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1
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Zhang J, Li Y, Wang Y, Li Z, Li X, Bao H, Li J, Zhou D. Transcriptome Sequencing and Metabolite Analysis Revealed the Single and Combined Effects of Microplastics and Di-(2-ethylhexyl) Phthalate on Mouse Liver. Int J Mol Sci 2025; 26:4943. [PMID: 40430083 PMCID: PMC12112587 DOI: 10.3390/ijms26104943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2025] [Revised: 05/12/2025] [Accepted: 05/17/2025] [Indexed: 05/29/2025] Open
Abstract
The widespread use of plastics has led to a substantial increase in plastic waste, resulting in the dissemination of plastic debris throughout ecosystems and posing significant threats to biota. Bis(2-ethylhexyl) phthalate (DEHP), a commonly used plasticizer, enhances plastic flexibility but may also exert subtle toxic effects. This study aimed to investigate the potential toxicological impacts and underlying mechanisms of microplastics (MPs), di-(2-ethylhexyl) phthalate (DEHP), and their combined exposure (MPs + DEHP) on oxidative stress, apoptotic damage, transcriptomic alterations, and metabolic disturbances in mice. The results demonstrated that exposure to MPs, DEHP, and MPs + DEHP impaired the antioxidant defense system and reduced overall antioxidant capacity. Concurrently, all three exposure conditions significantly increased biochemical markers, particularly those associated with liver dysfunction, prompting further analysis of hepatic tissues. Histopathological examination revealed apoptotic damage in hepatocytes. Integrated transcriptomic and metabolomic analyses indicated that exposure to MPs, DEHP, and MPs + DEHP disrupted carbohydrate, amino acid, and lipid metabolism, induced the expression of genes related to hepatocarcinogenesis, and impaired purine metabolism. Moreover, MP and DEHP exposure aggravated hepatic apoptosis and inflammatory responses via activation of the PI3K/AKT signaling pathway, thereby eliciting notable biotoxic effects. These findings provide new scientific evidence regarding the individual and combined toxicological effects of MPs and the plastic additive DEHP on living organisms.
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Affiliation(s)
| | | | | | | | | | | | - Jiakui Li
- College of Animal Medicine, Huazhong Agricultural University, Wuhan 430070, China; (J.Z.); (Y.L.); (Y.W.); (Z.L.); (X.L.); (H.B.)
| | - Donghai Zhou
- College of Animal Medicine, Huazhong Agricultural University, Wuhan 430070, China; (J.Z.); (Y.L.); (Y.W.); (Z.L.); (X.L.); (H.B.)
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2
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To J, Ghosh S, Zhao X, Pasini E, Fischer S, Sapisochin G, Ghanekar A, Jaeckel E, Bhat M. Deep learning-based pathway-centric approach to characterize recurrent hepatocellular carcinoma after liver transplantation. Hum Genomics 2024; 18:58. [PMID: 38840185 PMCID: PMC11151487 DOI: 10.1186/s40246-024-00624-6] [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: 01/17/2024] [Accepted: 05/23/2024] [Indexed: 06/07/2024] Open
Abstract
BACKGROUND Liver transplantation (LT) is offered as a cure for Hepatocellular carcinoma (HCC), however 15-20% develop recurrence post-transplant which tends to be aggressive. In this study, we examined the transcriptome profiles of patients with recurrent HCC to identify differentially expressed genes (DEGs), the involved pathways, biological functions, and potential gene signatures of recurrent HCC post-transplant using deep machine learning (ML) methodology. MATERIALS AND METHODS We analyzed the transcriptomic profiles of primary and recurrent tumor samples from 7 pairs of patients who underwent LT. Following differential gene expression analysis, we performed pathway enrichment, gene ontology (GO) analyses and protein-protein interactions (PPIs) with top 10 hub gene networks. We also predicted the landscape of infiltrating immune cells using Cibersortx. We next develop pathway and GO term-based deep learning models leveraging primary tissue gene expression data from The Cancer Genome Atlas (TCGA) to identify gene signatures in recurrent HCC. RESULTS The PI3K/Akt signaling pathway and cytokine-mediated signaling pathway were particularly activated in HCC recurrence. The recurrent tumors exhibited upregulation of an immune-escape related gene, CD274, in the top 10 hub gene analysis. Significantly higher infiltration of monocytes and lower M1 macrophages were found in recurrent HCC tumors. Our deep learning approach identified a 20-gene signature in recurrent HCC. Amongst the 20 genes, through multiple analysis, IL6 was found to be significantly associated with HCC recurrence. CONCLUSION Our deep learning approach identified PI3K/Akt signaling as potentially regulating cytokine-mediated functions and the expression of immune escape genes, leading to alterations in the pattern of immune cell infiltration. In conclusion, IL6 was identified to play an important role in HCC recurrence.
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Affiliation(s)
- Jeffrey To
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Soumita Ghosh
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Xun Zhao
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Elisa Pasini
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Sandra Fischer
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Gonzalo Sapisochin
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Anand Ghanekar
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Elmar Jaeckel
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Mamatha Bhat
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada.
- Division of Gastroenterology & Hepatology, University of Toronto, Toronto, ON, Canada.
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada.
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
- Department of Medicine, University of Toronto, Toronto, ON, Canada.
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Wang Y, Chen Z, Li J, Wan T, Hu R, Zhang L, Qin L, Zang L, Gu W, Chen R, Liu C, Li R. Gestational exposure to PM 2.5 disrupts fetal development by suppressing placental trophoblast syncytialization via progranulin/mTOR signaling. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 921:171101. [PMID: 38387595 DOI: 10.1016/j.scitotenv.2024.171101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 02/06/2024] [Accepted: 02/18/2024] [Indexed: 02/24/2024]
Abstract
Recent epidemiological and animal studies have indicated that ambient fine particulate matter (PM2.5) exposure during pregnancy is closely associated with intrauterine growth restriction (IUGR). However, the underlying mechanisms remain to be revealed. In this study, we found that gestational exposure to PM2.5 significantly decreased fetal weight and crown-rump length in mice, accompanied by insufficient placental trophoblast syncytialization and increased expression of progranulin (PGRN) in mice placenta. Administering PGRN neutralizing antibody to pregnant mice alleviated growth restriction and insufficient placental trophoblast syncytialization caused by PM2.5, accompanied with suppressed activation of the mTOR signaling pathway. Furthermore, in vitro experiments using human placental BeWo cells showed that 10 μg·mL-1 PM2.5 activated PGRN/mTOR signaling and suppressed forskolin-induced cell fusion, which was blocked by knockdown of PGRN. Taken together, our results demonstrated that PM2.5 exposure during pregnancy inhibited placental trophoblast syncytialization by activating PGRN/mTOR signaling, leading to abnormal placental development and IUGR. This study reveals a novel mechanism underlying the developmental toxicity of PM2.5 exposure during pregnancy.
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Affiliation(s)
- Yirun Wang
- School of Public Health, Zhejiang International Science and Technology Cooperation Base of Air Pollution and Health, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhuan Chen
- School of Public Health, Zhejiang International Science and Technology Cooperation Base of Air Pollution and Health, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jie Li
- School of Public Health, Zhejiang International Science and Technology Cooperation Base of Air Pollution and Health, Zhejiang Chinese Medical University, Hangzhou, China
| | - Teng Wan
- School of Public Health, Zhejiang International Science and Technology Cooperation Base of Air Pollution and Health, Zhejiang Chinese Medical University, Hangzhou, China
| | - Renjie Hu
- School of Public Health, Zhejiang International Science and Technology Cooperation Base of Air Pollution and Health, Zhejiang Chinese Medical University, Hangzhou, China
| | - Lu Zhang
- School of Public Health, Zhejiang International Science and Technology Cooperation Base of Air Pollution and Health, Zhejiang Chinese Medical University, Hangzhou, China
| | - Li Qin
- School of Public Health, Zhejiang International Science and Technology Cooperation Base of Air Pollution and Health, Zhejiang Chinese Medical University, Hangzhou, China
| | - Lu Zang
- School of Public Health, Zhejiang International Science and Technology Cooperation Base of Air Pollution and Health, Zhejiang Chinese Medical University, Hangzhou, China
| | - Weijia Gu
- School of Public Health, Zhejiang International Science and Technology Cooperation Base of Air Pollution and Health, Zhejiang Chinese Medical University, Hangzhou, China
| | - Rucheng Chen
- School of Public Health, Zhejiang International Science and Technology Cooperation Base of Air Pollution and Health, Zhejiang Chinese Medical University, Hangzhou, China
| | - Cuiqing Liu
- School of Public Health, Zhejiang International Science and Technology Cooperation Base of Air Pollution and Health, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Ran Li
- School of Public Health, Zhejiang International Science and Technology Cooperation Base of Air Pollution and Health, Zhejiang Chinese Medical University, Hangzhou, China.
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4
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Berger K, Persson E, Gregersson P, Ruiz-Martínez S, Jonasson E, Ståhlberg A, Rhost S, Landberg G. Interleukin-6 Induces Stem Cell Propagation through Liaison with the Sortilin-Progranulin Axis in Breast Cancer. Cancers (Basel) 2023; 15:5757. [PMID: 38136303 PMCID: PMC10741783 DOI: 10.3390/cancers15245757] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 10/25/2023] [Accepted: 12/06/2023] [Indexed: 12/24/2023] Open
Abstract
Unraveling the complex network between cancer cells and their tumor microenvironment is of clinical importance, as it might allow for the identification of new targets for cancer treatment. Cytokines and growth factors secreted by various cell types present in the tumor microenvironment have the potential to affect the challenging subpopulation of cancer stem cells showing treatment-resistant properties as well as aggressive features. By using various model systems, we investigated how the breast cancer stem cell-initiating growth factor progranulin influenced the secretion of cancer-associated proteins. In monolayer cultures, progranulin induced secretion of several inflammatory-related cytokines, such as interleukin (IL)-6 and -8, in a sortilin-dependent manner. Further, IL-6 increased the cancer stem fraction similarly to progranulin in the breast cancer cell lines MCF7 and MDA-MB-231 monitored by the surrogate mammosphere-forming assay. In a cohort of 63 patient-derived scaffold cultures cultured with breast cancer cells, we observed significant correlations between IL-6 and progranulin secretion, clearly validating the association between IL-6 and progranulin also in human-based microenvironments. In conclusion, the interplay between progranulin and IL-6 highlights a dual breast cancer stem cell-promoting function via sortilin, further supporting sortilin as a highly relevant therapeutic target for aggressive breast cancer.
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Affiliation(s)
- Karoline Berger
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
| | - Emma Persson
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
| | - Pernilla Gregersson
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
| | - Santiago Ruiz-Martínez
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
| | - Emma Jonasson
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
| | - Anders Ståhlberg
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
- Wallenberg Center for Molecular and Translational Medicine, University of Gothenburg, 41390 Gothenburg, Sweden
- Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, 41346 Gothenburg, Sweden
| | - Sara Rhost
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
| | - Göran Landberg
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
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Moroney J, Trivella J, George B, White SB. A Paradigm Shift in Primary Liver Cancer Therapy Utilizing Genomics, Molecular Biomarkers, and Artificial Intelligence. Cancers (Basel) 2023; 15:2791. [PMID: 37345129 PMCID: PMC10216313 DOI: 10.3390/cancers15102791] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 05/02/2023] [Accepted: 05/10/2023] [Indexed: 06/23/2023] Open
Abstract
Primary liver cancer is the sixth most common cancer worldwide and the third leading cause of cancer-related death. Conventional therapies offer limited survival benefit despite improvements in locoregional liver-directed therapies, which highlights the underlying complexity of liver cancers. This review explores the latest research in primary liver cancer therapies, focusing on developments in genomics, molecular biomarkers, and artificial intelligence. Attention is also given to ongoing research and future directions of immunotherapy and locoregional therapies of primary liver cancers.
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Affiliation(s)
- James Moroney
- Division of Vascular and Interventional Radiology, Department of Radiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Juan Trivella
- Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Ben George
- Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Sarah B. White
- Division of Vascular and Interventional Radiology, Department of Radiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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6
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Xi Y, Zhang XL, Luo QX, Gan HN, Liu YS, Shao SH, Mao XH. Helicobacter pylori regulates stomach diseases by activating cell pathways and DNA methylation of host cells. Front Cell Dev Biol 2023; 11:1187638. [PMID: 37215092 PMCID: PMC10192871 DOI: 10.3389/fcell.2023.1187638] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 04/25/2023] [Indexed: 05/24/2023] Open
Abstract
One of the most prevalent malignant tumors of the digestive tract is gastric cancer (GC). Age, high salt intake, Helicobacter pylori (H. pylori) infection, and a diet deficient in fruits and vegetables are risk factors for the illness. A significant risk factor for gastric cancer is infection with H. pylori. Infecting gastric epithelial cells with virulence agents secreted by H. pylori can cause methylation of tumor genes or carcinogenic signaling pathways to be activated. Regulate downstream genes' aberrant expression, albeit the precise mechanism by which this happens is unclear. Oncogene, oncosuppressor, and other gene modifications, as well as a number of different gene change types, are all directly associated to the carcinogenesis of gastric cancer. In this review, we describe comprehensive H. pylori and its virulence factors, as well as the activation of the NF-κB, MAPK, JAK/STAT signaling pathways, and DNA methylation following infection with host cells via virulence factors, resulting in abnormal gene expression. As a result, host-related proteins are regulated, and gastric cancer progression is influenced. This review provides insight into the H. pylori infection, summarizes a series of relevant papers, discusses the complex signaling pathways underlying molecular mechanisms, and proposes new approach to immunotherapy of this important disease.
