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Chen L, Gao M, Ong SB, Gong G. Functions of FGF21 and its role in cardiac hypertrophy. J Adv Res 2025:S2090-1232(25)00148-1. [PMID: 40089060 DOI: 10.1016/j.jare.2025.03.007] [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: 12/04/2024] [Revised: 03/03/2025] [Accepted: 03/03/2025] [Indexed: 03/17/2025] Open
Abstract
BACKGROUND FGF21 is a stress-inducible hormone that operates in the autocrine or paracrine manner. Recent reports have revealed that FGF21 is highly expressed in cardiac hypertrophy to protect against heart injury and dysfunction. FGF21 is used to treat cardiac hypertrophy in mouse models. However, preclinical and clinical trials are restricted. AIM OF REVIEW This review mainly elucidates the diverse functions of FGF21 and explores the relationship between these functions and cardiac hypertrophy. It also discusses challenges and future perspectives in treating cardiac hypertrophy with FGF21. KEY SCIENTIFIC CONCEPTS OF REVIEW This review first illustrates the functions of FGF21, including energy metabolism, inflammation, oxidative stress, apoptosis, and autophagy. We also summarize vital functions and the underlying mechanisms through which FGF21 regulates the initiation and development of cardiac hypertrophy, connecting energy metabolism, inflammation, oxidative stress, apoptosis, and autophagy. Finally, we propose that FGF21 may be a potential therapeutic strategy for cardiac hypertrophy.
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Affiliation(s)
- Lei Chen
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China; Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Meng Gao
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China; Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Sang-Bing Ong
- Department of Medicine and Therapeutics, Faculty of Medicine, Chinese University of Hong Kong (CUHK), China
| | - Guohua Gong
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325035, China; Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
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Mahadevan A, Yazdanpanah O, Patel V, Benjamin DJ, Kalebasty AR. Ophthalmologic toxicities of antineoplastic agents in genitourinary cancers: Mechanisms, management, and clinical implications. Curr Probl Cancer 2025; 54:101171. [PMID: 39708456 DOI: 10.1016/j.currproblcancer.2024.101171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 11/19/2024] [Accepted: 11/29/2024] [Indexed: 12/23/2024]
Abstract
Genitourinary cancers affect over 480,000 patients in the United States annually. While promising therapeutic modalities continue to emerge, notably immune checkpoint inhibitors, molecular targeted therapies, antibody-drug conjugates, and radioligand therapies, these treatments are associated with a spectrum of adverse side-effects, including ophthalmologic toxicities. In this review, we cover the most commonly used antineoplastic agents for the kidneys, bladder, urinary tracts, prostate, testis, and penis, detailing mechanism, indication, and recent trials supporting their use. For each category of antineoplastic therapy, we describe the epidemiology, management, and clinical presentation, of common ophthalmologic toxicities stemming from these agents. This review serves to augment awareness and recognition of possible ophthalmologic manifestations resulting from the use of antineoplastic agents in genitourinary malignancy. Early identification of these side effects can hasten ophthalmology referral and ultimately improve visual outcomes in patients experiencing medication-induced ocular toxicities.
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Affiliation(s)
- Aditya Mahadevan
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
| | - Omid Yazdanpanah
- Division of Hematology/Oncology, University of California Irvine Health, Orange, CA, USA.
| | - Vivek Patel
- Department of Ophthalmology, University of California Irvine Health, Orange, CA, USA.
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Wilson R, Mukherjee-Roy N, Gattineni J. The role of fibroblast growth factor 23 in regulation of phosphate balance. Pediatr Nephrol 2024; 39:3439-3451. [PMID: 38874635 DOI: 10.1007/s00467-024-06395-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 04/22/2024] [Accepted: 04/22/2024] [Indexed: 06/15/2024]
Abstract
Phosphate is essential for numerous biological processes, and serum levels are tightly regulated to accomplish these functions. The regulation of serum phosphate in a narrow physiological range is a well-orchestrated process and involves the gastrointestinal (GI) tract, bone, kidneys, and several hormones, namely, parathyroid hormone, fibroblast growth factor 23 (FGF23), and 1,25-dihydroxyvitamin D (1,25 Vitamin D). Although primarily synthesized in the bone, FGF23, an endocrine FGF, acts on the kidney to regulate phosphate and Vitamin D homeostasis by causing phosphaturia and reduced levels of 1,25 Vitamin D. Recent studies have highlighted the complex regulation of FGF23 including transcriptional and post-translational modification and kidney-bone cross talk. Understanding FGF23 biology has led to the identification of novel therapeutic agents to treat diseases that disrupt phosphate metabolism secondary to FGF23. The focus of this review is to provide an overview of phosphate homeostasis, FGF23 biology, and the role of FGF23 in phosphate balance.
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Affiliation(s)
| | - Neije Mukherjee-Roy
- Division of Pediatric Nephrology, Department of Pediatrics, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, USA
| | - Jyothsna Gattineni
- Division of Pediatric Nephrology, Department of Pediatrics, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, USA.
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Wiens KR, Wasti N, Ulloa OO, Klegeris A. Diversity of Microglia-Derived Molecules with Neurotrophic Properties That Support Neurons in the Central Nervous System and Other Tissues. Molecules 2024; 29:5525. [PMID: 39683685 DOI: 10.3390/molecules29235525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 11/12/2024] [Accepted: 11/18/2024] [Indexed: 12/18/2024] Open
Abstract
Microglia, the brain immune cells, support neurons by producing several established neurotrophic molecules including glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF). Modern analytical techniques have identified numerous phenotypic states of microglia, each associated with the secretion of a diverse set of substances, which likely include not only canonical neurotrophic factors but also other less-studied molecules that can interact with neurons and provide trophic support. In this review, we consider the following eight such candidate cytokines: oncostatin M (OSM), leukemia inhibitory factor (LIF), activin A, colony-stimulating factor (CSF)-1, interleukin (IL)-34, growth/differentiation factor (GDF)-15, fibroblast growth factor (FGF)-2, and insulin-like growth factor (IGF)-2. The available literature provides sufficient evidence demonstrating murine cells produce these cytokines and that they exhibit neurotrophic activity in at least one neuronal model. Several distinct types of neurotrophic activity are identified that only partially overlap among the cytokines considered, reflecting either their distinct intrinsic properties or lack of comprehensive studies covering the full spectrum of neurotrophic effects. The scarcity of human-specific studies is another significant knowledge gap revealed by this review. Further studies on these potential microglia-derived neurotrophic factors are warranted since they may be used as targeted treatments for diverse neurological disorders.
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Affiliation(s)
- Kennedy R Wiens
- Laboratory of Cellular and Molecular Pharmacology, Department of Biology, University of British Columbia, Okanagan Campus, Kelowna, BC V1V 1V7, Canada
| | - Naved Wasti
- Laboratory of Cellular and Molecular Pharmacology, Department of Biology, University of British Columbia, Okanagan Campus, Kelowna, BC V1V 1V7, Canada
| | - Omar Orlando Ulloa
- Laboratory of Cellular and Molecular Pharmacology, Department of Biology, University of British Columbia, Okanagan Campus, Kelowna, BC V1V 1V7, Canada
| | - Andis Klegeris
- Laboratory of Cellular and Molecular Pharmacology, Department of Biology, University of British Columbia, Okanagan Campus, Kelowna, BC V1V 1V7, Canada
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Morita H, Hoshiga M. Fibroblast Growth Factors in Cardiovascular Disease. J Atheroscler Thromb 2024; 31:1496-1511. [PMID: 39168622 PMCID: PMC11537794 DOI: 10.5551/jat.rv22025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 07/03/2024] [Indexed: 08/23/2024] Open
Abstract
Despite advancements in managing traditional cardiovascular risk factors, many cardiovascular diseases (CVDs) persist. Fibroblast growth factors (FGFs) have emerged as potential diagnostic markers and therapeutic targets for CVDs. FGF1, FGF2, and FGF4 are primarily used for therapeutic angiogenesis. Clinical applications are being explored based on animal studies using approaches such as recombinant protein administration and adenovirus-mediated gene delivery, targeting patients with coronary artery disease and lower extremity arterial disease. Although promising results have been observed in animal models and early-stage clinical trials, further studies are required to assess their therapeutic potential. The FGF19 subfamily, consisting of FGF19, FGF21, and FGF23, act via endocrine signaling in various organs. FGF19, primarily expressed in the small intestine, plays important roles in glucose, lipid, and bile acid metabolism and has therapeutic potential for metabolic disorders. FGF21, found in various tissues, improves glucose metabolism and insulin sensitivity, suggesting potential for treating obesity and diabetes. FGF23, primarily secreted by osteocytes, regulates vitamin D and phosphate metabolism and serves as an important biomarker for chronic kidney disease and CVDs. Thus, FGFs holds promise for both therapeutic and diagnostic applications in metabolic and cardiovascular diseases. Understanding the mechanisms of FGF may pave the way for novel strategies to prevent and manage CVDs, potentially addressing the limitations of current treatments. This review explores the roles of FGF1, FGF2, FGF4, and the FGF19 subfamily in maintaining cardiovascular health. Further research and clinical trials are crucial to fully understand the therapeutic potential of FGFs in managing cardiovascular health.
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Affiliation(s)
- Hideaki Morita
- Department of Cardiology, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Masaaki Hoshiga
- Department of Cardiology, Osaka Medical and Pharmaceutical University, Osaka, Japan
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Xiao W, Xu L, Wang J, Yu K, Xu B, Que Y, Zhao J, Pan Q, Gao C, Zhou P, Zhang X. FGFR4-specific CAR-T cells with inducible caspase-9 suicide gene as an approach to treat rhabdomyosarcoma. Cancer Gene Ther 2024; 31:1571-1584. [PMID: 39183354 PMCID: PMC11489081 DOI: 10.1038/s41417-024-00823-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 07/24/2024] [Accepted: 08/12/2024] [Indexed: 08/27/2024]
Abstract
Metastatic rhabdomyosarcoma is associated with poor survival and unsatisfactory treatment outcomes. Therefore, new immunotherapeutic methods are urgently required. Fibroblast growth factor receptor 4 (FGFR4), a new therapeutic target for rhabdomyosarcoma, plays a crucial role in its onset and development. This study aimed to generate FGFR4 single-chain variable fragment-based chimeric antigen receptor (CAR) T cells without causing evident toxicity and incorporating an inducible caspase-9 (iCasp9) suicide gene system to enhance their safety. FGFR4 antigen expression was evaluated in normal murine tissues, normal human tissues, and specimens from patients with rhabdomyosarcoma. Combined with a 4-1BB co-stimulatory domain, a CD3ζ signaling domain, and an iCasp9 suicide gene, CAR-T cells with an FGFR4-specific single-chain variable fragment were developed. The specific cytotoxic effects, T-cell proliferation, cytokine secretion, apoptosis induction by chemical dimerization (AP20187), and toxicity of FGFR4 CAR-T cells were investigated in vitro and in vivo. FGFR4 CAR-T cells generated a variety of immune-promoting cytokines, including tumor necrosis factor α, interleukin 2, and interferon γ, and displayed effective cytotoxic activity against FGFR4-overexpressing rhabdomyosarcoma cells in vitro. FGFR4 CAR-T cells were relatively effective against FGFR4-overexpressing rhabdomyosarcoma, with tumor regression and poor survival in a subcutaneous xenograft model. The iCasp9 gene was incorporated into FGFR4 CAR-T cells and it was demonstrated that effective and reliable suicide gene activity depends on the administration of AP20187. By making use of the cross-reaction of FGFR4 CAR-T cells with murine FGFR4 in a syngeneic tumor model, this study found that FGFR4 CAR-T cells could regulate the growth of tumors without evident toxicity. Our study demonstrates that FGFR4 is a prospective target for CAR-T cell therapy in rhabdomyosarcoma without serious on-target off-tumor toxicity. FGFR4 CAR-T cells with the iCasp9 suicide gene system as a safety switch to limit toxicity may broaden the clinical applications of cellular therapy.
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MESH Headings
- Rhabdomyosarcoma/therapy
- Rhabdomyosarcoma/genetics
- Animals
- Humans
- Mice
- Receptor, Fibroblast Growth Factor, Type 4/genetics
- Receptor, Fibroblast Growth Factor, Type 4/metabolism
- Genes, Transgenic, Suicide
- Receptors, Chimeric Antigen/genetics
- Receptors, Chimeric Antigen/immunology
- Receptors, Chimeric Antigen/metabolism
- Caspase 9/genetics
- Caspase 9/metabolism
- Immunotherapy, Adoptive/methods
- Cell Line, Tumor
- Xenograft Model Antitumor Assays
- Apoptosis
- Female
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Affiliation(s)
- Wei Xiao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, China
- Melanoma and Sarcoma Medical Oncology Unit, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, China
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-sen University, 628 Zhenyuan Road, Guangming District, Shenzhen, Guangdong, 518107, China
| | - Liping Xu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, China
- Department of Experimental Research, Sun Yat-Sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, China
| | - Jinghua Wang
- Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, China
| | - Kuai Yu
- Department of Blood Transfusion, The First Affiliated Hospital of Nanchang University, 17 Yongwaizheng Street, Nanchang, Jiangxi, 330209, China
- Key Laboratory of Jiangxi Province for Transfusion Medicine, The First Affiliated Hospital of Nanchang University, 17 Yongwaizheng Street, Nanchang, Jiangxi, 330209, China
| | - Bushu Xu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, China
- Melanoma and Sarcoma Medical Oncology Unit, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, China
| | - Yi Que
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, China
- Melanoma and Sarcoma Medical Oncology Unit, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, China
| | - Jingjing Zhao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, China
- Melanoma and Sarcoma Medical Oncology Unit, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, China
| | - Qiuzhong Pan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, China
- Melanoma and Sarcoma Medical Oncology Unit, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, China
| | - Chengqi Gao
- Department of Blood Transfusion, The First Affiliated Hospital of Nanchang University, 17 Yongwaizheng Street, Nanchang, Jiangxi, 330209, China
- Key Laboratory of Jiangxi Province for Transfusion Medicine, The First Affiliated Hospital of Nanchang University, 17 Yongwaizheng Street, Nanchang, Jiangxi, 330209, China
| | - Penghui Zhou
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, China.
