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Feng ML, Sun MJ, Xu BY, Liu MY, Zhang HJ, Wu C. Mechanism of ELL-associated factor 2 and vasohibin 1 regulating invasion, migration, and angiogenesis in colorectal cancer. World J Gastroenterol 2023; 29:3770-3792. [PMID: 37426316 PMCID: PMC10324531 DOI: 10.3748/wjg.v29.i24.3770] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 04/08/2023] [Accepted: 05/12/2023] [Indexed: 06/28/2023] Open
Abstract
BACKGROUND As a novel endogenous anti-angiogenic molecule, vasohibin 1 (VASH1) is not only expressed in tumor stroma, but also in tumor tissue. Moreover, studies have shown that VASH1 may be a prognostic marker in colorectal cancer (CRC). Knockdown of VASH1 enhanced transforming growth factor-β1 (TGF-β1)/Smad3 pathway activity and type I/III collagen production. Our previous findings suggest that ELL-associated factor 2 (EAF2) may play a tumor suppressor and protective role in the development and progression of CRC by regulating signal transducer and activator of transcription 3 (STAT3)/TGF-β1 signaling pathway. However, the functional role and mechanism of VASH1-mediated TGF-β1 related pathway in CRC has not been elucidated.
AIM To investigate the expression of VASH1 in CRC and its correlation with the expression of EAF2. Furthermore, we studied the functional role and mechanism of VASH1 involved in the regulation and protection of EAF2 in CRC cells in vitro.
METHODS We collected colorectal adenocarcinoma and corresponding adjacent tissues to investigate the clinical expression of EAF2 protein and VASH1 protein in patients with advanced CRC. Following, we investigated the effect and mechanism of EAF2 and VASH1 on the invasion, migration and angiogenesis of CRC cells in vitro using plasmid transfection.
RESULTS Our findings indicated that EAF2 was down-regulated and VASH1 was up-regulated in advanced CRC tissue compared to normal colorectal tissue. Kaplan-Meier survival analysis showed that the higher EAF2 Level group and the lower VASH1 Level group had a higher survival rate. Overexpression of EAF2 might inhibit the activity of STAT3/TGF-β1 pathway by up-regulating the expression of VASH1, and then weaken the invasion, migration and angiogenesis of CRC cells.
CONCLUSION This study suggests that EAF2 and VASH1 may serve as new diagnostic and prognostic markers for CRC, and provide a clinical basis for exploring new biomarkers for CRC. This study complements the mechanism of EAF2 in CRC cells, enriches the role and mechanism of CRC cell-derived VASH1, and provides a new possible subtype of CRC as a therapeutic target of STAT3/TGF-β1 pathway.
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Affiliation(s)
- Ming-Liang Feng
- Department of Endoscopy, The First Hospital Affiliated to China Medical University, Shenyang 110001, Liaoning Province, China
| | - Ming-Jun Sun
- Department of Endoscopy, The First Hospital Affiliated to China Medical University, Shenyang 110001, Liaoning Province, China
| | - Bo-Yang Xu
- Department of Endoscopy, The First Hospital Affiliated to China Medical University, Shenyang 110001, Liaoning Province, China
| | - Meng-Yuan Liu
- Department of Endoscopy, The First Hospital Affiliated to China Medical University, Shenyang 110001, Liaoning Province, China
| | - Hui-Jing Zhang
- Department of Endoscopy, The First Hospital Affiliated to China Medical University, Shenyang 110001, Liaoning Province, China
| | - Can Wu
- Department of Endoscopy, The First Hospital Affiliated to China Medical University, Shenyang 110001, Liaoning Province, China
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LAZOGLU A, KELEŞ MS, LALOĞLU E, YILMAZEL UCAR E, YILMAZ S. Determining the Vasohibin-1 Levels of the Serum and Broncoalveolar Lavage Fluid in the Patients with Lung Cancer”. KONURALP TIP DERGISI 2022. [DOI: 10.18521/ktd.1066032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
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Xiong HL, Zhong XH, Guo XH, Liao HJ, Yuan X. circASS1 overexpression inhibits the proliferation, invasion and migration of colorectal cancer cells by regulating the miR-1269a/VASH1 axis. Exp Ther Med 2021; 22:1155. [PMID: 34504600 PMCID: PMC8393656 DOI: 10.3892/etm.2021.10589] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 07/09/2021] [Indexed: 12/25/2022] Open
Abstract
Colorectal cancer (CRC), the third most common cancer worldwide, poses a threat to human life. However, its underlying mechanism is unclear and no satisfactory treatment is available. The present study aimed to investigate the role of circular RNA argininosuccinate synthase 1 (circASS1) in CRC cells and tissues to identify the potential mechanism underlying the pathogenesis of CRC. The expression of circASS1 in CRC cells and tissues was determined by reverse transcription-quantitative PCR. Following circASS1 overexpression in HT29 cells, cell viability, colony formation and apoptosis were measured using MTT, colony formation and TUNEL assays, respectively. Cell invasion and migration were also assessed. After confirming the associations among circASS1, microRNA (miR)-1269a and vasohibin 1 (VASH1), the characteristics of the HT29 cell line were assessed by performing the aforementioned assays. circASS1 expression was decreased in CRC cells and tissues, and circASS1 overexpression suppressed CRC cell proliferation, invasion and migration. circASS1 adsorbed miR-1269a and regulated its expression, and VASH1 was a target protein of miR-1269a. circASS1 overexpression decreased cell proliferation, invasion and migration, but enhanced cell apoptosis in HT29 cells, which was reversed by co-transfection with miR-1269a mimic or short hairpin RNA-VASH1. In conclusion, circASS1 overexpression inhibited CRC cell proliferation, invasion and migration by regulating miR-1269a/VASH1, which indicated a potential molecular mechanism underlying the pathogenesis of CRC.