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Affiliation(s)
- Yue Xi
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Xiao-Li Zhang
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Wuxi, China
| | - Qing-Xin Luo
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Hai-Ning Gan
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yu-Shi Liu
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Shi-He Shao
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Xu-Hua Mao
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Wuxi, China
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7
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Ventura E, Ducci G, Benot Dominguez R, Ruggiero V, Belfiore A, Sacco E, Vanoni M, Iozzo RV, Giordano A, Morrione A. Progranulin Oncogenic Network in Solid Tumors. Cancers (Basel) 2023; 15:cancers15061706. [PMID: 36980592 PMCID: PMC10046331 DOI: 10.3390/cancers15061706] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 03/06/2023] [Accepted: 03/08/2023] [Indexed: 03/16/2023] Open
Abstract
Progranulin is a pleiotropic growth factor with important physiological roles in embryogenesis and maintenance of adult tissue homeostasis. While-progranulin deficiency is associated with a broad range of pathological conditions affecting the brain, such as frontotemporal dementia and neuronal ceroid lipofuscinosis, progranulin upregulation characterizes many tumors, including brain tumors, multiple myeloma, leiomyosarcoma, mesothelioma and epithelial cancers such as ovarian, liver, breast, bladder, adrenal, prostate and kidney carcinomas. The increase of progranulin levels in tumors might have diagnostic and prognostic significance. In cancer, progranulin has a pro-tumorigenic role by promoting cancer cell proliferation, migration, invasiveness, anchorage-independent growth and resistance to chemotherapy. In addition, progranulin regulates the tumor microenvironment, affects the function of cancer-associated fibroblasts, and modulates tumor immune surveillance. However, the molecular mechanisms of progranulin oncogenic function are not fully elucidated. In bladder cancer, progranulin action relies on the activation of its functional signaling receptor EphA2. Notably, more recent data suggest that progranulin can also modulate a functional crosstalk between multiple receptor-tyrosine kinases, demonstrating a more complex and context-dependent role of progranulin in cancer. Here, we will review what is currently known about the function of progranulin in tumors, with a focus on its molecular mechanisms of action and regulation.
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Affiliation(s)
- Elisa Ventura
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
- Correspondence: (E.V.); (A.M.); Tel.: +1-215-204-2450 (A.M.)
| | - Giacomo Ducci
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
- SYSBIO (Centre of Systems Biology), ISBE (Infrastructure Systems Biology Europe), 20126 Milan, Italy
| | - Reyes Benot Dominguez
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
| | - Valentina Ruggiero
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
- Department of Pharmacological Sciences, Master Program in Pharmaceutical Biotechnologies, University of Padua, 35131 Padua, Italy
| | - Antonino Belfiore
- Department of Clinical and Experimental Medicine, Endocrinology Unit, University of Catania, Garibaldi-Nesima Hospital, 95122 Catania, Italy
| | - Elena Sacco
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
- SYSBIO (Centre of Systems Biology), ISBE (Infrastructure Systems Biology Europe), 20126 Milan, Italy
| | - Marco Vanoni
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
- SYSBIO (Centre of Systems Biology), ISBE (Infrastructure Systems Biology Europe), 20126 Milan, Italy
| | - Renato V. Iozzo
- Department of Pathology, Anatomy and Cell Biology, Translational Cellular Oncology Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Antonio Giordano
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
- Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy
| | - Andrea Morrione
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
- Correspondence: (E.V.); (A.M.); Tel.: +1-215-204-2450 (A.M.)
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Tabakhiyan F, Mir A, Vahedian V. Potential tumor marker for hepatocellular carcinoma identification: PI3K and pro-inflammatory cytokines (TGF-β, IL-1, and IL-6). Horm Mol Biol Clin Investig 2022; 43:389-396. [PMID: 35709206 DOI: 10.1515/hmbci-2022-0028] [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: 03/11/2022] [Accepted: 05/14/2022] [Indexed: 12/24/2022]
Abstract
OBJECTIVES Hepatocellular carcinoma (HCC), the most common form of liver cancer, is a leading cause of tumor-associated mortality worldwide. Diagnosis based upon non-invasive criteria is currently challenged by the need for molecular information that requires tissue or liquid biopsies. The progression of HCC is often associated with chronic inflammation, expression levels of inflammatory mediators, chemokine, and cytokines. In this study, we try to evaluate the PI3K and pro-inflammatory cytokines, TGF-β, IL-1, and IL-6 expression level in patients with liver cancer. MATERIALS AND METHODS The kupffer cells were isolated from patient's specimens. Real-time PCR was applied to evaluate the expression level of PI3K in cell lines or tumors. The concentrations of TGF-β, IL-1, and IL-6 were measured by the quantitative ELISA kit. RESULTS PI3K mRNA expression in cancer cells was increased markedly vs. normal cells. The ELISA results demonstrated over expression of TGF-β, IL-1, and IL-6 in patients and positive correlation between tumor size and stage. DISCUSSION This study suggests that targeting the expression level of PI3K and pro-inflammatory chemokine and cytokines, TGF-β, IL-1, and IL-6, may be a potential diagnostic strategy in HCC patients.
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Affiliation(s)
| | - Amirabbas Mir
- Institute of Nano Science and Nano Technology, University of Kashan, Kashan, Islamic Republic of Iran
| | - Vahid Vahedian
- Cancer Biology Research Group, Faculty of Medicine Institute of Biotechnology (FMB-IBTEC) Sao Paulo State University (UNESP), Sao Paulo, Brazil
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9
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Guizhen Z, Guanchang J, Liwen L, Huifen W, Zhigang R, Ranran S, Zujiang Y. The tumor microenvironment of hepatocellular carcinoma and its targeting strategy by CAR-T cell immunotherapy. Front Endocrinol (Lausanne) 2022; 13:918869. [PMID: 36093115 PMCID: PMC9452721 DOI: 10.3389/fendo.2022.918869] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 08/05/2022] [Indexed: 12/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the major subtype of liver cancer, which ranks sixth in cancer incidence and third in mortality. Although great strides have been made in novel therapy for HCC, such as immunotherapy, the prognosis remains less than satisfactory. Increasing evidence demonstrates that the tumor immune microenvironment (TME) exerts a significant role in the evolution of HCC and has a non-negligible impact on the efficacy of HCC treatment. In the past two decades, the success in hematological malignancies made by chimeric antigen receptor-modified T (CAR-T) cell therapy leveraging it holds great promise for cancer treatment. However, in the face of a hostile TME in solid tumors like HCC, the efficacy of CAR-T cells will be greatly compromised. Here, we provide an overview of TME features in HCC, discuss recent advances and challenges of CAR-T immunotherapy in HCC.
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Affiliation(s)
- Zhang Guizhen
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Presion Medicine Cencter Gene Hospital of Henan Province, Zhengzhou, China
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Ji Guanchang
- Department of Urology People’s Hospital of Puyang, Puyang, China
| | - Liu Liwen
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Presion Medicine Cencter Gene Hospital of Henan Province, Zhengzhou, China
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Wang Huifen
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Presion Medicine Cencter Gene Hospital of Henan Province, Zhengzhou, China
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Ren Zhigang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Sun Ranran
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yu Zujiang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Presion Medicine Cencter Gene Hospital of Henan Province, Zhengzhou, China
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10
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Combined miR-486 and GP88 (Progranulin) Serum Levels Are Suggested as Supportive Biomarkers for Therapy Decision in Elderly Prostate Cancer Patients. Life (Basel) 2022; 12:life12050732. [PMID: 35629399 PMCID: PMC9143270 DOI: 10.3390/life12050732] [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: 04/26/2022] [Revised: 05/10/2022] [Accepted: 05/10/2022] [Indexed: 11/16/2022] Open
Abstract
Our study aimed to assess the applicability of miR-486 in combination with soluble GP88 protein as a diagnostic and/or predictive biomarker for prostate cancer (PCa) patients. miR-486 and GP88 levels in serum samples from 136 patients undergoing MRI-guided biopsy of the prostate were assessed by qRT−PCR and ELISA, respectively. Of these, 86 patients received a histologically confirmed diagnosis of PCa. Neither marker showed an association with the diagnosis of cancer. PCa patients were separated based on (i) treatment into patients with active surveillance or patients with any type of curative treatment and (ii) age into elderly (>68 years) patients and younger patients (≤68 years). In elderly patients (N = 41) with the intention of curative treatment at optimized cut-off values, significantly higher GP88 levels (p = 0.018) and lower miR-486 levels (p = 0.014) were observed. The total PSA level and ISUP biopsy grade were used in a baseline model for predicting definitive therapy. The baseline model exhibited an area under the curve (AUC) of 0.783 (p = 0.005). The addition of the serum biomarkers miR-486 and GP88 to the baseline model yielded an improved model with an AUC of 0.808 (p = 0.002). Altogether, combined miR-486 and GP88 serum levels are associated with and are therefore suggested as supportive biomarkers for therapy decisions, particularly in elderly PCa patients.
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11
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The PI3K/AKT signaling pathway in cancer: Molecular mechanisms and possible therapeutic interventions. Exp Mol Pathol 2022; 127:104787. [DOI: 10.1016/j.yexmp.2022.104787] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 04/15/2022] [Accepted: 05/21/2022] [Indexed: 01/02/2023]
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12
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Chiang KY, Li YW, Li YH, Huang SJ, Wu CL, Gong HY, Wu JL. Progranulin A Promotes Compensatory Hepatocyte Proliferation via HGF/c-Met Signaling after Partial Hepatectomy in Zebrafish. Int J Mol Sci 2021; 22:ijms222011217. [PMID: 34681875 PMCID: PMC8538350 DOI: 10.3390/ijms222011217] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/14/2021] [Accepted: 10/16/2021] [Indexed: 01/11/2023] Open
Abstract
Compensatory hepatocyte proliferation and other liver regenerative processes are activated to sustain normal physiological function after liver injury. A major mitogen for liver regeneration is hepatocyte growth factor (HGF), and a previous study indicated that progranulin could modulate c-met, the receptor for HGF, to initiate hepatic outgrowth from hepatoblasts during embryonic development. However, a role for progranulin in compensatory hepatocyte proliferation has not been shown previously. Therefore, this study was undertaken to clarify whether progranulin plays a regulatory role during liver regeneration. To this end, we established a partial hepatectomy regeneration model in adult zebrafish that express a liver-specific fluorescent reporter. Using this model, we found that loss of progranulin A (GrnA) function by intraperitoneal-injection of a Vivo-Morpholino impaired and delayed liver regeneration after partial hepatectomy. Furthermore, transcriptome analysis and confirmatory quantitative real-time PCR suggested that cell cycle progression and cell proliferation was not as active in the morphants as controls, which may have been the result of comparative downregulation of the HGF/c-met axis by 36 h after partial hepatectomy. Finally, liver-specific overexpression of GrnA in transgenic zebrafish caused more abundant cell proliferation after partial hepatectomy compared to wild types. Thus, we conclude that GrnA positively regulates HGF/c-met signaling to promote hepatocyte proliferation during liver regeneration.
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Affiliation(s)
- Keng-Yu Chiang
- Department of Life Science, National Taiwan University, Taipei 10617, Taiwan;
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11529, Taiwan; (Y.-W.L.); (Y.-H.L.); (S.-J.H.)
| | - Ya-Wen Li
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11529, Taiwan; (Y.-W.L.); (Y.-H.L.); (S.-J.H.)
| | - Yen-Hsing Li
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11529, Taiwan; (Y.-W.L.); (Y.-H.L.); (S.-J.H.)
| | - Shin-Jie Huang
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11529, Taiwan; (Y.-W.L.); (Y.-H.L.); (S.-J.H.)
| | - Chih-Lu Wu
- Department of Chemistry and Biochemistry, National Chung Cheng University, Chiayi 62145, Taiwan;
| | - Hong-Yi Gong
- Department of Aquaculture, National Taiwan Ocean University, Keelung 20224, Taiwan;
- Center of Excellence for the Oceans, National Taiwan Ocean University, Keelung 20224, Taiwan
| | - Jen-Leih Wu
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 11529, Taiwan; (Y.-W.L.); (Y.-H.L.); (S.-J.H.)
- College of Life Sciences, National Taiwan Ocean University, Keelung 20224, Taiwan
- Correspondence: ; Tel.: +886-2-27899568
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13
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Wang XM, Zeng P, Fang YY, Zhang T, Tian Q. Progranulin in neurodegenerative dementia. J Neurochem 2021; 158:119-137. [PMID: 33930186 DOI: 10.1111/jnc.15378] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 03/28/2021] [Accepted: 04/16/2021] [Indexed: 01/21/2023]
Abstract
Long-term or severe lack of protective factors is important in the pathogenesis of neurodegenerative dementia. Progranulin (PGRN), a neurotrophic factor expressed mainly in neurons and microglia, has various neuroprotective effects such as anti-inflammatory effects, promoting neuron survival and neurite growth, and participating in normal lysosomal function. Mutations in the PGRN gene (GRN) have been found in several neurodegenerative dementias, including frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). Herein, PGRN deficiency and PGRN hydrolytic products (GRNs) in the pathological changes related to dementia, including aggregation of tau and TAR DNA-binding protein 43 (TDP-43), amyloid-β (Aβ) overproduction, neuroinflammation, lysosomal dysfunction, neuronal death, and synaptic deficit have been summarized. Furthermore, as some therapeutic strategies targeting PGRN have been developed in various models, we highlighted PGRN as a potential anti-neurodegeneration target in dementia.
