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Srinivasan S, Sherwood DR. The life cycle of type IV collagen. Matrix Biol 2025; 139:14-28. [PMID: 40306374 PMCID: PMC12146070 DOI: 10.1016/j.matbio.2025.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 04/21/2025] [Accepted: 04/27/2025] [Indexed: 05/02/2025]
Abstract
Type IV collagen is a large triple helical molecule that forms a covalently cross-linked network within basement membranes (BMs). Type IV collagen networks play key roles in mechanically supporting tissues, shaping organs, filtering blood, and cell signaling. To ensure tissue health and function, all aspects of the type IV collagen life cycle must be carried out accurately. However, the large triple helical structure and complex life-cycle of type IV collagen, poses many challenges to cells and tissues. Type IV collagen predominantly forms heterotrimers and to ensure proper construction, expression of the distinct α-chains that comprise a heterotrimer needs tight regulation. The α-chains must also be accurately modified by several enzymes, some of which are specific to collagens, to build and stabilize the triple helical trimer. In addition, type IV collagen is exceptionally long (400 nm) and thus the packaging and trafficking of the triple helical trimer from the ER to the Golgi must be modified to accommodate the large type IV collagen molecule. During ER-to-Golgi trafficking, as well as during secretion and transport in the extracellular space, type IV collagen also associates with specific chaperone molecules that maintain the structure and solubility of collagen IV. Type IV collagen trimers are then delivered to BMs from local and distant sources where they are integrated into BMs by interactions with cell surface receptors and many diverse BM resident proteins. Within BMs type IV collagen self-associates into a network and is crosslinked by BM resident enzymes. Finally, homeostatic type IV collagen levels in BMs are maintained by poorly understood mechanisms involving proteolysis and endocytosis. Here, we provide an overview of the life cycle of collagen IV, highlighting unique mechanisms and poorly understood aspects of type IV collagen regulation.
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Affiliation(s)
- Sandhya Srinivasan
- Department of Biology, Duke University, 130 Science Drive, Box 90338, Durham, NC 27708, USA
| | - David R Sherwood
- Department of Biology, Duke University, 130 Science Drive, Box 90338, Durham, NC 27708, USA.
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2
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Huang K, Schofield C, Nguy T, Dere R, Wolowski V, Siebourg-Polster J, Dieckmann A, Garweg JG, Chang M, Honigberg L, Hackney J, Indjeian VB. Proteomics approach identifies aqueous humor biomarkers in retinal diseases. COMMUNICATIONS MEDICINE 2025; 5:134. [PMID: 40274966 PMCID: PMC12022036 DOI: 10.1038/s43856-025-00862-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 04/11/2025] [Indexed: 04/26/2025] Open
Abstract
BACKGROUND Geographic atrophy (GA) secondary to age-related macular degeneration (AMD) is one of the main causes of blindness in the elderly population, but the molecular pathophysiology is difficult to study due to limited access to retinal tissue. We investigated aqueous humor (AH) as an accessible surrogate for studying retinal pathophysiology. METHODS We applied affinity-based Olink proteomics on AH samples obtained from 30 non-AMD control, 30 intermediate AMD (iAMD) and 28 GA subjects to identify AH biomarkers associated with GA. Quantile normalization was applied to the Olink data, followed by differential abundance analysis using the limma R package. To contextualize our findings, we cross-referenced the identified proteins to gene expression datasets and AH proteomics data from diabetic retinopathy (DR) subjects. RESULTS Our differential abundance analysis reveals 82 significantly altered proteins in GA compared to non-AMD control. Cross-referencing with gene expression datasets indicates a majority of them are robustly expressed in the retina, particularly in retinal pigment epithelium cells. Comparison with AH proteomics data from DR subjects reveals both unique and shared biomarkers between GA and DR. Integrating these findings, we identify SMOC2 and IL-6 as top candidate GA biomarkers, warranting further investigation. CONCLUSIONS Our integrative analysis demonstrates a robust framework for AH biomarker discovery and identifies SMOC2 and IL-6 as promising biomarkers for GA. Our findings underscore the potential of AH proteomic profiling to advance our understanding of the underlying pathophysiology of retinal diseases.
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Affiliation(s)
- Kevin Huang
- Computational Sciences, gRED, Genentech, South San Francisco, CA, USA.
| | - Cheryl Schofield
- Translational Medicine, gRED, Genentech, South San Francisco, CA, USA
| | - Trung Nguy
- Bioanalytical Sciences, gRED, Genentech, South San Francisco, CA, USA
| | - Randall Dere
- Bioanalytical Sciences, gRED, Genentech, South San Francisco, CA, USA
| | | | | | | | - Justus G Garweg
- Swiss Eye Institute and Berner Augenklinik, Bern, Switzerland
- Department of Ophthalmology, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Michael Chang
- Translational Medicine, gRED, Genentech, South San Francisco, CA, USA
| | - Lee Honigberg
- Translational Medicine, gRED, Genentech, South San Francisco, CA, USA
| | - Jason Hackney
- Computational Sciences, gRED, Genentech, South San Francisco, CA, USA
| | - Vahan B Indjeian
- Translational Medicine, gRED, Genentech, South San Francisco, CA, USA.
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3
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Wang C, Han Y, Huo D, Li X, Liang G. Plasma Extracellular Matrix Protein 2 Level as a Predictive Biomarker for Rupture of Small Intracranial Aneurysms. J Mol Neurosci 2025; 75:33. [PMID: 40080244 DOI: 10.1007/s12031-024-02305-4] [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: 11/13/2024] [Accepted: 12/18/2024] [Indexed: 03/15/2025]
Abstract
As the neuroimaging technology improves, the detection rate of unruptured intracranial aneurysms (UIA) is gradually increasing. However, there is currently no effective means to evaluate and predict the risk of rupture for small intracranial aneurysm (sIA, diameter < 7 mm). We previously identified extracellular matrix protein 2 (ECM2) as a potential candidate biomarker for predicting intracranial aneurysm (IA) rupture through iTRAQ combined with LC-MS/MS protein quantification technology, so this study aimed to further validate the ability of plasma ECM2 expression levels to predict IA rupture. This prospective, observational, single-center cohort study enrolled 322 individuals with ruptured intracranial aneurysm (RIA, N = 123), UIA (N = 89), traumatic subarachnoid hemorrhage (tSAH, N = 55), or healthy controls (HC, N = 55). ECM2 plasma levels were quantified using enzyme-linked immunosorbent assay (ELISA). The Spearman rank correlation analysis was employed to examine the relationship between variables. Independent risk factors of sIA rupture were identified using logistic regression analysis. The ROC curve assessed the predictive capability for sIA rupture. Plasma ECM2 was notably higher in RIA patients than in UIA, tSAH, and HC groups. Plasma ECM2 levels showed no significant difference among the asymptomatic UIA, HC, and tSAH groups. There was also no significant difference in plasma ECM2 levels between symptomatic UIA patients and RIA patients. Furthermore, the plasma ECM2 level was closely related to hypertension history in sIA patients. ECM2 plasma level was an independent risk factor for sIA rupture. The plasma ECM2 cutoff level for predicting IA rupture was determined to be 1540.67 pg/ml. The combination of ECM2 levels and aneurysm location increased predictive accuracy (AUC = 0.828, sensitivity 87.0%, specificity 68.8%, accuracy 83.2%), surpassing the performance of PHASES and ELPASS scores. ECM2 could potentially act as an early warning biomarker for predicting the rupture of sIAs.
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Affiliation(s)
- Chenchen Wang
- Institute of Neurology, General Hospital of Northern Theater Command, Shenyang, 110016, Liaoning, China
| | - Yuwei Han
- Institute of Neurology, General Hospital of Northern Theater Command, Shenyang, 110016, Liaoning, China
| | - Da Huo
- Institute of Neurology, General Hospital of Northern Theater Command, Shenyang, 110016, Liaoning, China
| | - Xiaoming Li
- Institute of Neurology, General Hospital of Northern Theater Command, Shenyang, 110016, Liaoning, China.
| | - Guobiao Liang
- Institute of Neurology, General Hospital of Northern Theater Command, Shenyang, 110016, Liaoning, China.
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4
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Matsuura Y, Onuma K, Coppo R, Uematsu H, Kondo J, Miyagawa‐Hayashino A, Takeda‐Miyata N, Kameyama K, Furuya T, Okada S, Shimomura M, Inoue M, Inoue M. Dynamic change of polarity in spread through air spaces of pulmonary malignancies. J Pathol 2025; 265:260-273. [PMID: 39804150 PMCID: PMC11794978 DOI: 10.1002/path.6382] [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: 04/04/2024] [Revised: 10/16/2024] [Accepted: 11/22/2024] [Indexed: 02/06/2025]
Abstract
Spread through air spaces (STAS) is a histological finding of lung tumours where tumour cells exist within the air space of the lung parenchyma beyond the margin of the main tumour. Although STAS is an important prognostic factor, the pathobiology of STAS remains unclear. Here, we investigated the mechanism of STAS by analysing the relationship between STAS and polarity switching in vivo and in vitro. Histopathological analysis revealed that apical membranes were observed outside the STAS lesions around colorectal cancer (CRC) lung metastases and lung adenocarcinomas. When apical-out CRC organoids were administered intratracheally to mice, the organoids had greater metastatic potential than did single cells. To investigate the pathobiology of STAS, we established an in vitro model of STAS in which CRC or lung cancer organoids were co-cultured with 2D-cultured mouse airway epithelial organoids (2D-MAOs). Adhesion of cancer organoids to 2D-MAOs was much less than to type I collagen or endothelial cells, suggesting a protective role of the airway epithelium against adhesion. Loss of the apical membrane of CRC organoids at the contact surface with 2D-MAOs after adhesion was responsible for establishing adhesion. When airway epithelium was stimulated by transforming growth factor beta 1 (TGF-β1), adhesion of CRC organoids was enhanced. Among TGF-β1-induced genes in airway epithelium, follistatin-like protein 1 (FSTL1) increased CRC organoid adhesion by promoting loss of the apical membrane. These results suggested that TGF-β1-induced FSTL1 may promote metastatic progression of STAS by altering the polarity status. Elucidating the mechanism of STAS could contribute to the improvement of survival in patients with pulmonary malignancies associated with STAS. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Grants
- 21cm0106203h0006 Japan Agency for Medical Research and Development
- 18H02648 Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan
- 20H03772 Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan
- 20K08286 Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan
- 22K08982 Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan
- 23K07395 Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan
- Japan Agency for Medical Research and Development
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Affiliation(s)
- Yoshiaki Matsuura
- Department of Clinical Bio‐resource Research and Development, Graduate School of MedicineKyoto UniversityKyotoJapan
- Divison of Thoracic Surgery, Department of Surgery, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan
| | - Kunishige Onuma
- Department of Clinical Bio‐resource Research and Development, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Roberto Coppo
- Department of Clinical Bio‐resource Research and Development, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Hiroyuki Uematsu
- Department of Clinical Bio‐resource Research and Development, Graduate School of MedicineKyoto UniversityKyotoJapan
- KBBM Inc.KyotoJapan
| | - Jumpei Kondo
- Department of Clinical Bio‐resource Research and Development, Graduate School of MedicineKyoto UniversityKyotoJapan
- Department of Molecular Biology and Clinical Investigation, Graduate School of MedicineOsaka UniversityOsakaJapan
| | | | - Naoko Takeda‐Miyata
- Department of Surgical PathologyKyoto Prefectural University of MedicineKyotoJapan
| | - Kenji Kameyama
- Department of Clinical Bio‐resource Research and Development, Graduate School of MedicineKyoto UniversityKyotoJapan
- Divison of Thoracic Surgery, Department of Surgery, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan
| | - Tatsuo Furuya
- Divison of Thoracic Surgery, Department of Surgery, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan
| | - Satoru Okada
- Divison of Thoracic Surgery, Department of Surgery, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan
| | - Masanori Shimomura
- Divison of Thoracic Surgery, Department of Surgery, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan
| | - Masayoshi Inoue
- Divison of Thoracic Surgery, Department of Surgery, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan
| | - Masahiro Inoue
- Department of Clinical Bio‐resource Research and Development, Graduate School of MedicineKyoto UniversityKyotoJapan
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Yang H, Xiang Y, Wang J, Ke Z, Zhou W, Yin X, Zhang M, Chen Z. Modulating the blood-brain barrier in CNS disorders: A review of the therapeutic implications of secreted protein acidic and rich in cysteine (SPARC). Int J Biol Macromol 2025; 288:138747. [PMID: 39674451 DOI: 10.1016/j.ijbiomac.2024.138747] [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: 11/26/2024] [Revised: 12/09/2024] [Accepted: 12/11/2024] [Indexed: 12/16/2024]
Abstract
Secreted protein acidic and rich in cysteine (SPARC), an essential stromal cell protein, plays a crucial role in angiogenesis and maintaining endothelial barrier function. This protein is expressed by diverse cell types, including endothelial cells, fibroblasts, and macrophages, with increased expression found in regions of tissues undergoing active remodeling, repair, and proliferation. The role of SPARC in non-neural tissues is of significant interest. In the central nervous system (CNS), SPARC is highly expressed in blood vessels during early development. It becomes down-regulated as the brain matures, a pattern consistent with its role in angiogenesis and blood-brain barrier (BBB) establishment. In this review, we explore the multifaceted roles of SPARC in regulating CNS disorders, particularly its action in angiogenesis, inflammatory responses, neural system development and repair, barrier establishment, maintenance of BBB function, and the pathogenesis of CNS disorders triggered by BBB dysfunction.
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Affiliation(s)
- Hui Yang
- Department of Neurology, Clinical Medical School of Jiujiang University, Jiujiang, Jiangxi 332000, China; Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi 332000, China; School of Basic Medicine, Jiujiang University, Jiujiang, Jiangxi 332000, China
| | - Yuanyuan Xiang
- Department of Neurology, Clinical Medical School of Jiujiang University, Jiujiang, Jiangxi 332000, China
| | - Jiaxuan Wang
- Department of Neurology, Clinical Medical School of Jiujiang University, Jiujiang, Jiangxi 332000, China; Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi 332000, China; School of Basic Medicine, Jiujiang University, Jiujiang, Jiangxi 332000, China
| | - Zunliang Ke
- Department of Neurosurgery, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi 332000, China
| | - Weixin Zhou
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi 332000, China
| | - Xiaoping Yin
- Department of Neurology, Clinical Medical School of Jiujiang University, Jiujiang, Jiangxi 332000, China; Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi 332000, China
| | - Manqing Zhang
- School of Basic Medicine, Jiujiang University, Jiujiang, Jiangxi 332000, China.
| | - Zhiying Chen
- Department of Neurology, Clinical Medical School of Jiujiang University, Jiujiang, Jiangxi 332000, China; Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi 332000, China.