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Affiliation(s)
- Hai-Lin Xiong
- Department of Medical Oncology, Huizhou Municipal Central Hospital of Guangdong Province, Huizhou, Guangdong 516000, P.R. China
| | - Xiao-Hua Zhong
- Department of Gastroenterological Surgery, Huizhou Municipal Central Hospital of Guangdong Province, Huizhou, Guangdong 516000, P.R. China
| | - Xiao-Hong Guo
- Department of Medical Oncology, Huizhou Municipal Central Hospital of Guangdong Province, Huizhou, Guangdong 516000, P.R. China
| | - Hao-Jie Liao
- Department of Medical Oncology, Huizhou Municipal Central Hospital of Guangdong Province, Huizhou, Guangdong 516000, P.R. China
| | - Xia Yuan
- Department of Medical Oncology, Huizhou Municipal Central Hospital of Guangdong Province, Huizhou, Guangdong 516000, P.R. China
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Ren H, Shao Y, Wu C, Lv C, Zhou Y, Wang Q. VASH-1 Regulates Oxidative Stress and Fibrosis in Diabetic Kidney Disease via SIRT1/HIF1α and TGFβ1/Smad3 Signaling Pathways. Front Mol Biosci 2020; 7:137. [PMID: 32754616 PMCID: PMC7365843 DOI: 10.3389/fmolb.2020.00137] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 06/08/2020] [Indexed: 11/13/2022] Open
Abstract
Aims: To investigate the role of Vasohibin-1 (VASH-1), silence information adjustment factor 2-related enzyme 1 (SIRT1)/hypoxic-inducible factor 1α (HIF1α) and transforming growth factor-β1 (TGFβ1) /Smad3 signaling pathways in oxidative stress and fibrosis of diabetic kidney disease (DKD). Materials and Methods: A diabetic rat model was established in vivo and rat mesangial cells (RMCs) were cultured in vitro with high glucose via transfection with Vash1 small interfering RNA (siRNA), Hif1a siRNA, Sirt1 siRNA and TGFβ1/Smad3 pathway inhibitor (SB431542). Renal histology was used to detect renal changes. Real-time PCR and western blot were used to analyze the expression of VASH-1, SIRT1, HIF1α, TGFβ1, Smad3, vascular endothelial growth factor (VEGF), connective tissue growth factor (CTGF) and fibronectin (FN). Expression levels of tumor necrosis factor-α (TNFα), TGFβ1, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-PX), and malondialdehyde (MDA) in rat tissues and cell culture supernatant were detected by ELISA and chemiluminescence assay, while cell proliferation was detected by CCK-8. Results: The level of VASH-1 in renal tissues of diabetic rats was decreased, while both high glucose and Vash1 siRNA inhibited the expression of VASH-1 and SIRT1, increased the levels of HIF1α, TGFβ1, and Smad3 in RMCs, thus up-regulating oxidative stress and fibrosis factors, and abnormally increasing cell proliferation activity (P < 0.05). However, inhibition of SIRT1/HIF1α signaling pathway only reduced TGFβ1 and Smad3 (P < 0.05), while VASH-1 remained unchanged (P > 0.05). Conclusion: VASH-1 was under-expressed in renal tissues of diabetic rats and regulated the pathological process of oxidative stress and fibrosis in DKD via downstream SIRT1/HIF1α and TGFβ1/Smad3 signaling pathways.
