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Sugiura H, Tsunezumi J, Yanagisawa H, Futaya M, Nitta K, Tsuchiya K. Fibulin7 aggravates calcium oxalate-induced acute kidney injury by binding to calcium oxalate crystals. J Cell Physiol 2023; 238:165-178. [PMID: 36370444 DOI: 10.1002/jcp.30914] [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: 07/04/2022] [Revised: 10/20/2022] [Accepted: 10/27/2022] [Indexed: 11/13/2022]
Abstract
Fibulin7 (Fbln7) is a matricellular protein that is structurally similar to short fibulins but does not possess elastogenic abilities. Fbln7 is localized on the cell surface of the renal tubular epithelium in the adult kidney. We previously reported that Fbln7 binds artificial calcium phosphate particles in vitro, and that heparin counteracts this binding by releasing Fbln7 from the cell surface. Fbln7 gene (Fbln7) deletion in vivo decreased interstitial fibrosis and improved renal function in a high phosphate diet-induced chronic kidney disease mouse model. However, the contribution of Fbln7 during acute injury response remains largely unknown. We hypothesized that Fbln7 serves as an exacerbating factor in acute kidney injury (AKI). We employed three AKI models in vivo and in vitro, including unilateral ureteral obstruction (UUO), cisplatin-induced AKI, and calcium oxalate (CaOx)-induced AKI. Here, we report that Fbln7KO mice were protected from kidney damage in a CaOx-induced AKI model. Using HEK293T cells, we found that Fbln7 overexpression enhanced the CaOx-induced upregulation of EGR1 and LAMB3, and that heparin treatment canceled this effect. Interestingly, the protective function observed in Fbln7KO kidneys was limited to the CaOx-induced AKI model, while Fbln7KO mice were not protected against UUO-induced renal fibrosis or cisplatin-induced renal tubular damage. Taken together, our study indicates that Fbln7 mediates the local deposition of CaOx and damages the renal tubular epithelium. Releasing Fbln7 from the cell surface via heparin/heparin derivatives or Fbln7 inhibitory antibodies may provide a general strategy to mitigate calcium crystal-induced kidney injuries.
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Affiliation(s)
- Hidekazu Sugiura
- Department of Medicine, Kidney Center, Tokyo Women's Medical University, Shinjuku, Tokyo, Japan.,Department of Nephrology, Division of Medicine, Saiseikai Kazo Hospital, Kazo, Saitama, Japan.,Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Jun Tsunezumi
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan.,Department of Pharmaceutical Sciences, Kyushu University of Health and Welfare, Miyazaki, Japan
| | - Hiromi Yanagisawa
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan.,Department of Biomedical Science, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Mayuko Futaya
- Department of Medicine, Kidney Center, Tokyo Women's Medical University, Shinjuku, Tokyo, Japan
| | - Kosaku Nitta
- Department of Medicine, Kidney Center, Tokyo Women's Medical University, Shinjuku, Tokyo, Japan
| | - Ken Tsuchiya
- Department of Medicine, Kidney Center, Tokyo Women's Medical University, Shinjuku, Tokyo, Japan.,Department of Blood Purification, Kidney Center, Tokyo Women's Medical University, Shinjuku, Tokyo, Japan
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Zhao S, Wu W, Jiang H, Ma L, Pan C, Jin C, Mo J, Wang L, Wang K. Selective Inhibitor of the c-Met Receptor Tyrosine Kinase in Advanced Hepatocellular Carcinoma: No Beneficial Effect With the Use of Tivantinib? Front Immunol 2021; 12:731527. [PMID: 34804015 PMCID: PMC8600564 DOI: 10.3389/fimmu.2021.731527] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 10/18/2021] [Indexed: 12/12/2022] Open
Abstract
Advanced hepatocellular carcinoma (HCC) remains a formidable health challenge worldwide, with a 5-year survival rate of 2.4% in patients with distant metastases. The hepatocyte growth factor/cellular-mesenchymal-epithelial transition (HGF/c-Met) signaling pathway represents an encouraging therapeutic target for progressive HCC. Tivantinib, a non-adenosine triphosphate-competitive c-Met inhibitor, showed an attractive therapeutic effect on advanced HCC patients with high MET-expression in phase 2 study but failed to meet its primary endpoint of prolonging the overall survival (OS) in two phase 3 HCC clinical trials. Seven clinical trials have been registered in the "ClinicalTrials.gov" for investigating the safety and efficacy of tivantinib in treating advanced or unresectable HCC. Eight relevant studies have been published with results. The sample size ranged from 20 to 340 patients. The methods of tivantinib administration and dosage were orally 120/240/360 mg twice daily. MET overexpression was recorded at 34.6% to 100%. Two large sample phase 3 studies (the METIV-HCC study of Australia and European population and the JET-HCC study of the Japanese population) revealed that tivantinib failed to show survival benefits in advanced HCC. Common adverse events with tivantinib treatment include neutropenia, ascites, rash, and anemia, etc. Several factors may contribute to the inconsistency between the phase 2 and phase 3 studies of tivantinib, including the sample size, drug dosing, study design, and the rate of MET-High. In the future, high selective MET inhibitors combined with a biomarker-driven patient selection may provide a potentially viable therapeutic strategy for patients with advanced HCC.