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6
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Zhao ZY, Siow Y, Liu LY, Li X, Wang HL, Lei ZM. The SPARC-related modular calcium binding 1 ( Smoc1 ) regulated by androgen is required for mouse gubernaculum development and testicular descent. Asian J Androl 2025; 27:44-51. [PMID: 39119686 PMCID: PMC11784950 DOI: 10.4103/aja202449] [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: 12/08/2023] [Accepted: 05/22/2024] [Indexed: 08/10/2024] Open
Abstract
ABSTRACT Testicular descent occurs in two consecutive stages: the transabdominal stage and the inguinoscrotal stage. Androgens play a crucial role in the second stage by influencing the development of the gubernaculum, a structure that pulls the testis into the scrotum. However, the mechanisms of androgen actions underlying many of the processes associated with gubernaculum development have not been fully elucidated. To identify the androgen-regulated genes, we conducted large-scale gene expression analyses on the gubernaculum harvested from luteinizing hormone/choriogonadotropin receptor knockout ( Lhcgr KO) mice, an animal model of inguinoscrotal testis maldescent resulting from androgen deficiency. We found that the expression of secreted protein acidic and rich in cysteine (SPARC)-related modular calcium binding 1 ( Smoc1 ) was the most severely suppressed at both the transcript and protein levels, while its expression was the most dramatically induced by testosterone administration in the gubernacula of Lhcgr KO mice. The upregulation of Smoc1 expression by testosterone was curtailed by the addition of an androgen receptor antagonist, flutamide. In addition, in vitro studies demonstrated that SMOC1 modestly but significantly promoted the proliferation of gubernacular cells. In the cultures of myogenic differentiation medium, both testosterone and SMOC1 enhanced the expression of myogenic regulatory factors such as paired box 7 ( Pax7 ) and myogenic factor 5 ( Myf5 ). After short-interfering RNA-mediated knocking down of Smoc1 , the expression of Pax7 and Myf5 diminished, and testosterone alone did not recover, but additional SMOC1 did. These observations indicate that SMOC1 is pivotal in mediating androgen action to regulate gubernaculum development during inguinoscrotal testicular descent.
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Affiliation(s)
- Zhi-Yi Zhao
- Department of Andrology, The First Hospital of Jilin University, Changchun 130021, China
| | - Yong Siow
- Department of OB/GYN, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Ling-Yun Liu
- Department of Andrology, The First Hospital of Jilin University, Changchun 130021, China
| | - Xian Li
- Department of OB/GYN, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Hong-Liang Wang
- Department of Andrology, The First Hospital of Jilin University, Changchun 130021, China
| | - Zhen-Min Lei
- Department of OB/GYN, University of Louisville School of Medicine, Louisville, KY 40202, USA
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Chen X, Guo H, Li X, Liu Y, Li X, Cui Z, Ma H, He J, Zeng Z, Zhang H. Elevated Serum Extracellular Vesicle-Packaged SPARC in Hypertension: A Cross-Sectional Study in a Middle-Aged and Elderly Population. J Clin Hypertens (Greenwich) 2025; 27:e14954. [PMID: 39632586 PMCID: PMC11773675 DOI: 10.1111/jch.14954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 11/06/2024] [Accepted: 11/15/2024] [Indexed: 12/07/2024]
Abstract
Elevated blood pressure has previously been associated with increased levels of circulating extracellular vesicles (EVs). However, studies on the relevance of EV cargos to hypertension are limited. Secreted protein acidic and rich in cysteine (SPARC) is involved in many metabolic diseases and endothelial dysfunction pathological processes. This study aimed to explore the association of serum EV-derived SPARC with hypertension incidence. We conducted a cross-sectional study on 125 Chinese, including 76 hypertension patients and 49 normotensive patients. Serum EVs were prepared via ultracentrifugation. The concentrations of serum EV-derived SPARC and serum SPARC were measured by Luminex Assay. The correlations between serum EV-derived SPARC and clinical variables were analyzed. Multivariate logistic regression analysis determined the association of serum EV-derived SPARC levels with hypertension. Interaction subgroup analysis was used to evaluate the interaction of the relevant baselines on the association between serum EV-derived SPARC levels and hypertension. Our findings revealed that the levels of SPARC derived from serum EVs were markedly elevated in individuals with hypertension, averaging 20.60 ng/mL (p < 0.01), when contrasted with the levels observed in normotensive subjects, which were 14.25 ng/mL (p < 0.01) in average. Multivariate logistic regression analysis revealed that serum EV-derived SPARC levels were positively associated with hypertension (odds ratio [OR] 1.095; 95% confidence interval [CI] = 1.031-1.163; p value, 0.003), after adjusting for confounding factors. Interaction subgroup analysis demonstrated that no significant interaction with hypertension was observed for any particular covariate. The present study reveals that the elevated levels of serum EV-derived SPARC were independently associated with hypertension.
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Affiliation(s)
- Xueying Chen
- Beijing An Zhen HospitalCapital Medical University, The Key Laboratory of Remodeling Cardiovascular Diseases, Ministry of Education; Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart Lung and Blood Vessel DiseaseBeijingChina
| | - Han Guo
- Beijing An Zhen HospitalCapital Medical University, The Key Laboratory of Remodeling Cardiovascular Diseases, Ministry of Education; Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart Lung and Blood Vessel DiseaseBeijingChina
| | - Xinwei Li
- Beijing An Zhen HospitalCapital Medical University, The Key Laboratory of Remodeling Cardiovascular Diseases, Ministry of Education; Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart Lung and Blood Vessel DiseaseBeijingChina
| | - Yang Liu
- Beijing An Zhen HospitalCapital Medical University, The Key Laboratory of Remodeling Cardiovascular Diseases, Ministry of Education; Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart Lung and Blood Vessel DiseaseBeijingChina
| | - Xinxin Li
- Beijing An Zhen HospitalCapital Medical University, The Key Laboratory of Remodeling Cardiovascular Diseases, Ministry of Education; Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart Lung and Blood Vessel DiseaseBeijingChina
| | - Zhengshuo Cui
- Beijing An Zhen HospitalCapital Medical University, The Key Laboratory of Remodeling Cardiovascular Diseases, Ministry of Education; Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart Lung and Blood Vessel DiseaseBeijingChina
| | - Huijuan Ma
- Department of HypertensionBeijing An Zhen HospitalCapital Medical UniversityBeijingChina
| | - Jianxun He
- Beijing Anzhen Hospital Laboratory DepartmentBeijing Anzhen HospitalCapital Medical UniversityBeijingChina
| | - Zhechun Zeng
- Beijing An Zhen HospitalCapital Medical University, The Key Laboratory of Remodeling Cardiovascular Diseases, Ministry of Education; Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart Lung and Blood Vessel DiseaseBeijingChina
| | - Huina Zhang
- Beijing An Zhen HospitalCapital Medical University, The Key Laboratory of Remodeling Cardiovascular Diseases, Ministry of Education; Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart Lung and Blood Vessel DiseaseBeijingChina
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Fu S, Du H, Dai Y, Zheng K, Cao G, Xu L, Zhong Y, Niu C, Kong Y, Wang X. Screening and molecular mechanism research on bile microRNAs associated with chemotherapy efficacy in perihilar cholangiocarcinoma. iScience 2024; 27:111437. [PMID: 39717085 PMCID: PMC11664176 DOI: 10.1016/j.isci.2024.111437] [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: 12/23/2023] [Revised: 08/22/2024] [Accepted: 11/18/2024] [Indexed: 12/25/2024] Open
Abstract
The efficacy of hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin (OXA) and 5-fluorouracil (5-Fu) for treating advanced perihilar cholangiocarcinoma (pCCA) has been demonstrated, yet the survival benefits of HAIC for pCCA patients vary. Here, we aimed to screen out HAIC resistance-related bile microRNAs (miRNAs) and explore the functions of specific bile miRNAs in pCCA based on high-throughput sequencing. Levels of bile miR-532-3p, miR-1250-5p, and miR-4772-5p were related to the survival of advanced pCCA patients after HAIC. However, only overexpression of miR-532-3p promoted OXA/5-Fu resistance, and downregulation of its expression improved sensitivity to OXA/5-Fu. Mechanistic investigations revealed secreted protein acidic and rich in cysteine (SPARC) as the direct target of miR-532-3p. Our study reveals that bile miR-532-3p, miR-1250-5p, and miR-4772-5p may serve as survival biomarkers in advanced pCCA patients after HAIC and that bile miR-532-3p promotes resistance to HAIC with OXA and 5-Fu via negatively regulating SPARC expression.
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Affiliation(s)
- Shijie Fu
- Department of Interventional Radiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100000, China
| | - Haizhen Du
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Yuyang Dai
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Kanglian Zheng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Guang Cao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Liang Xu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Yujie Zhong
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Chuanxin Niu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Yan Kong
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Xiaodong Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
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9
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Ono M, Nakajima K, Tomizawa SI, Shirakawa T, Okada I, Saitsu H, Matsumoto N, Ohbo K. Spatial and temporal expression analysis of BMP signal modifiers, Smoc1 and Smoc2, from postnatal to adult developmental stages in the mouse testis. Gene Expr Patterns 2024; 54:119383. [PMID: 39510490 DOI: 10.1016/j.gep.2024.119383] [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: 06/23/2024] [Revised: 10/31/2024] [Accepted: 11/04/2024] [Indexed: 11/15/2024]
Abstract
Smoc1 and Smoc2, members of the SPARC family of genes, encode signaling molecules downstream of growth factors such as the TGF-β, FGF, and PDGF families. Smoc1 has been implicated in playing a crucial role in microphthalmia with limb anomalies in humans and mice, while Smoc2 deficiency causes dental developmental defects. Although developmental cytokines/growth factors including TGF-β superfamily have been shown to play critical roles in postnatal spermatogenesis, there are no reports analyzing the spatial and temporal expression of Smoc1 and Smoc2 in the postnatal testis. In this study, we investigated the mRNA and protein expression of Smoc1 and Smoc2 in neonatal, juvenile, and adult mouse testes by RNA in situ hybridization, immunofluorescence, and single-cell RNA-seq analysis. We show that Smoc1 and Smoc2 have distinct expression patterns in male germ cells: Smoc1 is more highly expressed than Smoc2 in the germline. In contrast, Smoc2 is highly expressed in testicular somatic cells from neonatal to juvenile stages. The Smoc2-expressing cells then switch from somatic cells to germ cells in adults. Thus, although SMOC1 and SMOC2 proteins are structurally very similar, their spatial and temporal expression patterns in the postnatal testis differ significantly, suggesting their distinct roles in reproduction.
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Affiliation(s)
- Michio Ono
- Department of Histology and Cell Biology, School of Medicine, Yokohama City University, 3-9, Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Kuniko Nakajima
- Department of Histology and Cell Biology, School of Medicine, Yokohama City University, 3-9, Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Shin-Ichi Tomizawa
- Department of Histology and Cell Biology, School of Medicine, Yokohama City University, 3-9, Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Takayuki Shirakawa
- Department of Histology and Cell Biology, School of Medicine, Yokohama City University, 3-9, Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Ippei Okada
- Department of Human Genetics, School of Medicine, Yokohama City University, 3-9, Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Hirotomo Saitsu
- Biochemistry Department, Hamamatsu University School of Medicine, 1-20-1, Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
| | - Naomichi Matsumoto
- Department of Human Genetics, School of Medicine, Yokohama City University, 3-9, Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan
| | - Kazuyuki Ohbo
- Department of Histology and Cell Biology, School of Medicine, Yokohama City University, 3-9, Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
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10
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Li C, Zhang M, Du Y, Liu S, Li D, Zhang S, Ji F, Zhang J, Jiao J. Compromised cell competition exhausts neural stem cells pool. Cell Prolif 2024; 57:e13710. [PMID: 39010274 PMCID: PMC11628731 DOI: 10.1111/cpr.13710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Revised: 06/05/2024] [Accepted: 06/22/2024] [Indexed: 07/17/2024] Open
Abstract
Blood vessels play a crucial role in maintaining the stem cell niche in both tumours and developing organs. Cell competition is critical for tumour progression. We hypothesise that blood vessels may act as a regulator of this process. As a pioneer, the secretions of blood vessels regulate the intensity of cell competition, which is essential for tumour invasion and developmental organ extension. Brd4 expresses highly in endothelial cells within various tumours and is positively correlated with numerous invasive genes, making it an ideal focal point for further research on the relationship between blood vessels and cell competition. Our results indicated that the absence of endothelial Brd4 led to a reduction in neural stem cell mortality and compromised cell competition. Endothelial Brd4 regulated cell competition was dependent on Testican2. Testican2 was capable of depositing Sparc and acted as a suppressor of Sparc. Compromised cell competition resulted in the depletion of neural stem cells and accelerated brain ageing. Testican2 could rescue the run-off of neural stem cells and accelerate the turnover rate of neurons. AD patients show compromised cell competition. Through the cloning of a point mutant of Brd4 identified in a subset of AD patients, it was demonstrated that the mutant lacked the ability to promote cell competition. This study suggests a novel approach for treating age-related diseases by enhancing the intensity of cell competition.
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Affiliation(s)
- Chenxiao Li
- Affiliated Hospital of Guangdong Medical University & Key Laboratory of Zebrafish Model for Development and Disease of Guangdong Medical UniversityZhanjiangChina
- Key Laboratory of Organ Regeneration and Reconstruction, Chinese Academy of ScienceBeijingChina
- University of Chinese Academy of SciencesBeijingChina
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of SciencesBeijingChina
| | - Mengtian Zhang
- Key Laboratory of Organ Regeneration and Reconstruction, Chinese Academy of ScienceBeijingChina
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of SciencesBeijingChina
| | - Yushan Du
- College of Basic Medicine, Qingdao UniversityQingdaoChina
| | - Shuang Liu
- Jiaozuo Hospital of Traditional Chinese MedicineHenanChina
| | - Da Li
- Key Laboratory of Organ Regeneration and Reconstruction, Chinese Academy of ScienceBeijingChina
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of SciencesBeijingChina
| | - Shukui Zhang
- Key Laboratory of Organ Regeneration and Reconstruction, Chinese Academy of ScienceBeijingChina
| | - Fen Ji
- Key Laboratory of Organ Regeneration and Reconstruction, Chinese Academy of ScienceBeijingChina
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of SciencesBeijingChina
| | - Jingjing Zhang
- Affiliated Hospital of Guangdong Medical University & Key Laboratory of Zebrafish Model for Development and Disease of Guangdong Medical UniversityZhanjiangChina
| | - Jianwei Jiao
- Key Laboratory of Organ Regeneration and Reconstruction, Chinese Academy of ScienceBeijingChina
- University of Chinese Academy of SciencesBeijingChina
- Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of SciencesBeijingChina
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11
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Abstract
The extracellular matrix (ECM) is the complex meshwork of proteins and glycans that forms the scaffold that surrounds and supports cells. It exerts key roles in all aspects of metazoan physiology, from conferring physical and mechanical properties on tissues and organs to modulating cellular processes such as proliferation, differentiation and migration. Understanding the mechanisms that orchestrate the assembly of the ECM scaffold is thus crucial to understand ECM functions in health and disease. This Review discusses novel insights into the compositional diversity of matrisome components and the mechanisms that lead to tissue-specific assemblies and architectures tailored to support specific functions. The Review then highlights recently discovered mechanisms, including post-translational modifications and metabolic pathways such as amino acid availability and the circadian clock, that modulate ECM secretion, assembly and remodelling in homeostasis and human diseases. Last, the Review explores the potential of 'matritherapies', that is, strategies to normalize ECM composition and architecture to achieve a therapeutic benefit.
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Affiliation(s)
- Alexandra Naba
- Department of Physiology and Biophysics, University of Illinois Chicago, Chicago, IL, USA.
- University of Illinois Cancer Center, Chicago, IL, USA.
