCA patients with high mRNA levels of SOCS3 (p < 0.01) and SOCS4 (p < 0.05) were predicted to have significantly longer overall survival (OS) times. Multivariate analysis showed that SOCS3 was an independent prognostic factor for OS. High mRNA expression levels of SOCS2 (p < 0.001), SOCS3 (p < 0.001), and SOCS4 (p < 0.01), and a low expression level of SOCS5 (p < 0.001) were predicted to be significantly associated with better recurrence-free survival (RFS). Multivariate analysis showed that SOCS2 was an independent prognostic factor for RFS. Lower expression levels of SOCS2 and SOCS3 were observed in patients with tumors of more advanced clinical stage (p < 0.05). Functional and pathway enrichment analyses, together with WGCNA and GSEA, showed that SOCS3 and its interacting genes were significantly involved in the JAK-STAT signaling pathway, suggesting that JAK-STAT signaling might play a critical role in BRCA angiogenesis and development. Western blot results showed that overexpression of SOCS3 inhibited the activity of the JAK-STAT signaling pathway in vitro. Conclusions SOCS family proteins play a very important role in BRCA. SOCS3 may be a prognostic factor and SOCS2 may be a potential therapeutic target in breast cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08434-y.
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Affiliation(s)
- Mingyu Sun
- Department of Breast Surgery, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, 221009, China
| | - Chuangang Tang
- Department of Breast Surgery, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, 221009, China
| | - Jun Liu
- Department of Breast Surgery, Xuzhou Central Hospital, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, 221009, China
| | - Wenli Jiang
- Department of Biochemistry and Molecular Biology, College of Basic Medical, Navy Medical University, Shanghai, 200433, China
| | - Haifeng Yu
- Department of General Surgery, Tianjin First Central Hospital, Tianjin, 300192, China
| | - Fang Dong
- Department of Vascular Surgery, Gansu Provincial Hospital, Lanzhou, 730000, China
| | - Caiguo Huang
- Department of Biochemistry and Molecular Biology, College of Basic Medical, Navy Medical University, Shanghai, 200433, China
| | - Youlutuziayi Rixiati
- Department of Pathology, Soochow University Medical School, Suzhou, 215123, China.
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Xie J, Wang M, Cheng A, Jia R, Zhu D, Liu M, Chen S, Zhao X, Yang Q, Wu Y, Zhang S, Luo Q, Wang Y, Xu Z, Chen Z, Zhu L, Liu Y, Yu Y, Zhang L, Chen X. The role of SOCS proteins in the development of virus- induced hepatocellular carcinoma. Virol J 2021; 18:74. [PMID: 33849568 PMCID: PMC8045357 DOI: 10.1186/s12985-021-01544-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 04/03/2021] [Indexed: 01/08/2023] Open
Abstract
Background Liver cancer has become one of the most common cancers and has a high mortality rate. Hepatocellular carcinoma is one of the most common liver cancers, and its occurrence and development process are associated with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Main body The serious consequences of chronic hepatitis virus infections are related to the viral invasion strategy. Furthermore, the viral escape mechanism has evolved during long-term struggles with the host. Studies have increasingly shown that suppressor of cytokine signaling (SOCS) proteins participate in the viral escape process. SOCS proteins play an important role in regulating cytokine signaling, particularly the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. Cytokines stimulate the expression of SOCS proteins, in turn, SOCS proteins inhibit cytokine signaling by blocking the JAK-STAT signaling pathway, thereby achieving homeostasis. By utilizing SOCS proteins, chronic hepatitis virus infection may destroy the host’s antiviral responses to achieve persistent infection. Conclusions This review provides recent knowledge regarding the role of SOCS proteins during chronic hepatitis virus infection and provides some new ideas for the future treatment of chronic hepatitis.
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Affiliation(s)
- Jinyan Xie
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Mingshu Wang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Anchun Cheng
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China. .,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China. .,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.
| | - Renyong Jia
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Dekang Zhu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Mafeng Liu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Shun Chen
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - XinXin Zhao
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Qiao Yang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Ying Wu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Shaqiu Zhang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Qihui Luo
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Yin Wang
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Zhiwen Xu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Zhengli Chen
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Ling Zhu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Yunya Liu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Yanling Yu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Ling Zhang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Xiaoyue Chen
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
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Yan Z, Hong S, Song Y, Bi M. microR-4449 Promotes Colorectal Cancer Cell Proliferation via Regulation of SOCS3 and Activation of STAT3 Signaling. Cancer Manag Res 2021; 13:3029-3039. [PMID: 33854373 PMCID: PMC8039016 DOI: 10.2147/cmar.s266153] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 10/21/2020] [Indexed: 12/28/2022] Open
Abstract
Introduction Dysregulation of microRNAs (miRNAs), which represented a critical level of gene expression modulation, regulated the development of colorectal cancer. However, the functions of numerous miRNAs remain unclear in colorectal cancer. Methods The microarray data of GSE115513 were retrieved; subsequently, the differentially expressed miRNAs between 411 colon tumors and 381 normal colon mucosa were analyzed. Real-time PCR (RT-qPCR) and bioinformatic analysis were applied to examine the expression of miR-4449 in collected colorectal tumors and published microarray data. The activity of signal transducer and activator of transcription 3 (STAT3) signaling was detected by Western blotting and RT-qPCR. Dual-Luciferase assay and bioinformatic analysis were used to confirm the interaction between suppressor of cytokine signaling 3 (SOCS3) and miR-4449. Loss of function and rescue assays were performed to study the involvement of miR-4449 and SOCS3 in cell proliferation and apoptosis of colorectal cancer. Results Herein, we identified miR-4449 as a novel upregulated miRNA in colorectal cancer. Our data suggested that miR-4449 downregulation blocked the proliferation of colorectal cancer cells accompanied with the elevation of cell apoptosis. Decreased expression of miR-4449 led to inactivation of STAT3 pathway as indicated by dephosphorylation of STAT3 and downregulation of STAT3 target genes, including vascular endothelial growth factor (VEGF), c-Myc, baculovirus inhibitor of apoptosis containing 5 (BIRC5). Furthermore, SOCS3, a negative regulator of STAT3 pathway, was found to be a target gene of miR-4449. The data also showed that the inactivation of STAT3 pathway by miR-4449 inhibitor was realized by targeting SOCS3. Moreover, the biological function of miR-4449 downregulation was reversed by SOCS3 knockdown in colorectal cancer cells. Conclusion The current study revealed that miR-4449 promoted cell proliferation of colorectal cancer and was a promising potential therapeutic target for colorectal cancer.