- Department of Experimental Research, Sun Yat-Sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, China.
| | - Xing Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, China.
- Melanoma and Sarcoma Medical Oncology Unit, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, China.
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Fujii I, Kinoshita R, Akiyama H, Nakamura A, Iwamori K, Fukada SI, Honda H, Shimizu K. Discovery of fibroblast growth factor 2-derived peptides for enhancing mice skeletal muscle satellite cell proliferation. Biotechnol J 2024; 19:e2400278. [PMID: 39212202 DOI: 10.1002/biot.202400278] [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: 04/24/2024] [Revised: 07/20/2024] [Accepted: 07/26/2024] [Indexed: 09/04/2024]
Abstract
Skeletal muscle satellite cells (SCs) are essential for muscle regeneration. Their proliferation and differentiation are influenced by fibroblast growth factor (FGF)-2. In this study, we screened for FGF-2-derived peptides that promote SC proliferation. Utilizing photocleavable peptide array technology, a library of 7-residue peptides was synthesized, and its effect on SC proliferation was examined using a mixture of five peptides. The results showed that peptides 1-5 (136%), 21-25 (136%), 26-30 (141%), 31-35 (159%), 71-75 (135%), 76-80 (144%), and 126-130 (137%) significantly increased SC proliferation. Further experiments revealed that peptide 33, CKNGGFF, enhanced SC proliferation. Furthermore, its extended form, peptide 33-13, CKNGGFFLRIHPD, promoted SC proliferation and increased the percentage of Pax7-positive cells, indicating that SCs were maintained in an undifferentiated state. The addition of FGF-2 and peptide 33-13 further induced cell proliferation but did not increase the percentage of Pax7-positive cells. A proliferation assay using an FGF receptor (FGFR) inhibitor suggested that peptide 33-13 acts through the FGFR-mediated and other pathways. Although further research is necessary to explore the mechanisms of action of these peptides and their potential for in vivo and in vitro use, the high sequence conservation of peptides 33 and 33-13 in FGF-2 across multiple species suggests their broad application prospects in biomedical engineering and biotechnology.
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Affiliation(s)
- Itsuki Fujii
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Nagoya, Japan
| | - Remi Kinoshita
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Nagoya, Japan
| | - Hirokazu Akiyama
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Nagoya, Japan
| | - Ayasa Nakamura
- Laboratory of Stem Cell Regeneration and Adaptation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Kanako Iwamori
- Laboratory of Stem Cell Regeneration and Adaptation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - So-Ichiro Fukada
- Laboratory of Stem Cell Regeneration and Adaptation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Hiroyuki Honda
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Nagoya, Japan
| | - Kazunori Shimizu
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Nagoya, Japan
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Zhao R, Yin F, Fredimoses M, Zhao J, Fu X, Xu B, Liang M, Chen H, Liu K, Lei M, Laster KV, Li Z, Kundu JK, Dong Z, Lee MH. Targeting FGFR1 by β,β-dimethylacrylalkannin suppresses the proliferation of colorectal cancer in cellular and xenograft models. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 129:155612. [PMID: 38669968 DOI: 10.1016/j.phymed.2024.155612] [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: 03/05/2024] [Accepted: 04/07/2024] [Indexed: 04/28/2024]
Abstract
BACKGROUND Colorectal cancer (CRC) continues to be a major global health challenge, ranking as a top cause of cancer-related mortality. Alarmingly, the five-year survival rate for CRC patients hovers around a mere 10-30 %. The disruption of fibroblast growth factor receptor (FGFRs) signaling pathways is significantly implicated in the onset and advancement of CRC, presenting a promising target for therapeutic intervention in CRC management. Further investigation is essential to comprehensively elucidate FGFR1's function in CRC and to create potent therapies that specifically target FGFR1. PURPOSE This study aims to demonstrate the oncogenic role of FGFR1 in colorectal cancer and to explore the potential of β,β-dimethylacrylalkannin (β,β-DMAA) as a therapeutic option to inhibit FGFR1. METHODS In this research, we employed a comprehensive suite of techniques including tissue array, kinase profiling, computational docking, knockdown assay to predict and explore the inhibitor of FGFR1. Furthermore, we utilized kinase assay, pull-down, cell proliferation tests, and Patient derived xenograft (PDX) mouse models to further investigate a novel FGFR1 inhibitor and its impact on the growth of CRC. RESULTS In our research, we discovered that FGFR1 protein is markedly upregulated in colorectal cancer tissues, suggesting a significant role in regulating cellular proliferation, particularly in patients with colorectal cancer. Furthermore, we conducted a computational docking, kinase profiling analysis, simulation and identified that β,β-DMAA could directly bind with FGFR1 within ATP binding pocket domain. Cell-based assays confirmed that β,β-DMAA effectively inhibited the proliferation of colon cancer cells and also triggered cell cycle arrest, apoptosis, and altered FGFR1-mediated signaling pathways. Moreover, β,β-DMAA effectively attenuated the development of PDX tumors in mice that were FGFR1-positive, with no notable toxicity observed. In summary, our study highlights the pivotal role of FGFR1 in colorectal cancer, suggesting that inhibiting FGFR1 activity could be a promising strategy for therapeutic intervention. We present strong evidence that targeting FGFR1 with β,β-DMAA is a viable approach for the management of colorectal cancer. Given its low toxicity and high efficacy, β,β-DMAA, as an FGFR1 inhibitor, warrants further investigation in clinical settings for the treatment of FGFR1-positive tumors.
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Affiliation(s)
- Ran Zhao
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China; Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou 450000, China
| | - Fanxiang Yin
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China; Translational Medical Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
| | | | - Jianhua Zhao
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China
| | - Xiaorong Fu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China
| | - Beibei Xu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China
| | - Mengrui Liang
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China
| | - Hanyong Chen
- The Hormel Institute, University of Minnesota, Austin, MN55912, USA
| | - Kangdong Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou 450000, China
| | - Mingjuan Lei
- China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China
| | | | - Zhi Li
- Department of General Surgery, the Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou 450000, China
| | - Joydeb Kumar Kundu
- Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton AB T6G 2R3, Canada
| | - Zigang Dong
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China; Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou 450000, China.
| | - Mee-Hyun Lee
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China; The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou 450000, China; College of Korean Medicine, Dongshin University, Naju 58245, Republic of Korea.
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9
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Cheng MF, Abdullah FS, Buechler MB. Essential growth factor receptors for fibroblast homeostasis and activation: Fibroblast Growth Factor Receptor (FGFR), Platelet Derived Growth Factor Receptor (PDGFR), and Transforming Growth Factor β Receptor (TGFβR). F1000Res 2024; 13:120. [PMID: 38988879 PMCID: PMC11234085 DOI: 10.12688/f1000research.143514.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/17/2024] [Indexed: 07/12/2024] Open
Abstract
Fibroblasts are cells of mesenchymal origin that are found throughout the body. While these cells have several functions, their integral roles include maintaining tissue architecture through the production of key extracellular matrix components, and participation in wound healing after injury. Fibroblasts are also key mediators in disease progression during fibrosis, cancer, and other inflammatory diseases. Under these perturbed states, fibroblasts can activate into inflammatory fibroblasts or contractile myofibroblasts. Fibroblasts require various growth factors and mitogenic molecules for survival, proliferation, and differentiation. While the activity of mitogenic growth factors on fibroblasts in vitro was characterized as early as the 1970s, the proliferation and differentiation effects of growth factors on these cells in vivo are unclear. Recent work exploring the heterogeneity of fibroblasts raises questions as to whether all fibroblast cell states exhibit the same growth factor requirements. Here, we will examine and review existing studies on the influence of fibroblast growth factor receptors (FGFRs), platelet-derived growth factor receptors (PDGFRs), and transforming growth factor β receptor (TGFβR) on fibroblast cell states.
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Affiliation(s)
- Maye F. Cheng
- Immunology, University of Toronto, Toronto, ON, M5S 1A8, Canada
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10
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Zamani M, Skagen K, Lindberg B, Bjerkeli V, Aukrust P, Halvorsen B, Skjelland M. Relationship between fibroblast growth factor in plasma and carotid plaque neovascularization: a pilot study. Front Immunol 2024; 15:1385377. [PMID: 38711510 PMCID: PMC11070475 DOI: 10.3389/fimmu.2024.1385377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 04/08/2024] [Indexed: 05/08/2024] Open
Abstract
Background Unstable atherosclerotic carotid plaques with intraplaque neovascularization (IPN) carry a substantial risk for ischemic stroke. Conventional ultrasound methods fall short in detecting IPN, where superb microvascular imaging (SMI) has emerged as a promising tool for both visualizing and quantification. High levels of fibroblast growth factor 23 (FGF-23) have, in observational studies, been suggested as related to cardiovascular morbidity and mortality. The association of FGF-23 to atherosclerotic carotid plaque instability remains relatively unexplored. Methods A cohort of twenty-nine patients with ≥50% atherosclerotic carotid stenosis underwent conventional carotid ultrasound, SMI, and blood tests, including measurement of FGF-23 in plasma. Nineteen patients were characterized as symptomatic and ten as asymptomatic. Results Our major findings were: i) Higher FGF-23 levels were strongly correlated with increased SMI-assessed IPN. ii) Neo-vessel count recorded by quantitative SMI was positively correlated to increased FGF-23 levels, but not with basic FGF levels. (iii) In contrast, traditional risk factors for plaque instability exhibited no noteworthy associations with SMI-assessed IPN or with FGF-23 levels. Conclusion This pilot study suggest the potential of FGF-23 as a valuable marker for neovascularization and atherosclerotic carotid plaque instability as a risk factor for ischemic stroke. Further research involving larger cohorts and prospective data is necessary to understand FGF-23's role in this context comprehensively.
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Affiliation(s)
- Mahtab Zamani
- Department of Neurology, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Karolina Skagen
- Department of Neurology, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Beate Lindberg
- Department of Cardiothoracic Surgery, Oslo University Hospital, Oslo, Norway
| | - Vigdis Bjerkeli
- Research Institute of Internal Medicine (RIIM), Oslo University Hospital, Oslo, Norway
| | - Pål Aukrust
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine (RIIM), Oslo University Hospital, Oslo, Norway
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Oslo, Norway
| | - Bente Halvorsen
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine (RIIM), Oslo University Hospital, Oslo, Norway
| | - Mona Skjelland
- Department of Neurology, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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11
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Chen X, Qian J, Liang S, Qian J, Luo W, Shi Y, Zhu H, Hu X, Wu G, Li X, Liang G. Hyperglycemia activates FGFR1 via TLR4/c-Src pathway to induce inflammatory cardiomyopathy in diabetes. Acta Pharm Sin B 2024; 14:1693-1710. [PMID: 38572108 PMCID: PMC10985127 DOI: 10.1016/j.apsb.2024.01.013] [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: 09/29/2023] [Revised: 12/11/2023] [Accepted: 01/05/2024] [Indexed: 04/05/2024] Open
Abstract
Protein tyrosine kinases (RTKs) modulate a wide range of pathophysiological events in several non-malignant disorders, including diabetic complications. To find new targets driving the development of diabetic cardiomyopathy (DCM), we profiled an RTKs phosphorylation array in diabetic mouse hearts and identified increased phosphorylated fibroblast growth factor receptor 1 (p-FGFR1) levels in cardiomyocytes, indicating that FGFR1 may contribute to the pathogenesis of DCM. Using primary cardiomyocytes and H9C2 cell lines, we discovered that high-concentration glucose (HG) transactivates FGFR1 kinase domain through toll-like receptor 4 (TLR4) and c-Src, independent of FGF ligands. Knocking down the levels of either TLR4 or c-Src prevents HG-activated FGFR1 in cardiomyocytes. RNA-sequencing analysis indicates that the elevated FGFR1 activity induces pro-inflammatory responses via MAPKs-NFκB signaling pathway in HG-challenged cardiomyocytes, which further results in fibrosis and hypertrophy. We then generated cardiomyocyte-specific FGFR1 knockout mice and showed that a lack of FGFR1 in cardiomyocytes prevents diabetes-induced cardiac inflammation and preserves cardiac function in mice. Pharmacological inhibition of FGFR1 by a selective inhibitor, AZD4547, also prevents cardiac inflammation, fibrosis, and dysfunction in both type 1 and type 2 diabetic mice. These studies have identified FGFR1 as a new player in driving DCM and support further testing of FGFR1 inhibitors for possible cardioprotective benefits.