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Affiliation(s)
- Shankun Zhao
- Department of Urology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Weizhou Wu
- Department of Urology, Maoming People's Hospital, Maoming, China
| | - Hao Jiang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Lei Ma
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Chengyi Pan
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Chong Jin
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Jinggang Mo
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Liezhi Wang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Kunpeng Wang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
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Topel H, Bağırsakçı E, Yılmaz Y, Güneş A, Bağcı G, Çömez D, Kahraman E, Korhan P, Atabey N. High glucose induced c-Met activation promotes aggressive phenotype and regulates expression of glucose metabolism genes in HCC cells. Sci Rep 2021; 11:11376. [PMID: 34059694 PMCID: PMC8166976 DOI: 10.1038/s41598-021-89765-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 04/26/2021] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is strongly associated with metabolic dysregulations/deregulations and hyperglycemia is a common metabolic disturbance in metabolic diseases. Hyperglycemia is defined to promote epithelial to mesenchymal transition (EMT) of cancer cells in various cancers but its molecular contribution to HCC progression and aggressiveness is relatively unclear. In this study, we analyzed the molecular mechanisms behind the hyperglycemia-induced EMT in HCC cell lines. Here, we report that high glucose promotes EMT through activating c-Met receptor tyrosine kinase via promoting its ligand-independent homodimerization. c-Met activation is critical for high glucose induced acquisition of mesenchymal phenotype, survival under high glucose stress and reprogramming of cellular metabolism by modulating glucose metabolism gene expression to promote aggressiveness in HCC cells. The crucial role of c-Met in high glucose induced EMT and aggressiveness may be the potential link between metabolic syndrome-related hepatocarcinogenesis and/or HCC progression. Considering c-Met inhibition in hyperglycemic patients would be an important complementary strategy for therapy that favors sensitization of HCC cells to therapeutics.
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Affiliation(s)
- Hande Topel
- Izmir Biomedicine and Genome Center (IBG), Balcova, 35340, Izmir, Turkey.,Department of Medical Biology and Genetics, Graduate School of Health Sciences, Dokuz Eylul University, Balcova, 35340, Izmir, Turkey
| | - Ezgi Bağırsakçı
- Izmir Biomedicine and Genome Center (IBG), Balcova, 35340, Izmir, Turkey.,Department of Molecular Biology and Genetics, Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Balcova, 35340, Izmir, Turkey
| | - Yeliz Yılmaz
- Izmir Biomedicine and Genome Center (IBG), Balcova, 35340, Izmir, Turkey.,Department of Medical Biology and Genetics, Graduate School of Health Sciences, Dokuz Eylul University, Balcova, 35340, Izmir, Turkey
| | - Ayşim Güneş
- Izmir Biomedicine and Genome Center (IBG), Balcova, 35340, Izmir, Turkey
| | - Gülsün Bağcı
- Izmir Biomedicine and Genome Center (IBG), Balcova, 35340, Izmir, Turkey.,Department of Molecular Biology and Genetics, Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Balcova, 35340, Izmir, Turkey
| | - Dehan Çömez
- Izmir Biomedicine and Genome Center (IBG), Balcova, 35340, Izmir, Turkey.,Department of Molecular Biology and Genetics, Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Balcova, 35340, Izmir, Turkey
| | - Erkan Kahraman
- Izmir Biomedicine and Genome Center (IBG), Balcova, 35340, Izmir, Turkey.,Department of Medical Biology and Genetics, Graduate School of Health Sciences, Dokuz Eylul University, Balcova, 35340, Izmir, Turkey
| | - Peyda Korhan
- Izmir Biomedicine and Genome Center (IBG), Balcova, 35340, Izmir, Turkey
| | - Neşe Atabey
- Izmir Biomedicine and Genome Center (IBG), Balcova, 35340, Izmir, Turkey.