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Affiliation(s)
- Huiwen Ren
- Department of Endocrinology, The First Affiliated Hospital of China Medical University, Shenyang, China
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
| | - Ying Shao
- Department of Endocrinology, The Second Affiliated Hospital of China Medical University, Shenyang, China
| | - Can Wu
- Department of Gastroenterology and Endoscopy, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Chuan Lv
- Department of Endocrinology, The People's Hospital of Liaoning Province, Shenyang, China
| | - Yang Zhou
- Department of Endocrinology, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Qiuyue Wang
- Department of Endocrinology, The First Affiliated Hospital of China Medical University, Shenyang, China
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Tang XW, Qin QX. miR-335-5p induces insulin resistance and pancreatic islet β-cell secretion in gestational diabetes mellitus mice through VASH1-mediated TGF-β signaling pathway. J Cell Physiol 2018; 234:6654-6666. [PMID: 30341900 DOI: 10.1002/jcp.27406] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 08/21/2018] [Indexed: 12/25/2022]
Abstract
Multiple studies have reported different methods in treating gestational diabetes mellitus (GDM); however, the relationship between miR-335-5p and GDM still remains unclear. Here, this study explores the effect of miR-335-5p on insulin resistance and pancreatic islet β-cell secretion via activation of the TGFβ signaling pathway by downregulating VASH1 expression in GDM mice. The GDM mouse model was established and mainly treated with miR-335-5p mimic, miR-335-5p inhibitor, si-VASH1, and miR-335-5p inhibitor + si-VASH1. Oral glucose tolerance test (OGTT) was conducted to detect fasting blood glucose (FBG) fasting insulin (FINS). The OGTT was also used to calculate a homeostasis model assessment of insulin resistance (HOMA-IR). A hyperglycemic clamp was performed to measure the glucose infusion rate (GIR), which estimated β-cell function. Expressions of miR-335-5p, VASH1, TGF-β1, and c-Myc in pancreatic islet β-cells were determined by RT-qPCR, western blot analysis, and insulin release by ELISA. The miR-335-5p mimic and si-VASH1 groups showed elevated blood glucose levels, glucose area under the curve (GAUC), and HOMA-IR, but a reduced GIR and positive expression of VASH1. Overexpression of miR-335-5p and inhibition of VASH1 contributed to activated TGFβ1 pathway, higher c-Myc, and lower VASH1 expressions, in addition to downregulated insulin and insulin release levels. These findings provided evidence that miR-335-5p enhanced insulin resistance and suppressed pancreatic islet β-cell secretion by inhibiting VASH1, eventually activating the TGF-β pathway in GDM mice, which provides more clinical insight on the GDM treatment.
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Affiliation(s)
- Xu-Wen Tang
- Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center Affiliated to, Guangzhou Medical University, Guangzhou, China
| | - Qing-Xin Qin
- Department of Endocrinology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
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Nakagawa S, Okabe H, Ouchi M, Tokunaga R, Umezaki N, Higashi T, Kaida T, Arima K, Kitano Y, Kuroki H, Mima K, Nitta H, Imai K, Hashimoto D, Yamashita YI, Chikamoto A, Baba H. Enhancer of zeste homolog 2 (EZH2) regulates tumor angiogenesis and predicts recurrence and prognosis of intrahepatic cholangiocarcinoma. HPB (Oxford) 2018; 20:939-948. [PMID: 29759640 DOI: 10.1016/j.hpb.2018.03.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 03/10/2018] [Accepted: 03/30/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and regulates tumor malignancy by gene silencing via histone methylation. In this study we investigate the role of EZH2 in angiogenesis of intrahepatic cholangiocarcinoma (ICC). METHODS The influence of EZH2 on tumor angiogenesis was examined by bioinformatics analysis of a public database. We also assessed the correlation between EZH2 and vasohibin 1 (VASH1) expression in 47 patients with ICC by immunohistochemical (IHC) staining and in vitro gene silencing assays. The prognostic significance of EZH2 and VASH1 expression by IHC was also examined in the ICC cohort. RESULTS Bioinformatics analysis showed that EZH2 was associated with several angiogenesis gene sets in the public database. EZH2 suppressed VASH1 expression in in vitro assays and IHC studies. EZH2-high/VASH1-low status was independently associated with poor disease-free survival (P = 0.019) and poor overall survival (P = 0.0055). CONCLUSION The current study demonstrated that high EZH2 expression was associated with activation of tumor angiogenesis, and activation of the EZH2-mediated angiogenesis pathway predicted the prognosis of patients with ICC.
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Affiliation(s)
- Shigeki Nakagawa
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan.
| | - Hirohisa Okabe
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | - Mayuko Ouchi
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | - Ryuma Tokunaga
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | - Naoki Umezaki
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | - Takaaki Higashi
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | - Takatoshi Kaida
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | - Kota Arima
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | - Yuki Kitano
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | - Hideyuki Kuroki
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | - Kosuke Mima
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | - Hidetoshi Nitta
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | - Katsunori Imai
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | | | | | - Akira Chikamoto
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
| | - Hideo Baba
- Kumamoto University - Gastroenterological Surgery, Kumamoto, Japan
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Watanabe T, Hosaka T, Ohmori‐Matsuda K, Suzuki Y, Suzuki H, Yabuki H, Matsuda Y, Noda M, Sakurada A, Okada Y, Sato Y. High preoperative plasma vasohibin-1 concentration predicts better prognosis in patients with non-small cell lung carcinoma. Health Sci Rep 2018; 1:e40. [PMID: 30623077 PMCID: PMC6266348 DOI: 10.1002/hsr2.40] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Revised: 01/12/2018] [Accepted: 02/21/2018] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND AND AIM Vasohibin-1 (VASH1) is an angiogenesis inhibitor synthesized and secreted by endothelial cells, whose expression is induced by angiogenic stimuli such as vascular endothelial growth factor. We have previously demonstrated that VASH1 is immunohistochemically evident in endothelial cells in the tumor microenvironment of patients with non-small cell lung cancer (NSCLC) and is positively correlated with that of vascular endothelial growth factor in cancer cells. Here, we determined the preoperative plasma concentration of VASH1 in patients with NSCLC and evaluated the association between the preoperative VASH1 levels and certain outcomes. METHODS We analyzed presurgical plasma VASH1 concentrations in a total of 79 lung cancer patients (51 males and 28 females; 34-83 y of age; 46 adenocarcinomas, 27 squamous cell carcinomas, and 6 other types) who underwent lung resection. The impact of preoperative VASH1 level was analyzed using clinical characteristics and prognosis. RESULTS Plasma VASH1 concentration ranged from 34.1 to 1190.4 fmol/mL. We divided the patients into 3 groups according to plasma VASH1 level for this assessment: low VASH1 group (n = 26), medium VASH1 group (n = 27), and high VASH1 group (n = 26). The death and recurrence rates of the high, medium, and low VASH1 groups were 5.5, 16.2, and 12.7 per 100 person-years, respectively. Multivariate adjusted hazard ratio of death and recurrence of the high VASH1 group was lower than that of the low VASH1 group (hazard ratio 0.42; 95% CI 0.17-0.99). CONCLUSION The present analysis suggests that high preoperative plasma VASH1 concentration is associated with better prognosis in patients with NSCLC. We propose preoperative VASH1 level as a biomarker for the prognosis of patients with non-small cell lung carcinoma.