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Affiliation(s)
- Xiong Chen
- Department of Endocrinology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
- Department of Wound Repair, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China
| | - Jinfu Qian
- Department of Cardiology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China
| | - Shiqi Liang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
- Department of Cardiology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China
| | - Jianchang Qian
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Wu Luo
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Yujuan Shi
- Department of Endocrinology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Hong Zhu
- Department of Endocrinology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China
| | - Xiang Hu
- Department of Endocrinology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China
| | - Gaojun Wu
- Department of Cardiology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China
| | - Xiaokun Li
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
- Department of Wound Repair, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China
| | - Guang Liang
- Department of Endocrinology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325035, China
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou 311399, China
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12
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Hsu J, Francis JH, Ahmad S. Ocular toxicities of fibroblast growth factor receptor inhibitors: A review. Surv Ophthalmol 2024; 69:34-41. [PMID: 37777119 DOI: 10.1016/j.survophthal.2023.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Revised: 09/24/2023] [Accepted: 09/25/2023] [Indexed: 10/02/2023]
Abstract
Fibroblast growth factor receptor (FGFR) inhibitors are an emerging class of small molecule targeted cancer drugs with promising therapeutic possibilities for a wide variety of malignancies. While ocular adverse events from FGFR inhibitors are reported in clinical trials, subsequent case studies continue to reveal new toxicities. Disease pathology affecting multiple parts of the eye has been reported, but the ocular surface and the retina are the most commonly encountered areas affected by FGFR inhibitors, manifesting as dry eye and FGFR inhibitor-associated retinopathy, respectively. Corneal thinning and melt is a rare but serious and potentially vision-threatening complication of FGFR inhibitor toxicity. Similarities between toxicities observed from other targeted cancer therapy drugs and FGFR inhibitors may help us understand underlying pathophysiological changes. The management of these adverse events requires close ophthalmologic follow-up and may require discontinuation of the offending agents in some cases.
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Affiliation(s)
- Jerry Hsu
- New York Eye and Ear Infirmary of Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jasmine H Francis
- Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Ophthalmology, Weill-Cornell Medical Center, New York, NY, USA
| | - Sumayya Ahmad
- New York Eye and Ear Infirmary of Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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13
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Yang J, Li D, Zhang M, Lin G, Hu S, Xu H. From the updated landscape of the emerging biologics for IBDs treatment to the new delivery systems. J Control Release 2023; 361:568-591. [PMID: 37572962 DOI: 10.1016/j.jconrel.2023.08.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/06/2023] [Accepted: 08/06/2023] [Indexed: 08/14/2023]
Abstract
Inflammatory bowel diseases (IBDs) treatments have shifted from small-molecular therapeutics to the oncoming biologics. The first-line biologics against the moderate-to-severe IBDs are mainly involved in antibodies against integrins, cytokines and cell adhesion molecules. Besides, other biologics including growth factors, antioxidative enzyme, anti-inflammatory peptides, nucleic acids, stem cells and probiotics have also been explored at preclinical or clinical studies. Biologics with variety of origins have their unique potentials in attenuating immune inflammation or gut mucosa healing. Great advances in use of biologics for IBDs treatments have been archived in recent years. But delivering issues for biologic have also been confronted due to their liable nature. In this review, we will focus on biologics for IBDs treatments in the recent publications; summarize the current landscapes of biologics and their promise to control disease progress. Alternatively, the confronted challenges for delivering biologics will also be analyzed. To combat these drawbacks, some new delivering strategies are provided: firstly, designing the functional materials with high affinity toward biologics; secondly, the delivering vehicle systems to encapsulate the liable biologics; thirdly, the topical adhering delivery systems as enema. To our knowledge, this review is the first study to summarize the updated usage of the oncoming biologics for IBDs, their confronted challenges in term of delivery and the potential combating strategies.
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Affiliation(s)
- Jiaojiao Yang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Dingwei Li
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Mengjiao Zhang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Gaolong Lin
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Sunkuan Hu
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province 325000, China
| | - Helin Xu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China.
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14
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Kohya R, Suda G, Ohara M, Sasaki T, Yoda T, Sakurai N, Yoshida S, Fu Q, Yang Z, Hosoda S, Maehara O, Ohnishi S, Tokuchi Y, Kitagataya T, Suzuki K, Kawagishi N, Nakai M, Sho T, Natsuizaka M, Ogawa K, Sakamoto N. Potential Correlation between Changes in Serum FGF21 Levels and Lenvatinib-Induced Appetite Loss in Patients with Unresectable Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:3257. [PMID: 37370867 DOI: 10.3390/cancers15123257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 06/16/2023] [Accepted: 06/18/2023] [Indexed: 06/29/2023] Open
Abstract
Lenvatinib, used for unresectable hepatocellular carcinoma (HCC), causes appetite loss, but the underlying mechanisms, clinical impact, and predictive factors have been unclear. The endocrine factor FGF21 modulates appetite and is involved in cachexia. We evaluated the association between FGF21 level changes during lenvatinib treatment for unresectable HCC and appetite loss. Sixty-three eligible unresectable HCC patients who started lenvatinib treatment between 2018 and 2021 were included. We analyzed FGF21 levels at baseline; 1, 2, and 4 weeks after lenvatinib initiation, and before the onset of appetite loss. Grade ≥ 2 lenvatinib-induced appetite loss led to liver functional reserve deterioration at disease progression and a poor prognosis. Baseline characteristics and serum FGF21 levels were similar between patients with and without appetite loss. However, the serum FGF21 change rate increased significantly at 4 weeks post-lenvatinib initiation in patients with grade ≥ 2 appetite loss, as compared to those without appetite loss. Similar significant increases in the serum FGF21 level change rate were observed prior to grade ≥ 2 appetite loss onset. This suggests that changes in FGF21 levels can be used to predict patients with a greater risk of marked appetite loss and provides insights into the mechanisms underlying lenvatinib-induced appetite loss in patients with HCC.
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Grants
- 23fk0210126h0001, 23fk0310501h0002, 23fk0210121h0001, 23fk0210112h0002, 23fk0210111h0002, 23fk0310524h0002, 23fk0210083h0003, 23fk0210113h0002, 23fk0210104h0002, 23fk0210103h0002, 23fk0310518h0002, 23fk0210123h0001 Japan Agency for Medical Research and Development
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Affiliation(s)
- Risako Kohya
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8648, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8648, Japan
| | - Masatsugu Ohara
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8648, Japan
| | - Takashi Sasaki
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8648, Japan
| | - Tomoka Yoda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8648, Japan
| | - Naofumi Sakurai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8648, Japan
| | - Sonoe Yoshida
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8648, Japan
| | - Qingjie Fu
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8648, Japan
| | - Zijian Yang
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8648, Japan
| | - Shunichi Hosoda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8648, Japan
| | - Osamu Maehara
- Laboratory of Molecular and Cellular Medicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-8648, Japan
| | - Shunsuke Ohnishi
- Laboratory of Molecular and Cellular Medicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-8648, Japan
| | - Yoshimasa Tokuchi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8648, Japan
| | - Takashi Kitagataya
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8648, Japan
| | - Kazuharu Suzuki
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8648, Japan
| | - Naoki Kawagishi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8648, Japan
| | - Masato Nakai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8648, Japan
| | - Takuya Sho
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8648, Japan
| | - Mitsuteru Natsuizaka
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8648, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8648, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8648, Japan
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15
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Yan B, Mei Z, Tang Y, Song H, Wu H, Jing Q, Zhang X, Yan C, Han Y. FGF21-FGFR1 controls mitochondrial homeostasis in cardiomyocytes by modulating the degradation of OPA1. Cell Death Dis 2023; 14:311. [PMID: 37156793 PMCID: PMC10167257 DOI: 10.1038/s41419-023-05842-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 04/25/2023] [Accepted: 04/28/2023] [Indexed: 05/10/2023]
Abstract
Fibroblast growth factor 21 (FGF21) is a pleiotropic hormone secreted primarily by the liver and is considered a major regulator of energy homeostasis. Recent research has revealed that FGF21 could play an important role in cardiac pathological remodeling effects and prevention of cardiomyopathy; however, the underlying mechanism remains largely unknown. This study aimed to determine the mechanism underlying the cardioprotective effects of FGF21. We engineered FGF21 knock out mice and subsequently elucidated the effects of FGF21 and its downstream mediators using western blotting, qRT-PCR, and mitochondrial morphological and functional analyses. FGF21 knockout mice showed cardiac dysfunction, accompanied by a decline in global longitudinal strain (GLS) and ejection fraction (EF), independent of metabolic disorders. Mitochondrial quality, quantity, and function were abnormal, accompanied by decreased levels of optic atrophy-1 (OPA1) in FGF21 KO mice. In contrast to FGF21 knockout, cardiac-specific overexpression of FGF21 alleviated the cardiac dysfunction caused by FGF21 deficiency. In an in vitro study, FGF21 siRNA deteriorated mitochondrial dynamics and impaired function induced by cobalt chloride (CoCl2). Both recombinant FGF21 and adenovirus-mediated FGF21 overexpression could alleviate CoCl2-induced mitochondrial impairment by restoring mitochondrial dynamics. FGF21 was essential for maintaining mitochondrial dynamics and function of the cardiomyocytes. As a regulator of cardiomyocyte mitochondrial homeostasis under oxidative stress, FGF21 could be an important new target for therapeutic options for patients with heart failure.
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Affiliation(s)
- Bing Yan
- National Key Laboratory of Frigid Zone Cardiovascular Disease, Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, 110016, China
- Department of Cardiology, Second Hospital of Jilin University, No. 218 Ziqiang Street, Changchun, 130041, China
| | - Zhu Mei
- National Key Laboratory of Frigid Zone Cardiovascular Disease, Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, 110016, China
| | - Yaohan Tang
- National Key Laboratory of Frigid Zone Cardiovascular Disease, Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, 110016, China
| | - Haixu Song
- National Key Laboratory of Frigid Zone Cardiovascular Disease, Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, 110016, China
| | - Hanlin Wu
- National Key Laboratory of Frigid Zone Cardiovascular Disease, Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, 110016, China
| | - Quanmin Jing
- National Key Laboratory of Frigid Zone Cardiovascular Disease, Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, 110016, China
| | - Xiaolin Zhang
- National Key Laboratory of Frigid Zone Cardiovascular Disease, Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, 110016, China
| | - Chenghui Yan
- National Key Laboratory of Frigid Zone Cardiovascular Disease, Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, 110016, China.
| | - Yaling Han
- National Key Laboratory of Frigid Zone Cardiovascular Disease, Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, 110016, China.
- Department of Cardiology, Second Hospital of Jilin University, No. 218 Ziqiang Street, Changchun, 130041, China.
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16
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Li Z, Zhang X, Zhu W, Zhang C, Sadak K, Halberstam AA, Brown JR, Perry CJ, Bunn A, Braun DA, Adeniran A, Lee S, Wang A, Perry RJ. FGF-21 Conducts a Liver-Brain-Kidney Axis to Promote Renal Cell Carcinoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.12.536558. [PMID: 37090652 PMCID: PMC10120688 DOI: 10.1101/2023.04.12.536558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/25/2023]
Abstract
Metabolic homeostasis is one of the most exquisitely tuned systems in mammalian physiology. Metabolic homeostasis requires multiple redundant systems to cooperate to maintain blood glucose concentrations in a narrow range, despite a multitude of physiological and pathophysiological pressures. Cancer is one of the canonical pathophysiological settings in which metabolism plays a key role. In this study, we utilized REnal Gluconeogenesis Analytical Leads (REGAL), a liquid chromatography-mass spectrometry/mass spectrometry-based stable isotope tracer method that we developed to show that in conditions of metabolic stress, the fasting hepatokine fibroblast growth factor-21 (FGF-21)1,2 coordinates a liver-brain-kidney axis to promote renal gluconeogenesis. FGF-21 promotes renal gluconeogenesis by enhancing β2 adrenergic receptor (Adrb2)-driven, adipose triglyceride lipase (ATGL)-mediated intrarenal lipolysis. Further, we show that this liver-brain-kidney axis promotes gluconeogenesis in the renal parenchyma in mice and humans with renal cell carcinoma (RCC). This increased gluconeogenesis is, in turn, associated with accelerated RCC progression. We identify Adrb2 blockade as a new class of therapy for RCC in mice, with confirmatory data in human patients. In summary, these data reveal a new metabolic function of FGF-21 in driving renal gluconeogenesis, and demonstrate that inhibition of renal gluconeogenesis by FGF-21 antagonism deserves attention as a new therapeutic approach to RCC.