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Affiliation(s)
- Zhenkun Yan
- Department of Endoscopy Center, The Third Hospital of Jilin University, Changchun, Jilin, 130022, People's Republic of China
| | - Sen Hong
- Department of Colorectal and Anal Surgery, The First Hospital of Jilin University, Changchun, Jilin, 130022, People's Republic of China
| | - Yumei Song
- Department of Thoracic Oncology, Tumor Hospital of Jilin Province, Changchun, Jilin, 130022, People's Republic of China
| | - Miaomiao Bi
- Department of Ophthalmology, The Third Hospital of Jilin University, Changchun, Jilin, 130022, People's Republic of China
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Dees C, Pötter S, Zhang Y, Bergmann C, Zhou X, Luber M, Wohlfahrt T, Karouzakis E, Ramming A, Gelse K, Yoshimura A, Jaenisch R, Distler O, Schett G, Distler JH. TGF-β-induced epigenetic deregulation of SOCS3 facilitates STAT3 signaling to promote fibrosis. J Clin Invest 2021; 130:2347-2363. [PMID: 31990678 DOI: 10.1172/jci122462] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 01/17/2020] [Indexed: 12/28/2022] Open
Abstract
Fibroblasts are key effector cells in tissue remodeling. They remain persistently activated in fibrotic diseases, resulting in progressive deposition of extracellular matrix. Although fibroblast activation may be initiated by external factors, prolonged activation can induce an "autonomous," self-maintaining profibrotic phenotype in fibroblasts. Accumulating evidence suggests that epigenetic alterations play a central role in establishing this persistently activated pathologic phenotype of fibroblasts. We demonstrated that in fibrotic skin of patients with systemic sclerosis (SSc), a prototypical idiopathic fibrotic disease, TGF-β induced the expression of DNA methyltransferase 3A (DNMT3A) and DNMT1 in fibroblasts in a SMAD-dependent manner to silence the expression of suppressor of cytokine signaling 3 (SOCS3) by promoter hypermethylation. Downregulation of SOCS3 facilitated activation of STAT3 to promote fibroblast-to-myofibroblast transition, collagen release, and fibrosis in vitro and in vivo. Reestablishment of the epigenetic control of STAT3 signaling by genetic or pharmacological inactivation of DNMT3A reversed the activated phenotype of SSc fibroblasts in tissue culture, inhibited TGF-β-dependent fibroblast activation, and ameliorated experimental fibrosis in murine models. These findings identify a pathway of epigenetic imprinting of fibroblasts in fibrotic disease with translational implications for the development of targeted therapies in fibrotic diseases.
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Affiliation(s)
- Clara Dees
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Sebastian Pötter
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Yun Zhang
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Christina Bergmann
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Xiang Zhou
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Markus Luber
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Thomas Wohlfahrt
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Emmanuel Karouzakis
- Center of Experimental Rheumatology, Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland
| | - Andreas Ramming
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Kolja Gelse
- Department of Trauma Surgery - Orthopedic Surgery, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Akihiko Yoshimura
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
| | - Rudolf Jaenisch
- Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA
| | - Oliver Distler
- Center of Experimental Rheumatology, Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland
| | - Georg Schett
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Jörg Hw Distler
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
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Wang F, Wang X, Li J, Lv P, Han M, Li L, Chen Z, Dong L, Wang N, Gu Y. CircNOL10 suppresses breast cancer progression by sponging miR-767-5p to regulate SOCS2/JAK/STAT signaling. J Biomed Sci 2021; 28:4. [PMID: 33397365 PMCID: PMC7780627 DOI: 10.1186/s12929-020-00697-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 11/26/2020] [Indexed: 12/20/2022] Open
Abstract
Background Circular RNAs (circRNAs) have caught increasing attentions and interests for their important involvement in cancer initiation and progression. This study aims to investigate the biological functions of circNOL10 and its potential molecular mechanisms in breast cancer (BC). Materials and methods qRT-PCR and western blot assays were performed to measure the expression of related genes. CCK-8, colony formation, flow cytomerty and transwell assays were used to assess cell proliferation, cell cycle, migration and invasion. RNA pull-down, luciferase reporter and RIP assays were applied to address the potential regulatory mechanism of circNOL10. Results CircNOL10 was down-regulated in BC tissues and cells. Low expression of circNOL10 was associated with larger tumor size, advanced TNM stage, lymph node metastasis and unfavorable prognosis. Overexpression of circNOL10 inhibited cell proliferation, migration, invasion and EMT in vitro and slowed xenograft tumor growth in vivo. Mechanistically, circNOL10 could act as a molecular sponge for miR-767-5p, leading to the up-regulation of suppressors of cytokine signaling 2 (SOCS2) and inactivation of JAK2/STAT5 pathway. Moreover, circNOL10-mediated suppression of malignant phenotypes was attenuated by miR-767-5p. Similar to circNOL10, enforced expression of SOCS2 also resulted in the suppression of cell proliferation and metastasis. Furthermore, knockdown of SOCS2 reversed the tumor-suppressive effect induced by circNOL10. Conclusions CircNOL10 repressed BC development via inactivation of JAK2/STAT5 signaling by regulating miR-767-5p/SOCS2 axis. Our findings offer the possibility of exploiting circNOL10 as a therapeutic and prognostic target for BC patients.