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Affiliation(s)
- Tatsuaki Watanabe
- Department of Thoracic Surgery, Institute of Development, Aging and CancerTohoku UniversitySendaiJapan
- Department of Vascular Biology, Institute of Development, Aging and CancerTohoku UniversitySendaiJapan
| | - Tomoko Hosaka
- Department of Vascular Biology, Institute of Development, Aging and CancerTohoku UniversitySendaiJapan
- Department of Thoracic SurgeryJapan Organization of Occupational Health and Safety Tohoku Rosai HospitalSendaiJapan
| | - Kaori Ohmori‐Matsuda
- Division of Epidemiology, Department of Public Health and Forensic MedicineTohoku University Graduate School of MedicineSendaiJapan
| | - Yasuhiro Suzuki
- Department of Vascular Biology, Institute of Development, Aging and CancerTohoku UniversitySendaiJapan
| | - Hirotoshi Suzuki
- Department of Thoracic Surgery, Institute of Development, Aging and CancerTohoku UniversitySendaiJapan
| | - Hiroshi Yabuki
- Department of Thoracic Surgery, Institute of Development, Aging and CancerTohoku UniversitySendaiJapan
| | - Yasushi Matsuda
- Department of Thoracic Surgery, Institute of Development, Aging and CancerTohoku UniversitySendaiJapan
| | - Masafumi Noda
- Department of Thoracic Surgery, Institute of Development, Aging and CancerTohoku UniversitySendaiJapan
| | - Akira Sakurada
- Department of Thoracic Surgery, Institute of Development, Aging and CancerTohoku UniversitySendaiJapan
| | - Yoshinori Okada
- Department of Thoracic Surgery, Institute of Development, Aging and CancerTohoku UniversitySendaiJapan
| | - Yasufumi Sato
- Department of Vascular Biology, Institute of Development, Aging and CancerTohoku UniversitySendaiJapan
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Huang W, Ren Y, Liu H. Vasohibin 1 inhibits Adriamycin resistance in osteosarcoma cells via the protein kinase B signaling pathway. Oncol Lett 2018; 15:5983-5988. [PMID: 29556314 DOI: 10.3892/ol.2018.8074] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 11/10/2017] [Indexed: 02/03/2023] Open
Abstract
Vasohibin (VASH)1 functions as a negative feedback modulator of angiogenesis in vascular endothelial cells. Mesenchymal VASH1 has been demonstrated to be negatively associated with tumor progression, however studies regarding VASH1 in tumor cells and its functions remain limited. The function of VASH1 in osteosarcoma remains unknown. In the present study, it was confirmed that osteosarcoma cells express decreased levels of VASH1 compared with that expressed by human osteoblast cells. 143B cells with decreased VASH1 expression revealed increased Adriamycin (ADR) resistance compared with U-2OS cells with increased VASH1 expression. Subsequent to manipulating VASH1 expression via transfection, results revealed that overexpression of VASH1 in 143B cells inhibited P-glycoprotein (P-gp) expression and ADR resistance significantly; silencing VASH1 in U-2OS cells enhanced P-gp expression and ADR resistance significantly. Research into the molecular mechanism was performed and the results identified that protein kinase B (AKT) and extracellular signal-related kinase signal pathways were both stimulated by VASH1, but only AKT inhibitor LY294002 was identified to efficiently counteract increases in P-gp expression that had been induced by silencing of VASH1 in U-2OS cells. ADR resistance promoted by silencing VASH1 in U-2OS cells was also counteracted by LY294002. In conclusion, the present study confirmed the low expression of VASH1 in osteosarcoma cells. It was identified that VASH1 was able to inhibit drug resistance in osteosarcoma cells through regulation of P-gp via the AKT signal pathway. This demonstrated a negative regulation function of VASH1 in osteosarcoma, deepened understanding of the function of VASH1 in tumors and suggests a basis for further studies in to the functions of VASH1.