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12
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Li C, Yuan H, Chen J, Shang K, He H. The oncogenic functions of SPARCL1 in bladder cancer. J Cell Mol Med 2024; 28:e70196. [PMID: 39548034 PMCID: PMC11567778 DOI: 10.1111/jcmm.70196] [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: 05/04/2024] [Revised: 10/14/2024] [Accepted: 10/27/2024] [Indexed: 11/17/2024] Open
Abstract
Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) belongs to the SPARC family of matricellular proteins. However, underlying functions of SPARCL1 in bladder cancer (BCa) remain understudied. We performed an integrated search for the expression patterns of SPARCL1 in relation to various clinicopathological features of BCa. We then carried out Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and gene set enrichment analysis (GSEA). Furthermore, we investigated the correlations between SPARCL1 and immunological features, such as tumour mutation burden (TMB), immune activation processes, immune checkpoint expression, tumour immune dysfunction and exclusion (TIDE) scores, and chemotherapeutic sensitivity in BCa. Our analysis revealed that SPARCL1 was downregulated across multiple cancers. In BCa, elevated SPARCL1 was linked with advanced histopathologic stage, higher T and N stage, and poorer prognosis in the clinical cohort. In vitro experiments demonstrated that increased SPARCL1 expression inhibited cell proliferation, migration, and invasion. Additionally, highly expressed SPARCL1 was linked to elevated immune, stromal and ESTIMATE scores, as well as an increase in naive B cells, M2 macrophages, and resting mast cells. We observed a moderate correlation between SPARCL1 expression and CD163, VSIG4 and MS4A4A, which are markers of M2 macrophages. Furthermore, SPARCL1 expression was positively related to TMB, immune activation processes, TIDE scores, immune checkpoint expression, and chemotherapeutic sensitivity in BCa. Our study highlights the potential involvement of SPARCL1 in macrophage recruitment and polarization and suggests its utility as a biomarker for prognosis in BCa.
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Affiliation(s)
- Changjiu Li
- Department of Urology, Affiliated Hangzhou First People's HospitalWestlake University School of MedicineHangzhouChina
| | - Hui Yuan
- The Fourth Clinical Medical CollegeZhejiang Chinese Medical UniversityHangzhouChina
- Department of UrologyNinghai First HospitalNingbo
| | - Jun Chen
- The Fourth Clinical Medical CollegeZhejiang Chinese Medical UniversityHangzhouChina
| | - Kun Shang
- The Fourth Clinical Medical CollegeZhejiang Chinese Medical UniversityHangzhouChina
| | - Huadong He
- Department of Urology, Affiliated Hangzhou First People's HospitalWestlake University School of MedicineHangzhouChina
- The Fourth Clinical Medical CollegeZhejiang Chinese Medical UniversityHangzhouChina
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13
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Toba H, Takai S. Exploring the roles of SPARC as a proinflammatory factor and its potential as a novel therapeutic target against cardiovascular disease. Am J Physiol Heart Circ Physiol 2024; 327:H1174-H1186. [PMID: 39269452 DOI: 10.1152/ajpheart.00565.2024] [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: 08/15/2024] [Revised: 09/09/2024] [Accepted: 09/09/2024] [Indexed: 09/15/2024]
Abstract
Cardiovascular disease (CVD) is a leading cause of death worldwide, and the number of patients with CVD continues to increase despite extensive research and developments in this field. Chronic inflammation is a pivotal pathological component of CVD, and unveiling new proinflammatory factors will help devise novel preventive and therapeutic strategies. The extracellular matrix (ECM) not only provides structural support between cells but also contributes to cellular functions. Secreted protein acidic and rich in cysteine (SPARC) is a collagen-binding matricellular protein that is particularly induced during development and tissue remodeling. A proinflammatory role for SPARC has been demonstrated in various animal models, such as in the lipopolysaccharide-induced footpad model and dextran sodium sulfate-induced colitis model. Recent clinical studies reported a positive correlation between elevated plasma SPARC levels and hypertension, obesity, and the inflammatory marker high-sensitive C-reactive protein. In addition, SPARC gene deletion attenuates the cardiac injury induced by aging, myocardial infarction, and pressure load, suggesting that SPARC has deleterious effects on CVD. This review summarizes the regulatory and proinflammatory mechanisms of SPARC on CVD, chronic kidney disease (CKD), and cerebrovascular disease and discusses the rationale behind measuring SPARC as a biomarker of CVD and the effects of inhibition of SPARC in the prevention and treatment of CVD.
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Affiliation(s)
- Hiroe Toba
- Division of Pathological Sciences, Department of Clinical Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan
- Department of Pharmacology, Educational Foundation of Osaka Medical and Pharmacological University, Takatsuki, Japan
| | - Shinji Takai
- Department of Pharmacology, Educational Foundation of Osaka Medical and Pharmacological University, Takatsuki, Japan
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14
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Li C, Li B, Han M, Tian H, Gao J, Han D, Ling Z, Jing Y, Li N, Hua J. SPARC overexpression in allogeneic adipose-derived mesenchymal stem cells in dog dry eye model induced by benzalkonium chloride. Stem Cell Res Ther 2024; 15:195. [PMID: 38956738 PMCID: PMC11218109 DOI: 10.1186/s13287-024-03815-z] [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: 12/19/2023] [Accepted: 06/24/2024] [Indexed: 07/04/2024] Open
Abstract
BACKGROUND Nowadays, companion and working dogs hold significant social and economic importance. Dry eye, also known as dry keratoconjunctivitis (KCS), a common disease in ophthalmology, can readily impact a dog's working capacity and lead to economic losses. Although there are several medications available for this disease, all of them only improve the symptoms on the surface of the eye, and they are irritating and not easy to use for long periods of time. Adipose-derived mesenchymal stem cells (ADMSC) are promising candidates for tissue regeneration and disease treatment. However, long-term in vitro passaging leads to stemness loss of ADMSC. Here, we aimed to use ADMSC overexpressing Secreted Protein Acidic and Rich in Cysteine (SPARC) to treat 0.25% benzalkonium chloride-treated dogs with dry eye to verify its efficacy. For in vitro validation, we induced corneal epithelial cell (HCECs) damage using 1 µg/mL benzalkonium chloride. METHODS Fifteen male crossbred dogs were randomly divided into five groups: normal, dry eye self-healing control, cyclosporine-treated, ADMSC-CMV-treated and ADMSC-OESPARC-treated. HCECs were divided into four groups: normal control group, untreated model group, ADMSC-CMV supernatant culture group and ADMSC-OESRARC supernatant culture group. RESULTS SPARC-modified ADMSC had the most significant effect on canine ocular surface inflammation, corneal injury, and tear recovery, and the addition of ADMSC-OESPARC cell supernatant also had a salvage effect on HCECs cellular damage, such as cell viability and cell proliferation ability. Moreover, analysis of the co-transcriptome sequencing data showed that SPARC could promote corneal epithelial cell repair by enhancing the in vitro viability, migration and proliferation and immunosuppression of ADMSC. CONCLUSION The in vitro cell test and in vivo model totally suggest that the combination of SPARC and ADMSC has a promising future in novel dry eye therapy.
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Affiliation(s)
- Chenchen Li
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Balun Li
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Miao Han
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Hongkai Tian
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Jiaqi Gao
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Dongyao Han
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Zixi Ling
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Yuanxiang Jing
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Na Li
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Jinlian Hua
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China.
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15
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Le AD, Fu M, Kumar R, Zacharias G, Garcia ADR. Astrocyte modulation of synaptic plasticity mediated by activity-dependent Sonic hedgehog signaling. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.05.588352. [PMID: 38915525 PMCID: PMC11195099 DOI: 10.1101/2024.04.05.588352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
The influence of neural activity on astrocytes and their reciprocal interactions with neurons has emerged as an important modulator of synapse function. Astrocytes exhibit activity-dependent changes in gene expression, yet the molecular mechanisms by which they accomplish this have remained largely unknown. The molecular signaling pathway, Sonic hedgehog (Shh), mediates neuron-astrocyte communication and regulates the organization of cortical synapses. Here, we demonstrate that neural activity stimulates Shh signaling in cortical astrocytes and upregulates expression of Hevin and SPARC, astrocyte derived molecules that modify synapses. Whisker stimulation and chemogenetic activation both increase Shh activity in deep layers of the somatosensory cortex, where neuron-astrocyte Shh signaling is predominantly found. Experience-dependent Hevin and SPARC require intact Shh signaling and selective loss of pathway activity in astrocytes occludes experience-dependent structural plasticity. Taken together, these data identify Shh signaling as an activity-dependent, neuronal derived cue that stimulates astrocyte interactions with synapses and promotes synaptic plasticity.
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Affiliation(s)
- Anh Duc Le
- Department of Biology, Drexel University
| | - Marissa Fu
- Department of Biology, Drexel University
| | - Riya Kumar
- Department of Biology, Drexel University
| | | | - A Denise R Garcia
- Department of Neurobiology and Anatomy, Drexel University College of Medicine
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16
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Wang Y, Liu X, Wang X, Lu J, Tian Y, Liu Q, Xue J. Matricellular proteins: Potential biomarkers in head and neck cancer. J Cell Commun Signal 2024; 18:e12027. [PMID: 38946720 PMCID: PMC11208127 DOI: 10.1002/ccs3.12027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 03/19/2024] [Accepted: 03/22/2024] [Indexed: 07/02/2024] Open
Abstract
The extracellular matrix (ECM) is a complex network of diverse multidomain macromolecules, including collagen, proteoglycans, and fibronectin, that significantly contribute to the mechanical properties of tissues. Matricellular proteins (MCPs), as a family of non-structural proteins, play a crucial role in regulating various ECM functions. They exert their biological effects by interacting with matrix proteins, cell surface receptors, cytokines, and proteases. These interactions govern essential cellular processes such as differentiation, proliferation, adhesion, migration as well as multiple signal transduction pathways. Consequently, MCPs are pivotal in maintaining tissue homeostasis while orchestrating intricate molecular mechanisms within the ECM framework. The expression level of MCPs in adult steady-state tissues is significantly low; however, under pathological conditions such as inflammation and cancer, there is a substantial increase in their expression. In recent years, an increasing number of studies have focused on elucidating the role and significance of MCPs in the development and progression of head and neck cancer (HNC). During HNC progression, there is a remarkable upregulation in MCP expression. Through their distinctive structure and function, they actively promote tumor growth, invasion, epithelial-mesenchymal transition, and lymphatic metastasis of HNC cells. Moreover, by binding to integrins and modulating various signaling pathways, they effectively execute their biological functions. Furthermore, MCPs also hold potential as prognostic indicators. Although the star proteins of various MCPs have been extensively investigated, there remains a plethora of MCP family members that necessitate further scrutiny. This article comprehensively examines the functionalities of each MCP and highlights the research advancements in the context of HNC, with an aim to identify novel biomarkers for HNC and propose promising avenues for future investigations.
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Affiliation(s)
- Yunsheng Wang
- Department of Head and Neck SurgeryGansu Provincial Cancer HospitalLanzhouChina
| | - Xudong Liu
- Department of Head and Neck SurgeryGansu Provincial Cancer HospitalLanzhouChina
| | - Xingyue Wang
- Department of Head and Neck SurgeryGansu Provincial Cancer HospitalLanzhouChina
| | - Jiyong Lu
- Department of Head and Neck SurgeryGansu Provincial Cancer HospitalLanzhouChina
| | - Youxin Tian
- Department of Head and Neck SurgeryGansu Provincial Cancer HospitalLanzhouChina
| | - Qinjiang Liu
- Department of Head and Neck SurgeryGansu Provincial Cancer HospitalLanzhouChina
| | - Jincai Xue
- Department of Head and Neck SurgeryGansu Provincial Cancer HospitalLanzhouChina
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17
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Chen ZT, Weng ZX, Lin JD, Meng ZX. Myokines: metabolic regulation in obesity and type 2 diabetes. LIFE METABOLISM 2024; 3:loae006. [PMID: 39872377 PMCID: PMC11749576 DOI: 10.1093/lifemeta/loae006] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 02/23/2024] [Accepted: 02/29/2024] [Indexed: 01/30/2025]
Abstract
Skeletal muscle plays a vital role in the regulation of systemic metabolism, partly through its secretion of endocrine factors which are collectively known as myokines. Altered myokine levels are associated with metabolic diseases, such as type 2 diabetes (T2D). The significance of interorgan crosstalk, particularly through myokines, has emerged as a fundamental aspect of nutrient and energy homeostasis. However, a comprehensive understanding of myokine biology in the setting of obesity and T2D remains a major challenge. In this review, we discuss the regulation and biological functions of key myokines that have been extensively studied during the past two decades, namely interleukin 6 (IL-6), irisin, myostatin (MSTN), growth differentiation factor 11 (GDF11), fibroblast growth factor 21 (FGF21), apelin, brain-derived neurotrophic factor (BDNF), meteorin-like (Metrnl), secreted protein acidic and rich in cysteine (SPARC), β-aminoisobutyric acid (BAIBA), Musclin, and Dickkopf 3 (Dkk3). Related to these, we detail the role of exercise in myokine expression and secretion together with their contributions to metabolic physiology and disease. Despite significant advancements in myokine research, many myokines remain challenging to measure accurately and investigate thoroughly. Hence, new research techniques and detection methods should be developed and rigorously tested. Therefore, developing a comprehensive perspective on myokine biology is crucial, as this will likely offer new insights into the pathophysiological mechanisms underlying obesity and T2D and may reveal novel targets for therapeutic interventions.
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Affiliation(s)
- Zhi-Tian Chen
- Department of Pathology and Pathophysiology and Department of Cardiology of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
- Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
- Zhejiang University-University of Edinburgh Institute (ZJE), School of Medicine, Zhejiang University, Haining, Zhejiang 314400, China
| | - Zhi-Xuan Weng
- Department of Pathology and Pathophysiology and Department of Cardiology of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
- Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Jiandie D Lin
- Life Sciences Institute and Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, United States
| | - Zhuo-Xian Meng
- Department of Pathology and Pathophysiology and Department of Cardiology of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
- Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
- Department of Geriatrics, Affiliated Hangzhou First People’s Hospital, Hangzhou, Zhejiang 310006, China
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18
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Ling H, Li Y, Peng C, Yang S, Seto E. HDAC10 inhibition represses melanoma cell growth and BRAF inhibitor resistance via upregulating SPARC expression. NAR Cancer 2024; 6:zcae018. [PMID: 38650694 PMCID: PMC11034028 DOI: 10.1093/narcan/zcae018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 03/08/2024] [Accepted: 04/09/2024] [Indexed: 04/25/2024] Open
Abstract
Secreted protein acidic and rich in cysteine (SPARC), a conserved secreted glycoprotein, plays crucial roles in regulating various biological processes. SPARC is highly expressed and has profound implications in several cancer types, including melanoma. Understanding the mechanisms that govern SPARC expression in cancers has the potential to lead to improved cancer diagnosis, prognosis, treatment strategies, and patient outcomes. Here, we demonstrate that histone deacetylase 10 (HDAC10) is a key regulator of SPARC expression in melanoma cells. Depletion or inhibition of HDAC10 upregulates SPARC expression, whereas overexpression of HDAC10 downregulates it. Mechanistically, HDAC10 coordinates with histone acetyltransferase p300 to modulate the state of acetylation of histone H3 at lysine 27 (H3K27ac) at SPARC regulatory elements and the recruitment of bromodomain-containing protein 4 (BRD4) to these regions, thereby fine-tuning SPARC transcription. HDAC10 depletion and resultant SPARC upregulation repress melanoma cell growth primarily by activating AMPK signaling and inducing autophagy. Moreover, SPARC upregulation due to HDAC10 depletion partly accounts for the resensitization of resistant cells to a BRAF inhibitor. Our work reveals the role of HDAC10 in gene regulation through indirect histone modification and suggests a potential therapeutic strategy for melanoma or other cancers by targeting HDAC10 and SPARC.