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Yılmaz Y, Batur T, Korhan P, Öztürk M, Atabey N. Targeting c-Met and AXL Crosstalk for the Treatment of Hepatocellular Carcinoma. LIVER CANCER IN THE MIDDLE EAST 2021:333-364. [DOI: 10.1007/978-3-030-78737-0_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Receptor tyrosine kinases and heparan sulfate proteoglycans: Interplay providing anticancer targeting strategies and new therapeutic opportunities. Biochem Pharmacol 2020; 178:114084. [DOI: 10.1016/j.bcp.2020.114084] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/04/2020] [Accepted: 06/04/2020] [Indexed: 12/13/2022]
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Topel H, Bagirsakci E, Comez D, Bagci G, Cakan-Akdogan G, Atabey N. lncRNA HOTAIR overexpression induced downregulation of c-Met signaling promotes hybrid epithelial/mesenchymal phenotype in hepatocellular carcinoma cells. Cell Commun Signal 2020; 18:110. [PMID: 32650779 PMCID: PMC7353702 DOI: 10.1186/s12964-020-00602-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 05/25/2020] [Indexed: 02/07/2023] Open
Abstract
Background Epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) are both reversible processes, and regulation of phenotypical transition is very important for progression of several cancers including hepatocellular carcinoma (HCC). Recently, it is defined that cancer cells can attain a hybrid epithelial/mesenchymal (hybrid E/M) phenotype. Cells with hybrid E/M phenotype comprise mixed epithelial and mesenchymal properties, they can be more resistant to therapeutics and also more capable of initiating metastatic lesions. However, the mechanisms regulating hybrid E/M in HCC are not well described yet. In this study, we investigated the role of the potential crosstalk between lncRNA HOTAIR and c-Met receptor tyrosine kinase, which are two essential regulators of EMT and MET, in acquiring of hybrid E/M phenotype in HCC. Methods Expression of c-Met and lncRNA HOTAIR were defined in HCC cell lines and patient tissues through HCC progression. lncRNA HOTAIR was overexpressed in SNU-449 cells and its effects on c-Met signaling were analyzed. c-Met was overexpressed in SNU-398 cells and its effect on HOTAIR expression was analyzed. Biological significance of HOTAIR/c-Met interplay was defined in means of adhesion, proliferation, motility behavior, invasion, spheroid formation and metastatic ability. Effect of ectopic lncRNA HOTAIR expression on phenotype was defined with investigation of molecular epithelial and mesenchymal traits. Results In vitro and in vivo experiments verified the pivotal role of lncRNA HOTAIR in acquisition of hybrid E/M phenotype through modulating expression and activation of c-Met and its membrane co-localizing partner Caveolin-1, and membrane organization to cope with the rate limiting steps of metastasis such as survival in adhesion independent microenvironment, escaping from anoikis and resisting to fluidic shear stress (FSS) in HCC. Conclusions Our work provides the first evidence suggesting a role for lncRNA HOTAIR in the modulation of c-Met to promote hybrid E/M phenotype. The balance between lncRNA HOTAIR and c-Met might be critical for cell fate decision and metastatic potential of HCC cells.
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