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Affiliation(s)
- Zongyu Li
- Department of Internal Medicine, Yale University School of Medicine
- Department of Cellular & Molecular Physiology, Yale University School of Medicine
| | - Xinyi Zhang
- Department of Internal Medicine, Yale University School of Medicine
- Department of Cellular & Molecular Physiology, Yale University School of Medicine
| | - Wanling Zhu
- Department of Internal Medicine, Yale University School of Medicine
- Department of Cellular & Molecular Physiology, Yale University School of Medicine
| | - Cuiling Zhang
- Department of Internal Medicine, Yale University School of Medicine
- Department of Immunobiology, Yale University School of Medicine
| | - Katherine Sadak
- Department of Internal Medicine, Yale University School of Medicine
| | - Alexandra A Halberstam
- Department of Internal Medicine, Yale University School of Medicine
- Department of Cellular & Molecular Physiology, Yale University School of Medicine
| | - Jason R Brown
- Department of Internal Medicine, Division of Medical Oncology, University Hospitals Seidman Cancer Center
- Case Western Reserve University
| | - Curtis J Perry
- Department of Internal Medicine, Yale University School of Medicine
| | - Azia Bunn
- Department of Internal Medicine, Yale University School of Medicine
- Yale Cancer Center, Yale University School of Medicine
| | - David A Braun
- Department of Internal Medicine, Yale University School of Medicine
- Yale Cancer Center, Yale University School of Medicine
| | | | - Sangwon Lee
- Department of Pharmacology, Yale University School of Medicine
| | - Andrew Wang
- Department of Internal Medicine, Yale University School of Medicine
- Department of Immunobiology, Yale University School of Medicine
| | - Rachel J Perry
- Department of Internal Medicine, Yale University School of Medicine
- Department of Cellular & Molecular Physiology, Yale University School of Medicine
- Yale Cancer Center, Yale University School of Medicine
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17
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Chikamatsu M, Watanabe H, Shintani Y, Murata R, Miyahisa M, Nishinoiri A, Imafuku T, Takano M, Arimura N, Yamada K, Kamimura M, Mukai B, Satoh T, Maeda H, Maruyama T. Albumin-fused long-acting FGF21 analogue for the treatment of non-alcoholic fatty liver disease. J Control Release 2023; 355:42-53. [PMID: 36690035 DOI: 10.1016/j.jconrel.2023.01.039] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 01/03/2023] [Accepted: 01/14/2023] [Indexed: 01/25/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) currently affects about 25% of the world's population, and the numbers continue to rise as the number of obese patients increases. However, there are currently no approved treatments for NAFLD. This study reports on the evaluation of the therapeutic effect of a recombinant human serum albumin-fibroblast growth factor 21 analogue fusion protein (HSA-FGF21) on the pathology of NAFLD that was induced by using two high-fat diets (HFD), HFD-60 and STHD-01. The HFD-60-induced NAFLD model mice with obesity, insulin resistance, dyslipidemia and hepatic lipid accumulation were treated with HSA-FGF21 three times per week for 4 weeks starting at 12 weeks after the HFD-60 feeding. The administration of HSA-FGF21 suppressed the increased body weight, improved hyperglycemia, hyperinsulinemia, and showed a decreased accumulation of plasma lipid and hepatic lipid levels. The elevation of C16:0, C18:0 and C18:1 fatty acids in the liver that were observed in the HFD-60 group was recovered by the HSA-FGF21 administration. The increased expression levels of the hepatic fatty acid uptake receptor (CD36) and fatty acid synthase (SREBP-1c, FAS, SCD-1, Elovl6) were also suppressed. In adipose tissue, HSA-FGF21 caused an improved adipocyte hypertrophy, a decrease in the levels of inflammatory cytokines and induced the expression of adiponectin and thermogenic factors. The administration of HSA-FGF21 to the STHD-01-induced NAFLD model mice resulted in suppressed plasma ALT and AST levels, oxidative stress, inflammatory cell infiltration and fibrosis. Together, HSA-FGF21 has some potential for use as a therapeutic agent for the treatment of NAFLD.
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Affiliation(s)
- Mayuko Chikamatsu
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Hiroshi Watanabe
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
| | - Yuhi Shintani
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Ryota Murata
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Masako Miyahisa
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Ayano Nishinoiri
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Tadashi Imafuku
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Mei Takano
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Nanaka Arimura
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Kohichi Yamada
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Miya Kamimura
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Baki Mukai
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Takao Satoh
- Kumamoto Industrial Research Institute, Kumamoto, Japan
| | - Hitoshi Maeda
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
| | - Toru Maruyama
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
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18
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Zhang YM, Lin CY, Li BZ, Xu WB, Dong WR, Shu MA. Characterization of fibroblast growth factor receptor 4 (FGFR4) from the red swamp crayfish Procambarus clarkii and its role in antiviral and antimicrobial immune responses. J Invertebr Pathol 2023; 196:107865. [PMID: 36436575 DOI: 10.1016/j.jip.2022.107865] [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: 07/15/2022] [Revised: 11/09/2022] [Accepted: 11/21/2022] [Indexed: 11/26/2022]
Abstract
FGFRs involved multiple physiological processes, such as endocrine homeostasis, wound repair, and cellular behaviors including proliferation, differentiation and survival. In the present study, the homologs of fibroblast growth factor receptor 4 (FGFR4) were identified and characterized from the red swamp crayfish Procambarus clarkii for the first time. The full-length cDNAs of pcFGFR4 were 2878 bp with 2451 bp open reading frame (ORF), respectively. The deduced pcFGFR4 protein contained an immunoglobulin, two immunoglobulin C-2 Type, a transmembrane region and a catalytic domain. Real-time PCR analysis showed that pcFGFR4 were highly expressed in muscle and hemocyte. Moreover, the expression levels of pcFGFR4 in the hepatopancreas and hemocyte were positively stimulated after challenge with Aeromonas hydrophila and WSSV, implying the involvement of pcFGFR4 against bacterial and viral infections in innate immune responses. While pcFGFR4 were silenced in vivo, the expression levels of antimicrobial peptide (AMP) genes (pcALF1-5,8 and pcCrustin1-2) and NF-κB signaling components (pcDrosal and pcRelish) were significantly reduced. Additionally, NF-κB signaling could be markedly activated by overexpression of pcFGFR4 in HEK293T cells. Finally, our results indicated that pcFGFR4 regulated crayfish's innate immunity by modulating NF-κB signaling. These findings may provide new insights into pcFGFR4-mediated signaling cascades in crustaceans and provide a better understanding of crustacean innate immune system.
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Affiliation(s)
- Yan-Mei Zhang
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Chen-Yang Lin
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Bang-Ze Li
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Wen-Bin Xu
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Wei-Ren Dong
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China.
| | - Miao-An Shu
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China.
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Negah SS, Forouzanfar F. Dual Role of Fibroblast Growth Factor Pathways in Sleep Regulation. Endocr Metab Immune Disord Drug Targets 2023; 23:63-69. [PMID: 35927892 DOI: 10.2174/1871530322666220802161031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 05/11/2022] [Accepted: 05/20/2022] [Indexed: 11/22/2022]
Abstract
Sleep plays an important function in neuro-immuno-endocrine homeostasis. Sleep disorders have been associated with an increased risk of metabolic and cognitive impairments. Among different factors that have an effect on sleep metabolism, a growing body of literature has investigated growth factors in the course of sleep quality and disorders. A good example of growth factors is fibroblast growth factors (FGFs), which are a large family of polypeptide growth factors. Evidence has shown that FGFs are involved in the modulation of sleep-wake behavior by their receptor subtypes and ligands, e.g., FFG1 plays an important role in the quality of sleep through somnogenic effects, while the high level of FGF23 is associated with secondary disorders in shift workers. Therefore, a controversial effect of FGFs can be seen in the course of sleep in physiologic and pathologic conditions. Further investigation on this topic would help us to understand the role of FGFs in sleep disorders as a therapeutic option and biomarker.
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Affiliation(s)
- Sajad Sahab Negah
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran.,Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Forouzanfar
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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20
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Bile acids and their receptors in regulation of gut health and diseases. Prog Lipid Res 2023; 89:101210. [PMID: 36577494 DOI: 10.1016/j.plipres.2022.101210] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 12/26/2022]
Abstract
It is well established that bile acids play important roles in lipid metabolism. In recent decades, bile acids have also been shown to function as signaling molecules via interacting with various receptors. Bile acids circulate continuously through the enterohepatic circulation and go through microbial transformation by gut microbes, and thus bile acids metabolism has profound effects on the liver and intestinal tissues as well as the gut microbiota. Farnesoid X receptor and G protein-coupled bile acid receptor 1 are two pivotal bile acid receptors that highly expressed in the intestinal tissues, and they have emerged as pivotal regulators in bile acids metabolism, innate immunity and inflammatory responses. There is considerable interest in manipulating the metabolism of bile acids and the expression of bile acid receptors as this may be a promising strategy to regulate intestinal health and disease. This review aims to summarize the roles of bile acids and their receptors in regulation of gut health and diseases.
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Yan B, Ma S, Yan C, Han Y. Fibroblast growth factor 21 and prognosis of patients with cardiovascular disease: A meta-analysis. Front Endocrinol (Lausanne) 2023; 14:1108234. [PMID: 36926038 PMCID: PMC10011636 DOI: 10.3389/fendo.2023.1108234] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 02/14/2023] [Indexed: 03/08/2023] Open
Abstract
BACKGROUND The role of fibroblast growth factor 21 (FGF21) in predicting the long-term prognosis of patients with cardiovascular disease (CVD) remains unknown. METHODS A comprehensive search in PubMed, Embase, and the Cochrane Library was performed to identify studies reporting the association between FGF21 and prognosis among patients with CVD. A meta-analysis was performed, with patients stratified by coronary artery disease (CAD) or heart failure (HF). The endpoint of CAD or HF was major adverse cardiovascular events defined by each study and a composite of death or HF readmission, respectively. The I2 method and linear regression test of funnel plot asymmetry were used to test heterogeneity (I2 > 50% indicates substantial heterogeneity) and publication bias (asymmetry P < 0.05, indicating publication bias). RESULTS A total of 807 records were retrieved, and nine studies were finally included. Higher FGF21 levels were significantly associated with the risk of major adverse cardiovascular events in patients with CAD (multivariate hazard ratio [HR]: 1.77, 95% confidence interval [CI]: 1.40-2.23, P < 0.05, I2 = 0%, fixed-effect model). Increased FGF21 levels were also associated with the risk of all-cause death among patients with CAD (multivariate HR: 2.67, 95% CI: 1.25-5.72, P < 0.05, I2 = 64%, random-effect model). No association was found between FGF21 and the endpoint among patients with HF (HR: 1.57, 95% CI: 0.99-2.48, P > 0.05, random-effect model), but a large heterogeneity (I2 = 95%) and potential publication bias (Asymmetry P < 0.05) existed in the analysis. CONCLUSION Increased FGF21 levels were independently associated with poor prognosis of CAD, whereas the role of FGF21 in predicting clinical outcomes of HF requires further investigation.
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Affiliation(s)
- Bing Yan
- Department of Cardiology, The Second Hospital of Jilin University, Changchun, Jilin, China
- Department of Cardiology and Cardiovascular Research Institute, Chinese People's Liberation Army, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
| | - Sicong Ma
- Department of Cardiology, The Second Hospital of Jilin University, Changchun, Jilin, China
- Department of Cardiology and Cardiovascular Research Institute, Chinese People's Liberation Army, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
| | - Chenghui Yan
- Department of Cardiology and Cardiovascular Research Institute, Chinese People's Liberation Army, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
- *Correspondence: Chenghui Yan, ; Yaling Han,
| | - Yaling Han
- Department of Cardiology, The Second Hospital of Jilin University, Changchun, Jilin, China
- Department of Cardiology and Cardiovascular Research Institute, Chinese People's Liberation Army, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
- *Correspondence: Chenghui Yan, ; Yaling Han,
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22
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Matsiukevich D, House SL, Weinheimer C, Kovacs A, Ornitz DM. Fibroblast growth factor receptor signaling in cardiomyocytes is protective in the acute phase following ischemia-reperfusion injury. Front Cardiovasc Med 2022; 9:1011167. [PMID: 36211556 PMCID: PMC9539275 DOI: 10.3389/fcvm.2022.1011167] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 08/29/2022] [Indexed: 11/29/2022] Open
Abstract
Fibroblast growth factor receptors (FGFRs) are expressed in multiple cell types in the adult heart. Previous studies have shown a cardioprotective effect of some FGF ligands in cardiac ischemia-reperfusion (I/R) injury and a protective role for endothelial FGFRs in post-ischemic vascular remodeling. To determine the direct role FGFR signaling in cardiomyocytes in acute cardiac I/R injury, we inactivated Fgfr1 and Fgfr2 (CM-DCKO) or activated FGFR1 (CM-caFGFR1) in cardiomyocytes in adult mice prior to I/R injury. In the absence of injury, inactivation of Fgfr1 and Fgfr2 in adult cardiomyocytes had no effect on cardiac morphometry or function. When subjected to I/R injury, compared to controls, CM-DCKO mice had significantly increased myocyte death 1 day after reperfusion, and increased infarct size, cardiac dysfunction, and myocyte hypertrophy 7 days after reperfusion. No genotype-dependent effect was observed on post-ischemic cardiomyocyte cross-sectional area and vessel density in areas remote to the infarct. By contrast, transient activation of FGFR1 signaling in cardiomyocytes just prior to the onset of ischemia did not affect outcomes after cardiac I/R injury at 1 day and 7 days after reperfusion. These data demonstrate that endogenous cell-autonomous cardiomyocyte FGFR signaling supports the survival of cardiomyocytes in the acute phase following cardiac I/R injury and that this cardioprotection results in continued improved outcomes during cardiac remodeling. Combined with the established protective role of some FGF ligands and endothelial FGFR signaling in I/R injury, this study supports the development of therapeutic strategies that promote cardiomyocyte FGF signaling after I/R injury.
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Affiliation(s)
- Dzmitry Matsiukevich
- Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
- Department of Developmental Biology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
| | - Stacey L. House
- Department of Developmental Biology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
- Department of Emergency Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
| | - Carla Weinheimer
- Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
| | - Attila Kovacs
- Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
| | - David M. Ornitz
- Department of Developmental Biology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
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23
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Tamburello M, Altieri B, Sbiera I, Sigala S, Berruti A, Fassnacht M, Sbiera S. FGF/FGFR signaling in adrenocortical development and tumorigenesis: novel potential therapeutic targets in adrenocortical carcinoma. Endocrine 2022; 77:411-418. [PMID: 35583844 PMCID: PMC9385797 DOI: 10.1007/s12020-022-03074-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 05/08/2022] [Indexed: 12/14/2022]
Abstract
FGF/FGFR signaling regulates embryogenesis, angiogenesis, tissue homeostasis and wound repair by modulating proliferation, differentiation, survival, migration and metabolism of target cells. Understandably, compelling evidence for deregulated FGF signaling in the development and progression of different types of tumors continue to emerge and FGFR inhibitors arise as potential targeted therapeutic agents, particularly in tumors harboring aberrant FGFR signaling. There is first evidence of a dual role of the FGF/FGFR system in both organogenesis and tumorigenesis, of which this review aims to provide an overview. FGF-1 and FGF-2 are expressed in the adrenal cortex and are the most powerful mitogens for adrenocortical cells. Physiologically, they are involved in development and maintenance of the adrenal gland and bind to a family of four tyrosine kinase receptors, among which FGFR1 and FGFR4 are the most strongly expressed in the adrenal cortex. The repeatedly proven overexpression of these two FGFRs also in adrenocortical cancer is thus likely a sign of their participation in proliferation and vascularization, though the exact downstream mechanisms are not yet elucidated. Thus, FGFRs potentially offer novel therapeutic targets also for adrenocortical carcinoma, a type of cancer resistant to conventional antimitotic agents.