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Affiliation(s)
- Wei Huang
- Department of Orthopedics, Shanxian Central Hospital of Shandong Province, Heze, Shandong 274300, P.R. China
| | - Yangguang Ren
- Department of Hand and Foot Surgery, First People's Hospital of Jining City, Jining, Shandong 272000, P.R. China
| | - Hui Liu
- Clinical Laboratory of Shanxian Central Hospital of Shandong Province, Heze, Shandong 274300, P.R. China
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Zhang B, Wu Z, Xie W, Tian D, Chen F, Qin C, Du Z, Tang G, Gao Q, Qiu X, Wu C, Tian J, Hu H. The expression of vasohibin-1 and its prognostic significance in bladder cancer. Exp Ther Med 2017; 14:3477-3484. [PMID: 29042936 PMCID: PMC5639433 DOI: 10.3892/etm.2017.4969] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Accepted: 05/19/2017] [Indexed: 11/05/2022] Open
Abstract
Angiogenesis is important in the development of solid tumors. Vasohibin-1 (VASH-1) is an endothelium-derived protein that acts as an inhibitor of angiogenesis in many different types of cancer. However, the expression of VASH-1 and its clinical value in bladder cancer remain unknown. The current study analyzed the expression of VASH-1, as well as the expression of the angiogenesis-related factors vascular endothelial growth factor-A, hypoxia inducible factor-1α and cluster of differentiation 34 in bladder cancer tissues from 50 patients using immunohistochemistry. The associations between the expression of these factors and the clinicopathological characteristics of the patients were assessed. The current study demonstrated that VASH-1 is primarily expressed in the cytoplasm of bladder cancer cells and in a fraction of vascular endothelial cells. Furthermore, the expression of VASH-1 was positively associated with the tumor stage (P<0.01), pathological grade (P<0.01) and distant metastasis (P<0.05) but not with patient age or sex (P>0.05). Spearman rank correlation tests indicated that levels of those four factors were positively correlated with each other. Kaplan-Meier analysis indicated that high expression of these four factors was significantly associated with lower 5-year overall survival and progression-free survival rates. Collectively, the results of the current study suggest that VASH-1 is clinically significant in bladder cancer and its high expression may predict the progression and prognosis of patients with bladder cancer. The present study also implies that VASH-1 may be a novel target for vascular targeting therapy.
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Affiliation(s)
- Bo Zhang
- Department of Urology, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China.,Department of Ultrasound, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China.,Tianjin Key Laboratory of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Zhouliang Wu
- Department of Urology, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China.,Tianjin Key Laboratory of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Wanqin Xie
- Key Laboratory of Genetics and Birth Health of Hunan, The Family Planning Research Institute of Hunan, Changsha, Hunan 410126, P.R. China
| | - Dawei Tian
- Department of Urology, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China.,Tianjin Key Laboratory of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Feiran Chen
- Department of Urology, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China.,Tianjin Key Laboratory of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Chuan Qin
- Department of Urology, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China.,Tianjin Key Laboratory of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Zhiyong Du
- Department of Urology, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China.,Tianjin Key Laboratory of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Gang Tang
- Department of Urology, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China.,Tianjin Key Laboratory of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Qiongqiong Gao
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300211, P.R. China
| | - Xiaoyu Qiu
- College of Management and Economics, Tianjin University, Tianjin 300211, P.R. China
| | - Changli Wu
- Department of Urology, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China.,Tianjin Key Laboratory of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Jing Tian
- Department of Ultrasound, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China.,Tianjin Key Laboratory of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
| | - Hailong Hu
- Department of Urology, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China.,Tianjin Key Laboratory of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China
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Mikami S, Oya M, Kosaka T, Mizuno R, Miyazaki Y, Sato Y, Okada Y. Increased vasohibin-1 expression is associated with metastasis and poor prognosis of renal cell carcinoma patients. J Transl Med 2017; 97:854-862. [PMID: 28287633 DOI: 10.1038/labinvest.2017.26] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 01/19/2017] [Accepted: 01/26/2017] [Indexed: 02/01/2023] Open
Abstract
The microvascular density detected by markers of endothelial cells (ECs), such as CD31 and CD34, is considered to be a biomarker for angiogenesis, and it is generally associated with the malignant potential of solid tumors. However, there is a conflicting relationship between the microvascular density and prognosis in clear-cell renal cell carcinoma (ccRCC) patients. It may be explained by the suggestion that the microvascular density cannot fully reflect the angiogenic activity in ccRCC, as the markers of ECs are expressed by both quiescent and activated ECs. To investigate the real angiogenic activity, we examined vasohibin-1 (VASH1), a recently identified regulator of angiogenesis, which was demonstrated to be specifically expressed by ECs of newly formed blood vessels. Expression of VASH1 and CD34 were immunohistochemically examined in 116 primary untreated ccRCCs, 10 metastatic untreated ccRCCs, and 9 metastatic ccRCCs treated with sunitinib. ECs in the tumor microvessels were sporadically immunostained for VASH1, although no VASH1 staining was observed in the non-neoplastic renal tissues. CD34 was ubiquitously expressed by all ECs in both ccRCC and non-neoplastic renal tissues. Multivariate Cox analysis indicated that an elevated VASH1 density, but not microvascular density, was a significant and independent predictor of overall survival (odds ratio, 7.71; P=0.003). The microvascular density was significantly decreased in the sunitinib-treated metastases compared with untreated tumors (P=0.001). On the other hand, the VASH1 density was significantly higher in the metastatic ccRCCs treated with sunitinib compared with non-treated ones (P=0.010), indicating that VASH1 may be associated with the resistance of ECs to sunitinib treatment. Thus, VASH1 expression may reflect the actual activity of angiogenesis, and VASH1 can serve as a new prognostic and predictive biomarker in patients with ccRCC.