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Affiliation(s)
- Xiao-Ming Wang
- Department of Pathology and Pathophysiology, School of Basic Medicine, Tongji Medical College, Key Laboratory of Neurological Disease of National Education Ministry, Huazhong University of Science and Technology, Wuhan, China
| | - Peng Zeng
- Department of Pathology and Pathophysiology, School of Basic Medicine, Tongji Medical College, Key Laboratory of Neurological Disease of National Education Ministry, Huazhong University of Science and Technology, Wuhan, China
| | - Ying-Yan Fang
- Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Hubei Polytechnic University School of Medicine, Huangshi, China
| | - Teng Zhang
- Department of Neurology, Shanxian Central Hospital, The Affiliated Huxi Hospital of Jining Medical College, Heze, China
| | - Qing Tian
- Department of Pathology and Pathophysiology, School of Basic Medicine, Tongji Medical College, Key Laboratory of Neurological Disease of National Education Ministry, Huazhong University of Science and Technology, Wuhan, China
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14
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Michel M, Kaps L, Maderer A, Galle PR, Moehler M. The Role of p53 Dysfunction in Colorectal Cancer and Its Implication for Therapy. Cancers (Basel) 2021; 13:2296. [PMID: 34064974 PMCID: PMC8150459 DOI: 10.3390/cancers13102296] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/28/2021] [Accepted: 05/03/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common and fatal cancers worldwide. The carcinogenesis of CRC is based on a stepwise accumulation of mutations, leading either to an activation of oncogenes or a deactivation of suppressor genes. The loss of genetic stability triggers activation of proto-oncogenes (e.g., KRAS) and inactivation of tumor suppression genes, namely TP53 and APC, which together drive the transition from adenoma to adenocarcinoma. On the one hand, p53 mutations confer resistance to classical chemotherapy but, on the other hand, they open the door for immunotherapy, as p53-mutated tumors are rich in neoantigens. Aberrant function of the TP53 gene product, p53, also affects stromal and non-stromal cells in the tumor microenvironment. Cancer-associated fibroblasts together with other immunosuppressive cells become valuable assets for the tumor by p53-mediated tumor signaling. In this review, we address the manifold implications of p53 mutations in CRC regarding therapy, treatment response and personalized medicine.
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Affiliation(s)
- Maurice Michel
- I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany; (M.M.); (L.K.); (A.M.); (P.R.G.)
| | - Leonard Kaps
- I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany; (M.M.); (L.K.); (A.M.); (P.R.G.)
- Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center Mainz, 55131 Mainz, Germany
| | - Annett Maderer
- I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany; (M.M.); (L.K.); (A.M.); (P.R.G.)
| | - Peter R. Galle
- I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany; (M.M.); (L.K.); (A.M.); (P.R.G.)
| | - Markus Moehler
- I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany; (M.M.); (L.K.); (A.M.); (P.R.G.)
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15
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Yamanaka T, Harimoto N, Yokobori T, Muranushi R, Hoshino K, Hagiwara K, Gantumur D, Handa T, Ishii N, Tsukagoshi M, Igarashi T, Watanabe A, Kubo N, Araki K, Umezawa K, Shirabe K. Conophylline Inhibits Hepatocellular Carcinoma by Inhibiting Activated Cancer-associated Fibroblasts Through Suppression of G Protein-coupled Receptor 68. Mol Cancer Ther 2021; 20:1019-1028. [PMID: 33722852 DOI: 10.1158/1535-7163.mct-20-0150] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 09/19/2020] [Accepted: 02/26/2021] [Indexed: 12/09/2022]
Abstract
Treatment of hepatocellular carcinoma (HCC) is currently challenging. Cancer-associated fibroblasts (CAFs) promote the malignancy of HCC cells via production of cytokines. Conophylline (CnP), a vinca alkaloid obtained from Ervatamia microphylla leaves, has been reported to suppress activation of hepatic stellate cells and liver fibrosis in rats. We examined the efficacy of CnP in suppressing tumor growth in HCC. Specifically, we investigated whether CnP could inhibit CAFs, which were derived from HCC tissues in vitro and in vivo Same as previous reports, CAFs promoted proliferative and invasive ability of HCC cells. CnP suppressed α-smooth muscle actin expression of CAFs, and inhibited their cancer-promoting effects. CnP significantly suppressed CAFs producting cytokines such as IL6, IL8, C-C motif chemokine ligand 2, angiogenin, and osteopontin (OPN). Combined therapy with sorafenib and CnP against HCC cells and CAFs in vivo showed to inhibit tumor growth the most compared with controls and single treatment with CnP or sorafenib. Transcriptome analysis revealed that GPR68 in CAFs was strongly suppressed by CnP. The cancer-promoting effects of cytokines were eliminated by knockdown of GPR68 in CAFs. CnP inhibited the HCC-promoting effects of CAFs by suppressing several HCC-promoting cytokines secreted by CAFs expressing GPR68. Combination therapy with CnP and existing anticancer agents may be a promising strategy for treating refractory HCC associated with activated CAFs.
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Affiliation(s)
- Takahiro Yamanaka
- Department of General Surgical Science, Division of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Gunma, Japan
| | - Norifumi Harimoto
- Department of General Surgical Science, Division of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Gunma, Japan.
| | | | - Ryo Muranushi
- Department of General Surgical Science, Division of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Gunma, Japan
| | - Kouki Hoshino
- Department of General Surgical Science, Division of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Gunma, Japan
| | - Kei Hagiwara
- Department of General Surgical Science, Division of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Gunma, Japan
| | - Dolgormaa Gantumur
- Department of General Surgical Science, Division of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Gunma, Japan
| | - Tadashi Handa
- Department of Diagnostic Pathology, Gunma University, Graduate School of Medicine, Gunma, Japan.,Department of Social Welfare, Gunma University of Health and Welfare, Gunma, Japan
| | - Norihiro Ishii
- Department of General Surgical Science, Division of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Gunma, Japan
| | - Mariko Tsukagoshi
- Department of General Surgical Science, Division of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Gunma, Japan.,Department of Innovative Cancer Immunotherapy, Gunma University, Graduate School of Medicine, Gunma, Japan
| | - Takamichi Igarashi
- Department of General Surgical Science, Division of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Gunma, Japan
| | - Akira Watanabe
- Department of General Surgical Science, Division of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Gunma, Japan
| | - Norio Kubo
- Department of General Surgical Science, Division of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Gunma, Japan
| | - Kenichiro Araki
- Department of General Surgical Science, Division of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Gunma, Japan
| | - Kazuo Umezawa
- Department of Molecular Target Medicine, Aichi Medical University, School of Medicine, Aichi, Japan
| | - Ken Shirabe
- Department of General Surgical Science, Division of Hepatobiliary and Pancreatic Surgery, Gunma University, Graduate School of Medicine, Gunma, Japan
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16
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Yabe K, Yamamoto Y, Takemura M, Hara T, Tsurumi H, Serrero G, Nabeshima T, Saito K. Progranulin depletion inhibits proliferation via the transforming growth factor beta/SMAD family member 2 signaling axis in Kasumi-1 cells. Heliyon 2021; 7:e05849. [PMID: 33490663 PMCID: PMC7809376 DOI: 10.1016/j.heliyon.2020.e05849] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 11/27/2020] [Accepted: 12/22/2020] [Indexed: 11/30/2022] Open
Abstract
Progranulin is an autocrine growth factor that promotes proliferation, migration, invasion, and chemoresistance of various cancer cells. These mechanisms mainly depend on the protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) pathway. Recent studies have shown that patients with hematopoietic cancer have elevated serum progranulin levels. Thus, the current study aimed to investigate the role of progranulin in hematopoietic cancer cells and how it modulates their proliferation. Both knockdown of progranulin and progranulin neutralizing antibody treatment inhibited proliferation in several human hematopoietic cancer cell lines. Moreover, progranulin depletion not only decreases the phosphorylation level of the Akt/mTOR pathway but also, surprisingly, increases the expression of transforming growth factor-beta (TGF-β) and phosphorylation of mothers against decapentaplegic homolog 2 (SMAD2) in Kasumi-1 cell. Furthermore, LY2109761, an inhibitor of TGF-β receptor type I/II kinase, and TGF-β neutralizing antibody blocked the inhibition of proliferation induced by progranulin depletion. These data provide new insights that progranulin alters cell proliferation via the TGF-β axis and progranulin could be a new therapeutic target for hematopoietic cancers.
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Affiliation(s)
- Kuniaki Yabe
- Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, Aichi, Japan.,A&T corporation, Kanagawa, Japan
| | - Yasuko Yamamoto
- Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, Aichi, Japan
| | - Masao Takemura
- Advanced Diagnostic System Research Laboratory, Fujita Health University, Graduate School of Health Sciences, Aichi, Japan
| | - Takeshi Hara
- Department of Hematology, Matsunami General Hospital, Gifu, Japan
| | - Hisashi Tsurumi
- Department of Hematology, Matsunami General Hospital, Gifu, Japan
| | - Ginette Serrero
- University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA.,A&G Pharmaceutical, Inc., Columbia, MD, USA
| | - Toshitaka Nabeshima
- Advanced Diagnostic System Research Laboratory, Fujita Health University, Graduate School of Health Sciences, Aichi, Japan.,Japanese Drug Organization of Appropriate Use and Research, Nagoya, 468-0069, Japan
| | - Kuniaki Saito
- Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, Aichi, Japan.,Advanced Diagnostic System Research Laboratory, Fujita Health University, Graduate School of Health Sciences, Aichi, Japan.,Japanese Drug Organization of Appropriate Use and Research, Nagoya, 468-0069, Japan.,Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, Japan
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17
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Liu C, Li J, Shi W, Zhang L, Liu S, Lian Y, Liang S, Wang H. Progranulin Regulates Inflammation and Tumor. Antiinflamm Antiallergy Agents Med Chem 2021; 19:88-102. [PMID: 31339079 PMCID: PMC7475802 DOI: 10.2174/1871523018666190724124214] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 06/09/2019] [Accepted: 06/10/2019] [Indexed: 12/15/2022]
Abstract
Progranulin (PGRN) mediates cell cycle progression and cell motility as a pleiotropic growth factor and acts as a universal regulator of cell growth, migration and transformation, cell cycle, wound healing, tumorigenesis, and cytotoxic drug resistance as a secreted glycoprotein. PGRN overexpression can induce the secretion of many inflammatory cytokines, such as IL-8, -6,-10, TNF-α. At the same time, this protein can promote tumor proliferation and the occurrence and development of many related diseases such as gastric cancer, breast cancer, cervical cancer, colorectal cancer, renal injury, neurodegeneration, neuroinflammatory, human atherosclerotic plaque, hepatocarcinoma, acute kidney injury, amyotrophic lateral sclerosis, Alzheimer’s disease and Parkinson’s disease. In short, PGRN plays a very critical role in injury repair and tumorigenesis, it provides a new direction for succeeding research and serves as a target for clinical diagnosis and treatment, thus warranting further investigation. Here, we discuss the potential therapeutic utility and the effect of PGRN on the relationship between inflammation and cancer.
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Affiliation(s)
- Chunxiao Liu
- Pathogenic Microbiology, Clinical Medical College, Weifang Medical University, Shandong 261053, China
| | - Jiayi Li
- Pathogenic Microbiology, Clinical Medical College, Weifang Medical University, Shandong 261053, China
| | - Wenjing Shi
- Department of Gynecology, Weifang Medical University Affiliated Hospital, Weifang, Shandong 261031, China
| | - Liujia Zhang
- Clinical Medical College, Weifang Medical University, Shandong 261053, China
| | - Shuang Liu
- Clinical Medical College, Weifang Medical University, Shandong 261053, China
| | - Yingcong Lian
- Clinical Medical College, Weifang Medical University, Shandong 261053, China
| | - Shujuan Liang
- Key Lab for Immunology in Universities of Shandong Province, Clinical Medical College, Weifang Medical University, Shandong 261053, China
| | - Hongyan Wang
- Pathogenic Microbiology, Clinical Medical College, Weifang Medical University, Shandong 261053, China
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18
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Li W, Liu J, Tan W, Zhou Y. The role and mechanisms of Microglia in Neuromyelitis Optica Spectrum Disorders. Int J Med Sci 2021; 18:3059-3065. [PMID: 34400876 PMCID: PMC8364446 DOI: 10.7150/ijms.61153] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 06/03/2021] [Indexed: 12/11/2022] Open
Abstract
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune neurological disease that can cause blindness and disability. As the major mediators in the central nervous system, microglia plays key roles in immunological regulation in neuroinflammatory diseases, including NMOSD. Microglia can be activated by interleukin (IL)-6 and type I interferons (IFN-Is) during NMOSD, leading to signal transducer and activator of transcription (STAT) activation. Moreover, complement C3a secreted from activated astrocytes may induce the secretion of complement C1q, inflammatory cytokines and progranulin (PGRN) by microglia, facilitating injury to microglia, neurons, astrocytes and oligodendrocytes in an autocrine or paracrine manner. These processes involving activated microglia ultimately promote the pathological course of NMOSD. In this review, recent research progress on the roles of microglia in NMOSD pathogenesis is summarized, and the mechanisms of microglial activation and microglial-mediated inflammation, and the potential research prospects associated with microglial activation are also discussed.