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Affiliation(s)
- Hongbo Ling
- George Washington Cancer Center, Department of Biochemistry & Molecular Medicine, The George Washington University School of Medicine & Health Sciences, Washington, DC 20037, USA
| | - Yixuan Li
- George Washington Cancer Center, Department of Biochemistry & Molecular Medicine, The George Washington University School of Medicine & Health Sciences, Washington, DC 20037, USA
| | - Changmin Peng
- George Washington Cancer Center, Department of Biochemistry & Molecular Medicine, The George Washington University School of Medicine & Health Sciences, Washington, DC 20037, USA
| | - Shengyu Yang
- Department of Cellular and Molecular Physiology, Penn State Cancer Institute, The Penn State University, 400 University Drive, Hershey, PA 17033, USA
| | - Edward Seto
- George Washington Cancer Center, Department of Biochemistry & Molecular Medicine, The George Washington University School of Medicine & Health Sciences, Washington, DC 20037, USA
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19
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Xia L, Kano F, Hashimoto N, Liu Y, Khurel-Ochir T, Ogasawara N, Ding C, Xu Y, Hibi H, Iwasaki T, Tanaka E, Yamamoto A. Conditioned Medium From Stem Cells of Human Exfoliated Deciduous Teeth Alleviates Mouse Osteoarthritis by Inducing sFRP1-Expressing M2 Macrophages. Stem Cells Transl Med 2024; 13:399-413. [PMID: 38366885 PMCID: PMC11016837 DOI: 10.1093/stcltm/szae006] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 01/11/2024] [Indexed: 02/18/2024] Open
Abstract
Intravenous administration of conditioned medium from stem cells of human exfoliated deciduous teeth (SHED-CM) regenerates mechanically injured osteochondral tissues in mouse temporomandibular joint osteoarthritis (TMJOA). However, the underlying therapeutic mechanisms remain unclear. Here, we showed that SHED-CM alleviated injured TMJ by inducing anti-inflammatory M2 macrophages in the synovium. Depletion of M2 by Mannosylated Clodrosome abolished the osteochondral repair activities of SHED-CM. Administration of CM from M2-induced by SHED-CM (M2-CM) effectively ameliorated mouse TMJOA by inhibiting chondrocyte inflammation and matrix degradation while enhancing chondrocyte proliferation and matrix formation. Notably, in vitro, M2-CM directly suppressed the catabolic activities while enhancing the anabolic activities of interleukin-1β-stimulated mouse primary chondrocytes. M2-CM also inhibited receptor activator of nuclear factor NF-κB ligand-induced osteoclastogenesis in RAW264.7 cells. Secretome analysis of M2-CM and M0-CM revealed that 5 proteins related to anti-inflammation and/or osteochondrogenesis were enriched in M2-CM. Of these proteins, the Wnt signal antagonist, secreted frizzled-related protein 1 (sFRP1), was the most abundant and played an essential role in the shift to anabolic chondrocytes, suggesting that M2 ameliorated TMJOA partly through sFRP1. This study suggests that secretome from SHED exerted remarkable osteochondral regeneration activities in TMJOA through the induction of sFRP1-expressing tissue-repair M2 macrophages.
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Affiliation(s)
- Linze Xia
- Department of Tissue Regeneration, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
- Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Fumiya Kano
- Department of Tissue Regeneration, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Noboru Hashimoto
- Department of Tissue Regeneration, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Yao Liu
- Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, People’s Republic of China
| | - Tsendsuren Khurel-Ochir
- Department of Orthodontics, School of Dentistry, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Naoko Ogasawara
- Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Cheng Ding
- Department of Tissue Regeneration, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Yang Xu
- Department of Tissue Regeneration, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Hideharu Hibi
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tomonori Iwasaki
- Department of Pediatric Dentistry, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Eiji Tanaka
- Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Akihito Yamamoto
- Department of Tissue Regeneration, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
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20
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Kondo Y, Li Y, Okajima T. Efficient Escorting Strategy for Aggregation-Prone Notch EGF Repeats with Sparcl1. Molecules 2024; 29:1031. [PMID: 38474544 DOI: 10.3390/molecules29051031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 02/26/2024] [Accepted: 02/26/2024] [Indexed: 03/14/2024] Open
Abstract
Epidermal growth factor (EGF) repeats are present in various proteins and form well-defined structures with three disulfide bonds. One representative protein is the Notch receptor. Each EGF repeat contains unique atypical O-linked glycans, such as O-linked N-acetylglucosamine (O-GlcNAc). To generate a monoclonal antibody against the O-GlcNAc moiety in mouse Notch1, we expressed the recombinant C-terminal His6-tagged Notch1 EGF14-15 protein in HEK293T cells to prepare the immunogen. Most of the proteins were not secreted and showed higher molecular weight ladders in the cell lysate, suggesting protein aggregation. To overcome this issue, we fused Sparcl1 as an extracellular escorting tag to the N-terminus of Notch1 EGF14-15. The fusion protein was efficiently secreted extracellularly without protein aggregates in the lysates. Following PreScission protease treatment, Notch1 EGF14-15 was efficiently released from the escorting tag. Notch1 EGF14-15 prepared using this method was indeed O-GlcNAcylated. The optimal length of the escorting tag was determined by generating deletion mutants to improve the extracellular secretion of EGF14-15. Hence, a large amount of EGF14-15 was successfully prepared from the culture supernatant of HEK293T cells, which were otherwise prone to aggregation.
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Affiliation(s)
- Yuji Kondo
- Department of Molecular Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
- Institute for Glyco-core Research (iGCORE), Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
| | - Yuxin Li
- Department of Molecular Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Tetsuya Okajima
- Department of Molecular Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
- Institute for Glyco-core Research (iGCORE), Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
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Nakagiri T, Amatya VJ, Kushitani K, Kambara T, Aoe K, Endo I, Miyata Y, Okada M, Takeshima Y. SPARC Is a Novel Positive Immunohistochemical Marker of Epithelioid Mesothelioma to Differentiate It From Lung Adenocarcinoma and/or Squamous Cell Carcinoma. Am J Surg Pathol 2024; 48:140-149. [PMID: 37899530 DOI: 10.1097/pas.0000000000002147] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2023]
Abstract
Epithelioid mesothelioma with a solid histologic pattern (solid epithelioid mesothelioma) is difficult to distinguish from a poorly differentiated squamous cell lung carcinoma and/or solid lung adenocarcinoma. Thus, immunohistochemical markers are essential for diagnosis; however, the sensitivity and specificity of pre-existing mesothelial markers are suboptimal, particularly for differentiation from squamous cell carcinoma. Using a cancer-dependency map, we analyzed gene expression data of pleural mesothelioma and non-small cell lung cancer cell lines (squamous cell carcinoma and adenocarcinoma) and identified secreted protein acidic and cysteine-rich (SPARC) as a promising candidate for the differential diagnosis of epithelioid mesothelioma from lung squamous cell carcinoma and/or lung adenocarcinoma. SPARC expression in mesothelioma and lung cancer cell lines was validated using reverse-transcription polymerase chain reaction, western blotting, and immunohistochemistry. Immunohistochemical staining was performed using anti-SPARC antibodies against solid epithelioid mesothelioma, solid lung adenocarcinoma, and poorly differentiated lung squamous cell carcinoma. SPARC positivity was seen in 42/45 (93.3%) of solid epithelioid mesothelioma, 2/40 (5%) solid lung adenocarcinoma, and 2/45 (4.5%) of lung squamous cell carcinomas. The sensitivity, specificity, and diagnostic accuracy for differentiating solid epithelioid mesothelioma from lung cancer (solid lung adenocarcinoma and poorly differentiated lung squamous cell carcinoma) were 93.3, 95.2, and 94.6%, respectively. In conclusion, SPARC is a novel mesothelial marker that can be used to differentiate epithelioid mesothelioma from squamous cell carcinoma and lung adenocarcinoma.
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Affiliation(s)
- Tetsuya Nakagiri
- Department of Pathology, Graduate School of Biomedical and Health Sciences
| | - Vishwa J Amatya
- Department of Pathology, Graduate School of Biomedical and Health Sciences
| | - Kei Kushitani
- Department of Pathology, Graduate School of Biomedical and Health Sciences
| | - Takahiro Kambara
- Department of Pathology, Graduate School of Biomedical and Health Sciences
| | - Kohei Aoe
- Department of Pathology, Graduate School of Biomedical and Health Sciences
| | - Ihiro Endo
- Department of Pathology, Graduate School of Biomedical and Health Sciences
| | - Yoshihiro Miyata
- Department of Surgical Oncology, Research Center for Radiation Casualty Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Morihito Okada
- Department of Surgical Oncology, Research Center for Radiation Casualty Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Yukio Takeshima
- Department of Pathology, Graduate School of Biomedical and Health Sciences
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22
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Ling H, Li Y, Peng C, Yang S, Seto E. HDAC10 blockade upregulates SPARC expression thereby repressing melanoma cell growth and BRAF inhibitor resistance. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.05.570182. [PMID: 38106051 PMCID: PMC10723323 DOI: 10.1101/2023.12.05.570182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2023]
Abstract
Secreted Protein Acidic and Rich in Cysteine (SPARC), a highly conserved secreted glycoprotein, is crucial for various bioprocesses. Here we demonstrate that histone deacetylase 10 (HDAC10) is a key regulator of SPARC expression. HDAC10 depletion or inhibition upregulates, while overexpression of HDAC10 downregulates, SPARC expression. Mechanistically, HDAC10 coordinates with histone acetyltransferase p300 to modulate the acetylation state of histone H3 lysine 27 (H3K27ac) at SPARC regulatory elements and the recruitment of bromodomain-containing protein 4 (BRD4) to these regions, thereby tuning SPARC transcription. HDAC10 depletion and resultant SPARC upregulation repress melanoma cell growth, primarily by induction of autophagy via activation of AMPK signaling. Moreover, SPARC upregulation due to HDAC10 depletion partly accounts for the resensitivity of resistant cells to a BRAF inhibitor. Our work reveals the role of HDAC10 in gene regulation through epigenetic modification and suggests a potential therapeutic strategy for melanoma or other cancers by targeting HDAC10 and SPARC. Highlights HDAC10 is the primary HDAC member that tightly controls SPARC expression. HDAC10 coordinates with p300 in modulating the H3K27ac state at SPARC regulatory elements and the recruitment of BRD4 to these regions. HDAC10 depletion and resultant SPARC upregulation inhibit melanoma cell growth by inducing autophagy via activation of AMPK signaling.SPARC upregulation as a result of HDAC10 depletion resensitizes resistant cells to BRAF inhibitors.
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23
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Liu Z, Zhang H, Hu X. Analysis of the expression and mechanism of follistatin‑like protein 1 in cervical cancer. Oncol Rep 2023; 50:215. [PMID: 37888756 PMCID: PMC10636721 DOI: 10.3892/or.2023.8652] [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: 06/30/2023] [Accepted: 10/03/2023] [Indexed: 10/28/2023] Open
Abstract
The abnormal expression of follistatin‑like protein 1 (FSTL1) in various tumors is a crucial regulator of the biological process of tumorigenesis. Nonetheless, the regulatory role of FSTL1 in cervical cancer is yet to be elucidated. Hence, the present study aimed to explore the expression, function, and molecular mechanism of FSTL1 in cervical cancer. The expression of FSTL1 in normal and cervical cancer tissues was examined using quantitative reverse transcription‑polymerase chain reaction and immunohistochemistry assays. The effects of abnormal expression of FSTL1 on cervical cancer cells were assessed using colony formation, MTT, wound‑healing, Transwell, apoptosis, and nude mouse tumorigenicity assays. FSTL1‑related molecular mechanisms were screened using gene chip analysis. Western blotting analysis was used to verify the regulatory mechanisms of FSTL1 in cervical cancer. The results indicated that the expression of FSTL1 was downregulated in cervical cancer tissues and that its downregulation was associated with tumor differentiation, pathologic type, and infiltration depth. Moreover, FSTL1 inhibited the proliferation, migration, and invasion of cervical cancer cells as well as xenograft tumor growth and promoted cell apoptosis. In addition, the findings of gene chip analysis suggested that the differentially expressed genes of FSTL1 were predominantly enriched in multiple signaling pathways, of which the insulin‑like growth factor (IGF)‑1 signaling pathway was significantly activated. Western blotting suggested the involvement of FSTL1 in the regulation of the IGF‑1R/PI3K/AKT/BCL‑2 signaling pathway. These data establish the downregulation of FSTL1 in cervical cancer tissues. FSTL1 inhibited the proliferation, migration, and invasion of cervical cancer cells and promoted their apoptosis. Furthermore, xenograft tumor growth in nude mice was inhibited. FSTL1 may be involved in the regulation of the IGF‑1R/PI3K/AKT/BCL‑2 signaling pathway in cervical cancer. Therefore, FSTL1 may be employed as a novel biomarker to determine the extent of disease progression in patients with cervical cancer.
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Affiliation(s)
- Zhen Liu
- Department of Gynecology, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Hong Zhang
- Department of Gynecology, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Xiaoxia Hu
- Department of Gynecology, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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24
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Ghanemi A, Mac-Way F. Obesity and Bone Mineral Density Protection Paradox in Chronic Kidney Disease: Secreted Protein Acidic and Rich in Cysteine as a Piece of the Puzzle? Life (Basel) 2023; 13:2172. [PMID: 38004312 PMCID: PMC10672555 DOI: 10.3390/life13112172] [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: 09/07/2023] [Revised: 10/08/2023] [Accepted: 10/31/2023] [Indexed: 11/26/2023] Open
Abstract
Obesity is a health condition that represents a risk factor for numerous diseases and complications. However, obesity might also have-to some extent-some "benefits" in certain situations. This includes potential bone protection in patients suffering from chronic kidney disease. In an attempt to explain such a paradox, we highlight secreted protein acidic and rich in cysteine (SPARC) as a hypothetical mediator of this protection. Indeed, SPARC properties provide a logical rationale to describe such bone protection via its overexpression combined with its calcium-binding and collagen-binding properties. We believe that exploring such hypotheses could open new doors to elucidate unknown pathways towards developing a new generation of molecular therapies.
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Affiliation(s)
- Abdelaziz Ghanemi
- Endocrinology and Nephrology Axis, L’Hôtel-Dieu de Québec Hospital, CHU de Québec Research Center, Quebec, QC G1R 2J6, Canada;
- Department of Medicine, Faculty of Medicine, Laval University, Quebec, QC G1V 0A6, Canada
| | - Fabrice Mac-Way
- Endocrinology and Nephrology Axis, L’Hôtel-Dieu de Québec Hospital, CHU de Québec Research Center, Quebec, QC G1R 2J6, Canada;
- Department of Medicine, Faculty of Medicine, Laval University, Quebec, QC G1V 0A6, Canada
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Egashira K, Ino Y, Nakai Y, Ohira T, Akiyama T, Moriyama K, Yamamoto Y, Kimura M, Ryo A, Saito T, Inaba Y, Hirano H, Kumagai K, Kimura Y. Identification of gravity-responsive proteins in the femur of spaceflight mice using a quantitative proteomic approach. J Proteomics 2023; 288:104976. [PMID: 37482271 DOI: 10.1016/j.jprot.2023.104976] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 07/11/2023] [Accepted: 07/17/2023] [Indexed: 07/25/2023]
Abstract
Although the microgravity (μ-g) environment that astronauts encounter during spaceflight can cause severe acute bone loss, the molecular mechanism of this bone loss remains unclear. To investigate the gravity-response proteins involved in bone metabolism, it is important to comprehensively determine which proteins exhibit differential abundance associated with mechanical stimuli. However, comprehensive proteomic analysis using small bone samples is difficult because protein extraction in mineralized bone tissue is inefficient. Here, we established a high-sensitivity analysis system for mouse bone proteins using data-independent acquisition mass spectrometry. This system successfully detected 40 proteins in the femoral diaphysis showing differential abundance between mice raised in a μ-g environment, where the bone mass was reduced by gravity unloading, and mice raised in an artificial 1-gravity environment on the International Space Station. Additionally, 22 proteins, including noncollagenous bone matrix proteins, showed similar abundance between the two groups in the mandible, where bone mass was unaltered due to mastication stimuli, suggesting that these proteins are responsive to mechanical stimuli. One of these proteins, SPARCL1, is suggested to promote osteoclastogenesis induced by receptor activator of nuclear factor-κB ligand. We expect these findings to lead to new insights into the mechanisms of bone metabolism induced by mechanical stimuli. SIGNIFICANCE: We aimed to investigate the gravity-response proteins involved in bone metabolism. To this end, we established a comprehensive analysis system for mouse bone proteins using data-independent acquisition mass spectrometry, which is particularly useful in comprehensively analyzing the bone proteome using small sample volumes. In addition, a comprehensive proteomic analysis of the femoral diaphysis and mandible, which exhibit different degrees of bone loss in mice raised on the International Space Station, identified proteins that respond to mechanical stimuli. SPARCL1, a mechanical stimulus-responsive protein, was consequently suggested to be involved in osteoclast differentiation associated with bone remodeling. Our findings represent an important step toward elucidating the molecular mechanism of bone metabolism induced by mechanical stimuli.