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Affiliation(s)
- Shuji Mikami
- Division of Diagnostic Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Mototsugu Oya
- Department of Urology, Keio University School of Medicine, Tokyo, Japan
| | - Takeo Kosaka
- Department of Urology, Keio University School of Medicine, Tokyo, Japan
| | - Ryuichi Mizuno
- Department of Urology, Keio University School of Medicine, Tokyo, Japan
| | - Yasumasa Miyazaki
- Department of Urology, Keio University School of Medicine, Tokyo, Japan
| | - Yasufumi Sato
- Department of Vascular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Yasunori Okada
- Department of Pathophysiology for Locomotive and Neoplastic Diseases, Juntendo University Graduate School of Medicine, Tokyo, Japan
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Zhao G, Na R, Li L, Xiao H, Ding N, Sun Y, Han R. Vasohibin-1 inhibits angiogenesis and suppresses tumor growth in renal cell carcinoma. Oncol Rep 2017; 38:1021-1028. [DOI: 10.3892/or.2017.5746] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Accepted: 05/30/2017] [Indexed: 11/05/2022] Open
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12
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Ma D, Li J, Wang J, Sun Z, Wang K. Clinical implications of vasohibin-1 in esophageal carcinoma cells: Inhibition of cell growth and migration. Mol Med Rep 2017; 16:1479-1485. [PMID: 29067450 DOI: 10.3892/mmr.2017.6726] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 03/23/2017] [Indexed: 11/05/2022] Open
Abstract
As one of the first-established negative feedback regulators of angiogenesis, mesenchymal vasohibin-1 (VASH1) serves important roles in the progression and prognosis of various types of tumor. However, the clinical implications of VASH1 in esophageal carcinoma (EC) cells have not been reported and the direct effects of VASH1 on EC cells remain unknown. In the present study, the expression of VASH1 in EC cells was observed using immunohistochemistry and western blotting; a χ2 test was used to analyze the correlation of VASH1 with clinical parameters, and it was observed that VASH1 was negatively-correlated with tumor size (r=‑0.399; P<0.01) and invasion depth (r=‑0.318; P<0.01). Survival analysis demonstrated that VASH1 was positively‑correlated with increased overall survival (P=0.039) and disease free survival (P=0.012). The direct effects of VASH1 on EC cells were analyzed by altering VASH1 expression, and it was observed that downregulation of VASH1 increased proliferation, clone formation and the migratory ability of EC9706 cells, whereas upregulation of VASH1 inhibited proliferation, clone formation and the migratory ability of EC1 cells. The results of the present study demonstrated that VASH1 in EC cells was negatively‑correlated with progression and poor prognosis of patients with EC. VASH1 was able to directly inhibit the growth and migration of EC cells.
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Affiliation(s)
- Deliang Ma
- Department of Oncology, Yishui Central Hospital of Linyi, Linyi, Shandong 276400, P.R. China
| | - Jingye Li
- Department of Oncology, Yishui Central Hospital of Linyi, Linyi, Shandong 276400, P.R. China
| | - Jinbao Wang
- Department of General Surgery, Yishui Central Hospital of Linyi, Linyi, Shandong 276400, P.R. China
| | - Zhigang Sun
- Central Laboratory, Yishui Central Hospital of Linyi, Linyi, Shandong 276400, P.R. China
| | - Kai Wang
- Department of Breast Surgery, Weifang People's Hospital, Weifang, Shandong 261041, P.R. China
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Marien KM, Croons V, Waumans Y, Sluydts E, De Schepper S, Andries L, Waelput W, Fransen E, Vermeulen PB, Kockx MM, De Meyer GRY. Development and Validation of a Histological Method to Measure Microvessel Density in Whole-Slide Images of Cancer Tissue. PLoS One 2016; 11:e0161496. [PMID: 27583442 PMCID: PMC5008750 DOI: 10.1371/journal.pone.0161496] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Accepted: 08/05/2016] [Indexed: 12/17/2022] Open
Abstract
Despite all efforts made to develop predictive biomarkers for antiangiogenic therapies, no unambiguous markers have been identified so far. This is due to among others the lack of standardized tests. This study presents an improved microvessel density quantification method in tumor tissue based on stereological principles and using whole-slide images. Vessels in tissue sections of different cancer types were stained for CD31 by an automated and validated immunohistochemical staining method. The stained slides were digitized with a digital slide scanner. Systematic, uniform, random sampling of the regions of interest on the whole-slide images was performed semi-automatically with the previously published applications AutoTag and AutoSnap. Subsequently, an unbiased counting grid was combined with the images generated with these scripts. Up to six independent observers counted microvessels in up to four cancer types: colorectal carcinoma, glioblastoma multiforme, ovarian carcinoma and renal cell carcinoma. At first, inter-observer variability was found to be unacceptable. However, after a series of consensus training sessions and interim statistical analysis, counting rules were modified and inter-observer concordance improved considerably. Every CD31-positive object was counted, with exclusion of suspected CD31-positive monocytes, macrophages and tumor cells. Furthermore, if interconnected, stained objects were considered a single vessel. Ten regions of interest were sufficient for accurate microvessel density measurements. Intra-observer and inter-observer variability were low (intraclass correlation coefficient > 0.7) if the observers were adequately trained.