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Affiliation(s)
- Wenqun Li
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.,Institute of Clinical Pharmacy, Central South University, Changsha, 410011, Hunan, China
| | - Jiaqin Liu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.,Institute of Clinical Pharmacy, Central South University, Changsha, 410011, Hunan, China
| | - Wei Tan
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.,Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan 410011, China
| | - Yedi Zhou
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.,Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan 410011, China
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19
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Serrero G. Progranulin/GP88, A Complex and Multifaceted Player of Tumor Growth by Direct Action and via the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1329:475-498. [PMID: 34664252 DOI: 10.1007/978-3-030-73119-9_22] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Investigation of the role of progranulin/GP88 on the proliferation and survival of a wide variety of cells has been steadily increasing. Several human diseases stem from progranulin dysregulation either through its overexpression in cancer or its absence as in the case of null mutations in some form of frontotemporal dementia. The present review focuses on the role of progranulin/GP88 in cancer development, progression, and drug resistance. Various aspects of progranulin identification, biology, and signaling pathways will be described. Information will be provided about its direct role as an autocrine growth and survival factor and its paracrine effect as a systemic factor as well as via interaction with extracellular matrix proteins and with components of the tumor microenvironment to influence drug resistance, migration, angiogenesis, inflammation, and immune modulation. This chapter will also describe studies examining progranulin/GP88 tumor tissue expression as well as circulating level as a prognostic factor for several cancers. Due to the wealth of publications in progranulin, this review does not attempt to be exhaustive but rather provide a thread to lead the readers toward more in-depth exploration of this fascinating and unique protein.
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20
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Li H, Yang T, Fei Z. miR‑26a‑5p alleviates lipopolysaccharide‑induced acute lung injury by targeting the connective tissue growth factor. Mol Med Rep 2020; 23:5. [PMID: 33179083 PMCID: PMC7673325 DOI: 10.3892/mmr.2020.11643] [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: 04/10/2020] [Accepted: 08/18/2020] [Indexed: 02/06/2023] Open
Abstract
The aim of the present study was to investigate the regulatory functions of microRNA (miR)‑26a‑5p on lipopolysaccharide (LPS)‑induced acute lung injury (ALI) and its molecular mechanisms. The role of miR‑26a‑5p on an ALI mouse model was evaluated by examining the histological changes, wet/dry (W/D) ratio, myeloperoxidase (MPO) activity, malondialdehyde (MDA) expression levels in lung tissues and the survival of ALI mice. Moreover, the protein concentration and the number of neutrophils and lymphocytes in bronchoalveolar lavage fluid (BALF) was analyzed. To explore the effect of miR‑26a‑5p on inflammatory responses and apoptosis, the expression levels of tumour necrosis factor‑α (TNF‑α), interleukin (IL)‑1β and IL‑6 and apoptosis were measured by ELISA, terminal deoxynucleotidyl transferase‑mediated dUTP nick end labelling staining and flow cytometry in BALF, A549 cells and lung tissues. B‑cell lymphoma‑2 (Bcl‑2), Bax and cleaved caspase‑3 in lung tissues were measured by western blotting and reverse transcription‑quantitative PCR. Connective tissue growth factor (CTGF) was predicted as a direct target of miR‑26a‑5p using dual luciferase reporter assay. The present study sought to determine whether CTGF overexpression reversed the effect of miR‑26a‑5p on apoptosis and inflammatory responses in LPS‑induced A549 cells. The data revealed that miR‑26a‑5p overexpression ameliorated LPS‑induced ALI, which was implicated by fewer histopathological changes, W/D ratio, apoptosis in lung tissues and the survival of ALI mice. Moreover, miR‑26a‑5p overexpression alleviated LPS‑induced inflammatory responses in ALI mice via the reduction of total protein, neutrophil and lymphocyte counts and the expression levels of TNF‑α, IL‑1β, IL‑6, MDA and MPO activity in BALF. Similarly, miR‑26a‑5p overexpression decreased apoptosis and the expression of TNF‑α, IL‑1β and IL‑6 in LPS‑induced A549 cells. CTGF was a direct target of miR‑26a‑5p. CTGF overexpression reversed the effect of miR‑26a‑5p on cell apoptosis and inflammatory responses in LPS‑induced A549 cells. The present study demonstrated that miR‑26a‑5p could attenuate lung inflammation and apoptosis in LPS‑induced ALI by targeting CTGF.
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Affiliation(s)
- Hongyan Li
- Department of Child Healthcare, Zibo Women & Children Hospital, Zibo, Shandong 255000, P.R. China
| | - Tingting Yang
- Department of Child Healthcare, Zibo Women & Children Hospital, Zibo, Shandong 255000, P.R. China
| | - Zhaoxia Fei
- General Internal Medicine, Qingdao Hospital of Traditional Chinese Medicine (Qingdao Hiser Hospital), Qingdao, Shandong 266033, P.R. China
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21
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Zhang J, Gu C, Song Q, Zhu M, Xu Y, Xiao M, Zheng W. Identifying cancer-associated fibroblasts as emerging targets for hepatocellular carcinoma. Cell Biosci 2020; 10:127. [PMID: 33292459 PMCID: PMC7603733 DOI: 10.1186/s13578-020-00488-y] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 10/23/2020] [Indexed: 02/07/2023] Open
Abstract
The tumor microenvironment (TME) is a complex multicellular functional compartment that includes fibroblasts, myofibroblasts, endothelial cells, immune cells, and extracellular matrix (ECM) elements. The microenvironment provides an optimum condition for the initiation, growth, and dissemination of hepatocellular carcinoma (HCC). As one of the critical and abundant components in tumor microenvironment, cancer-associated fibroblasts (CAFs) have been implicated in the progression of HCC. Through secreting various growth factors and cytokines, CAFs contribute to the ECM remodeling, stem features, angiogenesis, immunosuppression, and vasculogenic mimicry (VM), which reinforce the initiation and development of HCC. In order to restrain the CAFs-initiated HCC progression, current strategies include targeting specific markers, engineering CAFs with tumor-suppressive phenotype, depleting CAFs’ precursors, and repressing the secretions or downstream signaling. In this review, we update the emerging understanding of CAFs in HCC, with particular emphasis on cellular origin, phenotypes, biological functions and targeted strategies. It provides insights into the targeting CAFs for HCC treatment.
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Affiliation(s)
- Jie Zhang
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, China
| | - Chaoyu Gu
- School of Medicine, Nantong University, 19 Qixiu Road, Nantong, 226001, Jiangsu, China
| | - Qianqian Song
- Department of Radiology, Wake Forest School of Medicine, One Medical Center Boulevard, Winston-Salem, NC, 27157, USA
| | - Mengqi Zhu
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, China
| | - Yuqing Xu
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, China
| | - Mingbing Xiao
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, China.
| | - Wenjie Zheng
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, China.
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22
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Targeting Cancer Associated Fibroblasts in Liver Fibrosis and Liver Cancer Using Nanocarriers. Cells 2020; 9:cells9092027. [PMID: 32899119 PMCID: PMC7563527 DOI: 10.3390/cells9092027] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 08/26/2020] [Accepted: 08/31/2020] [Indexed: 12/13/2022] Open
Abstract
Cancer associated fibroblasts (CAF) and the extracellular matrix (ECM) produced by them have been recognized as key players in cancer biology and emerged as important targets for cancer treatment and drug discovery. Apart from their presence in stroma rich tumors, such as biliary, pancreatic and subtypes of hepatocellular cancer (HCC), both CAF and certain ECM components are also present in cancers without an overt intra-tumoral desmoplastic reaction. They support cancer development, growth, metastasis and resistance to chemo- or checkpoint inhibitor therapy by a multitude of mechanisms, including angiogenesis, ECM remodeling and active immunosuppression by secretion of tumor promoting and immune suppressive cytokines, chemokines and growth factors. CAF resemble activated hepatic stellate cells (HSC)/myofibroblasts, expressing α-smooth muscle actin and especially fibroblast activation protein (FAP). Apart from FAP, CAF also upregulate other functional cell surface proteins like platelet-derived growth factor receptor β (PDGFRβ) or the insulin-like growth factor receptor II (IGFRII). Notably, if formulated with adequate size and zeta potential, injected nanoparticles home preferentially to the liver. Several nanoparticular formulations were tested successfully to deliver dugs to activated HSC/myofibroblasts. Thus, surface modified nanocarriers with a cyclic peptide binding to the PDGFRβ or with mannose-6-phosphate binding to the IGFRII, effectively directed drug delivery to activated HSC/CAF in vivo. Even unguided nanohydrogel particles and lipoplexes loaded with siRNA demonstrated a high in vivo uptake and functional siRNA delivery in activated HSC, indicating that liver CAF/HSC are also addressed specifically by well-devised nanocarriers with optimized physicochemical properties. Therefore, CAF have become an attractive target for the development of stroma-based cancer therapies, especially in the liver.
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Sällberg M, Pasetto A. Liver, Tumor and Viral Hepatitis: Key Players in the Complex Balance Between Tolerance and Immune Activation. Front Immunol 2020; 11:552. [PMID: 32292409 PMCID: PMC7119224 DOI: 10.3389/fimmu.2020.00552] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 03/10/2020] [Indexed: 12/12/2022] Open
Abstract
Liver cancer is the third most common cause of cancer related death in the World. From an epidemiological point of view the risk factors associated to primary liver cancer are mainly viral hepatitis infection and alcohol consumption. Even though there is a clear correlation between liver inflammation, cirrhosis and cancer, other emerging liver diseases (like fatty liver) could also lead to liver cancer. Moreover, the liver is the major site of metastasis from colon, breast, ovarian and other cancers. In this review we will address the peculiar status of the liver as organ that has to balance between tolerance and immune activation. We will focus on macrophages and other key cellular components of the liver microenvironment that play a central role during tumor progression. We will also discuss how current and future therapies may affect the balance toward immune activation.
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Affiliation(s)
- Matti Sällberg
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Anna Pasetto
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
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24
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Lei Y, Zhou S, Hu Q, Chen X, Gu J. Carbohydrate response element binding protein (ChREBP) correlates with colon cancer progression and contributes to cell proliferation. Sci Rep 2020; 10:4233. [PMID: 32144313 PMCID: PMC7060312 DOI: 10.1038/s41598-020-60903-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 02/07/2020] [Indexed: 02/05/2023] Open
Abstract
Cancers are characterized by reprogrammed glucose metabolisms to fuel cell growth and proliferation. Carbohydrate response element binding protein (ChREBP) is a glucose-mediated transcription factor that strongly regulates glycolytic and lipogenic pathways. It has been shown to associate with metabolic diseases, such as obesity, diabetes and non-alcoholic fatty liver diseases. However, how it associates with cancers has not been well understood. In this study, ChREBP expression was assessed by immunohistochemistry in colon tissue arrays containing normal colon tissue and cancer tissue at different clinical stages. Tissue mRNA levels of ChREBP were also measured in a cohort of colon cancer patients. We found that ChREBP mRNA and protein expression were significantly increased in colon cancer tissue compared to healthy colon (p < 0.001), and their expression was positively correlated to colon malignancy (for mRNA, p = 0.002; for protein p < 0.001). Expression of lipogenic genes (ELOVL6 and SCD1) in colon cancer was also positively associated with colon malignancy (for both genes, p < 0.001). In vitro, ChREBP knockdown with siRNA transfection inhibited cell proliferation and induced cell cycle arrest without changes in apoptosis in colon cancer cell lines (HT29, DLD1 and SW480). Glycolytic and lipogenic pathways were inhibited but the p53 pathway was activated after ChREBP knockdown. Taken together, ChREBP expression is associated with colon malignancy and it might contribute to cell proliferation via promoting anabolic pathways and inhibiting p53. In addition, ChREBP might represent a novel clinical useful biomarker to evaluate the malignancy of colon cancer.
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Affiliation(s)
- Yu Lei
- Department of Pathology and Provincial Key Laboratory of Infectious Diseases and Immunopathology, Collaborative and Creative Center, Shantou University Medical College, Shantou, 515041, Guangdong, China
- Jinxin Research Institute for Reproductive Medicine and Genetics, Chengdu Jinjiang Hospital for Maternal and Child Health Care, 66 Jingxiu Road, Chengdu, 610066, China
| | - Shuling Zhou
- Department of Pathology and Provincial Key Laboratory of Infectious Diseases and Immunopathology, Collaborative and Creative Center, Shantou University Medical College, Shantou, 515041, Guangdong, China
- Jinxin Research Institute for Reproductive Medicine and Genetics, Chengdu Jinjiang Hospital for Maternal and Child Health Care, 66 Jingxiu Road, Chengdu, 610066, China
| | - Qiaoling Hu
- Department of Pathology and Provincial Key Laboratory of Infectious Diseases and Immunopathology, Collaborative and Creative Center, Shantou University Medical College, Shantou, 515041, Guangdong, China
| | - Xueling Chen
- Department of Pathology and Provincial Key Laboratory of Infectious Diseases and Immunopathology, Collaborative and Creative Center, Shantou University Medical College, Shantou, 515041, Guangdong, China
| | - Jiang Gu
- Department of Pathology and Provincial Key Laboratory of Infectious Diseases and Immunopathology, Collaborative and Creative Center, Shantou University Medical College, Shantou, 515041, Guangdong, China.