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Affiliation(s)
- Kenji Egashira
- Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan; R&D Headquarters, LION Corporation, Tokyo 132-0035, Japan
| | - Yoko Ino
- Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan
| | - Yusuke Nakai
- Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan
| | - Takashi Ohira
- Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan; Department of Physiology and Regenerative Medicine, Kindai University Faculty of Medicine, Osaka 589-8511, Japan
| | - Tomoko Akiyama
- Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan
| | - Kayano Moriyama
- Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan
| | - Yu Yamamoto
- Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan; R&D Headquarters, LION Corporation, Tokyo 132-0035, Japan
| | - Mitsuo Kimura
- R&D Headquarters, LION Corporation, Tokyo 132-0035, Japan
| | - Akihide Ryo
- Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan
| | - Tomoyuki Saito
- Yokohama Brain and Spine Center, Yokohama 235-0012, Japan
| | - Yutaka Inaba
- Department of Orthopaedic Surgery, Yokohama City University, Yokohama 236-0004, Japan
| | - Hisashi Hirano
- Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan
| | - Ken Kumagai
- Department of Orthopaedic Surgery, Yokohama City University, Yokohama 236-0004, Japan
| | - Yayoi Kimura
- Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan.
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26
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Szwed-Georgiou A, Płociński P, Kupikowska-Stobba B, Urbaniak MM, Rusek-Wala P, Szustakiewicz K, Piszko P, Krupa A, Biernat M, Gazińska M, Kasprzak M, Nawrotek K, Mira NP, Rudnicka K. Bioactive Materials for Bone Regeneration: Biomolecules and Delivery Systems. ACS Biomater Sci Eng 2023; 9:5222-5254. [PMID: 37585562 PMCID: PMC10498424 DOI: 10.1021/acsbiomaterials.3c00609] [Citation(s) in RCA: 73] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 07/31/2023] [Indexed: 08/18/2023]
Abstract
Novel tissue regeneration strategies are constantly being developed worldwide. Research on bone regeneration is noteworthy, as many promising new approaches have been documented with novel strategies currently under investigation. Innovative biomaterials that allow the coordinated and well-controlled repair of bone fractures and bone loss are being designed to reduce the need for autologous or allogeneic bone grafts eventually. The current engineering technologies permit the construction of synthetic, complex, biomimetic biomaterials with properties nearly as good as those of natural bone with good biocompatibility. To ensure that all these requirements meet, bioactive molecules are coupled to structural scaffolding constituents to form a final product with the desired physical, chemical, and biological properties. Bioactive molecules that have been used to promote bone regeneration include protein growth factors, peptides, amino acids, hormones, lipids, and flavonoids. Various strategies have been adapted to investigate the coupling of bioactive molecules with scaffolding materials to sustain activity and allow controlled release. The current manuscript is a thorough survey of the strategies that have been exploited for the delivery of biomolecules for bone regeneration purposes, from choosing the bioactive molecule to selecting the optimal strategy to synthesize the scaffold and assessing the advantages and disadvantages of various delivery strategies.
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Affiliation(s)
- Aleksandra Szwed-Georgiou
- Department
of Immunology and Infectious Biology, Faculty of Biology and Environmental
Protection, University of Lodz, Lodz 90-136, Poland
| | - Przemysław Płociński
- Department
of Immunology and Infectious Biology, Faculty of Biology and Environmental
Protection, University of Lodz, Lodz 90-136, Poland
| | - Barbara Kupikowska-Stobba
- Biomaterials
Research Group, Lukasiewicz Research Network
- Institute of Ceramics and Building Materials, Krakow 31-983, Poland
| | - Mateusz M. Urbaniak
- Department
of Immunology and Infectious Biology, Faculty of Biology and Environmental
Protection, University of Lodz, Lodz 90-136, Poland
- The
Bio-Med-Chem Doctoral School, University of Lodz and Lodz Institutes
of the Polish Academy of Sciences, University
of Lodz, Lodz 90-237, Poland
| | - Paulina Rusek-Wala
- Department
of Immunology and Infectious Biology, Faculty of Biology and Environmental
Protection, University of Lodz, Lodz 90-136, Poland
- The
Bio-Med-Chem Doctoral School, University of Lodz and Lodz Institutes
of the Polish Academy of Sciences, University
of Lodz, Lodz 90-237, Poland
| | - Konrad Szustakiewicz
- Department
of Polymer Engineering and Technology, Faculty of Chemistry, Wroclaw University of Technology, Wroclaw 50-370, Poland
| | - Paweł Piszko
- Department
of Polymer Engineering and Technology, Faculty of Chemistry, Wroclaw University of Technology, Wroclaw 50-370, Poland
| | - Agnieszka Krupa
- Department
of Immunology and Infectious Biology, Faculty of Biology and Environmental
Protection, University of Lodz, Lodz 90-136, Poland
| | - Monika Biernat
- Biomaterials
Research Group, Lukasiewicz Research Network
- Institute of Ceramics and Building Materials, Krakow 31-983, Poland
| | - Małgorzata Gazińska
- Department
of Polymer Engineering and Technology, Faculty of Chemistry, Wroclaw University of Technology, Wroclaw 50-370, Poland
| | - Mirosław Kasprzak
- Biomaterials
Research Group, Lukasiewicz Research Network
- Institute of Ceramics and Building Materials, Krakow 31-983, Poland
| | - Katarzyna Nawrotek
- Faculty
of Process and Environmental Engineering, Lodz University of Technology, Lodz 90-924, Poland
| | - Nuno Pereira Mira
- iBB-Institute
for Bioengineering and Biosciences, Department of Bioengineering, Instituto Superior Técnico, Universidade de
Lisboa, Lisboa 1049-001, Portugal
- Associate
Laboratory i4HB-Institute for Health and Bioeconomy at Instituto Superior
Técnico, Universidade de Lisboa, Lisboa 1049-001, Portugal
- Instituto
Superior Técnico, Universidade de Lisboa, Lisboa 1049-001, Portugal
| | - Karolina Rudnicka
- Department
of Immunology and Infectious Biology, Faculty of Biology and Environmental
Protection, University of Lodz, Lodz 90-136, Poland
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Aghamaliyev U, Su K, Weniger M, Koch D, D'Haese JG, Werner J, Bazhin AV. SPOCK2 gene expression is downregulated in pancreatic ductal adenocarcinoma cells and correlates with prognosis of patients with pancreatic cancer. J Cancer Res Clin Oncol 2023; 149:9191-9200. [PMID: 37188984 PMCID: PMC10374688 DOI: 10.1007/s00432-023-04845-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 05/07/2023] [Indexed: 05/17/2023]
Abstract
OBJECTIVES Pancreatic ductal adenocarcinoma (PDAC) represents a widespread form of malignant pancreatic neoplasms and a leading oncologic cause of death in Europe and the USA. Despite advances in understanding its molecular biology, the 5-year survival rate remains low at 10%. The extracellular matrix in PDAC contains proteins, including SPOCK2, which are essential for tumorigenicity and drug resistance. The present study aims to explore the possible role of SPOCK2 in the pathogenesis of PDAC. MATERIALS AND METHODS Expression of SPOCK2 was evaluated in 7 PDAC cell lines and 1 normal pancreatic cell line using quantitative RT-PCR. Demethylation of the gene was carried out using 5-aza-2'-deoxycytidine (5-aza-dC) treatment with subsequent validation Western Blot analysis. In vitro downregulation of SPOCK2 gene was performed using siRNA transfection. MTT and transwell assays were employed to evaluate the impact of the SPOK2 demethylation on the proliferation and migration of PDAC cells. KM Plotter was applied to analyze a correlation between SPOCK2 mRNA expression and the survival of PDAC patients. RESULTS In contrast to the normal pancreatic cell line, SPOCK2 expression was significantly downregulated in PDAC cell lines. Treatment with 5-aza-dC, led to increase in SPOCK2 expression in the cell lines tested. Importantly, compared with control cells, transfected with SPOCK2 siRNA cells exhibited increased growth rates and more migration ability. Finally, we demonstrated that a high SPOCK2 expression level correlated with longer overall survival of patients with PDAC. CONCLUSION The expression of SPOCK2 is downregulated in PDAC as a result of hypermethylation of its corresponding gene. SPOCK2 expression as well as the demethylation of its gene could be a potential marker for PDAC.
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Affiliation(s)
- Ughur Aghamaliyev
- Department of General, Visceral, and Transplant Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Kaifeng Su
- Department of General, Visceral, and Transplant Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Maximilian Weniger
- Department of General, Visceral, and Transplant Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Dominik Koch
- Department of General, Visceral, and Transplant Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Jan G D'Haese
- Department of General, Visceral, and Transplant Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Bavarian Cancer Research Center (BZKF), Erlangen, Germany
| | - Alexandr V Bazhin
- Department of General, Visceral, and Transplant Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377, Munich, Germany.
- German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Bavarian Cancer Research Center (BZKF), Erlangen, Germany.
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Liu D, Wang L, Hu Z, Ma Z, Yang Q. Association Between SPARC Polymorphisms and Ankylosing Spondylitis and Its mRNA and Protein Expression in a Chinese Han Population: A Case-Control Study. Int J Gen Med 2023; 16:3533-3542. [PMID: 37605781 PMCID: PMC10440112 DOI: 10.2147/ijgm.s419094] [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: 04/27/2023] [Accepted: 08/05/2023] [Indexed: 08/23/2023] Open
Abstract
Objective We explore the association of polymorphisms in Secreted protein acidic and rich in cysteine (SPARC) with ankylosing spondylitis (AS) and detect SPARC mRNA and protein expression in a Chinese Han population. Methods Nine single-nucleotide polymorphisms (SNPs) of SPARC were genotyped in 768 AS patients and 768 controls by TaqMan genotyping assay. mRNA expression of SPARC was detected by real-time polymerase chain reaction (RT-PCR), and serum level of SPARC protein was detected by ELISA. Results The frequency of A allele of rs171121187 was significantly higher in AS patients than in controls (Pc=0.003, odds ratio [OR]=1.45, 95% confidence interval [95% CI] = 1.18-1.77), the AA and AC genotypes increased the risk of AS when compared with CC genotype (Pc=0.003, OR=3.96, 95% CI=1.80-8.75, and Pc=0.003, OR=1.27, 95% CI=1.01-1.61, respectively). The frequency of G allele of rs4958487 was significantly lower in AS than in controls (Pc=0.001, OR=0.60, 95% CI=0.47-0.68), the GG and GA genotypes reduced the risk of AS when compared with AA genotype (Pc=0.005, OR=0.46, 95% CI 0.18-1.14, and Pc=0.005, OR=0.60, 95% CI=0.45-0.79, respectively). The haplotype AA of rs17112187/rs4958487 significantly increased the risk of AS (P=2.31E-5, OR=1.60, 95% CI=1.28-1.98), while haplotype CG decreased the risk of AS (P=5.42E-5, OR=0.55, 95% CI=0.41-0.74). Expression levels of SPARC mRNA were significantly lower in both Peripheral blood mononuclear cells (PBMC) and granulocytes in AS patients than in controls (P=0.008 and P=0.005, respectively). SPARC protein levels were also reduced in AS patients versus the controls (P=0.002). Conclusion This study indicates that polymorphisms in SPARC are associated with AS susceptibility, and both mRNA and protein levels of SPARC are decreased in AS patients in a Chinese Han population.
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Affiliation(s)
- Dongxia Liu
- Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, People’s Republic of China
| | - Liya Wang
- Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, People’s Republic of China
- Department of Rheumatology and Immunology, Heze Medical College, Heze, 274000, People’s Republic of China
| | - Zhongdan Hu
- Tianjin Zhonghe Clinic Co. Ltd. of Heping District, Tianjin, 300450, People’s Republic of China
| | - Zhenzhen Ma
- Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, People’s Republic of China
| | - Qingrui Yang
- Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, People’s Republic of China
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DeGroot MS, Williams B, Chang TY, Maas Gamboa ML, Larus IM, Hong G, Fromme JC, Liu J. SMOC-1 interacts with both BMP and glypican to regulate BMP signaling in C. elegans. PLoS Biol 2023; 21:e3002272. [PMID: 37590248 PMCID: PMC10464977 DOI: 10.1371/journal.pbio.3002272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 08/29/2023] [Accepted: 07/22/2023] [Indexed: 08/19/2023] Open
Abstract
Secreted modular calcium-binding proteins (SMOCs) are conserved matricellular proteins found in organisms from Caenorhabditis elegans to humans. SMOC homologs characteristically contain 1 or 2 extracellular calcium-binding (EC) domain(s) and 1 or 2 thyroglobulin type-1 (TY) domain(s). SMOC proteins in Drosophila and Xenopus have been found to interact with cell surface heparan sulfate proteoglycans (HSPGs) to exert both positive and negative influences on the conserved bone morphogenetic protein (BMP) signaling pathway. In this study, we used a combination of biochemical, structural modeling, and molecular genetic approaches to dissect the functions of the sole SMOC protein in C. elegans. We showed that CeSMOC-1 binds to the heparin sulfate proteoglycan GPC3 homolog LON-2/glypican, as well as the mature domain of the BMP2/4 homolog DBL-1. Moreover, CeSMOC-1 can simultaneously bind LON-2/glypican and DBL-1/BMP. The interaction between CeSMOC-1 and LON-2/glypican is mediated specifically by the EC domain of CeSMOC-1, while the full interaction between CeSMOC-1 and DBL-1/BMP requires full-length CeSMOC-1. We provide both in vitro biochemical and in vivo functional evidence demonstrating that CeSMOC-1 functions both negatively in a LON-2/glypican-dependent manner and positively in a DBL-1/BMP-dependent manner to regulate BMP signaling. We further showed that in silico, Drosophila and vertebrate SMOC proteins can also bind to mature BMP dimers. Our work provides a mechanistic basis for how the evolutionarily conserved SMOC proteins regulate BMP signaling.