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Affiliation(s)
- Fang Wang
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Erqi, Zhengzhou, 450000, China
| | - Xiaochun Wang
- Department of Breast Surgery, Affiliated Hospital of Hebei University, Baoding, 071000, China
| | - Jingruo Li
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Erqi, Zhengzhou, 450000, China
| | - Pengwei Lv
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Erqi, Zhengzhou, 450000, China
| | - Mingli Han
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Erqi, Zhengzhou, 450000, China
| | - Lin Li
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Erqi, Zhengzhou, 450000, China
| | - Zhuo Chen
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Erqi, Zhengzhou, 450000, China
| | - Lingling Dong
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Erqi, Zhengzhou, 450000, China
| | - Nan Wang
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Erqi, Zhengzhou, 450000, China
| | - Yuanting Gu
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Erqi, Zhengzhou, 450000, China.
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35
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Park JM, An JM, Han YM, Surh YJ, Hwang SJ, Kim SJ, Hahm KB. Walnut polyphenol extracts inhibit Helicobacter pylori-induced STAT3 Tyr705 phosphorylation through activation of PPAR-γ and SOCS1 induction. J Clin Biochem Nutr 2021. [DOI: 10.3164/jcbn.20-105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Affiliation(s)
| | - Jeong Min An
- CHA Cancer Preventive Research Center, CHA Bio Complex, CHA University
| | | | | | | | | | - Ki Baik Hahm
- CHA Cancer Preventive Research Center, CHA Bio Complex, CHA University
- Medpacto Research Institute, Medpacto
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36
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Qin Y, Bollin K, de Macedo MP, Carapeto F, Kim KB, Roszik J, Wani KM, Reuben A, Reddy ST, Williams MD, Tetzlaff MT, Wang WL, Gombos DS, Esmaeli B, Lazar AJ, Hwu P, Patel SP. Immune profiling of uveal melanoma identifies a potential signature associated with response to immunotherapy. J Immunother Cancer 2020; 8:jitc-2020-000960. [PMID: 33203661 PMCID: PMC7674090 DOI: 10.1136/jitc-2020-000960] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/27/2020] [Indexed: 12/14/2022] Open
Abstract
Background To date, no systemic therapy, including immunotherapy, exists to improve clinical outcomes in metastatic uveal melanoma (UM) patients. To understand the role of immune infiltrates in the genesis, metastasis, and response to treatment for UM, we systematically characterized immune profiles of UM primary and metastatic tumors, as well as samples from UM patients treated with immunotherapies. Methods Relevant immune markers (CD3, CD8, FoxP3, CD68, PD-1, and PD-L1) were analyzed by immunohistochemistry on 27 primary and 31 metastatic tumors from 47 patients with UM. Immune gene expression profiling was conducted by NanoString analysis on pre-treatment and post-treatment tumors from patients (n=6) receiving immune checkpoint blockade or 4-1BB and OX40 dual costimulation. The immune signature of UM tumors responding to immunotherapy was further characterized by Ingenuity Pathways Analysis and validated in The Cancer Genome Atlas data set. Results Both primary and metastatic UM tumors showed detectable infiltrating lymphocytes. Compared with primary tumors, treatment-naïve metastatic UM showed significantly higher levels of CD3+, CD8+, FoxP3+ T cells, and CD68+ macrophages. Notably, levels of PD-1+ infiltrates and PD-L1+ tumor cells were low to absent in primary and metastatic UM tumors. No metastatic organ-specific differences were seen in immune infiltrates. Our NanoString analysis revealed significant differences in a set of immune markers between responders and non-responders. A group of genes relevant to the interferon-γ signature was differentially up-expressed in the pre-treatment tumors of responders. Among these genes, suppressor of cytokine signaling 1 was identified as a marker potentially contributing to the response to immunotherapy. A panel of genes that encoded pro-inflammatory cytokines and molecules were expressed significantly higher in pre-treatment tumors of non-responders compared with responders. Conclusion Our study provides critical insight into immune profiles of UM primary and metastatic tumors, which suggests a baseline tumor immune signature predictive of response and resistance to immunotherapy in UM.
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Affiliation(s)
- Yong Qin
- Pharmaceutical Sciences, School of Pharmacy, The University of Texas at El Paso, El Paso, Texas, USA
| | - Kathryn Bollin
- Medical Oncology, Scripps MD Anderson Cancer Center, San Diego, California, USA
| | | | - Fernando Carapeto
- Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Kevin B Kim
- Center for Melanoma Research and Treatment, California Pacific Medical Center Research Institute, San Francisco, California, USA
| | - Jason Roszik
- Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Khalida M Wani
- Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Alexandre Reuben
- Thoracic/Head & Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Sujan T Reddy
- Neurology, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Michelle D Williams
- Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Michael T Tetzlaff
- Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.,Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Wei-Lien Wang
- Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.,Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Dan S Gombos
- Department of Head and Neck Surgery, Section of Ophthalmology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Bita Esmaeli
- Orbital Oncology & Ophthalmic Plastic Surgery, Department of Plastic Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Alexander J Lazar
- Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.,Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Patrick Hwu
- Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Sapna P Patel
- Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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37
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Han X, Chen X, Han J, Zhong Y, Li Q, An Y. MiR-324/SOCS3 Axis Protects Against Hypoxia/Reoxygenation-Induced Cardiomyocyte Injury and Regulates Myocardial Ischemia via TNF/NF-κB Signaling Pathway. Int Heart J 2020; 61:1258-1269. [PMID: 33191336 DOI: 10.1536/ihj.19-687] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
We aimed at exploring the function of microRNA-324/cytokine signaling 3 (miR-324/SOCS3) axis in hypoxia/reoxygenation (H/R) -induced cardiomyocyte injury and its underlying mechanism. The differential expression genes were analyzed based on the GSE83500 and GSE48060 datasets from the Gene Expression Omnibus (GEO) database. Then, to conduct the function enrichment analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were used. The upstream regulatory microRNAs (miRNAs) of the identified genes were predicted by miRanda, miRWalk, and TargetScan websites. MiR-324 expression was measured with quantitative real-time polymerase chain reaction (qRT-PCR). The target binding of miR-324 and SOCS3 was established by dual-luciferase reporter assay. Cardiomyocyte proliferation was analyzed by cell counting kit-8 (CCK-8) assay, whereas the apoptosis was investigated via flow cytometry. The expression of TNF pathway-related proteins was detected by western blot analysis. SOCS3 was upregulated in patients with myocardial infarction (MI), and function enrichment analyses proved that SOCS3 was enriched in TNF signaling pathway. Moreover, we found that miR-324 was the upstream regulatory miRNA of SOCS3 and negatively regulated SOCS3 expression. MiR-324 was downregulated in cardiomyocytes with H/R-induced injury, inhibiting cell proliferation. In the H/R model, SOCS3 suppresses cardiomyocyte proliferation, which was recovered by miR-324, and induces cell apoptosis, which was repressed by miR-324 via regulating the expression of cleaved caspase-3 and p P38-MAPK. MiR-324 upregulation decreased the protein levels of TNF-α, p-P65, and p-IκBα in cardiomyocytes that suffered from H/R, which was reversed with SOCS3 overexpression. MiR-324/SOCS3 axis could improve the H/R-induced injury of cardiomyocytes via regulating TNF/NF-κB signaling pathway, and this might provide a new therapy strategy for myocardial ischemia.