- Jinxin Research Institute for Reproductive Medicine and Genetics, Chengdu Jinjiang Hospital for Maternal and Child Health Care, 66 Jingxiu Road, Chengdu, 610066, China.
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25
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Yang H, Xuefeng Y, Jianhua X. Systematic review of the roles of interleukins in hepatocellular carcinoma. Clin Chim Acta 2020; 506:33-43. [PMID: 32142718 DOI: 10.1016/j.cca.2020.03.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 03/02/2020] [Accepted: 03/02/2020] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is a primary liver cancer with high morbidity and mortality that is often accompanied by immune system disorders and local lymphocyte infiltration. Tumor-infiltrating lymphocytes, cancer cells, stromal cells, and the numerous cytokines they produce, such as chemokines, interferons, tumor necrosis factors, and interleukins, collectively constitute the tumor microenvironment. As a main type of immune effector, interleukin plays opposing roles in regulating tumor cell progression, adhesion, and migration according to its different subtypes. Many reports have concentrated on the roles that interleukins play in HCC, but understanding them systematically remains challenging. This study reviewed the current data to comprehensively summarize the relationships between HCC progression and human interleukin gene families.
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Affiliation(s)
- Hu Yang
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, Hunan, China; Department of Gastroenterology, Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan 421002, China
| | - Yang Xuefeng
- Department of Gastroenterology, Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan 421002, China
| | - Xiao Jianhua
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang 421001, Hunan, China.
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26
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Dong Z, Liao B, Shen W, Sui C, Yang J. Expression of Programmed Death Ligand 1 Is Associated with the Prognosis of Intrahepatic Cholangiocarcinoma. Dig Dis Sci 2020; 65:480-488. [PMID: 31410753 DOI: 10.1007/s10620-019-05787-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 08/07/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Programmed death ligand 1 (PD-L1) is expressed in many malignancies and plays a critical role in escape from immune surveillance through inhibition of its receptor programmed death 1. The role of PD-L1 in intrahepatic cholangiocarcinoma (ICC) and mechanisms of its regulation, however, remain largely unknown. AIMS To analyze the expression and prognostic significance of PD-L1 in ICC and to study the regulatory mechanisms of PD-L1. METHODS Samples were obtained from 125 patients diagnosed with ICC in the Eastern Hepatobiliary Surgery Hospital from January 2012 to January 2013. The records of each patient were analyzed to examine the relationship between PD-L1 and clinical data. In vitro experiments were performed to investigate the relationship between PD-L1 and the IL-6/mTOR signaling pathway and the feedback mechanism pathway of PD-L1. RESULTS Expression of PD-L1 is closely related to tumor vascular invasion, lymphatic metastasis and TNM staging. High PD-L1 expression is closely related to poor prognosis in ICC. Mechanically, IL-6 induces PD-L1 expression through mTOR signaling in ICC cells. In addition, PD-L1 has a negative feedback inhibition effect on AKT signaling. CONCLUSIONS In summary, high PD-L1 expression was found to be associated with poor prognosis. The IL-6/mTOR pathway upregulates expression of PD-L1, thus promoting tumor invasion, and PD-L1 negatively inhibits the AKT pathway.
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Affiliation(s)
- Zhitao Dong
- Department of Special Medical Care, Shanghai Eastern Hepatobiliary Surgery Hospital, The 13th Floor, No. 700 North Moyu Road, Jiading District, Shanghai, 200438, China
| | - Boyi Liao
- Department of Special Medical Care, Shanghai Eastern Hepatobiliary Surgery Hospital, The 13th Floor, No. 700 North Moyu Road, Jiading District, Shanghai, 200438, China
| | - Weifeng Shen
- Department of Special Medical Care, Shanghai Eastern Hepatobiliary Surgery Hospital, The 13th Floor, No. 700 North Moyu Road, Jiading District, Shanghai, 200438, China
| | - Chengjun Sui
- Department of Special Medical Care, Shanghai Eastern Hepatobiliary Surgery Hospital, The 13th Floor, No. 700 North Moyu Road, Jiading District, Shanghai, 200438, China
| | - Jiamei Yang
- Department of Special Medical Care, Shanghai Eastern Hepatobiliary Surgery Hospital, The 13th Floor, No. 700 North Moyu Road, Jiading District, Shanghai, 200438, China.
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Perez-Juarez CE, Arechavaleta-Velasco F, Zeferino-Toquero M, Alvarez-Arellano L, Estrada-Moscoso I, Diaz-Cueto L. Inhibition of PI3K/AKT/mTOR and MAPK signaling pathways decreases progranulin expression in ovarian clear cell carcinoma (OCCC) cell line: a potential biomarker for therapy response to signaling pathway inhibitors. Med Oncol 2019; 37:4. [PMID: 31713081 DOI: 10.1007/s12032-019-1326-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 10/22/2019] [Indexed: 12/24/2022]
Abstract
Patients with advanced stage ovarian clear cell carcinoma (OCCC) have a poor prognosis due to resistance to conventional platinum chemotherapy. Recent studies have demonstrated that PI3K/AKT/mTOR and ERK1/2 signaling pathways are involved in this chemoresistance. Progranulin (PGRN) overexpression contributes to cisplatin resistance of epithelial ovarian cancer cell lines. Also, PGRN expression is regulated by AKT/mTOR and ERK1/2 signaling pathways in different cell types. Thus, the present study was designed to identify if PGRN expression is regulated by AKT, mTOR, and ERK1/2 signaling pathways in the OCCC cell line TOV-21G. Cultured TOV-21G cells were incubated with different concentrations of pharmacological cell signaling inhibitors. PGRN expression and phosphorylation of ERK1/2, AKT, and mTOR were assessed by Western blotting. Inhibition of AKT, mTOR, and ERK1/2 significantly reduced PGRN expression. Cell viability was not affected, while cell proliferation significantly decreased with all inhibitors used in this study. These observations demonstrated that inhibition of PI3K/AKT/mTOR and ERK1/2 signaling pathways reduces PGRN expression in TOV-21G cells. Thus, PGRN could be considered as a candidate for explaining the high resistance to platinum-based treatment and a potential biomarker for therapy response to cell signaling inhibitors in patients with OCCC.
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Affiliation(s)
- Carlos Eduardo Perez-Juarez
- Unidad de Investigacion Medica en Medicina Reproductiva, UMAE Hospital de Gineco Obstetricia No. 4 "Luis Castelazo Ayala", Instituto Mexicano del Seguro Social, Av. Rio Magdalena No. 289, Sexto piso, Tizapan San Angel, 01090, Ciudad de Mexico, Mexico.,Posgrado en Ciencias Biologicas, Universidad Nacional Autonoma de Mexico, Ciudad de Mexico, Mexico
| | - Fabian Arechavaleta-Velasco
- Unidad de Investigacion Medica en Medicina Reproductiva, UMAE Hospital de Gineco Obstetricia No. 4 "Luis Castelazo Ayala", Instituto Mexicano del Seguro Social, Av. Rio Magdalena No. 289, Sexto piso, Tizapan San Angel, 01090, Ciudad de Mexico, Mexico
| | - Moises Zeferino-Toquero
- Departamento de Oncologia Ginecologica, UMAE Hospital de Gineco-Obstetricia No. 4 "Luis Castelazo Ayala", Instituto Mexicano del Seguro Social, Ciudad de Mexico, Mexico.,Departamento de Cirugia Oncologica, Hospital de Gineco-Obstetricia No.3, Centro Medico Nacional La Raza, Instituto Mexicano del Seguro Social, Ciudad de Mexico, Mexico
| | | | - Isaias Estrada-Moscoso
- Departamento de Patologia, UMAE Hospital de Gineco-Obstetricia No. 4 "Luis Castelazo Ayala", IMSS, Ciudad de Mexico, Mexico
| | - Laura Diaz-Cueto
- Unidad de Investigacion Medica en Medicina Reproductiva, UMAE Hospital de Gineco Obstetricia No. 4 "Luis Castelazo Ayala", Instituto Mexicano del Seguro Social, Av. Rio Magdalena No. 289, Sexto piso, Tizapan San Angel, 01090, Ciudad de Mexico, Mexico.
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Li Y, Jann T, Vera-Licona P. Benchmarking time-series data discretization on inference methods. Bioinformatics 2019; 35:3102-3109. [PMID: 30657860 DOI: 10.1093/bioinformatics/btz036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 12/10/2018] [Accepted: 01/14/2019] [Indexed: 12/15/2022] Open
Abstract
SUMMARY The rapid development in quantitatively measuring DNA, RNA and protein has generated a great interest in the development of reverse-engineering methods, that is, data-driven approaches to infer the network structure or dynamical model of the system. Many reverse-engineering methods require discrete quantitative data as input, while many experimental data are continuous. Some studies have started to reveal the impact that the choice of data discretization has on the performance of reverse-engineering methods. However, more comprehensive studies are still greatly needed to systematically and quantitatively understand the impact that discretization methods have on inference methods. Furthermore, there is an urgent need for systematic comparative methods that can help select between discretization methods. In this work, we consider four published intracellular networks inferred with their respective time-series datasets. We discretized the data using different discretization methods. Across all datasets, changing the data discretization to a more appropriate one improved the reverse-engineering methods' performance. We observed no universal best discretization method across different time-series datasets. Thus, we propose DiscreeTest, a two-step evaluation metric for ranking discretization methods for time-series data. The underlying assumption of DiscreeTest is that an optimal discretization method should preserve the dynamic patterns observed in the original data across all variables. We used the same datasets and networks to show that DiscreeTest is able to identify an appropriate discretization among several candidate methods. To our knowledge, this is the first time that a method for benchmarking and selecting an appropriate discretization method for time-series data has been proposed. AVAILABILITY AND IMPLEMENTATION All the datasets, reverse-engineering methods and source code used in this paper are available in Vera-Licona's lab Github repository: https://github.com/VeraLiconaResearchGroup/Benchmarking_TSDiscretizations. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Yuezhe Li
- R.D. Berlin Center for Cell Analysis and Modeling, University of Connecticut School of Medicine, Farmington, CT, USA
| | - Tiffany Jann
- Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, CA, USA
| | - Paola Vera-Licona
- Center for Quantitative Medicine, University of Connecticut School of Medicine, Farmington, CT, USA.,Department of Cell Biology, University of Connecticut School of Medicine, Farmington, CT, USA.,Department of Pediatrics, University of Connecticut School of Medicine, Farmington, CT, USA.,Institute for Systems Genomics, University of Connecticut School of Medicine, Farmington, CT, USA
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Lee E, Lee TA, Yoo HJ, Lee S, Park B. CNBP controls tumor cell biology by regulating tumor-promoting gene expression. Mol Carcinog 2019; 58:1492-1501. [PMID: 31087358 DOI: 10.1002/mc.23030] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 01/23/2019] [Accepted: 04/15/2019] [Indexed: 12/31/2022]
Abstract
Cellular nucleic acid-binding protein (CNBP) is associated with cell proliferation, and its expression is elevated in human tumors, but the molecular mechanisms of CNBP in tumor cell biology have not been fully elucidated. In this study, we report that CNBP is a transcription factor essential for regulating matrix metalloproteinases mmp-2, mmp-14, and transcription factor e2f2 gene expression by binding to their promoter regions via a sequence-specific manner. Importantly, epidermal growth factor stimulation is required to induce CNBP phosphorylation and nuclear transport, thereby promoting the expression of mmp-2, mmp-14, and e2f2 genes. As a consequence, loss of cnbp attenuates the ability of tumor cell growth, invasion, and migration. Conversely, overexpression of cnbp is associated with tumor cell biology. Collectively, our findings reveal CNBP as a key transcriptional regulator of tumor-promoting target genes to control tumor cell biology.
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Affiliation(s)
- Eunhye Lee
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
| | - Taeyun A Lee
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
| | - Hye Jin Yoo
- Division of Tumor Immunology, National Cancer Center, Goyang, South Korea
| | - Sungwook Lee
- Division of Tumor Immunology, National Cancer Center, Goyang, South Korea
| | - Boyoun Park
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
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30
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Du S, Liao S, Liu S, Xin Y. TM6SF2 E167K Variant Overexpression Promotes Expression of Inflammatory Cytokines in the HCC Cell Line HEPA 1-6. J Clin Transl Hepatol 2019; 7:27-31. [PMID: 30944816 PMCID: PMC6441636 DOI: 10.14218/jcth.2018.00055] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Revised: 12/20/2018] [Accepted: 12/27/2018] [Indexed: 12/27/2022] Open
Abstract
Background and Aims: Accumulated evidence has shown that chronic liver inflammation is one of the main risks of hepatocellular carcinoma (HCC), and E167K variant of the transmembrane 6 superfamily member 2 (TM6SF2) plays an important role in the progression of chronic liver diseases and HCC. The aim of this study was to explore effects of the TM6SF2 E167K variant on expression of the inflammatory cytokines TNF-α, IL-2, IL-6 and IL-8 in the HCC cell line HEPA 1-6. Methods: HEPA 1-6 cells were infected with lentivirus containing either the TM6SF2 E167K variant or TM6SF2 wild-type, or control plasmids. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were conducted to analyze the expression of the inflammatory cytokines TNF-α, IL-2, IL-6 and IL-8. A t-test was used for statistical analysis. Results: Compared with the control group and TM6SF2 overexpression group, the relative expression of IL-2 and IL-6 mRNAs were significantly elevated in the TM6SF2 E167K overexpression group (p < 0.05). The relative mRNA expression of IL-8 in the TM6SF2 and TM6SF2 E167K overexpression groups were increased compared to the control group (p < 0.05). No obvious differences were observed for the expression of TNF-α in each group. The expression of TNF-α, IL-2, IL-6 and IL-8 that was tested by western blotting showed the same trends as the qRT-PCR results. Conclusions: In conclusion, the E167K variant of the TM6SF2 gene could promote the expression of inflammatory cytokines IL-2 and IL-6 in HEPA 1-6 cells, suggesting that the TM6SF2 E167K variant may accelerate the progression of HCC.