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Affiliation(s)
- Melisa S. DeGroot
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America
| | - Byron Williams
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America
| | - Timothy Y. Chang
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America
| | - Maria L. Maas Gamboa
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America
| | - Isabel M. Larus
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America
| | - Garam Hong
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America
| | - J. Christopher Fromme
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America
| | - Jun Liu
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America
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Jiang S, Sun HF, Li S, Zhang N, Chen JS, Liu JX. SPARC: a potential target for functional nanomaterials and drugs. Front Mol Biosci 2023; 10:1235428. [PMID: 37577749 PMCID: PMC10419254 DOI: 10.3389/fmolb.2023.1235428] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 07/13/2023] [Indexed: 08/15/2023] Open
Abstract
Secreted protein acidic and rich in cysteine (SPARC), also termed osteonectin or BM-40, is a matricellular protein which regulates cell adhesion, extracellular matrix production, growth factor activity, and cell cycle. Although SPARC does not perform a structural function, it, however, modulates interactions between cells and the surrounding extracellular matrix due to its anti-proliferative and anti-adhesion properties. The overexpression of SPARC at sites, including injury, regeneration, obesity, cancer, and inflammation, reveals its application as a prospective target and therapeutic indicator in the treatment and assessment of disease. This article comprehensively summarizes the mechanism of SPARC overexpression in inflammation and tumors as well as the latest research progress of functional nanomaterials in the therapy of rheumatoid arthritis and tumors by manipulating SPARC as a new target. This article provides ideas for using functional nanomaterials to treat inflammatory diseases through the SPARC target. The purpose of this article is to provide a reference for ongoing disease research based on SPARC-targeted therapy.
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Affiliation(s)
- Shan Jiang
- School of Pharmacy, Heilongjiang University of Traditional Chinese Medicine, Harbin, China
- School of Pharmaceutical Sciences, Department of Rehabilitation and Healthcare, Hunan University of Medicine, Huaihua, China
| | - Hui-Feng Sun
- School of Pharmacy, Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Shuang Li
- School of Pharmaceutical Sciences, Department of Rehabilitation and Healthcare, Hunan University of Medicine, Huaihua, China
- College Pharmacy, Jiamusi University, Jiamusi, China
| | - Ning Zhang
- School of Pharmacy, Heilongjiang University of Traditional Chinese Medicine, Harbin, China
- School of Pharmaceutical Sciences, Department of Rehabilitation and Healthcare, Hunan University of Medicine, Huaihua, China
| | - Ji-Song Chen
- School of Pharmaceutical Sciences, Department of Rehabilitation and Healthcare, Hunan University of Medicine, Huaihua, China
| | - Jian-Xin Liu
- School of Pharmaceutical Sciences, Department of Rehabilitation and Healthcare, Hunan University of Medicine, Huaihua, China
- School of Pharmaceutical Sciences, University of South China, Hengyang, China
- Institute of Innovation and Applied Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
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Kałuzińska-Kołat Ż, Kołat D, Kośla K, Płuciennik E, Bednarek AK. Delineating the glioblastoma stemness by genes involved in cytoskeletal rearrangements and metabolic alterations. World J Stem Cells 2023; 15:302-322. [PMID: 37342224 PMCID: PMC10277965 DOI: 10.4252/wjsc.v15.i5.302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 02/03/2023] [Accepted: 03/08/2023] [Indexed: 05/26/2023] Open
Abstract
Literature data on glioblastoma ongoingly underline the link between metabolism and cancer stemness, the latter is one responsible for potentiating the resistance to treatment, inter alia due to increased invasiveness. In recent years, glioblastoma stemness research has bashfully introduced a key aspect of cytoskeletal rearrangements, whereas the impact of the cytoskeleton on invasiveness is well known. Although non-stem glioblastoma cells are less invasive than glioblastoma stem cells (GSCs), these cells also acquire stemness with greater ease if characterized as invasive cells and not tumor core cells. This suggests that glioblastoma stemness should be further investigated for any phenomena related to the cytoskeleton and metabolism, as they may provide new invasion-related insights. Previously, we proved that interplay between metabolism and cytoskeleton existed in glioblastoma. Despite searching for cytoskeleton-related processes in which the investigated genes might have been involved, not only did we stumble across the relation to metabolism but also reported genes that were found to be implicated in stemness. Thus, dedicated research on these genes in GSCs seems justifiable and might reveal novel directions and/or biomarkers that could be utilized in the future. Herein, we review the previously identified cytoskeleton/metabolism-related genes through the prism of glioblastoma stemness.
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Affiliation(s)
- Żaneta Kałuzińska-Kołat
- Department of Experimental Surgery, Medical University of Lodz, Lodz 90-136, Lodzkie, Poland
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland.
| | - Damian Kołat
- Department of Experimental Surgery, Medical University of Lodz, Lodz 90-136, Lodzkie, Poland
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
| | - Katarzyna Kośla
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
| | - Elżbieta Płuciennik
- Department of Functional Genomics, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
| | - Andrzej K Bednarek
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
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Cheng X, Chen X, Zhang M, Wan Y, Ge S, Cheng X. Sparcl1 and Atherosclerosis. J Inflamm Res 2023; 16:2121-2127. [PMID: 37220502 PMCID: PMC10200116 DOI: 10.2147/jir.s406907] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 05/03/2023] [Indexed: 05/25/2023] Open
Abstract
Atherosclerosis and its complications constitute some of the major diseases affecting humans worldwide. A core component of atherogenesis is endothelial cell damage and dysfunction, which also includes factors such as adhesion and proliferation of various cells. Multiple studies have shown that atherosclerosis and cancer share a common pathophysiological process and exhibit a degree of similarity. Sparcl-1 is a cysteine-rich secretory stromal cell protein present in the extracellular matrix and belongs to the Sparc family of proteins. Its role in tumor development has been widely investigated; however, its role in cardiovascular diseases has rarely been studied. Sparcl-1 is considered an oncogene correlated with the regulation of cell adhesion, migration, and proliferation and is also related to blood vessel integrity. In this review, the potential link between Sparcl-1 and atherosclerosis development is investigated, and recommendations on future research on the role of Sparcl-1 in atherogenesis are provided.
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Affiliation(s)
- Xu Cheng
- Department of Cardiovascular Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China
- Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China
| | - Xinyan Chen
- Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China
- Department of Clinical Laboratory, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China
| | - Min Zhang
- Department of Clinical Laboratory, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China
| | - Yufeng Wan
- Department of Otolaryngology-Head Neck Surgery, the Affiliated Chaohu Hospital of Anhui Medical University, Hefei, Anhui, 238001, People’s Republic of China
| | - Shenglin Ge
- Department of Cardiovascular Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China
| | - Xiaowen Cheng
- Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China
- Department of Clinical Laboratory, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China
- Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical College, Bengbu, Anhui, 233030, People’s Republic of China
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Nakajima H, Kawakita F, Oinaka H, Suzuki Y, Nampei M, Kitano Y, Nishikawa H, Fujimoto M, Miura Y, Yasuda R, Toma N, Suzuki H. Plasma SPARC Elevation in Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage. Neurotherapeutics 2023; 20:779-788. [PMID: 36781745 PMCID: PMC10275842 DOI: 10.1007/s13311-023-01351-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/30/2023] [Indexed: 02/15/2023] Open
Abstract
Matricellular proteins have been implicated in pathologies after subarachnoid hemorrhage (SAH). To find a new therapeutic molecular target, the present study aimed to clarify the relationships between serially measured plasma levels of a matricellular protein, secreted protein acidic and rich in cysteine (SPARC), and delayed cerebral ischemia (DCI) in 117 consecutive aneurysmal SAH patients with admission World Federation of Neurological Surgeons (WFNS) grades I-III. DCI developed in 25 patients with higher incidences of past history of hypertension and dyslipidemia, preoperative WFNS grade III, modified Fisher grade 4, spinal drainage, and angiographic vasospasm. Plasma SPARC levels were increased after SAH, and significantly higher in patients with than without DCI at days 7-9, and in patients with VASOGRADE-Yellow compared with VASOGRADE-Green at days 1-3 and 7-9. However, there were no relationships between plasma SPARC levels and angiographic vasospasm. Receiver-operating characteristic curves differentiating DCI from no DCI determined the cut-off value of plasma SPARC ≥ 82.1 ng/ml at days 7 - 9 (sensitivity, 0.800; specificity, 0.533; and area under the curve, 0.708), which was found to be an independent determinant of DCI development in multivariate analyses. This is the first study to show that SPARC is upregulated in peripheral blood after SAH, and that SPARC may be involved in the development of DCI without angiographic vasospasm in a clinical setting.
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Affiliation(s)
- Hideki Nakajima
- Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Fumihiro Kawakita
- Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Hiroki Oinaka
- Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Yume Suzuki
- Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Mai Nampei
- Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Yotaro Kitano
- Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Hirofumi Nishikawa
- Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Masashi Fujimoto
- Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Yoichi Miura
- Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Ryuta Yasuda
- Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Naoki Toma
- Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Hidenori Suzuki
- Department of Neurosurgery, Mie University Graduate School of Medicine, Tsu, Japan.
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Váncza L, Horváth A, Seungyeon L, Rókusz A, Dezső K, Reszegi A, Petővári G, Götte M, Kovalszky I, Baghy K. SPOCK1 Overexpression Suggests Poor Prognosis of Ovarian Cancer. Cancers (Basel) 2023; 15:cancers15072037. [PMID: 37046698 PMCID: PMC10093273 DOI: 10.3390/cancers15072037] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/20/2023] [Accepted: 03/26/2023] [Indexed: 04/03/2023] Open
Abstract
Purpose: Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1) has been found in a variety of malignant tumors and is associated with a poor prognosis. We aimed to explore the role of SPOCK1 in ovarian cancer. Methods: Ovarian cancer cell lines SKOV3 and SW626 were transfected with SPOCK1 overexpressing or empty vector using electroporation. Cells were studied by immunostaining and an automated Western blotting system. BrdU uptake and wound healing assays assessed cell proliferation and migration. SPOCK1 expression in human ovarian cancer tissues and in blood samples were studied by immunostaining and ELISA. Survival of patients with tumors exhibiting low and high SPOCK1 expression was analyzed using online tools. Results: Both transfected cell lines synthesized different SPOCK1 variants; SKOV3 cells also secreted the proteoglycan. SPOCK1 overexpression stimulated DNA synthesis and cell migration involving p21CIP1. Ovarian cancer patients had increased SPOCK1 serum levels compared to healthy controls. Tumor cells of tissues also displayed abundant SPOCK1. Moreover, SPOCK1 levels were higher in untreated ovarian cancer serum and tissue samples and lower in recipients of chemotherapy. According to in silico analyses, high SPOCK1 expression was correlated with shorter survival. Conclusion: Our findings suggest SPOCK1 may be a viable anti-tumor therapeutic target and could be used for monitoring ovarian cancer.
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Tumor decellularization reveals proteomic and mechanical characteristics of the extracellular matrix of primary liver cancer. BIOMATERIALS ADVANCES 2023; 146:213289. [PMID: 36724550 DOI: 10.1016/j.bioadv.2023.213289] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 01/09/2023] [Accepted: 01/10/2023] [Indexed: 01/19/2023]
Abstract
Tumor initiation and progression are critically dependent on interaction of cancer cells with their cellular and extracellular microenvironment. Alterations in the composition, integrity, and mechanical properties of the extracellular matrix (ECM) dictate tumor processes including cell proliferation, migration, and invasion. Also in primary liver cancer, consisting of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), the dysregulation of the extracellular environment by liver fibrosis and tumor desmoplasia is pertinent. Yet, the exact changes occurring in liver cancer ECM remain uncharacterized and underlying tumor-promoting mechanisms remain largely unknown. Herein, an integrative molecular and mechanical approach is used to extensively characterize the ECM of HCC and CCA tumors by utilizing an optimized decellularization technique. We identified a myriad of proteins in both tumor and adjacent liver tissue, uncovering distinct malignancy-related ECM signatures. The resolution of this approach unveiled additional ECM-related proteins compared to large liver cancer transcriptomic datasets. The differences in ECM protein composition resulted in divergent mechanical properties on a macro- and micro-scale that are tumor-type specific. Furthermore, the decellularized tumor ECM was employed to create a tumor-specific hydrogel that supports patient-derived tumor organoids, which provides a new avenue for personalized medicine applications. Taken together, this study contributes to a better understanding of alterations to composition, stiffness, and collagen alignment of the tumor ECM that occur during liver cancer development.
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Dang X, Fang L, Zhang Q, Liu B, Cheng JC, Sun YP. AREG upregulates secreted protein acidic and rich in cysteine expression in human granulosa cells. Mol Cell Endocrinol 2023; 561:111826. [PMID: 36462647 DOI: 10.1016/j.mce.2022.111826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 11/22/2022] [Accepted: 11/27/2022] [Indexed: 12/02/2022]
Abstract
The secreted protein acidic and rich in cysteine (SPARC) is a secreted glycoprotein and the expression of ovarian SPARC peaks during ovulation and luteinization. Besides, SPARC expression was induced by human chorionic gonadotropin (hCG) in rat granulosa cells. Amphiregulin (AREG) is the most abundant epidermal growth factor receptor (EGFR) ligand expressed in human granulosa cells and follicular fluid. AREG mediates the physiological functions of luteinizing hormone (LH)/hCG in the ovary. However, to date, the biological function of SPARC in the human ovary remains undetermined, and whether AREG regulates SPARC expression in human granulosa cells is unknown. In this study, we show that AREG upregulated SPARC expression via EGFR in a human granulosa-like tumor cell line, KGN. Treatment of AREG activated ERK1/2, JNK, p38 MAPK, and PI3K/AKT signaling pathways and all of them were required for the AREG-induced SPARC expression. Using RNA-sequencing, we identified that steroidogenic acute regulatory protein (StAR) was a downstream target gene of SPARC. In addition, we demonstrated that SPARC mRNA levels were positively correlated with the levels of StAR mRNA in the primary culture of human granulosa cells. Moreover, SPARC protein levels were positively correlated with progesterone levels in follicular fluid of in vitro fertilization patients. This study provides the regulatory role of AREG on the expression of SPARC and reveals the novel function of SPARC in progesterone production in granulosa cells.
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Affiliation(s)
- Xuan Dang
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Lanlan Fang
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
| | - Qian Zhang
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Boqun Liu
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jung-Chien Cheng
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Ying-Pu Sun
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
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Lin YW, Wen YC, Hsiao CH, Lai FR, Yang SF, Yang YC, Ho KH, Hsieh FK, Hsiao M, Lee WJ, Chien MH. Proteoglycan SPOCK1 as a Poor Prognostic Marker Promotes Malignant Progression of Clear Cell Renal Cell Carcinoma via Triggering the Snail/Slug-MMP-2 Axis-Mediated Epithelial-to-Mesenchymal Transition. Cells 2023; 12:cells12030352. [PMID: 36766694 PMCID: PMC9913795 DOI: 10.3390/cells12030352] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/12/2023] [Accepted: 01/13/2023] [Indexed: 01/19/2023] Open
Abstract
Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1) has been reported to play an oncogenic role in certain cancer types; however, the role of SPOCK1 in the progression of clear cell renal cell carcinoma (ccRCC) remains elusive. Here, higher SPOCK1 transcript and protein levels were observed in ccRCC tissues compared to normal tissues and correlated with advanced clinical stages, larger tumor sizes, and lymph node and distal metastases. Knockdown and overexpression of SPOCK1 in ccRCC cells led to decreased and increased cell clonogenic and migratory/invasive abilities in vitro as well as lower and higher tumor growth and invasion in vivo, respectively. Mechanistically, the gene set enrichment analysis (GSEA) database was used to identify the gene set of epithelial-to-mesenchymal transition (EMT) pathways enriched in ccRCC samples with high SPOCK1 expression. Further mechanistic investigations revealed that SPOCK1 triggered the Snail/Slug-matrix metalloproteinase (MMP)-2 axis to promote EMT and cell motility. Clinical ccRCC samples revealed SPOCK1 to be an independent prognostic factor for overall survival (OS), and positive correlations of SPOCK1 with MMP-2 and mesenchymal-related gene expression levels were found. We observed that patients with SPOCK1high/MMP2high tumors had the shortest OS times compared to others. In conclusion, our findings reveal that SPOCK1 can serve as a useful biomarker for predicting ccRCC progression and prognosis, and as a promising target for treating ccRCC.