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Affiliation(s)
- Xuefu Han
- Department of medicine, Qingdao University.,Department of Cardiology, Weifang People's Hospital
| | - Xi Chen
- Department of Stomatology, Weifang Maternal and Child Health Hospital
| | - Jiaqi Han
- Department of medicine, Qingdao University
| | - Yu Zhong
- Department of Personnel, Weifang Maternal and Child Health Hospital
| | - Qinghua Li
- School of Public Health, Weifang Medical University
| | - Yi An
- Department of Cardiology, The Affiliated Hospital of Qingdao University.,Qingdao University
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38
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Li S, Xu Z, Guo J, Zheng J, Sun X, Yu J. Farnesoid X receptor activation induces antitumour activity in colorectal cancer by suppressing JAK2/STAT3 signalling via transactivation of SOCS3 gene. J Cell Mol Med 2020; 24:14549-14560. [PMID: 33164339 PMCID: PMC7754034 DOI: 10.1111/jcmm.16083] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 10/20/2020] [Accepted: 10/25/2020] [Indexed: 12/14/2022] Open
Abstract
Farnesoid X receptor (FXR, encoded by NR1H4), a bile acid‐activated nuclear receptor, is widely implicated in human tumorigenesis. The FXR agonist obeticholic acid (OCA) has preliminarily displayed tumour suppressor potential. However, the anticancer effects of this agent on colorectal cancer (CRC) remain unclear. In this study, the treatment of colon cancer cells with OCA inhibited cell proliferation and invasion in vitro, retarded tumour growth in vivo and prevented the G0/G1 to S phase transition. Moreover, the expression of active caspase‐3, p21 and E‐cadherin was up‐regulated and the expression of cyclin D1, c‐Myc, vimentin, N‐cadherin and MMP9 was down‐regulated in OCA‐treated colon cancer cells. Mechanistic studies indicated that OCA treatment suppressed the activity of JAK2/STAT3 pathway by up‐regulating SOCS3 expression. Colivelin, an agonist of JAK2/STAT3 pathway, antagonized the tumour‐suppressive effect of OCA on colon cancer cells. Dual‐luciferase reporter and quantitative chromatin immunoprecipitation (qChIP) assays further confirmed that OCA promoted SOCS3 transcription by enhancing the binding of FXR to the FXRE/IR9 of the SOCS3 promoter. In conclusion, our study demonstrates that targeting FXR and improving its function might be a promising strategy for CRC treatment.
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Affiliation(s)
- Shan Li
- Department of Reproductive Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zhengshui Xu
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jing Guo
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jianbao Zheng
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xuejun Sun
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Junhui Yu
- Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Role of the JAK/STAT Pathway in Cervical Cancer: Its Relationship with HPV E6/E7 Oncoproteins. Cells 2020; 9:cells9102297. [PMID: 33076315 PMCID: PMC7602614 DOI: 10.3390/cells9102297] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 10/11/2020] [Accepted: 10/12/2020] [Indexed: 02/06/2023] Open
Abstract
The janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is associated with the regulation of essential cellular mechanisms, such as proliferation, invasion, survival, inflammation, and immunity. Aberrant JAK/STAT signaling contributes to cancer progression and metastatic development. STAT proteins play an essential role in the development of cervical cancer, and the inhibition of the JAK/STAT pathway may be essential for enhancing tumor cell death. Persistent activation of different STATs is present in a variety of cancers, including cervical cancer, and their overactivation may be associated with a poor prognosis and poor overall survival. The oncoproteins E6 and E7 play a critical role in the progression of cervical cancer and may mediate the activation of the JAK/STAT pathway. Inhibition of STAT proteins appears to show promise for establishing new targets in cancer treatment. The present review summarizes the knowledge about the participation of the different components of the JAK/STAT pathway and the participation of the human papillomavirus (HPV) associated with the process of cellular malignancy.
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40
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Park JM, An JM, Han YM, Surh YJ, Hwang SJ, Kim SJ, Hahm KB. Walnut polyphenol extracts inhibit Helicobacter pylori-induced STAT3 Tyr705 phosphorylation through activation of PPAR-γ and SOCS1 induction. J Clin Biochem Nutr 2020; 67:248-256. [PMID: 33293765 PMCID: PMC7705089 DOI: 10.3164/jcbn.20-89] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 06/13/2020] [Indexed: 12/14/2022] Open
Abstract
The health beneficial effects of walnut plentiful of n-3 polyunsaturated fatty acid had been attributed to its anti-inflammatory and anti-oxidative properties against various clinical diseases. Since we have published Fat-1 transgenic mice overexpressing 3-desaturase significantly mitigated Helicobacter pylori (H. pylori)-associated gastric pathologies including rejuvenation of chronic atrophic gastritis and prevention of gastric cancer, in this study, we have explored the underlying molecular mechanisms of walnut against H. pylori infection. Fresh walnut polyphenol extracts (WPE) were found to suppress the phosphorylation and nuclear translocation of signal transducer and activator of transcription 3 (STAT3) induced by H. pylori infection in RGM-1 gastric mucosal cells. Notably, H. pylori infection significantly decreased suppressor of cytokine signaling 1 (SOCS1), but WPE induced expression of SOCS1, by which the suppressive effect of walnut extracts on STAT3Tyr705 phosphorylation was not seen in SOCS1 KO cells. WPE induced significantly increased nuclear translocation nuclear translocation of PPAR-γ in RGM1 cells, by which PPAR-γ KO inhibited transcription of SOCS1 and suppressive effect of WPE on p-STAT3Tyr705 was not seen. WPE inhibited the expression of c-Myc and IL-6/IL-6R signaling, which was attenuated in the RGM1 cells harboring SOCS1 specific siRNA. Conclusively, WPE inhibits H. pylori-induced STAT3 phosphorylation in a PPAR-γ and SOCS1-dependent manner.