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Affiliation(s)
- Shuixian Du
- Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao, China
| | - Songling Liao
- Department of Gastroenterology, Dalian Medical University, Dalian, China
| | - Shousheng Liu
- Central Laboratories, Qingdao Municipal Hospital, Qingdao, China
- Digestive Disease Key Laboratory of Qingdao, Qingdao, China
| | - Yongning Xin
- Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao, China
- Department of Gastroenterology, Dalian Medical University, Dalian, China
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, China
- Digestive Disease Key Laboratory of Qingdao, Qingdao, China
- *Correspondence to: Yongning Xin, Department of Infectious Disease, Qingdao Municipal Hospital, 1 Jiaozhou Road, Qingdao, Shandong 266011, China. Tel: +86-532-82789463, Fax: +86-532-85968434, E-mail:
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31
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Microglial Progranulin: Involvement in Alzheimer's Disease and Neurodegenerative Diseases. Cells 2019; 8:cells8030230. [PMID: 30862089 PMCID: PMC6468562 DOI: 10.3390/cells8030230] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Revised: 03/06/2019] [Accepted: 03/07/2019] [Indexed: 12/12/2022] Open
Abstract
Neurodegenerative diseases such as Alzheimer’s disease have proven resistant to new treatments. The complexity of neurodegenerative disease mechanisms can be highlighted by accumulating evidence for a role for a growth factor, progranulin (PGRN). PGRN is a glycoprotein encoded by the GRN/Grn gene with multiple cellular functions, including neurotrophic, anti-inflammatory and lysosome regulatory properties. Mutations in the GRN gene can lead to frontotemporal lobar degeneration (FTLD), a cause of dementia, and neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Both diseases are associated with loss of PGRN function resulting, amongst other features, in enhanced microglial neuroinflammation and lysosomal dysfunction. PGRN has also been implicated in Alzheimer’s disease (AD). Unlike FTLD, increased expression of PGRN occurs in brains of human AD cases and AD model mice, particularly in activated microglia. How microglial PGRN might be involved in AD and other neurodegenerative diseases will be discussed. A unifying feature of PGRN in diseases might be its modulation of lysosomal function in neurons and microglia. Many experimental models have focused on consequences of PGRN gene deletion: however, possible outcomes of increasing PGRN on microglial inflammation and neurodegeneration will be discussed. We will also suggest directions for future studies on PGRN and microglia in relation to neurodegenerative diseases.
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Xie W, Lu Q, Wang K, Lu J, Gu X, Zhu D, Liu F, Guo Z. miR-34b-5p inhibition attenuates lung inflammation and apoptosis in an LPS-induced acute lung injury mouse model by targeting progranulin. J Cell Physiol 2018; 233:6615-6631. [PMID: 29150939 PMCID: PMC6001482 DOI: 10.1002/jcp.26274] [Citation(s) in RCA: 126] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2017] [Accepted: 11/14/2017] [Indexed: 12/14/2022]
Abstract
Inflammation and apoptosis play important roles in the initiation and progression of acute lung injury (ALI). Our previous study has shown that progranulin (PGRN) exerts lung protective effects during LPS-induced ALI. Here, we have investigated the potential roles of PGRN-targeting microRNAs (miRNAs) in regulating inflammation and apoptosis in ALI and have highlighted the important role of PGRN. LPS-induced lung injury and the protective roles of PGRN in ALI were first confirmed. The function of miR-34b-5p in ALI was determined by transfection of a miR-34b-5p mimic or inhibitor in intro and in vivo. The PGRN level gradually increased and subsequently significantly decreased, reaching its lowest value by 24 hr; PGRN was still elevated compared to the control. The change was accompanied by a release of inflammatory mediators and accumulation of inflammatory cells in the lungs. Using bioinformatics analysis and RT-PCR, we demonstrated that, among 12 putative miRNAs, the kinetics of the miR-34b-5p levels were closely associated with PGRN expression in the lung homogenates. The gain- and loss-of-function analysis, dual-luciferase reporter assays, and rescue experiments confirmed that PGRN was the functional target of miR-34b-5p. Intravenous injection of miR-34b-5p antagomir in vivo significantly inhibited miR-34b-5p up-regulation, reduced inflammatory cytokine release, decreased alveolar epithelial cell apoptosis, attenuated lung inflammation, and improved survival by targeting PGRN during ALI. miR-34b-5p knockdown attenuates lung inflammation and apoptosis in an LPS-induced ALI mouse model by targeting PGRN. This study shows that miR-34b-5p and PGRN may be potential targets for ALI treatments.
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Affiliation(s)
- Wang Xie
- Department of Respiratory MedicineShanghai East HospitalTongji University School of MedicinePudongShanghaiChina
| | - Qingchun Lu
- Department of Respiratory MedicineShanghai East HospitalTongji University School of MedicinePudongShanghaiChina
| | - Kailing Wang
- Department of Respiratory MedicineShanghai East HospitalTongji University School of MedicinePudongShanghaiChina
| | - Jingjing Lu
- Department of Respiratory MedicineShanghai East HospitalTongji University School of MedicinePudongShanghaiChina
| | - Xia Gu
- Department of Respiratory MedicineShanghai East HospitalTongji University School of MedicinePudongShanghaiChina
| | - Dongyi Zhu
- Department of Respiratory MedicineShanghai East HospitalTongji University School of MedicinePudongShanghaiChina
| | - Fanglei Liu
- Department of Respiratory MedicineShanghai East HospitalTongji University School of MedicinePudongShanghaiChina
| | - Zhongliang Guo
- Department of Respiratory MedicineShanghai East HospitalTongji University School of MedicinePudongShanghaiChina
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Circulating PGRN Levels Are Increased but Not Associated with Insulin Sensitivity or β-Cell Function in Chinese Obese Children. DISEASE MARKERS 2018; 2018:3729402. [PMID: 30151059 PMCID: PMC6087587 DOI: 10.1155/2018/3729402] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Revised: 06/05/2018] [Accepted: 06/25/2018] [Indexed: 11/17/2022]
Abstract
Progranulin (PGRN), a novel peptide that has recently emerged as an important regulatory adipokine, is relevant to energy homeostasis and obesity in animals and adult humans. Little is known about its roles in children. The aim of the current study was to determine the potential role of PGRN and explore its relationship to various obesity-related markers in obese children. This was a cross-sectional study composed of 77 children (43 obese and 34 healthy, age 8.68 ± 0.28 and 8.46 ± 0.45 years, resp.). The PGRN levels were significantly higher in obese children (102.44 ± 4.18 ng/mL) comparing to controls (69.32 ± 5.49 ng/mL) (P < 0.05). Moreover, the PGRN levels were positively correlated with triglyceride (TG), total cholesterol (TC), IL-6, systolic blood pressure (SBP), and diastolic blood pressure (DBP) in obese children after adjusted for BMI and age. However, there was no correlation of serum PGRN levels with OGTT-derived dynamic parameters, HOMA-IR, or HOMA-β in obese children. The results suggest that serum PGRN levels are significantly higher in obese children in China and correlate significantly with obesity-related markers. Increased PGRN levels may be involved in the pathological mechanism of childhood obesity.
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Lei HW, Cai J, Li CM, Yang F, Shi WQ, Shi WQ, Wang LP, Feng YY. Rapamycin Combi with TAE on the Growth, Metastasis, and Prognosis of Hepatocellular Carcinoma in Rat Models. Ann Hepatol 2018; 17:645-654. [PMID: 29893708 DOI: 10.5604/01.3001.0012.0948] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND AIM To investigate the effect of mTOR inhibitor Rapamycin combined with transcatheter arterial embolization (TAE) on the growth, metastasis, and prognosis of hepatocellular carcinoma (HCC) in rat model. MATERIAL AND METHOD McARH7777 cells were used to construct rat models of HCC, which were randomly divided into Model, Rapamycin, TAE, and Rapamycin + TAE groups. Quantitative reverse transcription-PCR (qRT-PCR) and Western Blot were used to detect the expression of Epithelial-Mesenchymal Transition (EMT)-related molecules, and immunohistochemical staining to determine the expression of EMTrelated proteins, angiogenic factors as well as microvessel density (MVD)-CD34. RESULTS The hepatic tumor volume of rats in the other three groups were all significantly smaller than the Model group on the 7th, 14th, and 21st day after treatment and the combination treatment was apparently more effective than either treatment alone. Besides, both the number and the size of metastatic nodules of HCC rats after combination treatment were remarkably reduced. In addition, compared with rats in the Rapamycin + TAE group, N-cadherin, Vimentin, HIF-1α, VEGF, and MVD-CD34 were obviously enhanced, while E-cadherin was lowered in those TAE group, which were the complete opposite to the Rapamycin group. Besides, the median survival time of rats in the Rapamycin + TAE group was evidently longer than the resting groups. CONCLUSION Rapamycin combined with TAE may effectively suppress the EMT formation and angiogenesis, thereby inhibiting the growth and lung metastasis of HCC rats, which provides a new idea for countering the recurrence and metastasis of HCC.
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Affiliation(s)
- Hong-Wei Lei
- Department of Interventional Radiology, the First People's Hospital of Jingzhou, Jingzhou, Hubei, P.R. China First Hospital affiliated to Yangtze University, Jingzhou, Hubei Province, China
| | - Jie Cai
- Department of Interventional Radiology, the First People's Hospital of Jingzhou, Jingzhou, Hubei, P.R. China First Hospital affiliated to Yangtze University, Jingzhou, Hubei Province, China
| | - Cheng-Ming Li
- Department of Interventional Radiology, the First People's Hospital of Jingzhou, Jingzhou, Hubei, P.R. China First Hospital affiliated to Yangtze University, Jingzhou, Hubei Province, China
| | - Fang Yang
- Department of Interventional Radiology, the First People's Hospital of Jingzhou, Jingzhou, Hubei, P.R. China First Hospital affiliated to Yangtze University, Jingzhou, Hubei Province, China
| | - Wan-Qing Shi
- Department of Interventional Radiology, the First People's Hospital of Jingzhou, Jingzhou, Hubei, P.R. China First Hospital affiliated to Yangtze University, Jingzhou, Hubei Province, China
| | - Wan-Qing Shi
- Department of Interventional Radiology, the First People's Hospital of Jingzhou, Jingzhou, Hubei, P.R. China First Hospital affiliated to Yangtze University, Jingzhou, Hubei Province, China
| | - Li-Ping Wang
- Department of Interventional Radiology, the First People's Hospital of Jingzhou, Jingzhou, Hubei, P.R. China First Hospital affiliated to Yangtze University, Jingzhou, Hubei Province, China
| | - You-Ying Feng
- Department of Central Sterile Supply, the First People's Hospital of Jingzhou, Jingzhou, Hubei, P.R. China First Hospital affiliated to Yangtze University, Jingzhou, Hubei Province, China
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Daya M, Loilome W, Techasen A, Thanee M, Sa-Ngiamwibool P, Titapun A, Yongvanit P, Namwat N. Progranulin modulates cholangiocarcinoma cell proliferation, apoptosis, and motility via the PI3K/pAkt pathway. Onco Targets Ther 2018; 11:395-408. [PMID: 29403285 PMCID: PMC5783154 DOI: 10.2147/ott.s155511] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Progranulin (PGRN) is a growth factor normally expressed in rapidly cycling epithelial cells for growth, differentiation, and motility. Several studies have shown the association of PGRN overexpression with the progression of numerous malignancies, including cholangiocarcinoma (CCA). However, the underlying mechanisms on how PGRN modulates CCA cell proliferation and motility is not clear. In this study, we investigated the prognostic significance of PGRN expression in human CCA tissue and the mechanisms of PGRN modulation of CCA cell proliferation and motility. We found that CCA tissues with high PGRN expression were correlated with poor prognosis and likelihood of metastasis. PGRN knockdown KKU-100 and KKU-213 cells demonstrated a reduced rate of proliferation and colony formation and decreased levels of phosphatidyl inositol-3-kinase (PI3K) and phosphorylated Akt (pAkt) proteins. Accumulation of cells at the G1 phase was observed and was accompanied by a reduction of cyclin D1 and CDK4 protein levels. Knockdown cells also induced apoptosis by increasing the Bax-to-Bcl-2 ratio. Increased cell apoptosis was confirmed by annexin V-FITC/PI staining. Moreover, suppression of PGRN reduced CCA cell migration and invasion in vitro. Investigating the biomarkers in epithelial–mesenchymal transition (EMT) revealed a decrease in the expression of vimentin, snail, and metalloproteinase-9. In conclusion, our findings imply that PGRN modulates cell proliferation by dysregulating the G1 phase, inhibiting apoptosis, and that it plays a role in the EMT affecting CCA cell motility, possibly via the PI3K/pAkt pathway.