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Affiliation(s)
- Koen M. Marien
- Division of Physiopharmacology, University of Antwerp, Antwerp, Belgium
- HistoGeneX NV, Antwerp, Belgium
- * E-mail:
| | | | | | | | | | | | - Wim Waelput
- Department of Pathology, University Hospital Brussels (UZ Brussel), Brussels, Belgium
| | - Erik Fransen
- StatUa Center for Statistics, University of Antwerp, Antwerp, Belgium
| | - Peter B. Vermeulen
- CORE (Translational Cancer Research Unit, GZA Hospitals), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
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14
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Liu S, Han B, Zhang Q, Dou J, Wang F, Lin W, Sun Y, Peng G. Vasohibin-1 suppresses colon cancer. Oncotarget 2016; 6:7880-98. [PMID: 25797264 PMCID: PMC4480723 DOI: 10.18632/oncotarget.3493] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 02/04/2015] [Indexed: 01/01/2023] Open
Abstract
Vasohibin-1 (VASH1) is an endogenous angiogenesis inhibitor.However, the clinical relevance of VASH1 in colon cancer and its regulations on cancer angiogenesis and cancer cell biological characteristics are still unknown. Here we showed that stromal VASH1 levels were negatively correlated with tumor size, advanced clinical stage and distant metastases in colon cancer patients. Overexpression of VASH1 in colon cancer cells induced apoptosis and senescence, inhibiting cancer cell growth and colony formation in vitro and tumor growth in vivo. In addition, knockdown of VASH1 in cancer cells promoted cell growth, adhesion and migration in vitro, and enhanced tumorigenesis and metastasis in vivo.
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Affiliation(s)
- Shuai Liu
- Department of Oncology, Jinan Central Hospital, Affiliated to Shandong University, Jinan, P. R. China.,Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, USA
| | - Bing Han
- Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, USA.,Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, P.R. China
| | - Qunyuan Zhang
- Department of Genetics, Washington University School of Medicine, Saint Louis, MO, USA
| | - Jie Dou
- Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, USA
| | - Fang Wang
- Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, USA
| | - Wenli Lin
- Department of Oncology, Jinan Central Hospital, Affiliated to Shandong University, Jinan, P. R. China
| | - Yuping Sun
- Department of Oncology, Jinan Central Hospital, Affiliated to Shandong University, Jinan, P. R. China
| | - Guangyong Peng
- Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, USA
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Saito M, Suzuki Y, Yano S, Miyazaki T, Sato Y. Proteolytic inactivation of anti-angiogenic vasohibin-1 by cancer cells. J Biochem 2016; 160:227-232. [PMID: 27169581 DOI: 10.1093/jb/mvw030] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 03/22/2016] [Indexed: 12/20/2022] Open
Abstract
Vasohibin-1 (VASH1) is an angiogenesis inhibitor synthesized by endothelial cells (ECs) under conditions associated with physiological and pathological angiogenesis including cancers. VASH1, which is a 44-kDa protein, is processed after its translation and secretion, and a 29 kDa product cleaved both N-terminal and C-terminal end loses its anti-angiogenic activity. Here, we tested whether cancer cells modulate the processing of VASH1. When mouse EC line MS1 stably overexpressing the human VASH1 gene (MS1-hVASH1) and various cancer cell lines were co-cultured, there was an increased processing of hVASH1 protein in the culture media. This augmented processing was abrogated by a general cysteine protease inhibitor, E-64, and also by a specific calpain inhibitor, MDL28170. Recombinant hVASH1 protein was degraded by µ-calpain in vitro, which degradation was blocked by calpeptin. Conditioned media from co-cultures had little effect on the migration of human umbilical vein endothelial cells, but exhibited an inhibitory effect on their migration when collected in the presence of MDL28170; and this inhibitory effect was blocked by neutralizing anti-hVASH1 mAb. These results indicate that cancer cells proteolytically inactivate VASH1 protein secreted by ECs in the tumour microenvironment.
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Affiliation(s)
- Megumu Saito
- Department of Vascular Biology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-Machi, Aoba-ku, Sendai 980-8575, Japan
| | - Yasuhiro Suzuki
- Department of Vascular Biology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-Machi, Aoba-ku, Sendai 980-8575, Japan
| | - Seiji Yano
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-Machi, Kanazawa, Ishikawa 920-0934, Japan
| | - Takuro Miyazaki
- Department of Biochemistry, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo 142-8555, Japan
| | - Yasufumi Sato
- Department of Vascular Biology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-Machi, Aoba-ku, Sendai 980-8575, Japan
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16
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Sato Y. Novel Link between Inhibition of Angiogenesis and Tolerance to Vascular Stress. J Atheroscler Thromb 2015; 22:327-34. [PMID: 25739825 DOI: 10.5551/jat.28902] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
The functional integrity of the vascular endothelium is an essential component required for the maintenance of vascular health, thus counteracting the onset of vascular diseases, including atherosclerosis and vascular complications of diabetes. In light of this important role, the vascular endothelium is expected to have a self-defense system. One candidate factor of such a system is vasohibin-1 (VASH1), a protein that is preferentially expressed in vascular endothelial cells (ECs). The unique features of VASH1 are its anti-angiogenic activity and ability to promote the stress tolerance and survival of ECs. This review summarizes current knowledge regarding VASH1 in terms of its roles in maintaining vascular integrity and protecting the vasculature against various forms of stress.