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Affiliation(s)
- Jong Min Park
- College of Oriental Medicine, Daejeon University, Daehak-ro 62, Dong-gu, Daejeon, 34520, Korea
| | - Jeong Min An
- CHA Cancer Preventive Research Center, CHA Bio Complex, 330 Pangyo-dong, Bundang-gu, Seongnam, 13497, Korea
| | - Young Min Han
- Western Seoul Center, Korea Basic Science Institute, University-Industry Cooperate Building, 150 Bugahyeon-ro, Seodaemun-gu, Seoul, 03759, Korea
| | - Young Joon Surh
- College of Pharmacy Seoul National University, Seoul, 08826, Korea
| | - Sun Jin Hwang
- Medpacto Research Institute, Medpacto Inc., 92, Myeongdal-ro, Seocho-gu, Seoul, 06668, Korea
| | - Seong Jin Kim
- Medpacto Research Institute, Medpacto Inc., 92, Myeongdal-ro, Seocho-gu, Seoul, 06668, Korea
| | - Ki Baik Hahm
- CHA Cancer Preventive Research Center, CHA Bio Complex, 330 Pangyo-dong, Bundang-gu, Seongnam, 13497, Korea.,Medpacto Research Institute, Medpacto Inc., 92, Myeongdal-ro, Seocho-gu, Seoul, 06668, Korea
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41
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Wang H, Wang MS, Wang Y, Huang YQ, Shi JP, Ding ZL, Wang WJ. Prognostic value of immune related genes in lung adenocarcinoma. Oncol Lett 2020; 20:259. [PMID: 32989393 PMCID: PMC7517630 DOI: 10.3892/ol.2020.12122] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 02/07/2020] [Indexed: 12/27/2022] Open
Abstract
Lung cancer has the highest incidence and mortality rates of all cancers in China. Immune-related genes and immune infiltrating lymphocytes are involved in tumor growth, and in the past decade, immunotherapy has become increasingly important in the treatment of lung cancer. Using the edgeR package, differentially expressed genes and immune-related genes (DEIRGs) were identified in patients with lung adenocarcinoma (LUAD). Functional enrichment analysis of DEIRGs was performed using Gene Ontology annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Survival-associated immune-related genes (IRGs) were selected using univariate Cox regression analysis and the prognostic model was assessed using multivariate Cox regression analysis. Overall, 273 DEIRGs were identified in LUAD, and KEGG pathway analysis of IRGs showed that ‘cytokine-cytokine receptor interaction’ was the most significantly enriched pathway. Furthermore, six survival associated IRGs were screened to establish a prognostic model; patients in the high risk score group had less favorable survival times, and the prognostic model was negatively associated with B cell infiltration. The present study established a prognostic model using analysis of survival-related immune-related genes, which were associated with B cell infiltration.
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Affiliation(s)
- Han Wang
- Department of Oncology, Jining Cancer Hospital, Jining, Shandong 272011, P.R. China
| | - Meng-Sen Wang
- Department of Oncology, Jining First People's Hospital, Jining, Shandong 272011, P.R. China
| | - Ying Wang
- Department of Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215001, P.R. China
| | - Yue-Qing Huang
- Department of General Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215001, P.R. China
| | - Jian-Ping Shi
- Department of Radio-Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215001, P.R. China
| | - Zhi-Liang Ding
- Department of Neurosurgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215001, P.R. China
| | - Wen-Jie Wang
- Department of Radio-Oncology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215001, P.R. China
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MiR-944/CISH mediated inflammation via STAT3 is involved in oral cancer malignance by cigarette smoking. Neoplasia 2020; 22:554-565. [PMID: 32961483 PMCID: PMC7505767 DOI: 10.1016/j.neo.2020.08.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 08/20/2020] [Accepted: 08/24/2020] [Indexed: 12/18/2022] Open
Abstract
Down-regulation of CISH in OSCC tissues and cell lines. CISH mediates cellular functions through STAT3 inhibition. MiR-944 regulates cellular functions through direct binding of CISH. Cigarette smoking-mediated miR-944/CISH/STAT3 axis plays a role in oral carcinogenesis. The cytokine-inducible Src homology 2-containing protein (CISH) is an endogenous suppressors of signal transduction and activator of transcription (STAT) and acts as a key negative regulator of inflammatory cytokine responses. Downregulation of CISH has been reported to associate with increased activation of STAT and enhanced inflammatory pathways. However, whether microRNAs (miRNAs) play a crucial role in CISH/STAT regulation in oral squamous cell carcinoma (OSCC) remains unknown. The expression of CISH on OSCC patients was determine by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. Specific targeting by miRNAs was determined by software prediction, luciferase reporter assay, and correlation with target protein expression. The functions of miR-944 and CISH were accessed by transwell migration and invasion analyses using gain- and loss-of-function approaches. Enzyme-linked immunosorbent assay (ELISA) and qRT-PCR were used to evaluate the pro-inflammation cytokines expression under the miR-944, CISH, NNK or combinations treatment. We found that the CISH protein, which modulates STAT3 activity, as a direct target of miR-944. CISH protein was significantly down-regulated in OSCC patients and cell lines and its level was inversely correlated with miR-944 expression. The miR-944-induced STAT3 phosphorylation, pro-inflammation cytokines secretion, migration and invasion were abolished by CISH restoration, suggesting that the oncogenic activity of miR-944 is CISH dependent. Furthermore, tobacco extract (NNK) may contribute to miR-944 induction and STAT3 activation. Antagomir-mediated inactivation of miR-944 prevented the NNK-induced STAT3 phosphorylation and pro-inflammation cytokines secretion. Altogether, these data demonstrate that NNK-induced miR944 expression plays an important role in CISH/STAT3-mediated inflammatory response and activation of tumor malignancy.