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Affiliation(s)
- Minerva Daya
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.,Department of Biochemistry, Faculty of Pharmacy, University of Santo Tomas, Sampaloc, Manila, Philippines.,Cholangiocarcinoma Research Institute
| | - Watcharin Loilome
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.,Cholangiocarcinoma Research Institute
| | - Anchalee Techasen
- Cholangiocarcinoma Research Institute.,Faculty of Associated Medical Science
| | | | | | - Attapol Titapun
- Department of Pathology.,Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | | | - Nisana Namwat
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.,Cholangiocarcinoma Research Institute
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Novikova MV, Khromova NV, Kopnin PB. Components of the Hepatocellular Carcinoma Microenvironment and Their Role in Tumor Progression. BIOCHEMISTRY (MOSCOW) 2017; 82:861-873. [PMID: 28941454 DOI: 10.1134/s0006297917080016] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
This review summarizes recently published data on the mechanisms of tumor cell interaction with the tumor microenvironment. Tumor stroma influences the processes of hepatocarcinogenesis, epithelial-to-mesenchymal transition, invasion, and metastasis. The tumor microenvironment includes both cellular and noncellular components. Main cellular components of hepatocellular carcinoma (HCC) stroma are tumor-associated fibroblasts, hepatic stellate cells, immune cells, and endothelial cells that produce extracellular components of tumor microenvironment such as extracellular matrix, various proteins, proteolytic enzymes, growth factors, and cytokines. The noncellular components of the stroma modulate signaling pathways in tumor cells and stimulate invasion and metastasis. The tumor microenvironment composition and organization can serve as prognostic factors in HCC pathogenesis. Current approaches in HCC targeted therapy are aimed at creating efficient strategies for interrupting tumor interactions with the stroma. Recent data on the composition and role of the microenvironment in HCC pathogenesis, as well as new developments in antitumor drug design are discussed.
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Affiliation(s)
- M V Novikova
- Blokhin Russian Cancer Research Center, Ministry of Health of Russia, Moscow, 115478, Russia.
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37
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Yang D, Li R, Wang H, Wang J, Han L, Pan L, Li X, Kong Q, Wang G, Su X. Clinical implications of progranulin in gastric cancer and its regulation via a positive feedback loop involving AKT and ERK signaling pathways. Mol Med Rep 2017; 16:9685-9691. [PMID: 29039535 DOI: 10.3892/mmr.2017.7796] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 08/24/2017] [Indexed: 11/06/2022] Open
Abstract
In previous years, progranulin (PGRN) has attracted increasing attention due to its oncogenic roles in several types of tumor. However, the clinical relevance of PGRN in gastric cancer remains to be elucidated. In the present study, 120 retrospective tissue samples were obtained from patients with primary gastric cancer, and the expression of PGRN was detected using immunohistochemistry. The results showed that 71 cases exhibited a high expression of PGRN, which was markedly higher than the 49 cases with a low expression of PGRN. Subsequent χ2 analysis confirmed for the first time, to the best of our knowledge, that a high level of PGRN was positively correlated with lymph node metastasis (P=0.048), lymphatic invasion (P=0.018) and advanced clinical stage (P=0.027). Survival analysis showed that PGRN was positively correlated with poorer overall survival (OS; P=0.0043) and progression‑free survival (PFS; P=0.0022). Univariate and multivariate Cox regression analysis showed that PGRN and clinical stage had a significant effect on the OS and PFS of the patients with gastric cancer. In addition, cell experiments confirmed that extracellular PGRN promoted the intracellular expression of PGRN in a concentration‑dependent manner in gastric cancer cells. The AKT and extracellular signal‑regulated kinase signaling pathways were involved in the upregulation of intracellular PGRN induced by extracellular PGRN in MKN‑45 and MGC‑803 gastric cancer cells. Taken together, the results of the present study suggested that PGRN may be important in the progression and prognosis of gastric cancer, and that the expression of PGRN was regulated in a positive feedback loop. These findings enhance current knowledge regarding PGRN in tumors.
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Affiliation(s)
- Dong Yang
- Department of Oncology, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, P.R. China
| | - Ruidong Li
- Department of Oncology, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, P.R. China
| | - Huili Wang
- Department of Oncology, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, P.R. China
| | - Junye Wang
- Department of Oncology, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, P.R. China
| | - Lei Han
- Department of Oncology, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, P.R. China
| | - Lihua Pan
- Department of Oncology, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, P.R. China
| | - Xueqin Li
- Department of Oncology, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, P.R. China
| | - Qingli Kong
- Department of Oncology, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, P.R. China
| | - Guijuan Wang
- Department of Oncology, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, P.R. China
| | - Xiujun Su
- Department of Oncology, Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, P.R. China
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Wang T, Chen Z, Zhang W. Regulation of autophagy inhibition and inflammatory response in glioma by Wnt signaling pathway. Oncol Lett 2017; 14:7197-7200. [PMID: 29344152 PMCID: PMC5754920 DOI: 10.3892/ol.2017.7103] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2017] [Accepted: 09/21/2017] [Indexed: 02/07/2023] Open
Abstract
The objective of this study was to investigate the mechanism of the function of Wnt signaling pathway in regulating autophagy and inflammatory response in glioma cells. Human brain glioma cells U118 were selected and divided into three groups: i) the Wnt signaling inhibitor IWR-1 group (the observation group); ii) the PBS negative control group (the PBS group) and iii) the blank control group. After 24 h culture, Wnt5a/β-catenin protein, autophagy marker, microtubule-associated-proteins-1A1B-light-chain-3C (LC-3) II and Beclin I, and inflammatory factors IL-6 and TNF-α protein expression levels were evaluated using western blotting. Compared with both control groups, Wnt5a/β-catenin, IL-6 and TNF-α protein expression levels were significantly lower, and LC-3II and Beclin I protein expression levels were significantly higher in the observation group. In conclusion, Wnt5a/β-catenin signaling pathway regulates autophagy and inflammatory response of glioma cells.
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Affiliation(s)
- Tongxin Wang
- Department of Neurosurgery, Yidu Central Hospital of Weifang, Qingzhou, Shandong 262500, P.R. China
| | - Zhixia Chen
- Department of Neurosurgery, Yidu Central Hospital of Weifang, Qingzhou, Shandong 262500, P.R. China
| | - Wei Zhang
- Department of Neurosurgery, Yidu Central Hospital of Weifang, Qingzhou, Shandong 262500, P.R. China
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Association between increased serum GP88 (progranulin) concentrations and prognosis in patients with malignant lymphomas. Clin Chim Acta 2017; 473:139-146. [PMID: 28823651 DOI: 10.1016/j.cca.2017.07.024] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2016] [Revised: 07/21/2017] [Accepted: 07/21/2017] [Indexed: 01/29/2023]
Abstract
BACKGROUND GP88 (progranulin; PGRN) is a secreted 88kDa glycosylated protein, with important functions, including inflammation and tumorigenesis. We assessed the significance of GP88 expression in survival outcomes of patients with malignant lymphoma (ML). METHODS Serum samples from 254 previously untreated ML patients were examined to measure GP88 concentrations using a sandwich human GP88 ELISA kit. Immunohistochemical analyses were performed to examine GP88 tumor tissue expression. RESULTS The median serum GP88 concentration of ML patients was 91.3ng/ml, and was significantly higher than that of the control group (median, 57.7ng/ml) (p<0.0001). Association between GP88 serum concentrations and overall survival (OS) was examined in patients with diffuse large B cell lymphoma (DLBCL) who had been stratified based on their serum GP88 concentrations. Kaplan Meier survival analysis showed that patients with serum GP88 concentrations of ≤116 and >116ng/ml, had 5-y OS rates of 70% and 50%, respectively (p=0.02). The immunohistochemical analyses of GP88 tumor expression revealed that DLBCL patients had lymphoma cells that were positive for GP88. CONCLUSIONS High serum GP88 concentrations are associated with poor prognosis in patients with DLBCL.
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Sun Y, Fan X, Zhang Q, Shi X, Xu G, Zou C. Cancer-associated fibroblasts secrete FGF-1 to promote ovarian proliferation, migration, and invasion through the activation of FGF-1/FGFR4 signaling. Tumour Biol 2017; 39:1010428317712592. [PMID: 28718374 DOI: 10.1177/1010428317712592] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Ovarian cancer is the most lethal gynecologic malignancy, due to its high propensity for metastasis. Cancer-associated fibroblasts, as the dominant component of tumor microenvironment, are crucial for tumor progression. However, the mechanisms underlying the regulation of ovarian cancer cells by cancer-associated fibroblasts remain little known. Here, we first isolated cancer-associated fibroblasts from patients' ovarian tissues and found that cancer-associated fibroblasts promoted SKOV3 cells' proliferation, migration, and invasion. Fibroblast growth factor-1 was identified as a highly increased factor in cancer-associated fibroblasts compared with normal fibroblasts by quantitative reverse transcription polymerase chain reaction (~4.6-fold, p < 0.01) and ELISA assays (~4-fold, p < 0.01). High expression of fibroblast growth factor-1 in cancer-associated fibroblasts either naturally or through gene recombination led to phosphorylation of fibroblast growth factor receptor 4 in SKOV3 cells, which is followed by the activation of mitogen-activated protein kinase/extracellular signal-regulated protein kinase pathway and epithelial-to-mesenchymal transition-associated gene Snail1 and MMP3 expression. Moreover, treatment of SKOV3 cell with fibroblast growth factor receptor inhibitor PD173074 terminated cellular proliferation, migration, and invasion, reduced the phosphorylation level of fibroblast growth factor receptor 4, and suppressed the activation of mitogen-activated protein kinase/extracellular signal-regulated protein kinase pathway. In addition, the expression level of Snail1 and MMP3 was reduced, while the expression level of E-cadherin increased. These observations suggest a crucial role for cancer-associated fibroblasts and fibroblast growth factor-1/fibroblast growth factor receptor 4 signaling in the progression of ovarian cancer. Therefore, this fibroblast growth factor-1/fibroblast growth factor receptor 4 axis may become a potential target for the treatment of ovarian cancer.
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Affiliation(s)
- Yuanzhen Sun
- 1 Department of Laboratory, Laiwu Maternal and Child Health Care Hospital, Laiwu, China
| | - Xiaoli Fan
- 2 Department of Occupational Poisoning, Shandong Academy of Occupational Health and Occupational Medicine, Jinan, China
| | - Qing Zhang
- 3 Department of Laboratory, Shandong Provincial Hospital, Jinan, China
| | - Xiaoyu Shi
- 1 Department of Laboratory, Laiwu Maternal and Child Health Care Hospital, Laiwu, China
| | - Guangwei Xu
- 4 Department of Laboratory, Weihaiwei People's Hospital, Weihai, China
| | - Cuimin Zou
- 4 Department of Laboratory, Weihaiwei People's Hospital, Weihai, China
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APOBEC3B and IL-6 form a positive feedback loop in hepatocellular carcinoma cells. SCIENCE CHINA-LIFE SCIENCES 2017. [DOI: 10.1007/s11427-016-9058-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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Li X, Li B, Ni Z, Zhou P, Wang B, He J, Xiong H, Yang F, Wu Y, Lyu X, Zhang Y, Zeng Y, Lian J, He F. Metformin Synergizes with BCL-XL/BCL-2 Inhibitor ABT-263 to Induce Apoptosis Specifically in p53-Defective Cancer Cells. Mol Cancer Ther 2017; 16:1806-1818. [DOI: 10.1158/1535-7163.mct-16-0763] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 03/30/2017] [Accepted: 05/15/2017] [Indexed: 11/16/2022]
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Jiang Y, Liu P, Jiao W, Meng J, Feng J. Gax suppresses chemerin/CMKLR1‐induced preadipocyte biofunctions through the inhibition of Akt/mTOR and ERK signaling pathways. J Cell Physiol 2017; 233:572-586. [DOI: 10.1002/jcp.25918] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 03/17/2017] [Indexed: 12/19/2022]
Affiliation(s)
- Yunqi Jiang
- Department of CardiologyThe Second Hospital of Shandong UniversityJinanShandongChina
| | - Ping Liu
- Department of CardiologyThe Second Hospital of Shandong UniversityJinanShandongChina
| | - Wenlin Jiao
- College of PharmacyShandong UniversityJinanShandongChina
| | - Juan Meng
- Department of CardiologyThe Second Hospital of Shandong UniversityJinanShandongChina
| | - Jinbo Feng
- Central LaboratoryThe Qilu Hospital of Shandong UniversityJinanShandongChina
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Kimura A, Takemura M, Saito K, Serrero G, Yoshikura N, Hayashi Y, Inuzuka T. Increased cerebrospinal fluid progranulin correlates with interleukin-6 in the acute phase of neuromyelitis optica spectrum disorder. J Neuroimmunol 2017; 305:175-181. [DOI: 10.1016/j.jneuroim.2017.01.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Revised: 12/26/2016] [Accepted: 01/11/2017] [Indexed: 01/16/2023]
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Quan Z, He Y, Luo C, Xia Y, Zhao Y, Liu N, Wu X. Interleukin 6 induces cell proliferation of clear cell renal cell carcinoma by suppressing hepaCAM via the STAT3-dependent up-regulation of DNMT1 or DNMT3b. Cell Signal 2017; 32:48-58. [PMID: 28093267 DOI: 10.1016/j.cellsig.2017.01.017] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Revised: 01/09/2017] [Accepted: 01/10/2017] [Indexed: 12/16/2022]
Abstract
Interleukin 6 (IL-6), a tumor promoting cytokine, has been largely implicated in the development of renal cell carcinoma (RCC). Hepatocyte cell adhesion molecule (hepaCAM) is a novel tumor suppressor, which is lost or down-regulated in many cancer types including RCC. In the present study, we intensively investigated the connection between IL-6 and hepaCAM in RCC. Our analysis of RCC tissues, adjacent tissues and paired serum samples from RCC patients revealed that IL-6 was elevated in patient serum and RCC tissue, whereas hepaCAM was completely lost or significantly down-regulated. Furthermore, we observed an association between IL-6 increase and hepaCAM decrease in RCC tissue samples. In the section of cytological researches, we found in RCC cell lines that IL-6 was a direct upstream regulator of hepaCAM, and that hepaCAM down-regulation was involved in IL-6-driven cell proliferation. We also demonstrated that IL-6-mediated promoter hypermethylation largely accounted for the hepaCAM loss in RCC, and it was STAT3-dependent. Additionally, our data showed that DNMT1 up-regulation induced by IL-6/STAT3 signaling was indispensable for IL-6-mediated hepaCAM loss in RCC cell lines ACHN and 769-P, while DNMT3b up-regulation was crucial for hepaCAM loss in A498. Our findings provide a novel signal pathway regulating cell proliferation, potentially representing a therapeutic target for RCC.