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Affiliation(s)
- Mariangela Tamburello
- Division of Endocrinology, Department of Internal Medicine I, University Hospital, University of Würzburg, Würzburg, Germany
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Barbara Altieri
- Division of Endocrinology, Department of Internal Medicine I, University Hospital, University of Würzburg, Würzburg, Germany
| | - Iuliu Sbiera
- Division of Endocrinology, Department of Internal Medicine I, University Hospital, University of Würzburg, Würzburg, Germany
| | - Sandra Sigala
- Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Alfredo Berruti
- Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia and ASST Spedali Civili di Brescia, Brescia, Italy
| | - Martin Fassnacht
- Division of Endocrinology, Department of Internal Medicine I, University Hospital, University of Würzburg, Würzburg, Germany
- Comprehenssive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany
| | - Silviu Sbiera
- Division of Endocrinology, Department of Internal Medicine I, University Hospital, University of Würzburg, Würzburg, Germany.
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24
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Mauer J, Kuckhahn A, Ramsperger-Gleixner M, Ensminger SM, Distler JH, Weyand M, Heim C. Nintedanib reduces alloimmune-induced chronic airway changes in murine tracheal allografts. Transpl Immunol 2022; 73:101608. [DOI: 10.1016/j.trim.2022.101608] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 04/12/2022] [Accepted: 04/23/2022] [Indexed: 01/01/2023]
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Brassinin Promotes the Degradation of Tie2 and FGFR1 in Endothelial Cells and Inhibits Triple-Negative Breast Cancer Angiogenesis. Cancers (Basel) 2022; 14:cancers14143540. [PMID: 35884601 PMCID: PMC9318525 DOI: 10.3390/cancers14143540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/19/2022] [Accepted: 07/19/2022] [Indexed: 11/24/2022] Open
Abstract
Simple Summary Brassinin is a natural compound enriched in several commonly consumed vegetables, such as broccoli and cabbages. It shows potent anti-cancer activity against several cancers. However, its effects on triple-negative breast cancer (TNBC), an aggressive subtype with limited treatment options, remain elusive so far. Therefore, we investigated the effects of brassinin on TNBC angiogenesis and growth. Our results demonstrate that brassinin inhibits TNBC growth preferentially through inhibiting the angiogenic activity of endothelial cells (ECs). Additional in-vitro analyses revealed that this effect may be mediated by brassinin-stimulated degradation of two pivotal angiogenesis-related receptors in ECs: Tie2 and fibroblast growth factor receptor 1. These findings provide novel insights into the cellular and molecular mechanisms underlying the anti-cancer activity of brassinin and indicate that this phytochemical may be a promising lead compound or drug candidate for TNBC treatment. Abstract Brassinin, a phytoalexin derived from cruciferous vegetables, has been reported to exhibit anti-cancer activity in multiple cancer types. However, its effects on triple-negative breast cancer (TNBC) development and the underlying mechanisms have not been elucidated so far. In this study, we demonstrated in vitro that brassinin preferentially reduces the viability of endothelial cells (ECs) when compared to other cell types of the tumor microenvironment, including TNBC cells, pericytes, and fibroblasts. Moreover, brassinin at non-cytotoxic doses significantly suppressed the proliferation, migration, tube formation, and spheroid sprouting of ECs. It also efficiently inhibited angiogenesis in an ex-vivo aortic ring assay and an in-vivo Matrigel plug assay. Daily intraperitoneal injection of brassinin significantly reduced tumor size, microvessel density, as well as the perfusion of tumor microvessels in a dorsal skinfold chamber model of TNBC. Mechanistic analyses showed that brassinin selectively stimulates the degradation of Tie2 and fibroblast growth factor receptor 1 in ECs, leading to the down-regulation of the AKT and extracellular signal-regulated kinase pathways. These findings demonstrate a preferential and potent anti-angiogenic activity of brassinin, which may be the main mechanism of its anti-tumor action. Accordingly, this phytochemical represents a promising candidate for the future anti-angiogenic treatment of TNBC.
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Guthrie G, Vonderohe C, Burrin D. Fibroblast growth factor 15/19 expression, regulation, and function: An overview. Mol Cell Endocrinol 2022; 548:111617. [PMID: 35301051 PMCID: PMC9038700 DOI: 10.1016/j.mce.2022.111617] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 01/18/2022] [Indexed: 12/12/2022]
Abstract
Since the discovery of fibroblast growth factor (FGF)-19 over 20 years ago, our understanding of the peptide and its role in human biology has moved forward significantly. A member of a superfamily of paracrine growth factors regulating embryonic development, FGF19 is unique in that it is a dietary-responsive endocrine hormone linked with bile acid homeostasis, glucose and lipid metabolism, energy expenditure, and protein synthesis during the fed to fasted state. FGF19 achieves this through targeting multiple tissues and signaling pathways within those tissues. The diverse functional capabilities of FGF19 is due to the unique structural characteristics of the protein and its receptor binding in various cell types. This review will cover the current literature on the protein FGF19, its target receptors, and the biological pathways they target through unique signaling cascades.
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Affiliation(s)
- Greg Guthrie
- USDA-ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, United States
| | - Caitlin Vonderohe
- USDA-ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, United States
| | - Douglas Burrin
- USDA-ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, United States.
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27
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FGFR3 Nuclear Translocation Contributes to Proliferative Potential and Poor Prognosis in Pancreatic Ductal Adenocarcinoma. Pancreas 2022; 51:476-482. [PMID: 35858182 DOI: 10.1097/mpa.0000000000002056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Fibroblast growth factor receptor 3 (FGFR3) was revealed to have divergent, even opposite roles in different neoplasms. In pancreatic ductal adenocarcinoma (PDAC), its impact on biological behavior and prognosis was not well elucidated. METHODS Fibroblast growth factor receptor 3 was downregulated by RNA interference to explore its impact on cell proliferative proclivity in PDAC cells. Furthermore, tissue microarray-based immunohistochemistry for FGFR3 was performed in 326 patients with PDAC who underwent radical resection, and its clinicopathologic and prognostic implications were then evaluated. RESULTS First, successful FGFR3 knockdown remarkably decreased its expression, cell proliferation, and S-phase ratio in the cell cycle in 2 PDAC cell lines, BxPC-3 and AsPC-1. Meanwhile, alterations in p-Akt, cyclin D1, cyclin B1, and p21 were also observed. Subsequently, high nuclear FGFR3 expression, but not cytoplasmic, was significantly common in tumor tissues and positively associated with N stage and dismal overall survival in the entire cohort. In addition, nuclear FGFR3 expression was also prognostic in 10 of 14 subsets. Univariate and multivariate Cox regression analyses identified nuclear expression of FGFR3 as an independent prognosticator in the entire cohort. CONCLUSIONS Our data showed that FGFR3 nuclear translocation contributes to cell proliferative potential and predicts poor long-term prognosis in PDAC after surgical resection.
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28
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Expanding horizons of achondroplasia treatment: current options and future developments. Osteoarthritis Cartilage 2022; 30:535-544. [PMID: 34864168 DOI: 10.1016/j.joca.2021.11.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 11/23/2021] [Accepted: 11/28/2021] [Indexed: 02/02/2023]
Abstract
Activating mutations in the FGFR3 receptor tyrosine kinase lead to most prevalent form of genetic dwarfism in humans, the achondroplasia. Many features of the complex function of FGFR3 in growing skeleton were characterized, which facilitated identification of therapy targets, and drove progress toward treatment. In August 2021, the vosoritide was approved for treatment of achondroplasia, which is based on a stable variant of the C-natriuretic peptide. Other drugs may soon follow, as several conceptually different inhibitors of FGFR3 signaling progress through clinical trials. Here, we review the current achondroplasia therapeutics, describe their mechanisms, and illuminate motivations leading to their development. We also discuss perspectives of curing achondroplasia, and options for repurposing achondroplasia drugs for dwarfing conditions unrelated to FGFR3.
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29
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Yano K, Yamaguchi K, Seko Y, Okishio S, Ishiba H, Tochiki N, Takahashi A, Kataoka S, Okuda K, Liu Y, Fujii H, Umemura A, Moriguchi M, Okanoue T, Itoh Y. Hepatocyte-specific fibroblast growth factor 21 overexpression ameliorates high-fat diet-induced obesity and liver steatosis in mice. J Transl Med 2022; 102:281-289. [PMID: 34732847 DOI: 10.1038/s41374-021-00680-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 09/11/2021] [Accepted: 09/15/2021] [Indexed: 11/09/2022] Open
Abstract
Fibroblast growth factor (FGF) 21 is an endocrine growth factor mainly secreted by the liver in response to a ketogenic diet and alcohol consumption. FGF21 signaling requires co-receptor β-klotho (KLB) co-acting with FGF receptors, which has pleiotropic metabolic effects, including induced hepatic fatty acid oxidation and ketogenesis, in human and animal models of obesity. We examined the hepatocyte-specific enhancer/promoter of FGF21 expression plasmids in high-fat diet-fed mice for 12 weeks. Hydrodynamic injection for FGF21 delivery every 6 weeks sustained high circulating levels of FGF21, resulting in marked reductions in body weight, epididymal fat mass, insulin resistance, and liver steatosis. FGF21-induced lipolysis in the adipose tissue enabled the liver to be flooded with fat-derived FFAs. The hepatic expression of Glut2 and Bdh1 was upregulated, whereas that of gluconeogenesis-related genes, G6p and Pepck, and lipogenesis-related genes, Srebp-1 and Srebp-2, was significantly suppressed. FGF21 induced the phosphorylation of AMPK at Thr172 and Raptor at ser792 and suppressed that of mTOR at ser2448, which downregulated mTORC1 signaling and reduced IRS-1 phosphorylation at ser1101. Finally, in the skeletal muscle, FGF21 increased Glut4 and Mct2, a membrane protein that acts as a carrier for ketone bodies. Enzymes for ketone body catabolism (Scot) and citrate cycle (Cs, Idh3a), and a marker of regenerating muscle (myogenin) were also upregulated via increased KLB expression. Thus, FGF21-induced lipolysis was continuously induced by a high-fat diet and fat-derived FFAs might cause liver damage. Hepatic fatty acid oxidation and ketone body synthesis may act as hepatic FFAs' disposal mechanisms and contribute to improved liver steatosis. Liver-derived ketone bodies might be used for energy in the skeletal muscle. The potential FGF21-related crosstalk between the liver and extraliver organs is a promising strategy to prevent and treat metabolic syndrome-related nonalcoholic steatohepatitis.
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Affiliation(s)
- Kota Yano
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kanji Yamaguchi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
| | - Yuya Seko
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Shinya Okishio
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hiroshi Ishiba
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Nozomi Tochiki
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Aya Takahashi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Seita Kataoka
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Keiichiroh Okuda
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yu Liu
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hideki Fujii
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Atsushi Umemura
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Michihisa Moriguchi
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Takeshi Okanoue
- Department of Gastroenterology & Hepatology, Saiseikai Suita Hospital, Osaka, Japan
| | - Yoshito Itoh
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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30
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Zhang H, Zhang W, Jiang L, Chen Y. Recent advances in systemic therapy for hepatocellular carcinoma. Biomark Res 2022; 10:3. [PMID: 35000616 PMCID: PMC8744248 DOI: 10.1186/s40364-021-00350-4] [Citation(s) in RCA: 121] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 09/26/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumors in the world. Therapeutic options for advanced HCC are limited. Systemic treatment, especially with conventional cytotoxic drugs, is usually ineffective. For more than a decade, sorafenib has been the only systemic drug that has been proven to be clinically effective for treating advanced HCC. However, over the past three years, the rapid progress of molecular targeted therapies has dramatically changed the treatment landscape for advanced HCC. Immune checkpoint therapies are now being incorporated into HCC therapies, and their combination with molecular targeted therapy is emerging as a tool to enhance the immune response. In this review, we summarize the development and progress of molecular targeted agents and immunotherapies in HCC.