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Cytokine-Mediated Dysregulation of Signaling Pathways in the Pathogenesis of Multiple Myeloma. Int J Mol Sci 2020; 21:ijms21145002. [PMID: 32679860 PMCID: PMC7403981 DOI: 10.3390/ijms21145002] [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: 01/21/2020] [Revised: 03/06/2020] [Accepted: 03/06/2020] [Indexed: 12/15/2022] Open
Abstract
Multiple myeloma (MM) is a hematologic disorder of B lymphocytes characterized by the accumulation of malignant plasma cells (PCs) in the bone marrow. The altered plasma cells overproduce abnormal monoclonal immunoglobulins and also stimulate osteoclasts. The host’s immune system and microenvironment are of paramount importance in the growth of PCs and, thus, in the pathogenesis of the disease. The interaction of MM cells with the bone marrow (BM) microenvironment through soluble factors and cell adhesion molecules causes pathogenesis of the disease through activation of multiple signaling pathways, including NF-κβ, PI3K/AKT and JAK/STAT. These activated pathways play a critical role in the inhibition of apoptosis, sustained proliferation, survival and migration of MM cells. Besides, these pathways also participate in developing resistance against the chemotherapeutic drugs in MM. The imbalance between inflammatory and anti-inflammatory cytokines in MM leads to an increased level of pro-inflammatory cytokines, which in turn play a significant role in dysregulation of signaling pathways and proliferation of MM cells; however, the association appears to be inadequate and needs more research. In this review, we are highlighting the recent findings on the roles of various cytokines and growth factors in the pathogenesis of MM and the potential therapeutic utility of aberrantly activated signaling pathways to manage the MM disease.
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Jiang L, Chen T, Xiong L, Xu JH, Gong AY, Dai B, Wu G, Zhu K, Lu E, Mathy NW, Chen XM. Knockdown of m6A methyltransferase METTL3 in gastric cancer cells results in suppression of cell proliferation. Oncol Lett 2020; 20:2191-2198. [PMID: 32782536 PMCID: PMC7400027 DOI: 10.3892/ol.2020.11794] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 05/21/2020] [Indexed: 12/14/2022] Open
Abstract
N6-methyladenosine (m6A) RNA modification regulates multiple biological functions. Methyltransferase like 3 (METTL3), one of the major N6-methyltransferases, is highly expressed in gastric cancer, but its potential role in disease is unclear. The current study knocked out METTL3 (METTL3-KO) in human gastric cancer AGS cells using CRISPR/Cas9. METTL3-KO AGS cells exhibited decreased m6A methylation levels. A significant inhibition of cell proliferation was observed in METTL3-KO AGS cells. Silencing METTL3 in AGS cells altered the expression profile of many effector molecules that were previously demonstrated to serve key roles in AGS cell proliferation, including the suppressor of cytokine signaling (SOCS) family of proteins. The results further demonstrated that SOCS2 upregulation in METTL3-KO AGS cells was associated with a decreased RNA decay rate. Furthermore, SOCS2 KO or SOCS2 overexpression caused a significant increase and decrease in AGS cell proliferation, respectively. The current data suggested that METTL3-KO in gastric cancer cells resulted in the suppression of cell proliferation by inducing SOCS2, suggesting a potential role of elevated METTL3 expression in gastric cancer progression.
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Affiliation(s)
- Li Jiang
- Department of Geriatrics, Zhongnan Hospital, Wuhan University, Wuhan, Hubei 430071, P.R. China.,Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, NE 68178, USA
| | - Ting Chen
- Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, NE 68178, USA.,National Demonstration Center for Experimental General Medicine Education, College of Clinical Medicine, Hubei University of Science and Technology, Xianning, Hubei 437100, P.R. China
| | - Li Xiong
- Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, NE 68178, USA.,National Demonstration Center for Experimental General Medicine Education, College of Clinical Medicine, Hubei University of Science and Technology, Xianning, Hubei 437100, P.R. China
| | - Ji-Hao Xu
- Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, NE 68178, USA.,Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Ai-Yu Gong
- Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, NE 68178, USA
| | - Bin Dai
- Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, NE 68178, USA.,National Demonstration Center for Experimental General Medicine Education, College of Clinical Medicine, Hubei University of Science and Technology, Xianning, Hubei 437100, P.R. China
| | - Ganlin Wu
- Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, NE 68178, USA.,National Demonstration Center for Experimental General Medicine Education, College of Clinical Medicine, Hubei University of Science and Technology, Xianning, Hubei 437100, P.R. China
| | - Kenny Zhu
- Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, NE 68178, USA
| | - Eugene Lu
- Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, NE 68178, USA
| | - Nicholas William Mathy
- Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, NE 68178, USA
| | - Xian-Ming Chen
- Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, NE 68178, USA
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Increased expression of Suppressor of cytokine signaling 2 (BmSOCS2) is correlated with suppression of Bombyx mori nucleopolyhedrovirus replication in silkworm larval tissues and cells. J Invertebr Pathol 2020; 174:107419. [PMID: 32535001 DOI: 10.1016/j.jip.2020.107419] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 05/29/2020] [Accepted: 06/03/2020] [Indexed: 12/13/2022]
Abstract
The resistance of silkworm to infection by Bombyx mori nuclear polyhedrosis virus (BmNPV) is a main focus of sericultural research. Previously, a BmNPV-resistant strain, NB, was identified among a collection of Chinese silkworm strains in our lab. To better understand the molecular mechanism of NB strain resistance, the patterns of host immune response gene transcription in resistant (NB) and susceptible (306) strains were examined. Quantative real-time PCR (qRT-PCR) revealed that multiple insect innate immune signaling pathways (Toll, Imd and JAK/STAT) were strongly activated upon infection with BmNPV. Notably, Suppressor of cytokine signaling 2 (BmSOCS2) mRNA expression was significantly up-regulated in midgut tissues of the resistant NB strain, suggesting that the BmSOCS2 gene product may be involved in host immune defense against BmNPV infection. A significant inhibition of BmNPV replication was also observed in BmN cells transfected with a vector encoding BmSOCS2. The results suggest that BmSOCS2 is a key gene involved in the resistance of the NB silkworm strain to BmNPV infection.