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Affiliation(s)
- Yasufumi Sato
- Department of Vascular Biology, Institute of Development, Aging and Cancer, Tohoku University
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17
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Vasohibin-1 expression detected by immunohistochemistry correlates with prognosis in non-small cell lung cancer. Med Oncol 2014; 31:963. [DOI: 10.1007/s12032-014-0963-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2014] [Accepted: 04/08/2014] [Indexed: 11/26/2022]
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Ito S, Miyashita H, Suzuki Y, Kobayashi M, Satomi S, Sato Y. Enhanced cancer metastasis in mice deficient in vasohibin-1 gene. PLoS One 2013; 8:e73931. [PMID: 24066086 PMCID: PMC3774736 DOI: 10.1371/journal.pone.0073931] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2013] [Accepted: 07/23/2013] [Indexed: 02/07/2023] Open
Abstract
Vasohibin-1 (VASH1) is isolated as an endogenous angiogenesis inhibitor produced by the vascular endothelium. We previously reported that tumor growth and tumor angiogenesis were augmented in VASH1 (−/−) mice. Here we examined whether VASH1 plays any role in cancer metastasis. When Lewis lung carcinoma (LLC) cells were inoculated in the footpad to observe spontaneous metastasis, a significant increase in lung metastasis together with inguinal lymph node metastasis was evident in the VASH1 (−/−) mice. Histological analyses revealed that vessels of the footpad tumor in VASH1 (−/−) mice were more immature, having fewer mural cells. However, when LLC cells were injected into a tail vein, the extent of lung metastasis was unchanged between wild-type mice and VASH1 (−/−) mice. When VASH1 in endothelial cells in culture was knocked-down by siRNA, we observed a decrease in the content of ZO-1, a component of tight junctions, which decrease resulted in increased transmigration of cancer cells across the endothelial cell monolayer. These results indicate that endogenous VASH1 tightens the endothelial barrier and makes tumor vessels resistant to cancer metastasis.
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Affiliation(s)
- Soichi Ito
- Department of Vascular Biology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan
- Department of Advanced Surgical Science and Technology, Tohoku University School of Medicine, Sendai, Japan
| | - Hiroki Miyashita
- Department of Vascular Biology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan
| | - Yasuhiro Suzuki
- Department of Vascular Biology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan
| | - Miho Kobayashi
- Department of Vascular Biology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan
| | - Susumu Satomi
- Department of Advanced Surgical Science and Technology, Tohoku University School of Medicine, Sendai, Japan
| | - Yasufumi Sato
- Department of Vascular Biology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan
- * E-mail:
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Kanomata N, Sato Y, Miyaji Y, Nagai A, Moriya T. Vasohibin-1 is a new predictor of disease-free survival in operated patients with renal cell carcinoma. J Clin Pathol 2013; 66:613-9. [DOI: 10.1136/jclinpath-2013-201444] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
BackgroundVasohibin-1 (VASH1) is an endothelium-produced angiogenesis inhibitor. Renal cell carcinoma is highly vascularised, but the significance of endogenous VASH1 in renal cell carcinoma has not been defined.AimsTo identify VASH1 expression and its possible relationship with various clinicopathological factors and prognosis in renal cell carcinoma.MethodsA retrospective analysis of 122 tumours obtained from 118 consecutive patients with renal cell carcinoma was performed. The expression patterns of VASH1, CD31, vascular endothelial growth factor (VEGF) and VEGF receptor type 2 (VEGFR2) were examined immunohistochemically and their relationships with clinicopathological factors were analysed.ResultsMicrovessel density, VASH1 and VEGFR2 expression were significantly higher in clear cell carcinoma than in other subtypes. The VEGF expression pattern differed significantly between clear cell carcinoma and other histological subtypes. VASH1, pT factor and TNM stage were significantly associated with disease-free survival (p=0.030, p = 0.0012 and p = 0.0018, respectively). Cox models of multivariable disease-free survival analyses indicated that VASH1 and stage are independent prognostic factors (p=0.019 and p = 0.024).ConclusionsVASH1 expression may be useful for estimating the prognosis of renal cell carcinoma. Further studies of the role of VASH1 in renal cell carcinoma involving larger sample sizes are warranted.
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Abstract
Angiogenesis, a formation of neovessels, is regulated by the local balance between angiogenesis stimulators and inhibitors. A number of such endogenous regulators of angiogenesis have been found in the body. Recently, vasohibin-1 (VASH1) was isolated as a negative feedback regulator of angiogenesis produced by endothelial cells (ECs) and subsequently vasohibin-2 (VASH2) as a homologue of VASH1. It was then explored that VASH1 is expressed in ECs to terminate angiogenesis, whereas VASH2 is expressed in cells other than ECs to promote angiogenesis in the mouse model of angiogenesis. This review will focus on the vasohibin family members, which are novel regulators of angiogenesis.
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Affiliation(s)
- Yasufumi Sato
- Department of Vascular Biology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Sendai 980-8575, Japan.
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