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Affiliation(s)
- Huajun Zhang
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Wuyang Zhang
- Clinical skills training center, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Longying Jiang
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
| | - Yongheng Chen
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
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Liu D, Liu W, Chen X, Yin J, Ma L, Liu M, Zhou X, Xian L, Li P, Tan X, Zhao J, Liao Y, Cao G. circKCNN2 suppresses the recurrence of hepatocellular carcinoma at least partially via regulating miR-520c-3p/methyl-DNA-binding domain protein 2 axis. Clin Transl Med 2022; 12:e662. [PMID: 35051313 PMCID: PMC8775140 DOI: 10.1002/ctm2.662] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 11/10/2021] [Accepted: 11/15/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Recurrence is the major cause of hepatocellular carcinoma (HCC) death. We aimed to identify circular RNA (circRNA) with predictive and therapeutic value for recurrent HCC. METHODS Tissue samples from recurrent and non-recurrent HCC patients were subjected to circRNA sequencing and transcriptome sequencing. circKCNN2 was identified through multi-omics analyses. The effects of circKCNN2 on HCC were evaluated in cells, animals, database of The Cancer Genome Atlas, and a cohort with 130 HCC patients. circRNA precipitation, chromatin immunoprecipitation assay, RNA pull-down, luciferase assay, and cell experiments were applied to evaluate the interaction of circKCNN2 with miRNAs and proteins. The association between circKCNN2 and the therapeutic effect of lenvatinib was investigated in HCC cell lines and HCC tissue-derived organoids. RESULTS The expression of circKCNN2 was downregulated in HCC tissues and predicted a favorable overall survival and recurrence-free survival. The expression of circKCNN2 was positively correlated with the parental gene, potassium calcium-activated channel subfamily N member (KCNN2). Nuclear transcription factor Y subunit alpha (NFYA) was proven to inhibit the promoter activity of KCNN2, downregulate the expression of KCNN2 and circKCNN2, and predict an unfavorable recurrence-free survival. Ectopic expression of circKCNN2 inhibited HCC cell proliferation, colony formation, migration, and tumor formation in a mouse model. miR-520c-3p sponged by circKCNN2 could reverse the inhibitory effect of circKCNN2 on HCC cells and down-regulate the expression of methyl-DNA-binding domain protein 2 (MBD2). The intratumoral expression of MBD2 predicted a favorable recurrence-free survival. circKCNN2 down-regulated the expression of fibroblast growth factor receptor 4 (FGFR4), which can be reversed by miR-520c-3p and knockdown of MBD2. Lenvatinib inhibited the expression of FGFR4 and upregulated the expression of circKCNN2 and MBD2. Ectopic expression of circKCNN2 in HCC cells enhanced the therapeutic effect of lenvatinib. However, the high inherent level of circKCNN2 in HCC cells was associated with lenvatinib resistance. CONCLUSIONS circKCNN2, transcriptionally repressed by NFYA, suppresses HCC recurrence via the miR-520c-3p/MBD2 axis. Inherent level of circKCNN2 in HCC cells predisposes anti-tumor effect of lenvatinib possibly because both circKCNN2 and lenvatinib repress the expression of FGFR4. circKCNN2 may be a promising predictive biomarker and therapeutic agent for HCC recurrence.
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Affiliation(s)
- Donghong Liu
- Key Laboratory of Molecular Biology for Infectious DiseasesMinistry of EducationChongqing Medical UniversityChongqingChina
- Institute for Viral HepatitisChongqing Medical UniversityChongqingChina
- Department of Infectious Diseasesthe Second Affiliated HospitalChongqing Medical UniversityChongqingChina
| | - Wenbin Liu
- Department of EpidemiologySecond Military Medical UniversityShanghaiChina
| | - Xi Chen
- Department of EpidemiologySecond Military Medical UniversityShanghaiChina
| | - Jianhua Yin
- Department of EpidemiologySecond Military Medical UniversityShanghaiChina
| | - Longteng Ma
- Department of EpidemiologySecond Military Medical UniversityShanghaiChina
| | - Mei Liu
- Department of EpidemiologySecond Military Medical UniversityShanghaiChina
| | - Xinyu Zhou
- Department of EpidemiologySecond Military Medical UniversityShanghaiChina
| | - Linfeng Xian
- Department of EpidemiologySecond Military Medical UniversityShanghaiChina
| | - Peng Li
- Department of EpidemiologySecond Military Medical UniversityShanghaiChina
| | - Xiaojie Tan
- Department of EpidemiologySecond Military Medical UniversityShanghaiChina
| | - Jun Zhao
- Department of Hepatic SurgeryEastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghaiChina
| | - Yong Liao
- Key Laboratory of Molecular Biology for Infectious DiseasesMinistry of EducationChongqing Medical UniversityChongqingChina
- Institute for Viral HepatitisChongqing Medical UniversityChongqingChina
- Department of Infectious Diseasesthe Second Affiliated HospitalChongqing Medical UniversityChongqingChina
| | - Guangwen Cao
- Department of EpidemiologySecond Military Medical UniversityShanghaiChina
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Lee TW, Chung CC, Lee TI, Lin YK, Kao YH, Chen YJ. Fibroblast Growth Factor 23 Stimulates Cardiac Fibroblast Activity through Phospholipase C-Mediated Calcium Signaling. Int J Mol Sci 2021; 23:ijms23010166. [PMID: 35008591 PMCID: PMC8745152 DOI: 10.3390/ijms23010166] [Citation(s) in RCA: 16] [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: 10/18/2021] [Revised: 12/08/2021] [Accepted: 12/21/2021] [Indexed: 12/19/2022] Open
Abstract
Fibroblast growth factor (FGF)-23 induces hypertrophy and calcium (Ca2+) dysregulation in cardiomyocytes, leading to cardiac arrhythmia and heart failure. However, knowledge regarding the effects of FGF-23 on cardiac fibrogenesis remains limited. This study investigated whether FGF-23 modulates cardiac fibroblast activity and explored its underlying mechanisms. We performed MTS analysis, 5-ethynyl-2′-deoxyuridine assay, and wound-healing assay in cultured human atrial fibroblasts without and with FGF-23 (1, 5 and 25 ng/mL for 48 h) to analyze cell proliferation and migration. We found that FGF-23 (25 ng/mL, but not 1 or 5 ng/mL) increased proliferative and migratory abilities of human atrial fibroblasts. Compared to control cells, FGF-23 (25 ng/mL)-treated fibroblasts had a significantly higher Ca2+ entry and intracellular inositol 1,4,5-trisphosphate (IP3) level (assessed by fura-2 ratiometric Ca2+ imaging and enzyme-linked immunosorbent assay). Western blot analysis showed that FGF-23 (25 ng/mL)-treated cardiac fibroblasts had higher expression levels of calcium release-activated calcium channel protein 1 (Orai1) and transient receptor potential canonical (TRPC) 1 channel, but similar expression levels of α-smooth muscle actin, collagen type IA1, collagen type Ⅲ, stromal interaction molecule 1, TRPC 3, TRPC6 and phosphorylated-calcium/calmodulin-dependent protein kinase II when compared with control fibroblasts. In the presence of ethylene glycol tetra-acetic acid (a free Ca2+ chelator, 1 mM) or U73122 (an inhibitor of phospholipase C, 1 μM), control and FGF-23-treated fibroblasts exhibited similar proliferative and migratory abilities. Moreover, polymerase chain reaction analysis revealed that atrial fibroblasts abundantly expressed FGF receptor 1 but lacked expressions of FGF receptors 2-4. FGF-23 significantly increased the phosphorylation of FGF receptor 1. Treatment with PD166866 (an antagonist of FGF receptor 1, 1 μM) attenuated the effects of FGF-23 on cardiac fibroblast activity. In conclusion, FGF-23 may activate FGF receptor 1 and subsequently phospholipase C/IP3 signaling pathway, leading to an upregulation of Orai1 and/or TRPC1-mediated Ca2+ entry and thus enhancing human atrial fibroblast activity.
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Affiliation(s)
- Ting-Wei Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (T.-W.L.); (T.-I.L.)
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
| | - Cheng-Chih Chung
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (C.-C.C.); (Y.-K.L.)
- Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
| | - Ting-I Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (T.-W.L.); (T.-I.L.)
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
- Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Yung-Kuo Lin
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (C.-C.C.); (Y.-K.L.)
- Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
| | - Yu-Hsun Kao
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
- Correspondence: (Y.-H.K.); (Y.-J.C.)
| | - Yi-Jen Chen
- Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Cardiovascular Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
- Correspondence: (Y.-H.K.); (Y.-J.C.)
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Nam Y, Shin I, Kim Y, Ryu S, Kim N, Ju E, Sim T. Anti-cancer effects of 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one derivatives on hepatocellular carcinoma harboring FGFR4 activation. Neoplasia 2021; 24:34-49. [PMID: 34864570 PMCID: PMC8649585 DOI: 10.1016/j.neo.2021.11.011] [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: 09/02/2021] [Revised: 11/09/2021] [Accepted: 11/22/2021] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is disease with a high mortality rate and limited treatment options. Alterations of fibroblast growth factor receptor 4 (FGFR4) has been regarded as an oncogenic driver for HCC and a promising target for HCC therapeutics. Herein, we report that GNF-7, a multi-targeted kinase inhibitor, and its derivatives including SIJ1263 (IC50 < 1 nM against FGFR4) are highly potent FGFR4 inhibitors and are capable of strongly suppressing proliferation of HCC cells and Ba/F3 cells transformed with wtFGFR4 or mtFGFR4. Compared with known FGFR4 inhibitors, both GNF-7 and SIJ1263 possess much higher (up to 100-fold) anti-proliferative activities via FGFR signaling blockade and apoptosis on HCC cells. Especially, SIJ1263 is 80-fold more potent (GI50 = 24 nM) on TEL-FGFR4 V550E Ba/F3 cells than BLU9931, which suggests that SIJ1263 would be effective for overriding drug resistance. In addition, both substances strongly suppress migration/invasion and colony formation of HCC cells. It is worth noting that SIJ1263 is superior to GNF-7 with regards to the fact that activities of SIJ1263 are higher than those of GNF-7 in all assays performed in this study. Collectively, this study provides insight into designing highly potent FGFR4 inhibitors capable of potentially overcoming drug-resistance for the treatment of HCC patients.
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Affiliation(s)
- Yunju Nam
- KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea; Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Injae Shin
- KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea; Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Younghoon Kim
- KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea; Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - SeongShick Ryu
- KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea; Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Namdoo Kim
- Voronoibio Inc., 32 Songdogwahak-ro, Yeonsu-gu, Incheon, 21984, Republic of Korea
| | - Eunhye Ju
- KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea
| | - Taebo Sim
- KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea; Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
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Dark and bright side of targeting fibroblast growth factor receptor 4 in the liver. J Hepatol 2021; 75:1440-1451. [PMID: 34364916 DOI: 10.1016/j.jhep.2021.07.029] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 07/09/2021] [Accepted: 07/26/2021] [Indexed: 12/12/2022]
Abstract
Fibroblast growth factor (FGF) receptor 4 (FGFR4) and its cognate ligand, FGF19, are implicated in a range of cellular processes, including differentiation, metabolism and proliferation. Indeed, their aberrant activation has been associated with the development of hepatic tumours. Despite great advances in early diagnosis and the development of new therapies, liver cancer is still associated with a high mortality rate, owing primarily to high molecular heterogeneity and unclear molecular targeting. The development of FGFR4 inhibitors is a promising tool in patients with concomitant supraphysiological levels of FGF19 and several clinical trials are testing these treatments for patients with advanced hepatocellular carcinoma (HCC). Conversely, using FGF19 analogues to activate FGFR4-KLOTHO β represents a novel therapeutic strategy in patients presenting with cholestatic liver disorders and non-alcoholic steatohepatitis, which could potentially prevent the development of metabolic HCC. Herein, we provide an overview of the currently available therapeutic options for targeting FGFR4 in HCC and other liver diseases, highlighting the need to carefully stratify patients and personalise therapeutic strategies.
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A Germinal Center-Associated Microenvironmental Signature Reflects Malignant Phenotype and Outcome of DLBCL. Blood Adv 2021; 6:2388-2402. [PMID: 34638128 PMCID: PMC9006269 DOI: 10.1182/bloodadvances.2021004618] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 08/29/2021] [Indexed: 12/03/2022] Open
Abstract
The DLBCL microenvironment signature scoring system was established using nCounter-based profiling of GC-related microenvironmental genes. DMS scores stratified DLBCL patients with different prognosis independently of existing prognostic models. Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy, with varying prognosis after the gold standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Several prognostic models have been established by focusing primarily on characteristics of lymphoma cells themselves, including cell-of-origin (COO), genomic alterations, and gene/protein expressions. However, the prognostic impact of the lymphoma microenvironment and its association with characteristics of lymphoma cells are not fully understood. Using the nCounter-based gene expression profiling of untreated DLBCL tissues, we assess the clinical impact of lymphoma microenvironment on the clinical outcomes and pathophysiological, molecular signatures in DLBCL. The presence of normal germinal center (GC)-microenvironmental cells, including follicular T cells, macrophage/dendritic cells, and stromal cells in lymphoma tissue indicates a positive therapeutic response. Our prognostic model, based on quantitation of transcripts from distinct GC-microenvironmental cell markers, clearly identified patients with graded prognosis independently of existing prognostic models. We observed increased incidences of genomic alterations and aberrant gene expression associated with poor prognosis in DLBCL tissues lacking GC-microenvironmental cells relative to those containing these cells. These data suggest that the loss of GC-associated microenvironmental signature dictates clinical outcomes of DLBCL patients reflecting the accumulation of “unfavorable” molecular signatures.
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SnapshotDx Quiz: June 2021. J Invest Dermatol 2021. [DOI: 10.1016/j.jid.2021.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Hu Y, Ai LS, Zhou LQ. Prognostic value of FGFR1 expression and amplification in patients with HNSCC: A systematic review and meta-analysis. PLoS One 2021; 16:e0251202. [PMID: 33989301 PMCID: PMC8121309 DOI: 10.1371/journal.pone.0251202] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 04/21/2021] [Indexed: 12/23/2022] Open
Abstract
Fibroblast growth factor receptor 1 (FGFR1) has recently been identified as a promising novel therapeutic target and prognostic marker in different types of cancer. In the present study, a meta-analysis was performed to clarify the correlation between FGFR1 and the survival outcomes of head and neck squamous cell carcinoma (HNSCC) patients. PubMed, Embase, and Web of Science were systematically searched for relevant studies in order to explore the prognostic significance of FGFR1 in HNSCC. Hazards ratios (HR) and 95% confidence intervals (CI) were collected to estimate the correlation between overexpression and amplification of FGFR1 and survival outcomes of HNSCC patients. Nine studies including 2708 patients with HNSCC were finally selected for the meta-analysis. The results indicated that FGFR1 predicted poor overall survival (OS) (HR, 1.97; 95% CI, 1.49–2.61, P<0.001) in HNSCC patients. Futhermore, FGFR1 was related to poor OS in human papillomavirus (HPV) negative HNSCC not in HPV positive HNSCC patients. Subgroup analysis stratified by molecular abnormalities, such as overexpression or amplification showed the similar results. The present study demonstrated that HNSCC patients with FGFR1 overexpression and amplification were more likely to exhibit poorer survival.