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Chen M, Zeng J, Chen S, Li J, Wu H, Dong X, Lei Y, Zhi X, Yao L. SPTBN1 suppresses the progression of epithelial ovarian cancer via SOCS3-mediated blockade of the JAK/STAT3 signaling pathway. Aging (Albany NY) 2020; 12:10896-10911. [PMID: 32516133 PMCID: PMC7346039 DOI: 10.18632/aging.103303] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Accepted: 03/03/2020] [Indexed: 12/16/2022]
Abstract
SPTBN1 plays an anticancer role in many kinds of tumors and participates in the chemotherapeutic resistance of epithelial ovarian cancer (EOC). Here, we reported that lower SPTBN1 expression was significantly related to advanced EOC stage and shorter progression-free survival. SPTBN1 expression was also higher in less invasive EOC cell lines. Moreover, SPTBN1 decreased the migration ability of the EOC cells A2780 and HO8910 and inhibited the growth of EOC cells in vitro and tumor xenografts in vivo. SPTBN1 suppression increased the epithelial mesenchymal transformation marker Vimentin while decreasing E-cadherin expression. By analyzing TCGA data and immunohistochemistry staining of tumor tissue, we found that SPTBN1 and SOCS3 were positively coexpressed in EOC patients. SOCS3 overexpression or JAK2 inhibition decreased the proliferation and migration of EOC cells as well as the expression of p-JAK2, p-STAT3 and Vimentin, which were enhanced by the downregulation of SPTBN1, while E-cadherin expression was also reversed. It was also verified in mouse embryonic fibroblasts (MEFs) that loss of SPTBN1 activated the JAK/STAT3 signaling pathway with suppression of SOCS3. Our results suggest that SPTBN1 suppresses the progression of epithelial ovarian cancer via SOCS3-mediated blockade of the JAK/STAT3 signaling pathway.
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Affiliation(s)
- Mo Chen
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China
| | - Jia Zeng
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China
| | - Shuyi Chen
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Jiajia Li
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China
| | - Huijie Wu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Xuhui Dong
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China
| | - Yuan Lei
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China
| | - Xiuling Zhi
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Liangqing Yao
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China
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Yang M, Chen H, Zhou L, Huang X, Su F, Wang P. Identification of SOCS family members with prognostic values in human ovarian cancer. Am J Transl Res 2020; 12:1824-1838. [PMID: 32509179 PMCID: PMC7269991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Accepted: 04/24/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND Suppressor of cytokine signaling (SOCS) family proteins regulate cytokine responses through inhibition of multiple signaling pathways. The expression profiles and prognostic significance of SOCS members in ovarian cancer (OC) patients still remains unclear. Here, we aimed to provide a comprehensive understanding of the prognostic values of SOCS family members in OC and to discover promising therapeutic targets for OC. METHODS We firstly analyzed the KEGG pathway enrichment to reveal the possible pathways associated with SOCS family. Next, we used public databases including cBioPortal, Human Protein Atlas and Oncomine to investigate genetic alterations and mRNA expression of SOCS family in OC patients. More importantly, we explored the prognostic value of each individual SOCS members in OC patients using Kaplan Meier plotter database. RESULTS SOCS family was markedly enriched in JAK-STAT signaling pathway. A high mutation rate in SOCSs was observed in patients with ovarian serous cancer (OSC). An increased mRNA expression of SOCS1 indicated a favorable overall survival (OS) in both OC and OSC patients, while increased SOCS5 and SOCS7 expressions were significantly associated with poorer OS. We also explored the diverse roles of SOCS members in OC patients with different clinicopathological features including grades, stages and therapies employed. CONCLUSION SOCS1, SOCS5 and SOCS7 may serve as prognostic biomarkers for OC patients. SOCS5 and SOCS7 may be potential therapeutic targets for OC treatment. Our results render novel insights into the association between SOCS family genes and OC development, and may highlight promising molecular targets for therapeutic interventions in OC patients.
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Affiliation(s)
- Mengqi Yang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen UniversityGuangzhou, China
- Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen UniversityGuangzhou, China
| | - Huanting Chen
- Department of General Surgery, People’s Hospital of Shenzhen Baoan District, Affiliated Shenzhen Baoan Hospital of Southern Medical UniversityShenzhen, China
| | - Lin Zhou
- Department of Critical Care Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen UniversityGuangzhou, China
| | - Xiaobo Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen UniversityGuangzhou, China
- Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen UniversityGuangzhou, China
- Department of Radiation Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen UniversityGuangzhou, China
| | - Fengxi Su
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen UniversityGuangzhou, China
- Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen UniversityGuangzhou, China
| | - Peng Wang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen UniversityGuangzhou, China
- Department of Emergency Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen UniversityGuangzhou, China
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La Manna S, Lopez-Sanz L, Mercurio FA, Fortuna S, Leone M, Gomez-Guerrero C, Marasco D. Chimeric Peptidomimetics of SOCS 3 Able to Interact with JAK2 as Anti-inflammatory Compounds. ACS Med Chem Lett 2020; 11:615-623. [PMID: 32435361 DOI: 10.1021/acsmedchemlett.9b00664] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 03/19/2020] [Indexed: 02/06/2023] Open
Abstract
The immunomodulatory effects of Suppressor of Cytokine Signaling (SOCS) proteins, that control the JAK/STAT pathway, indicate them as attractive candidates for immunotherapies. Recombinant SOCS3 protein suppresses the effects of inflammation, and its deletion in neurons or in immune cells increases pathological blood vessels growth. Recently, on the basis of the structure of the ternary complex among SOCS3, JAK2, and gp130, we focused on SOCS3 interfacing regions and designed several interfering peptides (IPs) that were able to mimic SOCS3 biological role in triple negative breast cancer (TNBC) models. Herein, to explore other protein regions involved in JAK2 recognition, several new chimeric peptides connecting noncontiguous SOCS3 regions and including a strongly aromatic fragment were investigated. Their ability to recognize the catalytic domain of JAK2 was evaluated through MST (microscale thermophoresis), and the most promising compound, named KIRCONG chim, exhibited a low micromolar value for dissociation constant. The conformational features of chimeric peptides were analyzed through circular dichroism and NMR spectroscopies, and their anti-inflammatory effects were assessed in cell cultures. Overall data suggest the importance of aromatic contribution in the recognition of JAK2 and that SOCS3 peptidomimetics could be endowed with a therapeutic potential in diseases with activated inflammatory cytokines.