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Affiliation(s)
- Zhen Quan
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Yunfeng He
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Chunli Luo
- Department of Laboratory Diagnosis, Chongqing Medical University, Chongqing, People's Republic of China
| | - Yang Xia
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Yan Zhao
- Department of Laboratory Diagnosis, Chongqing Medical University, Chongqing, People's Republic of China
| | - Nanjing Liu
- Department of Laboratory Diagnosis, Chongqing Medical University, Chongqing, People's Republic of China
| | - Xiaohou Wu
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
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Li Y, Poppoe F, Chen J, Yu L, Deng F, Luo Q, Xu Y, Cai Y, Shen J. Macrophages Polarized by Expression of ToxoGRA15 II Inhibit Growth of Hepatic Carcinoma. Front Immunol 2017; 8:137. [PMID: 28243242 PMCID: PMC5303709 DOI: 10.3389/fimmu.2017.00137] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 01/26/2017] [Indexed: 12/19/2022] Open
Abstract
A growing body of evidence suggests that tumor-associated macrophages are deeply involved in the hepatocellular carcinoma proliferation and account for the large proportion of infiltrated cells in tumor tissues and play a major role in promotion of tumor growth. On the other hand, studies have demonstrated that Toxoplasma gondii virulence-associated molecule of dense granule protein (ToxoGRA15II) tends to induce classically activated macrophages (M1) differentiation. Thus, we explored the M1 induced by ToxoGRA15IIin vitro and its inhibitory impact on the proliferation, invasion, and metastasis of hepatic carcinoma in murine model. Here, we constructed recombinant plasmid of pegfp-gra15II and subsequently ligate it to lentivirus (Lv) vector, with which RAW264.7 was transfected. The results showed that the transfected macrophages were polarized to M1. Coculture of the M1 with Hepa1-6 cells showed a remarkable inhibition of migration and invasion of the tumor cells and decreased expressions of matrix metalloproteinase (MMP)-9 and MMP-2 without notable apoptosis of Hepa1-6 cells. Subsequently, ToxoGRA15II-polarized macrophages inoculated to tumor-bearing C57BL/6 mice were seen in both spleen and tumor tissues, and tumor growth was sharply restricted. Particularly, interleukin-6 (IL-6) expression, which is closely associated with the cancer malignant behaviors, was significantly dampened in tumor tissues. In addition, expression of TNF-α and IL-12 mRNAs was increased, whereas IL-6 and interleukin-10 mRNAs were downregulated in splenocytes. Our results indicate that the effector molecule of ToxoGRA15II may induce macrophage polarization to M1 that has a restrictive effect on tumor growth via its related cytokines profile in tumor and spleen tissues. Besides, ToxoGRA15II, due to its early activation of specified cell population and non-toxicity to mammalians, has a potential value for a novel therapeutic strategy of enhancing host innate immunity against tumor development.
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Affiliation(s)
- Yuanling Li
- Department of Pathogen Biology and Provincial Laboratories of Pathogen Biology and Zoonoses, Anhui Medical University , Hefei , China
| | - Faustina Poppoe
- Department of Pathogen Biology and Provincial Laboratories of Pathogen Biology and Zoonoses, Anhui Medical University, Hefei, China; Department of Microbiology and Immunology, School of Medical Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Jian Chen
- Department of Pathogen Biology and Provincial Laboratories of Pathogen Biology and Zoonoses, Anhui Medical University , Hefei , China
| | - Li Yu
- Department of Pathogen Biology and Provincial Laboratories of Pathogen Biology and Zoonoses, Anhui Medical University , Hefei , China
| | - Fang Deng
- Department of Laboratory Medicine, Provincial West Hospital, Anhui Medical University , Hefei , China
| | - Qingli Luo
- Department of Pathogen Biology and Provincial Laboratories of Pathogen Biology and Zoonoses, Anhui Medical University , Hefei , China
| | - Yuanhong Xu
- Diagnostic Laboratory of the First Affiliated Hospital, Anhui Medical University , Hefei , China
| | - Yihong Cai
- Clinical Laboratory, Anhui Medical University , Hefei , China
| | - Jilong Shen
- Department of Pathogen Biology and Provincial Laboratories of Pathogen Biology and Zoonoses, Anhui Medical University, Hefei, China; Diagnostic Laboratory of the First Affiliated Hospital, Anhui Medical University, Hefei, China
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Shen J, Jiang F, Yang Y, Huang G, Pu F, Liu Q, Chen L, Ju L, Lu M, Zhou F, Zhang C, Luo X, Yang X, Jiao C, Li X, Li Z, Li Y, Zhang J. 14-3-3η is a novel growth-promoting and angiogenic factor in hepatocellular carcinoma. J Hepatol 2016; 65:953-962. [PMID: 27210426 DOI: 10.1016/j.jhep.2016.05.017] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 04/20/2016] [Accepted: 05/11/2016] [Indexed: 01/08/2023]
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The continued search for novel therapeutic strategies for HCC is urgently required. In this study, we aimed to investigate the functions and clinical significance of 14-3-3η protein in HCC. METHODS Expressions of genes and proteins were determined by quantitative reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry. Their functions were assessed by endothelial cell recruitment, tube formation, wound healing, flow cytometry, immunostaining, immunoprecipitation, and xenograft assay. A tissue microarray followed by univariate and multivariate analyses was performed to indicate the clinical significance. RESULTS In HCC specimens, overexpression of 14-3-3η was observed not only in tumors but also in intratumoral vessels. In HCC and vascular endothelial cells, 14-3-3η stimulated proliferation and angiogenesis, but attenuated the functions of sorafenib. Briefly, 14-3-3η facilitated the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2). Then, by binding to the phosphorylated-ERK1/2 (p-ERK1/2), formed a functional positive feed-back loop. A xenograft model showed that, blockage of either 14-3-3η or ERK1/2 inhibited the tumor growth. Finally, tissue microarray analyses showed that overexpression of 14-3-3η, either in tumors or intratumoral vessels, contributed to the poor survival. CONCLUSIONS The 14-3-3η-ERK1/2 feedback loop played a characteristic growth-promoting role in HCC, not only in tumors but also in intratumoral vessels. Further, 14-3-3η could be a potential therapeutic target for HCC and a biomarker for predicting sorafenib treatment response. LAY SUMMARY Here we found that, 14-3-3η protein exhibited a characteristic growth-promoting effect in both tumor and intratumoral vessels of hepatocellular carcinoma by interacting with ERK1/2 signaling.
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Affiliation(s)
- Jian Shen
- Department of General Surgery, The Second Affiliated Hospital, Nanjing Medical University, China
| | - Fei Jiang
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, China
| | - Ye Yang
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, China
| | - Guangming Huang
- Department of Medical Center for Digestive Diseases, The Second Affiliated Hospital, Nanjing Medical University, China
| | - Fuxing Pu
- Department of Medical Center for Digestive Diseases, The Second Affiliated Hospital, Nanjing Medical University, China
| | - Qinqiang Liu
- Department of General Surgery, The Second Affiliated Hospital, Nanjing Medical University, China
| | - Lijun Chen
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, China
| | - Liang Ju
- Department of General Surgery, The Second Affiliated Hospital, Nanjing Medical University, China
| | - Ming Lu
- Department of General Surgery, The Second Affiliated Hospital, Nanjing Medical University, China
| | - Fei Zhou
- Department of General Surgery, The Second Affiliated Hospital, Nanjing Medical University, China
| | - Chi Zhang
- Department of General Surgery, The Second Affiliated Hospital, Nanjing Medical University, China
| | - Xiagang Luo
- Department of General Surgery, The Second Affiliated Hospital, Nanjing Medical University, China
| | - Xiaojun Yang
- Department of General Surgery, The Second Affiliated Hospital, Nanjing Medical University, China
| | - Chengyu Jiao
- Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiangcheng Li
- Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhong Li
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, China
| | - Yuan Li
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, China.
| | - Jianping Zhang
- Department of General Surgery, The Second Affiliated Hospital, Nanjing Medical University, China.
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Kubo N, Araki K, Kuwano H, Shirabe K. Cancer-associated fibroblasts in hepatocellular carcinoma. World J Gastroenterol 2016; 22:6841-6850. [PMID: 27570421 PMCID: PMC4974583 DOI: 10.3748/wjg.v22.i30.6841] [Citation(s) in RCA: 137] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 06/09/2016] [Accepted: 07/06/2016] [Indexed: 02/06/2023] Open
Abstract
The hepatic stellate cells in the liver are stimulated sustainably by chronic injury of the hepatocytes, activating myofibroblasts, which produce abundant collagen. Myofibroblasts are the major source of extracellular proteins during fibrogenesis, and may directly, or secreted products, contribute to carcinogenesis and tumor progression. Cancer-associated fibroblasts (CAFs) are one of the components of the tumor microenvironment that promote the proliferation and invasion of cancer cells by secreting various growth factors and cytokines. CAFs crosstalk with cancer cells stimulates tumor progression by creating a favorable microenvironment for progression, invasion, and metastasis through the epithelial-mesenchymal transition. Basic studies on CAFs have advanced, and the role of CAFs in tumors has been elucidated. In particular, for hepatocellular carcinoma, carcinogenesis from cirrhosis is a known fact, and participation of CAFs in carcinogenesis is supported. In this review, we discuss the current literature on the role of CAFs and CAF-related signaling in carcinogenesis, crosstalk with cancer cells, immunosuppressive effects, angiogenesis, therapeutic targets, and resistance to chemotherapy. The role of CAFs is important in cancer initiation and progression. CAFtargeted therapy may be effective for suppression not only of fibrosis but also cancer progression.
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Gong Y, Zhan T, Li Q, Zhang G, Tan B, Yang X, Wu Y, Que W, Xing Y, Liu H, Hu X, Yu Z. Serum progranulin levels are elevated in patients with chronic hepatitis B virus infection, reflecting viral load. Cytokine 2016; 85:26-9. [PMID: 27281451 DOI: 10.1016/j.cyto.2016.05.026] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 05/26/2016] [Accepted: 05/30/2016] [Indexed: 12/13/2022]
Abstract
Progranulin (PGRN) is implicated in infection, immunity and host defense, but its role in the pathogenesis of HBV infection remains unknown. Here we investigated whether there is dysregulated production and the clinical significance of circulating PGRN in patients with chronic HBV infection. Serum concentrations of PGRN were analyzed by enzyme-linked immunosorbent assay. Serum PGRN levels were significantly higher in patients with chronic HBV infection than healthy subjects. PGRN levels were significantly associated with HBV-DNA levels, but did not correlate with the concentrations of alanine aminotransferase and aspartate aminotransferase. This study demonstrates increased circulating PGRN production and association between PGRN levels and viral loads in patients with chronic HBV infection, suggesting a functional role of PGRN in the pathogenesis of HBV infection.
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Affiliation(s)
- Yi Gong
- Department of Blood Transfusion, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Tingxi Zhan
- Department of Blood Transfusion, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qing Li
- Department of Blood Transfusion, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Guozhen Zhang
- Department of Blood Transfusion, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bing Tan
- Department of Blood Transfusion, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaoliang Yang
- Department of Blood Transfusion, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yan Wu
- Department of Blood Transfusion, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wenjuan Que
- Department of Blood Transfusion, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yan Xing
- Department of Blood Transfusion, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hui Liu
- Department of Blood Transfusion, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xue Hu
- Department of Blood Transfusion, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zebo Yu
- Department of Blood Transfusion, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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