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Affiliation(s)
- Yao Hu
- Department of Otorhinolaryngology, The Central Hospital of Wuhan, Wuhan, China
| | - Li-Sha Ai
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liu-Qing Zhou
- Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- * E-mail:
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Suoh M, Hagihara A, Yamamura M, Maruyama H, Taira K, Enomoto M, Tamori A, Fujiwara Y, Kawada N. Obstructive Jaundice Due to Duodenal Ulcer Induced by Lenvatinib Therapy for Hepatocellular Carcinoma. Intern Med 2021; 60:545-552. [PMID: 33028766 PMCID: PMC7946507 DOI: 10.2169/internalmedicine.5097-20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
An 82-year-old man with hepatocellular carcinoma presented with upper abdominal pain, vomiting, and jaundice. He had been taking a standard lenvatinib dose for three months. Although acute cholangitis was suggested, imaging studies failed to detect the biliary obstruction site. An endoscopic examination following discontinuation of lenvatinib and aspirin revealed multiple duodenal ulcers, one of which was formed on the ampulla of Vater and causing cholestasis. Endoscopic biliary drainage and antibiotics improved concomitant Enterobacter cloacae bacteremia. Ulcer healing was confirmed after rabeprazole was replaced with vonoprazan and misoprostol. Our case shows that lenvatinib can induce duodenal ulcers resulting in obstructive jaundice.
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Affiliation(s)
- Maito Suoh
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Japan
| | - Atsushi Hagihara
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Japan
| | - Masafumi Yamamura
- Department of Gastroenterology, Graduate School of Medicine, Osaka City University, Japan
| | - Hirotsugu Maruyama
- Department of Gastroenterology, Graduate School of Medicine, Osaka City University, Japan
| | - Koichi Taira
- Department of Gastroenterology, Graduate School of Medicine, Osaka City University, Japan
| | - Masaru Enomoto
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Japan
| | - Akihiro Tamori
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Japan
| | - Yasuhiro Fujiwara
- Department of Gastroenterology, Graduate School of Medicine, Osaka City University, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Japan
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Kurniawan DW, Booijink R, Pater L, Wols I, Vrynas A, Storm G, Prakash J, Bansal R. Fibroblast growth factor 2 conjugated superparamagnetic iron oxide nanoparticles (FGF2-SPIONs) ameliorate hepatic stellate cells activation in vitro and acute liver injury in vivo. J Control Release 2020; 328:640-652. [PMID: 32979454 DOI: 10.1016/j.jconrel.2020.09.041] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 09/01/2020] [Accepted: 09/20/2020] [Indexed: 12/17/2022]
Abstract
Liver diseases are the growing health problem with no clinically approved therapy available. Activated hepatic stellate cells (HSCs) are the key driver cells responsible for extracellular matrix deposition, the hallmark of liver fibrosis. Fibroblast growth factor 2 (FGF2) has shown to possess anti-fibrotic effects in fibrotic diseases including liver fibosis, and promote tissue regeneration. Among the fibroblast growth factor receptors (FGFRs), FGF2 interact primarily with FGFR1, highly overexpressed on activated HSCs, and inhibit HSCs activation. However, FGF2 poses several limitations including poor systemic half-life and stability owing to enzymatic degradation. The aim of this study is to improve the stability and half-life of FGF2 thereby improving the therapuetic efficacy of FGF2 for the treatment of liver fibrosis. We found that FGFR1-3 mRNA levels were overexpressed in cirrhotic human livers, while FGFR1c, 2c, 3c, 4 and FGF2 mRNA levels were overexpressed in TGFβ-activated HSCs (LX2 cells) and FGFR1 protein expression was highly increased in TGFβ-activated HSCs. Treatment with FGF2 inhibited TGFβ-induced HSCs activation, migration and contraction in vitro. FGF2 was conjugated to superparamagnetic iron-oxide nanoparticles (SPIONs) using carbodiimide chemistry, and the resulting FGF2-SPIONs were confirmed by dynamic light scattering (DLS), zeta potential, dot-blot analysis and Prussian Blue iron-staining. In vitro, treatment with FGF2-SPIONs evidenced increased therapeutic effects (attenuated TGFβ-induced HSCs activation, migration and contraction) of FGF2 in TGFβ-activated HSCs and ameliorated early liver fibrogenesis in vivo in acute carbon tetrachloride (CCl4)-induced liver injury mouse model. In contrast, free FGF2 showed no significant effects in vivo. Altogether, this study presents a promising therapeutic approach using FGF2-SPIONs for the treatment of liver fibrosis.
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Affiliation(s)
- Dhadhang Wahyu Kurniawan
- Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, the Netherlands; Department of Pharmacy, Universitas Jenderal Soedirman, Purwokerto, Indonesia
| | - Richell Booijink
- Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, the Netherlands
| | - Lena Pater
- Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, the Netherlands
| | - Irene Wols
- Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, the Netherlands
| | - Aggelos Vrynas
- Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, the Netherlands
| | - Gert Storm
- Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, the Netherlands; Department of Pharmaceutics, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands
| | - Jai Prakash
- Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, the Netherlands
| | - Ruchi Bansal
- Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, the Netherlands.
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Genetic background dependent modifiers of craniosynostosis severity. J Struct Biol 2020; 212:107629. [PMID: 32976998 DOI: 10.1016/j.jsb.2020.107629] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 09/13/2020] [Accepted: 09/17/2020] [Indexed: 12/14/2022]
Abstract
Craniosynostosis severity varies in patients with identical genetic mutations. To understand causes of this phenotypic variation, we backcrossed the FGFR2+/C342Y mouse model of Crouzon syndrome onto congenic C57BL/6 and BALB/c backgrounds. Coronal suture fusion was observed in C57BL/6 (88% incidence, p < .001 between genotypes) but not in BALB/c FGFR2+/C342Y mutant mice at 3 weeks after birth, establishing that that the two models differ in phenotype severity. To begin identifying pre-existing modifiers of craniosynostosis severity, we compared transcriptome signatures of cranial tissues from C57BL/6 vs. BALB/c FGFR2+/+ mice. We separately analyzed frontal bone with coronal suture tissue from parietal bone with sagittal suture tissues because the coronal suture but not the sagittal suture fuses in FGFR2+/C342Y mice. The craniosynostosis associated Twist and En1 transcription factors were down-regulated, while Runx2 was up-regulated, in C57BL/6 compared to BALB/c tissues, which could predispose to craniosynostosis. Transcriptome analyses under the GO term MAPK cascade revealed that genes associated with calcium ion channels, angiogenesis, protein quality control and cell stress response were central to transcriptome differences associated with genetic background. FGFR2 and HSPA2 protein levels plus ERK1/2 activity were higher in cells isolated from C57BL/6 than BALB/c cranial tissues. Notably, the HSPA2 protein chaperone is central to craniofacial genetic epistasis, and we find that FGFR2 protein is abnormally processed in primary cells from FGFR2+/C342Y but not FGFR2+/+ mice. Therefore, we propose that differences in protein quality control responses may contribute to genetic background influences on craniosynostosis phenotype severity.
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Krzyscik MA, Zakrzewska M, Otlewski J. Site-Specific, Stoichiometric-Controlled, PEGylated Conjugates of Fibroblast Growth Factor 2 (FGF2) with Hydrophilic Auristatin Y for Highly Selective Killing of Cancer Cells Overproducing Fibroblast Growth Factor Receptor 1 (FGFR1). Mol Pharm 2020; 17:2734-2748. [PMID: 32501706 PMCID: PMC7588128 DOI: 10.1021/acs.molpharmaceut.0c00419] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
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In
spite of significant progress in the field of targeted anticancer
therapy, the FDA has approved only five ADC-based drugs. Hence the
search for new targeted anticancer agents is an unfulfilled necessity.
Here, we present novel types of protein–drug conjugates (PDCs)
that exhibit superior anticancer activities. Instead of a monoclonal
antibody, we used fibroblast growth factor 2 (FGF2) as a targeting
molecule. FGF2 is a natural ligand of fibroblast growth factor receptor
1 (FGFR1), a transmembrane receptor overproduced in various types
of cancers. We synthesized site-specific and stoichiometric-controlled
conjugates of FGF2 with a highly potent, hydrophilic derivative of
auristatin called auristatin Y. To increase the hydrophilicity and
hydrodynamic radius of conjugates, we employed PEG4 and PEG27 molecules
as a spacer between the targeting molecule and the cytotoxic payload.
All conjugates were selective to FGFR1-positive cell lines, effectively
internalized via the FGFR1-dependent pathway, and exhibited a highly
cytotoxic effect only on FGFR1-positive cancer cell lines.
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Moawad AW, Szklaruk J, Lall C, Blair KJ, Kaseb AO, Kamath A, Rohren SA, Elsayes KM. Angiogenesis in Hepatocellular Carcinoma; Pathophysiology, Targeted Therapy, and Role of Imaging. J Hepatocell Carcinoma 2020; 7:77-89. [PMID: 32426302 PMCID: PMC7188073 DOI: 10.2147/jhc.s224471] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 12/24/2019] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide, usually occurring on a background of liver cirrhosis. HCC is a highly vascular tumor in which angiogenesis plays a major role in tumor growth and spread. Tumor-induced angiogenesis is usually related to a complex interplay between multiple factors and pathways, with vascular endothelial growth factor being a major player in angiogenesis. In the past decade, understanding of tumor-induced angiogenesis has led to the emergence of novel anti-angiogenic therapies, which act by reducing neo-angiogenesis, and improving patient survival. Currently, Sorafenib and Lenvatinib are being used as the first-line treatment for advanced unresectable HCC. However, a disadvantage of these agents is the presence of numerous side effects. A major challenge in the management of HCC patients being treated with anti-angiogenic therapy is effective monitoring of treatment response, which decides whether to continue treatment or to seek second-line treatment. Several criteria can be used to assess response to treatment, such as quantitative perfusion on cross-sectional imaging and novel/emerging MRI techniques, including a host of known and emerging biomarkers and radiogenomics. This review addresses the pathophysiology of angiogenesis in HCC, accurate imaging assessment of angiogenesis, monitoring effects of anti-angiogenic therapy to guide future treatment and assessing prognosis.
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Affiliation(s)
- Ahmed W Moawad
- Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Janio Szklaruk
- Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Chandana Lall
- Department of Radiology, University of Florida College of Medicine, Jacksonville, FL, USA
| | - Katherine J Blair
- Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Ahmed O Kaseb
- Department of Gastrointestinal Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Amita Kamath
- Department of Radiology, Icahn School of Medicine at Mount Sinai West, New York, NY, USA
| | - Scott A Rohren
- School of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Khaled M Elsayes
- Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
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Ji L, Lin Z, Wan Z, Xia S, Jiang S, Cen D, Cai L, Xu J, Cai X. miR-486-3p mediates hepatocellular carcinoma sorafenib resistance by targeting FGFR4 and EGFR. Cell Death Dis 2020; 11:250. [PMID: 32313144 PMCID: PMC7170966 DOI: 10.1038/s41419-020-2413-4] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 02/25/2020] [Accepted: 02/25/2020] [Indexed: 12/19/2022]
Abstract
HCC is a common malignancy worldwide and surgery or reginal treatments are deemed insufficient for advanced-stage disease. Sorafenib is an inhibitor of many kinases and was shown to benefit advanced HCC patients. However, resistance emerges soon after initial treatment, limiting the clinical benefit of sorafenib, and the mechanisms still remain elusive. Thus, this study aims to investigate the mechanisms of sorafenib resistance and to provide possible targets for combination therapies. Through miRNA sequencing, we found that miR-486-3p was downregulated in sorafenib resistant HCC cell lines. Cell viability experiments showed increased miR-486-3p expression could induce cell apoptosis while miR-486-3p knockdown by CRISPR-CAS9 technique could reduce cell apoptosis in sorafenib treatment. Clinical data also indicated that miR-486-3p level was downregulated in tumor tissue compared with adjacent normal tissue in HCC patients. Mechanism dissections showed that FGFR4 and EGFR were the targets of miR-486-3p, which was verified by luciferase reporter assay. Importantly, FGFR4 or EGFR selective inhibitor could enhance sorafenib efficacy in the resistant cells. Moreover, in vivo sorafenib resistant model identified that over-expressing miR-486-3p by lentivirus injection could overcome sorafenib resistance by significantly suppressing tumor growth in combination with the treatment of sorafenib. In conclusion, we found miR-486-3p was an important mediator regulating sorafenib resistance by targeting FGFR4 and EGFR, thus offering a potential target for HCC treatment.
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Affiliation(s)
- Lin Ji
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, 310016, Hangzhou, China
| | - Zhongjie Lin
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, 310016, Hangzhou, China
| | - Zhe Wan
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, 310016, Hangzhou, China
| | - Shunjie Xia
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, 310016, Hangzhou, China
| | - Shi Jiang
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, 310016, Hangzhou, China
| | - Dong Cen
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, 310016, Hangzhou, China
| | - Liuxin Cai
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, 310016, Hangzhou, China
| | - Junjie Xu
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, 310016, Hangzhou, China.
| | - Xiujun Cai
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, 310016, Hangzhou, China.