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Affiliation(s)
- Sara La Manna
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples “Federico II”, 80134 Naples, Italy
- Renal and Vascular Inflammation Group, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Autonoma University of Madrid (UAM), 28040 Madrid, Spain
| | - Laura Lopez-Sanz
- Renal and Vascular Inflammation Group, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Autonoma University of Madrid (UAM), 28040 Madrid, Spain
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain
| | | | - Sara Fortuna
- Department of Chemical and Pharmaceutical Sciences, University of Trieste, 34127 Trieste, Italy
| | - Marilisa Leone
- Institute of Biostructures and Bioimaging - CNR, 80134 Naples, Italy
| | - Carmen Gomez-Guerrero
- Renal and Vascular Inflammation Group, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Autonoma University of Madrid (UAM), 28040 Madrid, Spain
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain
| | - Daniela Marasco
- Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, University of Naples “Federico II”, 80134 Naples, Italy
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Interferon Response in Hepatitis C Virus-Infected Hepatocytes: Issues to Consider in the Era of Direct-Acting Antivirals. Int J Mol Sci 2020; 21:ijms21072583. [PMID: 32276399 PMCID: PMC7177520 DOI: 10.3390/ijms21072583] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 04/04/2020] [Accepted: 04/07/2020] [Indexed: 12/16/2022] Open
Abstract
When interferons (IFNs) bind to their receptors, they upregulate numerous IFN-stimulated genes (ISGs) with antiviral and immune regulatory activities. Hepatitis C virus (HCV) is a single-stranded, positive-sense RNA virus that affects over 71 million people in the global population. Hepatocytes infected with HCV produce types I and III IFNs. These endogenous IFNs upregulate a set of ISGs that negatively impact the outcome of pegylated IFN-α and ribavirin treatments, which were previously used to treat HCV. In addition, the IFNL4 genotype was the primary polymorphism responsible for a suboptimal treatment response to pegylated IFN-α and ribavirin. However, recently developed direct-acting antivirals have demonstrated a high rate of sustained virological response without pegylated IFN-α. Herein, we review recent studies on types I and III IFN responses to in HCV-infected hepatocytes. In particular, we focused on open issues related to IFN responses in the direct-acting antiviral era.
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Wang Z, Yang P, Xie J, Lin HP, Kumagai K, Harkema J, Yang C. Arsenic and benzo[a]pyrene co-exposure acts synergistically in inducing cancer stem cell-like property and tumorigenesis by epigenetically down-regulating SOCS3 expression. ENVIRONMENT INTERNATIONAL 2020; 137:105560. [PMID: 32062438 PMCID: PMC7099608 DOI: 10.1016/j.envint.2020.105560] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Revised: 02/05/2020] [Accepted: 02/06/2020] [Indexed: 05/23/2023]
Abstract
Arsenic and benzo[a]pyrene (BaP) are among the most common environmental carcinogens causing lung cancer. Millions of people are exposed to arsenic through consuming arsenic-contaminated drinking water. High levels of BaP are found in well-done barbecued meat and other food in addition to cigarette smoke. Hence, arsenic and BaP co-exposure in humans is common. However, the combined health effect and the underlying mechanism of arsenic and BaP co-exposure have not been well-understood. In this study we investigate the combined tumorigenic effect of arsenic and BaP co-exposure and the mechanism using both cell culture and mouse models. It was found that arsenic (sodium arsenite, 1.0 µM) and BaP (2.5 µM) co-exposure for 30 weeks synergizes in inducing malignant transformation of immortalized non-tumorigenic human bronchial epithelial cells and cancer stem cell (CSC)-like property to enhance their tumorigenicity. In animal studies, A/J mice were exposed to arsenic in drinking water (sodium arsenite, 20 ppm) starting from gestation day 18. After birth, the dams continuously received arsenic water throughout lactation. At weaning (3 weeks of age), male offspring were exposed to either arsenic alone via drinking the same arsenic water or exposed to arsenic plus BaP. BaP was administered via oral gavage (3 µmol per mouse per week) once a week starting from 3 weeks of age for 8 weeks. All mice were euthanized 34-weeks after the first BaP exposure. It was found that mice in control and arsenic exposure alone group did not develop lung tumors. All mice in BaP exposure alone group developed lung adenomas. However, arsenic and BaP co-exposure synergized in increasing lung tumor multiplicity and tumor burden. Furthermore, 30% of mice in arsenic and BaP co-exposure group also developed lung adenocarcinomas. Mechanistic studies revealed that arsenic and BaP co-exposure does not produce more BPDE-DNA adducts than BaP exposure alone; but acts synergistically in activating aryl hydrocarbon receptor (AhR) to up-regulate the expression of a histone H3 lysine 9 methyltransferase SUV39H1 and increase the level of suppressive H3 lysine 9 dimethylation (H3K9me2), which down-regulates the expression of tumor suppressive SOCS3 leading to enhanced activation of Akt and Erk1/2 to promote cell transformation, CSC-like property and tumorigenesis. Together, these findings suggest that arsenic and BaP co-exposure synergizes in causing epigenetic dysregulation to enhance cell transformation, CSC-like property and tumorigenesis.
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Affiliation(s)
- Zhishan Wang
- Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY, USA.
| | - Ping Yang
- Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY, USA; School of Public Health, Guangzhou Medical University, Guangzhou, Guangdong, PR China
| | - Jie Xie
- Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY, USA; School of Health Sciences, Wuhan University, Wuhan, Hubei, PR China
| | - Hsuan-Pei Lin
- Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Kazuyoshi Kumagai
- Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA
| | - Jack Harkema
- Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA
| | - Chengfeng Yang
- Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY, USA
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