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Affiliation(s)
- Yung-Wei Lin
- International Master/Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Department of Urology, School of Medicine, College of Medicine and TMU Research Center of Urology and Kidney (TMU-RCUK), Taipei Medical University, Taipei 11031, Taiwan
- Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
| | - Yu-Ching Wen
- Department of Urology, School of Medicine, College of Medicine and TMU Research Center of Urology and Kidney (TMU-RCUK), Taipei Medical University, Taipei 11031, Taiwan
- Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
| | - Chi-Hao Hsiao
- Department of Urology, School of Medicine, College of Medicine and TMU Research Center of Urology and Kidney (TMU-RCUK), Taipei Medical University, Taipei 11031, Taiwan
- Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
| | - Feng-Ru Lai
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung 404, Taiwan
| | - Yi-Chieh Yang
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Department of Medical Research, Tungs’ Taichung MetroHarbor Hospital, Taichung 435403, Taiwan
| | - Kuo-Hao Ho
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Feng-Koo Hsieh
- The Genome Engineering & Stem Cell Center, School of Medicine, Washington University, St. Louis, MO 63105, USA
| | - Michael Hsiao
- The Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan
| | - Wei-Jiunn Lee
- Department of Urology, School of Medicine, College of Medicine and TMU Research Center of Urology and Kidney (TMU-RCUK), Taipei Medical University, Taipei 11031, Taiwan
- 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: (W.-J.L.); (M.-H.C.); Tel.: +886-2-27-361-661 (ext. 3237) (M.-H.C.); Fax: +886-2-27-390-500 (M.-H.C.)
| | - Ming-Hsien Chien
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
- Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei 110301, Taiwan
- Correspondence: (W.-J.L.); (M.-H.C.); Tel.: +886-2-27-361-661 (ext. 3237) (M.-H.C.); Fax: +886-2-27-390-500 (M.-H.C.)
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DeGroot MS, Williams B, Chang TY, Maas Gamboa ML, Larus I, Fromme JC, Liu J. C. elegans SMOC-1 interacts with both BMP and glypican to regulate BMP signaling. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.06.523017. [PMID: 36711863 PMCID: PMC9881921 DOI: 10.1101/2023.01.06.523017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Secreted modular calcium binding (SMOC) proteins are conserved matricellular proteins found in organisms from C. elegans to humans. SMOC homologs characteristically contain one or two extracellular calcium (EC) binding domain(s) and one or two thyroglobulin type-1 (TY) domain(s). SMOC proteins in Drosophila and Xenopus have been found to interact with cell surface heparan sulfate protein glycans (HSPGs) to exert both positive and negative influences on the conserved bone morphogenetic protein (BMP) signaling pathway. In this study, we used a combination of biochemical, structural modeling, and molecular genetic approaches to dissect the functions of the sole SMOC protein in C. elegans . We showed that SMOC-1 binds LON-2/glypican, as well as the mature domain of DBL-1/BMP. Moreover, SMOC-1 can simultaneously bind LON-2/glypican and DBL-1/BMP. The interaction between SMOC-1 and LON-2/glypican is mediated by the EC domain of SMOC-1, while the interaction between SMOC-1 and DBL-1/BMP involves full-length SMOC-1. We further showed that while SMOC-1(EC) is sufficient to promote BMP signaling when overexpressed, both the EC and TY domains are required for SMOC-1 function at the endogenous locus. Finally, when overexpressed, SMOC-1 can promote BMP signaling in the absence of LON-2/glypican. Taken together, our findings led to a model where SMOC-1 functions both negatively in a LON-2-dependent manner and positively in a LON-2-independent manner to regulate BMP signaling. Our work provides a mechanistic basis for how the evolutionarily conserved SMOC proteins regulate BMP signaling.
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Affiliation(s)
- Melisa S. DeGroot
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853
| | - Byron Williams
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853
| | - Timothy Y Chang
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853
| | - Maria L. Maas Gamboa
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853
| | - Isabel Larus
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853
| | | | - Jun Liu
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853
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Feldt J, Garriz A, Rodriguez Benavente MC, Woodward AM, Zoukhri D, Argüeso P. The Matricellular Protein SPARC Decreases in the Lacrimal Gland At Adulthood and During Inflammation. Invest Ophthalmol Vis Sci 2022; 63:8. [PMID: 36479944 PMCID: PMC9742964 DOI: 10.1167/iovs.63.13.8] [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] [Indexed: 12/13/2022] Open
Abstract
Purpose Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein abundantly expressed in basement membranes and capsules surrounding a variety of organs and tissues. It mediates extracellular matrix organization and has been implicated in cell contraction. Here, we evaluated the expression of SPARC in the murine lacrimal gland at adulthood and during inflammation. Methods Lacrimal glands of young mice (4-6 weeks old) and adult mice (32-40 weeks old) were used for extraction of DNA, RNA, and protein. The presence of SPARC was assessed by quantitative PCR, ELISA, and immunofluorescence microscopy. 5-Methylcytosine and DNA methylation were evaluated using ELISA and bisulfite genomic sequencing, respectively. The effects of cytokines and inflammation in Sparc expression were evaluated in vitro and in the non-obese diabetic (NOD) mouse model of Sjögren's syndrome. Results The mRNA and protein levels of SPARC were downregulated in lacrimal glands of mature adult mice presenting age-related histological alterations such as increased deposition of lipofuscin and lipids. Epigenetic analyses indicated that glands in adult mice contain higher levels of global DNA methylation and show increased hypermethylation of specific CpG sites within the Sparc gene promoter. Analysis of smooth muscle actin (SMA)-green fluorescent protein (GFP) transgenic mice revealed that SPARC localizes primarily to myoepithelial cells within the gland. Treatment of myoepithelial cells with IL-1β or TNF-α and the development of inflammation in the NOD mice led to decreased transcription of Sparc. Conclusions SPARC is a novel matricellular glycoprotein expressed by myoepithelial cells in the lacrimal gland. Loss of SPARC during adulthood and chronic inflammation might have detrimental consequences on myoepithelial cell contraction and the secretion of tear fluid.
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Affiliation(s)
- Jessica Feldt
- Schepens Eye Research Institute, Mass. Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
| | - Angela Garriz
- Department of Comprehensive Care, Tufts University School of Dental Medicine, Boston, Massachusetts, United States
| | - Maria C. Rodriguez Benavente
- Schepens Eye Research Institute, Mass. Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
| | - Ashley M. Woodward
- Schepens Eye Research Institute, Mass. Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
| | - Driss Zoukhri
- Department of Comprehensive Care, Tufts University School of Dental Medicine, Boston, Massachusetts, United States,Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts, United States
| | - Pablo Argüeso
- Schepens Eye Research Institute, Mass. Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
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Cárdenas-León CG, Mäemets-Allas K, Klaas M, Lagus H, Kankuri E, Jaks V. Matricellular proteins in cutaneous wound healing. Front Cell Dev Biol 2022; 10:1073320. [PMID: 36506087 PMCID: PMC9730256 DOI: 10.3389/fcell.2022.1073320] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 11/14/2022] [Indexed: 11/25/2022] Open
Abstract
Cutaneous wound healing is a complex process that encompasses alterations in all aspects of the skin including the extracellular matrix (ECM). ECM consist of large structural proteins such as collagens and elastin as well as smaller proteins with mainly regulative properties called matricellular proteins. Matricellular proteins bind to structural proteins and their functions include but are not limited to interaction with cell surface receptors, cytokines, or protease and evoking a cellular response. The signaling initiated by matricellular proteins modulates differentiation and proliferation of cells having an impact on the tissue regeneration. In this review we give an overview of the matricellular proteins that have been found to be involved in cutaneous wound healing and summarize the information known to date about their functions in this process.
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Affiliation(s)
| | - Kristina Mäemets-Allas
- Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
| | - Mariliis Klaas
- Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
| | - Heli Lagus
- Department of Plastic Surgery and Wound Healing Centre, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Esko Kankuri
- Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Viljar Jaks
- Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia,Dermatology Clinic, Tartu University Clinics, Tartu, Estonia,*Correspondence: Viljar Jaks,
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Horak M, Fairweather D, Kokkonen P, Bednar D, Bienertova-Vasku J. Follistatin-like 1 and its paralogs in heart development and cardiovascular disease. Heart Fail Rev 2022; 27:2251-2265. [PMID: 35867287 PMCID: PMC11140762 DOI: 10.1007/s10741-022-10262-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/10/2022] [Indexed: 11/29/2022]
Abstract
Cardiovascular diseases (CVDs) are a group of disorders affecting the heart and blood vessels and a leading cause of death worldwide. Thus, there is a need to identify new cardiokines that may protect the heart from damage as reported in GBD 2017 Causes of Death Collaborators (2018) (The Lancet 392:1736-1788). Follistatin-like 1 (FSTL1) is a cardiokine that is highly expressed in the heart and released to the serum after cardiac injury where it is associated with CVD and predicts poor outcome. The action of FSTL1 likely depends not only on the tissue source but also post-translation modifications that are target tissue- and cell-specific. Animal studies examining the effect of FSTL1 in various models of heart disease have exploded over the past 15 years and primarily report a protective effect spanning from inhibiting inflammation via transforming growth factor, preventing remodeling and fibrosis to promoting angiogenesis and hypertrophy. A better understanding of FSTL1 and its homologs is needed to determine whether this protein could be a useful novel biomarker to predict poor outcome and death and whether it has therapeutic potential. The aim of this review is to provide a comprehensive description of the literature for this family of proteins in order to better understand their role in normal physiology and CVD.
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Affiliation(s)
- Martin Horak
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic
- Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic
| | - DeLisa Fairweather
- Department of Cardiovascular Medicine, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
| | - Piia Kokkonen
- Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic
| | - David Bednar
- Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic
| | - Julie Bienertova-Vasku
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic.
- Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic.
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Wang W, Zhu T, Wan P, Wei Q, He J, Lai F, Fu Q. SPARC plays an important role in the oviposition and nymphal development in Nilaparvata lugens Stål. BMC Genomics 2022; 23:682. [PMID: 36192692 PMCID: PMC9531499 DOI: 10.1186/s12864-022-08903-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 09/22/2022] [Indexed: 11/10/2022] Open
Abstract
Background The brown planthopper (Nilaparvata lugens Stål)is a notorious rice pest in many areas of Asia. Study on the molecular mechanisms underlying its development and reproduction will provide scientific basis for effective control. SPARC (Secreted Protein, Acidic and Rich in Cysteine) is one of structural component of the extracellular matrix, which influences a diverse array of biological functions. In this study, the gene for SPARC was identified and functionally analysed from N.lugens. Results The result showed that the NlSPARC mRNA was highly expressed in fat body, hemolymph and early embryo. The mortality increased significantly when NlSPARC was downregulated after RNA interference (RNAi) in 3 ~ 4th instar nymphs. Downregulation of NlSPARC in adults significantly reduced the number of eggs and offspring, as well as the transcription level of NlSPARC in newly hatched nymphs and survival rate in progeny. The observation with microanatomy on individuals after NlSPARC RNAi showed smaller and less abundant fat body than that in control. No obvious morphological abnormalities in the nymphal development and no differences in development of internal reproductive organ were observed when compared with control. Conclusion NlSPARC is required for oviposition and nymphal development mainly through regulating the tissue of fat body in N.lugens. NlSPARC could be a new candidate target for controlling the rapid propagation of N.lugens population. Our results also demonstrated that the effect of NlSPARC RNAi can transfer to the next generation in N.lugens. Supplementary Information The online version contains supplementary material available at 10.1186/s12864-022-08903-z.
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Affiliation(s)
- Weixia Wang
- State Key Laboratory of Rice Biology, China National Rice Research Institute, Hangzhou, 310006, China
| | - Tingheng Zhu
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, China.
| | - Pinjun Wan
- State Key Laboratory of Rice Biology, China National Rice Research Institute, Hangzhou, 310006, China
| | - Qi Wei
- State Key Laboratory of Rice Biology, China National Rice Research Institute, Hangzhou, 310006, China
| | - Jiachun He
- State Key Laboratory of Rice Biology, China National Rice Research Institute, Hangzhou, 310006, China
| | - Fengxiang Lai
- State Key Laboratory of Rice Biology, China National Rice Research Institute, Hangzhou, 310006, China
| | - Qiang Fu
- State Key Laboratory of Rice Biology, China National Rice Research Institute, Hangzhou, 310006, China.
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Jiao M, Sun W, Li L, Li C, Zhou J, Li Q, Duan L. Clinical significance of SPOCK2 expression signature for high-grade serous ovarian cancer patients. Front Genet 2022; 13:878123. [PMID: 36246613 PMCID: PMC9554533 DOI: 10.3389/fgene.2022.878123] [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: 02/17/2022] [Accepted: 09/05/2022] [Indexed: 11/19/2022] Open
Abstract
Background: SPOCK2 is a member of the SPOCK family, a 424-amino acid protein that binds to glycosaminoglycans to form proteoglycans. The purpose of this study was to explore expression profile of SPOCK2, and evaluate prognostic potential and its correlation with immune infiltration in high-grade serous ovarian cancer (HGSOC). Methods: Expression of SPOCK2 mRNA and protein between normal and tumor tissues were analyzed using the Cancer Genome Atlas database (TCGA), Gene Expression Omnibus (GEO), Clinical Proteomic Tumor Analysis Consortium (CPTAC), and the Human Protein Atlas (HPA) databases. Receiver operating characteristic (ROC) curve was used to evaluate diagnostic performance of SPOCK2. Kaplan-Meier method and Cox regression analysis were conducted to assess the effect of SPOCK2 on survival. Nomogram was used to predict the impact of SPOCK2 on prognosis. LinkedOmics were used to find correlated genes and perform functional enrichment analyses. The relationships between SPOCK2 and tumor infiltrating lymphocytes (TILs) were determined by tumor-immune system interaction database (TISIDB) and GSVA package (V1.34.0). Results: SPOCK2 was highly expressed in HGSOC tissue compared to normal tissue at both mRNA (p < 0.001) and protein (p = 0.03) levels. The area under the curve (AUC) is 0.894 (CI: 0.865–0.923). Kaplan-Meier analysis showed that HGSOC patients with high-level SPOCK2 mRNA expression had a worse overall survival (OS) than those with a low expression (HR = 1.45, p = 0.005). Univariate logistic regression analysis found that age, primary therapy outcome, tumor status, tumor residual, and SPOCK2 expression level were significantly associated with OS (p < 0.05). The nomogram model indicated an effective predictive performance of SPOCK2. Kyoto encyclopedia of genes and genomes (KEGG) and gene ontology (GO) term analyses showed that SPOCK2 were mainly involved in regulating extracellular matrix. Immune infiltration analysis showed that SPOCK2 may correlate with abundance of TILs. Conclusion: SPOCK2 has potentials to estimate diagnosis and prognosis for HGSOC and is involved in regulating extracellular matrix and immune cell infiltration.