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44
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Zhou C, Zou QY, Jiang YZ, Zheng J. Role of oxygen in fetoplacental endothelial responses: hypoxia, physiological normoxia, or hyperoxia? Am J Physiol Cell Physiol 2020; 318:C943-C953. [PMID: 32267717 DOI: 10.1152/ajpcell.00528.2019] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
During pregnancy, placental vascular growth, which is essential for supporting the rapidly growing fetus, is associated with marked elevations in blood flow. These vascular changes take place under chronic physiological low O2 (less than 2-8% O2 in human; chronic physiological normoxia, CPN) throughout pregnancy. O2 level below CPN pertinent to the placenta results in placental hypoxia. Such hypoxia can cause severe endothelial dysfunction, which is associated with adverse pregnancy outcomes (e.g., preeclampsia) and high risk of adult-onset cardiovascular diseases in children born to these pregnancy complications. However, our current knowledge about the mechanisms underlying fetoplacental endothelial function is derived primarily from cell models established under atmospheric O2 (~21% O2 at sea level, hyperoxia). Recent evidence has shown that fetoplacental endothelial cells cultured under CPN have distinct gene expression profiles and cellular responses compared with cells cultured under chronic hyperoxia. These data indicate the critical roles of CPN in programming fetal endothelial function and prompt us to re-examine the mechanisms governing fetoplacental endothelial function under CPN. Better understanding these mechanisms will facilitate us to develop preventive and therapeutic strategies for endothelial dysfunction-associated diseases (e.g., preeclampsia). This review will provide a brief summary on the impacts of CPN on endothelial function and its underlying mechanisms with a focus on fetoplacental endothelial cells.
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Affiliation(s)
- Chi Zhou
- Perinatal Research Laboratories, Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, Wisconsin
| | - Qing-Yun Zou
- Department of Vascular Surgery, First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, China
| | - Yi-Zhou Jiang
- Institute for Advanced Study, Shenzhen University, Shenzhen, Guangdong, China
| | - Jing Zheng
- Perinatal Research Laboratories, Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, Wisconsin.,Cardiovascular Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
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45
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Destructive thyroiditis presenting as thyrotoxicosis followed by hypothyroidism during lenvatinib therapy for hepatocellular carcinoma. Clin J Gastroenterol 2020; 13:860-866. [PMID: 32128670 DOI: 10.1007/s12328-020-01107-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 02/16/2020] [Indexed: 02/08/2023]
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46
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Ocker M. Fibroblast growth factor signaling in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis: Paving the way to hepatocellular carcinoma. World J Gastroenterol 2020; 26:279-290. [PMID: 31988589 PMCID: PMC6969880 DOI: 10.3748/wjg.v26.i3.279] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 12/17/2019] [Accepted: 01/01/2020] [Indexed: 02/06/2023] Open
Abstract
Metabolic disorders are increasingly leading to non-alcoholic fatty liver disease, subsequent steatohepatitis, cirrhosis and hepatocellular carcinoma. Fibroblast growth factors and their receptors play an important role in maintaining metabolic homeostasis also in the liver and disorders in signaling have been identified to contribute to those pathophysiologic conditions leading to hepatic lipid accumulation and chronic inflammation. While specific and well tolerated inhibitors of fibroblast growth factor receptor activity are currently developed for (non-liver) cancer therapy, treatment of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis is still limited. Fibroblast growth factor-mimicking or restoring approaches have recently evolved as a novel therapeutic option and the impact of such interactions with the fibroblast growth factor receptor signaling network during non-alcoholic fatty liver disease/non-alcoholic steatohepatitis development is reviewed here.
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Affiliation(s)
- Matthias Ocker
- Department of Gastroenterology (CBF), Charité University Medicine Berlin, Berlin 10117, Germany
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47
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Nurcombe V, Ling L, Hondermarck H, Cool SM, Smith RAA. Bringing Heparan Sulfate Glycomics Together with Proteomics for the Design of Novel Therapeutics: A Historical Perspective. Proteomics 2019; 19:e1800466. [PMID: 31197945 DOI: 10.1002/pmic.201800466] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 05/31/2019] [Indexed: 01/29/2023]
Abstract
Increasing knowledge of how peptides bind saccharides, and of how saccharides bind peptides, is starting to revolutionize understanding of cell-extracellular matrix relationships. Here, a historical perspective is taken of the relationship between heparan sulfate glycosaminoglycans and how they interact with peptide growth factors in order to both drive and modulate signaling through the appropriate cognate receptors. Such knowledge is guiding the preparation of targeted sugar mimetics that will impact the treatment of many different kinds of diseases, including cancer.
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Affiliation(s)
- Victor Nurcombe
- Institute of Medical Biology, Glycotherapeutics Group, A*STAR, 138648, Singapore.,Lee Kong Chian School of Medicine, Nanyang Technology University-Imperial College London, 636921, Singapore
| | - Ling Ling
- Institute of Medical Biology, Glycotherapeutics Group, A*STAR, 138648, Singapore
| | - Hubert Hondermarck
- School of Biomedical Sciences and Pharmacy, University of Newcastle, NSW, 2308, Australia
| | - Simon M Cool
- Institute of Medical Biology, Glycotherapeutics Group, A*STAR, 138648, Singapore.,Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 119228, Singapore
| | - Raymond A A Smith
- Institute of Medical Biology, Glycotherapeutics Group, A*STAR, 138648, Singapore
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48
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Raja A, Park I, Haq F, Ahn SM. FGF19- FGFR4 Signaling in Hepatocellular Carcinoma. Cells 2019; 8:E536. [PMID: 31167419 PMCID: PMC6627123 DOI: 10.3390/cells8060536] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 05/28/2019] [Accepted: 05/29/2019] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common type of cancer, with an increasing mortality rate. Aberrant expression of fibroblast growth factor 19-fibroblast growth factor receptor 4 (FGF19-FGFR4) is reported to be an oncogenic-driver pathway for HCC patients. Thus, the FGF19-FGFR4 signaling pathway is a promising target for the treatment of HCC. Several pan-FGFR (1-4) and FGFR4-specific inhibitors are in different phases of clinical trials. In this review, we summarize the information, recent developments, binding modes, selectivity, and clinical trial phases of different available FGFR4/pan-FGF inhibitors. We also discuss future perspectives and highlight the points that should be addressed to improve the efficacy of these inhibitors.
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Affiliation(s)
- Aroosha Raja
- Department of Biosciences, Comsats University, Islamabad 45550, Pakistan.
| | - Inkeun Park
- Division of Medical Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon 21565, Korea.
| | - Farhan Haq
- Department of Biosciences, Comsats University, Islamabad 45550, Pakistan.
| | - Sung-Min Ahn
- Division of Medical Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon 21565, Korea.
- Department of Genome Medicine and Science, College of Medicine, Gachon University, Incheon 21565, Korea.
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Lin S, Yang X, Yuan P, Yang J, Wang P, Zhong H, Zhang X, Che L, Feng B, Li J, Zhuo Y, Lin Y, Xu S, Wu D, Burrin DG, Fang Z. Undernutrition Shapes the Gut Microbiota and Bile Acid Profile in Association with Altered Gut-Liver FXR Signaling in Weaning Pigs. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2019; 67:3691-3701. [PMID: 30864445 DOI: 10.1021/acs.jafc.9b01332] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Bile acids, synthesized in the liver and metabolized by microbiota, have emerged as important signaling molecules regulating immune responses and cell proliferation. However, the crosstalk among nutrition, microbiota, and bile acids remains unclear. Our study indicated that undernutrition in weaning piglets led to intestinal atrophy, increased colonic production, and systemic accumulation of lithocholic acid (LCA), deoxycholic acid (DCA), or their conjugated forms, which might be associated with decreased Lactobacillus abundance. Moreover, undernutrition led to increased portal fibroblast growth factor 19 ( FGF19) level, upregulated hepatic heterodimer partner ( SHP), and downregulated cholesterol 7a-hydroxylase ( CYP7A1) expression. The detrimental effects of DCA and LCA on proliferation and barrier function were confirmed in porcine enterocytes, whereas their roles in weaning piglets warrant further research. In summary, undernutrition in weaning piglets led to increased secondary bile acids production, which might be related to altered gut microbiome and enhanced farnesoid X receptor (FXR) signaling while CYP7A1 expression was suppressed.
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Affiliation(s)
- Sen Lin
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute , Sichuan Agricultural University , Chengdu 611130 , People's Republic of China
| | - Xiaomin Yang
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute , Sichuan Agricultural University , Chengdu 611130 , People's Republic of China
| | - Peiqiang Yuan
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute , Sichuan Agricultural University , Chengdu 611130 , People's Republic of China
| | - Jiameng Yang
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute , Sichuan Agricultural University , Chengdu 611130 , People's Republic of China
| | - Peng Wang
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute , Sichuan Agricultural University , Chengdu 611130 , People's Republic of China
| | - Heju Zhong
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute , Sichuan Agricultural University , Chengdu 611130 , People's Republic of China
| | - Xiaoling Zhang
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute , Sichuan Agricultural University , Chengdu 611130 , People's Republic of China
| | - Lianqiang Che
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute , Sichuan Agricultural University , Chengdu 611130 , People's Republic of China
| | - Bin Feng
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute , Sichuan Agricultural University , Chengdu 611130 , People's Republic of China
| | - Jian Li
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute , Sichuan Agricultural University , Chengdu 611130 , People's Republic of China
| | - Yong Zhuo
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute , Sichuan Agricultural University , Chengdu 611130 , People's Republic of China
| | - Yan Lin
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute , Sichuan Agricultural University , Chengdu 611130 , People's Republic of China
| | - Shengyu Xu
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute , Sichuan Agricultural University , Chengdu 611130 , People's Republic of China
| | - De Wu
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute , Sichuan Agricultural University , Chengdu 611130 , People's Republic of China
| | - Douglas G Burrin
- USDA-ARS Children's Nutrition Research Center, Department of Pediatrics , Baylor College of Medicine , Houston , Texas 77030 , United States
| | - Zhengfeng Fang
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute , Sichuan Agricultural University , Chengdu 611130 , People's Republic of China
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50
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Wimmer E, Ihrler S, Gires O, Streit S, Issing W, Bergmann C. Fibroblast growth factor receptor 4 single nucleotide polymorphism Gly388Arg in head and neck carcinomas. World J Clin Oncol 2019; 10:136-148. [PMID: 30949443 PMCID: PMC6441662 DOI: 10.5306/wjco.v10.i3.136] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 01/16/2019] [Accepted: 01/30/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Head and neck squamous cell carcinoma (HNSCC) is considered to be a progressive disease resulting from alterations in multiple genes regulating cell proliferation and differentiation like receptor tyrosine kinases (RTKs) and members of the fibroblast growth factor receptors (FGFR)-family. Single-nucleotide polymorphism (SNP) Arg388 of the FGFR4 is associated with a reduced overall survival in patients with cancers of various types. We speculate that FGFR4 expression and SNP is associated with worse survival in patients with HSNCC.
AIM To investigate the potential clinical significance of FGFR4 Arg388 in the context of tumors arising in HNSCC, a comprehensive analysis of FGFR4 receptor expression and genotype in tumor tissues and correlated results with patients’ clinical data in a large cohort of patients with HNSCC was conducted.
METHODS Surgical specimens from 284 patients with HNSCC were retrieved from the Institute of Pathology at the Ludwig-Maximilian-University in Germany. Specimens were analyzed using immunohistochemistry and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The expression of FGFR4 was analyzed in 284 surgical specimens of HNSCC using immunohistochemstry. FGFR4 polymorphism was detected by PCR-RFLP. Patients’ clinical data with a minimum follow-up of 5 years were statistically evaluated with a special emphasis on survival analysis employing Kaplan-Meier estimator and Cox regression analysis.
RESULTS Concerning the invasive tumor areas the intensity of the FGFR4 expression was evaluated in a four-grade system: no expression, low expression, intermediate and high expression. FGFR4 expression was scored as “high” (+++) in 74 (26%), “intermediate” (++) in 103 (36.3%), and “low” (+) in 107 (36.7%) cases. Analyzing the FGFR4 mutation it was found in 96 tumors (33.8%), 84 of them (29.6%) having a heterozygous and 12 (4.2%) homozygous mutated Arg388 allele. The overall frequency concerning the mutant alleles demonstrated 65% vs 34% mutated alleles in general. FGFR4 Arg388 was significantly associated with advanced tumor stage (P < 0.004), local metastasis (P < 0.0001) and reduced disease-free survival (P < 0.01). Furthermore, increased expression of FGFR4 correlated significantly with worse overall survival (P < 0.003).
CONCLUSION In conclusion, the FGFR4 Arg388 genotype and protein expression of FGFR4 impacts tumor progression in patients with HNSCC and may present a useful target within a multimodal therapeutic intervention.
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Affiliation(s)
- Eva Wimmer
- Department of Otorhinolaryngology, Ludwig-Maximilians-University, Munich 81377, Germany
| | - Stephan Ihrler
- Institute of Pathology, Ludwig-Maximilians-University, Munich 80337, Germany
| | - Olivier Gires
- Department of Otorhinolaryngology, Ludwig-Maximilians-University, Munich 81377, Germany
- Clinical Cooperation Group Personalized Radiotherapy of Head and Neck Tumors, Neuherberg 71083, Germany
| | - Sylvia Streit
- Department of Molecular Biology, Max-Planck-Institute for Biochemistry, Planegg 82152, Germany
| | - Wolfgang Issing
- Department of Otorhinolaryngology, Ludwig-Maximilians-University, Munich 81377, Germany
- ENT Department, Freeman Hospital, Newcastle upon Tyne, NE7 7DN, United Kingdom
| | - Christoph Bergmann
- Department of Otorhinolaryngology, Ludwig-Maximilians-University, Munich 81377, Germany
- Department of Otorhinolaryngology, University of Duisburg-Essen, Essen 45147, Germany
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