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Affiliation(s)
- Mi Jiao
- Xi’an Jiaotong University Health Science Center, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Department of Medical Oncology, Shaanxi Provincial Cancer Hospital Affiliated to Xi’an Jiaotong University Medical College, Xi’an, Shaanxi, China
| | - Wenbo Sun
- Department of Medical Oncology, Shaanxi Provincial Cancer Hospital Affiliated to Xi’an Jiaotong University Medical College, Xi’an, Shaanxi, China
| | - Lina Li
- Department of Medical Oncology, Shaanxi Provincial Cancer Hospital Affiliated to Xi’an Jiaotong University Medical College, Xi’an, Shaanxi, China
| | - Chunyan Li
- Department of Medical Oncology, Shaanxi Provincial Cancer Hospital Affiliated to Xi’an Jiaotong University Medical College, Xi’an, Shaanxi, China
| | - Jing Zhou
- Department of Medical Oncology, Shaanxi Provincial Cancer Hospital Affiliated to Xi’an Jiaotong University Medical College, Xi’an, Shaanxi, China
| | - Qian Li
- Department of Medical Oncology, Shaanxi Provincial Cancer Hospital Affiliated to Xi’an Jiaotong University Medical College, Xi’an, Shaanxi, China
| | - Lian Duan
- Xi’an Jiaotong University Health Science Center, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- *Correspondence: Lian Duan,
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The potential applications of microparticles in the diagnosis, treatment, and prognosis of lung cancer. Lab Invest 2022; 20:404. [PMID: 36064415 PMCID: PMC9444106 DOI: 10.1186/s12967-022-03599-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 08/18/2022] [Indexed: 12/02/2022]
Abstract
Microparticles (MPs) are 100–1000 nm heterogeneous submicron membranous vesicles derived from various cell types that express surface proteins and antigenic profiles suggestive of their cellular origin. MPs contain a diverse array of bioactive chemicals and surface receptors, including lipids, nucleic acids, and proteins, which are essential for cell-to-cell communication. The tumour microenvironment (TME) is enriched with MPs that can directly affect tumour progression through their interactions with receptors. Liquid biopsy, a minimally invasive test, is a promising alternative to tissue biopsy for the early screening of lung cancer (LC). The diverse biomolecular information from MPs provides a number of potential biomarkers for LC risk assessment, early detection, diagnosis, prognosis, and surveillance. Remodelling the TME, which profoundly influences immunotherapy and clinical outcomes, is an emerging strategy to improve immunotherapy. Tumour-derived MPs can reverse drug resistance and are ideal candidates for the creation of innovative and effective cancer vaccines. This review described the biogenesis and components of MPs and further summarised their main isolation and quantification methods. More importantly, the review presented the clinical application of MPs as predictive biomarkers in cancer diagnosis and prognosis, their role as therapeutic drug carriers, particularly in anti-tumour drug resistance, and their utility as cancer vaccines. Finally, we discussed current challenges that could impede the clinical use of MPs and determined that further studies on the functional roles of MPs in LC are required.
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Downregulation of Sparc-like protein 1 during cisplatin-induced inhibition of myogenic differentiation of C2C12 myoblasts. Biochem Pharmacol 2022; 204:115234. [PMID: 36041542 DOI: 10.1016/j.bcp.2022.115234] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 08/19/2022] [Accepted: 08/23/2022] [Indexed: 11/20/2022]
Abstract
Patients with cancer often experience muscle atrophy, which worsens their prognosis. Decreased muscle regenerative capacity plays an important role in the complex processes involved in muscle atrophy. Administration of cisplatin, a cancer chemotherapeutic agent, has been implicated as a cause of muscle atrophy. In this study, we examined whether cisplatin affects the differentiation of myoblasts into myotubes. We treated C2C12 myoblasts with a differentiation medium containing cisplatin and its vehicle during for 8 days and observed the changes in the expression of myosin heavy chain (MyHC) and myogenin in the myoblasts. Cisplatin was injected in mice for 4 consecutive days; on Day 5, the mice quadriceps muscles were sampled and examined. The expression of MyHCs increased and that of myogenin decreased after cisplatin treatment. The secretion of acidic cysteine-rich proteins (e.g., Sparc proteins) reportedly promotes C2C12 myoblast differentiation. Therefore, we investigated the Sparc family gene expression during myogenesis in C2C12 myoblasts after cisplatin treatment. Of all the genes investigated, Sparc-like protein 1 (Sparcl1) expression was significantly suppressed by cisplatin on Days 4-8. Simultaneous treatment with recombinant mouse Sparcl1 almost inhibited the cisplatin-induced suppression of total MyHC and myogenin protein levels. Moreover, Sparcl1 expression decreased in the skeletal muscles of mice, leading to cisplatin-induced muscle atrophy. Our results suggest that cisplatin-induced myogenesis suppression causes muscle atrophy and inhibits the expression of Sparcl1, which promotes C2C12 cell differentiation during myogenesis.
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Mishra N, Agarwal R. Research models of sulfur mustard- and nitrogen mustard-induced ocular injuries and potential therapeutics. Exp Eye Res 2022; 223:109209. [PMID: 35961426 DOI: 10.1016/j.exer.2022.109209] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 07/27/2022] [Accepted: 08/02/2022] [Indexed: 11/20/2022]
Abstract
Sulfur mustard (SM) is a notorious, bifunctional alkylating vesicant that was first used in warfare during World War I in 1917 and since then has been deployed in numerous skirmishes with its most recent documented use being during the Middle Eastern conflicts. Apart from its use in combat and terrorist activities, continual threat of accidental exposure from old stockpiles and improperly discarded munitions is ever present, especially to the innocent and unassuming civilian populations. SM can cause devastating injuries, depending on the dosage of SM exposure, route of exposure, as well as the physiological conditions of the individuals exposed. The most common routes of exposure are ocular, dermal, and exposure to the lungs and respiratory tissues through inhalation. Eyes are the most susceptible organ to SM-induced toxicities owing to their high moisture content and rapidly dividing cells. Additionally, ocular injury causes the most expeditious disablement of individuals even upon whole-body exposures. Therefore, it is imperative to understand the mechanisms underlying SM-induced ocular toxicity and design therapeutic interventions to prevent/mitigate ocular injuries. Ocular SM exposure may cause a wide range of symptoms such as inflammation, lacrimation, itching, dryness, photophobia, edema of the cornea/sclera/retina/iris, conjunctivitis, degradation of the corneal layer, fusion of two or more ocular layers, neovascularization, fibrosis, and temporary or permanent structural damage to one or more ocular layers. These symptoms may lead to vision impairments, resulting in partial or complete blindness that may be permanent. The highly toxic and exceedingly notorious nature of SM makes it a highly regulated chemical, requiring very expensive licensing, security, and safety requirements; thus, the more easily accessible analogue, nitrogen mustard (NM) that mimics SM-induced toxicity and injuries is employed in plethora of studies conducted in different animal models and culture systems. This review provides a comprehensive account of the injuries and symptoms that occur upon ocular SM exposures in human patients as well as studies in animal (in vivo, ex vivo) and cell (in vitro) models of SM and NM ocular exposures. Special emphasis has been laid on highlighting the strengths and lacunae in the research as well as the possible unexplored avenues of mechanisms underlying mustard-induced ocular injury that can be explored in future research endeavors. Furthermore, development of therapeutic interventions and targets of interest in the ocular system exposed to SM and NM, based on studies in human patients as well as in vivo, ex vivo, and in vitro models has been discussed in great depth, providing a valuable knowledge database to delineate pathways associated with vesicant-induced toxicity, and strategies/diagnostic tools against SM-induced toxicity.
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Affiliation(s)
- Neha Mishra
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Rajesh Agarwal
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
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Ukan Ü, Delgado Lagos F, Kempf S, Günther S, Siragusa M, Fisslthaler B, Fleming I. Effect of Thrombin on the Metabolism and Function of Murine Macrophages. Cells 2022; 11:cells11101718. [PMID: 35626753 PMCID: PMC9139186 DOI: 10.3390/cells11101718] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/19/2022] [Accepted: 05/20/2022] [Indexed: 02/01/2023] Open
Abstract
Macrophages are plastic and heterogeneous immune cells that adapt pro- or anti-inflammatory phenotypes upon exposure to different stimuli. Even though there has been evidence supporting a crosstalk between coagulation and innate immunity, the way in which protein components of the hemostasis pathway influence macrophages remains unclear. We investigated the effect of thrombin on macrophage polarization. On the basis of gene expression and cytokine secretion, our results suggest that polarization with thrombin induces an anti-inflammatory, M2-like phenotype. In functional studies, thrombin polarization promoted oxLDL phagocytosis by macrophages, and conditioned medium from the same cells increased endothelial cell proliferation. There were, however, clear differences between the classical M2a polarization and the effects of thrombin on gene expression. Finally, the deletion and inactivation of secreted modular Ca2+-binding protein 1 (SMOC1) attenuated phagocytosis by thrombin-stimulated macrophages, a phenomenon revered by the addition of recombinant SMOC1. Manipulation of SMOC1 levels also had a pronounced impact on the expression of TGF-β-signaling-related genes. Taken together, our results show that thrombin induces an anti-inflammatory macrophage phenotype with similarities as well as differences to the classical alternatively activated M2 polarization states, highlighting the importance of tissue levels of SMOC1 in modifying thrombin-induced macrophage polarization.
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Affiliation(s)
- Ürün Ukan
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, 60596 Frankfurt am Main, Germany; (Ü.U.); (F.D.L.); (S.K.); (M.S.); (B.F.)
| | - Fredy Delgado Lagos
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, 60596 Frankfurt am Main, Germany; (Ü.U.); (F.D.L.); (S.K.); (M.S.); (B.F.)
| | - Sebastian Kempf
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, 60596 Frankfurt am Main, Germany; (Ü.U.); (F.D.L.); (S.K.); (M.S.); (B.F.)
| | - Stefan Günther
- Bioinformatics and Deep Sequencing Platform, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany;
| | - Mauro Siragusa
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, 60596 Frankfurt am Main, Germany; (Ü.U.); (F.D.L.); (S.K.); (M.S.); (B.F.)
| | - Beate Fisslthaler
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, 60596 Frankfurt am Main, Germany; (Ü.U.); (F.D.L.); (S.K.); (M.S.); (B.F.)
| | - Ingrid Fleming
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, 60596 Frankfurt am Main, Germany; (Ü.U.); (F.D.L.); (S.K.); (M.S.); (B.F.)
- German Center of Cardiovascular Research (DZHK), Partner Site RheinMain, 60596 Frankfurt am Main, Germany
- CardioPulmonary Institute, Goethe University, 60596 Frankfurt am Main, Germany
- Correspondence:
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Gibel-Russo R, Benacom D, Di Nardo AA. Non-Cell-Autonomous Factors Implicated in Parvalbumin Interneuron Maturation and Critical Periods. Front Neural Circuits 2022; 16:875873. [PMID: 35601531 PMCID: PMC9115720 DOI: 10.3389/fncir.2022.875873] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 04/04/2022] [Indexed: 02/04/2023] Open
Abstract
From birth to adolescence, the brain adapts to its environmental stimuli through structural and functional remodeling of neural circuits during critical periods of heightened plasticity. They occur across modalities for proper sensory, motor, linguistic, and cognitive development. If they are disrupted by early-life adverse experiences or genetic deficiencies, lasting consequences include behavioral changes, physiological and cognitive deficits, or psychiatric illness. Critical period timing is orchestrated not only by appropriate neural activity but also by a multitude of signals that participate in the maturation of fast-spiking parvalbumin interneurons and the consolidation of neural circuits. In this review, we describe the various signaling factors that initiate critical period onset, such as BDNF, SPARCL1, or OTX2, which originate either from local neurons or glial cells or from extracortical sources such as the choroid plexus. Critical period closure is established by signals that modulate extracellular matrix and myelination, while timing and plasticity can also be influenced by circadian rhythms and by hormones and corticosteroids that affect brain oxidative stress levels or immune response. Molecular outcomes include lasting epigenetic changes which themselves can be considered signals that shape downstream cross-modal critical periods. Comprehensive knowledge of how these signals and signaling factors interplay to influence neural mechanisms will help provide an inclusive perspective on the effects of early adversity and developmental defects that permanently change perception and behavior.
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Váncza L, Tátrai P, Reszegi A, Baghy K, Kovalszky I. SPOCK1 with unexpected function. The start of a new career. Am J Physiol Cell Physiol 2022; 322:C688-C693. [PMID: 35235422 DOI: 10.1152/ajpcell.00033.2022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
SPOCK1, 2 and 3 are considered as matricellular proteoglycans without structural role. Their functions are only partly elucidated. SPOCK1 was detected in the brain as a member of the neural synapses, then in the neuromuscular junctions. It plays a role in the regulation of blood-brain barrier. Its best characterized activity was its oncogenic potential discovered in 2012. Its deleterious effect on tumor progression was detected on 36 different types of tumors by the end of 2020. However, its mode of actions is still not completely understood. Furthermore, even less was discovered about its physiological function. The fact that it was found to localize in the mitochondria and interfered with the lipid metabolism indicated, that the full discovery of SPOCK1 still waiting for us.
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Affiliation(s)
- Lóránd Váncza
- Semmelweis University 1st Department of Pathology and Experimental Cancer Research, Budapest, Hungary
| | | | - Andrea Reszegi
- Semmelweis University 1st Department of Pathology and Experimental Cancer Research, Budapest, Hungary
| | - Kornelia Baghy
- Semmelweis University 1st Department of Pathology and Experimental Cancer Research, Budapest, Hungary
| | - Ilona Kovalszky
- Semmelweis University 1st Department of Pathology and Experimental Cancer Research, Budapest, Hungary
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Lepucki A, Orlińska K, Mielczarek-Palacz A, Kabut J, Olczyk P, Komosińska-Vassev K. The Role of Extracellular Matrix Proteins in Breast Cancer. J Clin Med 2022; 11:jcm11051250. [PMID: 35268340 PMCID: PMC8911242 DOI: 10.3390/jcm11051250] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 01/16/2022] [Accepted: 02/22/2022] [Indexed: 12/12/2022] Open
Abstract
The extracellular matrix is a structure composed of many molecules, including fibrillar (types I, II, III, V, XI, XXIV, XXVII) and non-fibrillar collagens (mainly basement membrane collagens: types IV, VIII, X), non-collagenous glycoproteins (elastin, laminin, fibronectin, thrombospondin, tenascin, osteopontin, osteonectin, entactin, periostin) embedded in a gel of negatively charged water-retaining glycosaminoglycans (GAGs) such as non-sulfated hyaluronic acid (HA) and sulfated GAGs which are linked to a core protein to form proteoglycans (PGs). This highly dynamic molecular network provides critical biochemical and biomechanical cues that mediate the cell–cell and cell–matrix interactions, influence cell growth, migration and differentiation and serve as a reservoir of cytokines and growth factors’ action. The breakdown of normal ECM and its replacement with tumor ECM modulate the tumor microenvironment (TME) composition and is an essential part of tumorigenesis and metastasis, acting as key driver for malignant progression. Abnormal ECM also deregulate behavior of stromal cells as well as facilitating tumor-associated angiogenesis and inflammation. Thus, the tumor matrix modulates each of the classically defined hallmarks of cancer promoting the growth, survival and invasion of the cancer. Moreover, various ECM-derived components modulate the immune response affecting T cells, tumor-associated macrophages (TAM), dendritic cells and cancer-associated fibroblasts (CAF). This review article considers the role that extracellular matrix play in breast cancer. Determining the detailed connections between the ECM and cellular processes has helped to identify novel disease markers and therapeutic targets.
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Affiliation(s)
- Arkadiusz Lepucki
- Department of Community Pharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland; (A.L.); (K.O.)
| | - Kinga Orlińska
- Department of Community Pharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland; (A.L.); (K.O.)
| | - Aleksandra Mielczarek-Palacz
- Department of Immunology and Serology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 41-200 Sosnowiec, Poland; (A.M.-P.); (J.K.)
| | - Jacek Kabut
- Department of Immunology and Serology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 41-200 Sosnowiec, Poland; (A.M.-P.); (J.K.)
| | - Pawel Olczyk
- Department of Community Pharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland; (A.L.); (K.O.)
- Correspondence:
| | - Katarzyna Komosińska-Vassev
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 41-200 Sosnowiec, Poland;
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