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Qin Y, Liao S, Sun J, Ye H, Li J, Pan J, He J, Xia Z, Shao Y. RECK as a Potential Crucial Molecule for the Targeted Treatment of Sepsis. J Inflamm Res 2025; 18:1787-1813. [PMID: 39931174 PMCID: PMC11809362 DOI: 10.2147/jir.s501856] [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: 10/21/2024] [Accepted: 01/19/2025] [Indexed: 02/13/2025] Open
Abstract
Reversion inducing cysteine rich protein with kazal motifs (RECK), a Kazal motif-containing protein, regulates pro-inflammatory cytokines production, migration of inflammatory cells, vascular endothelial growth factor (VEGF) and Wnt pathways and plays critical roles in septic inflammatory storms and vascular endothelial dysfunction. Recently, RECK has been defined as the negative regulator of adisintegrin and metalloproteinases (ADAMs) and matrix metalloproteinases (MMPs), which are both membrane "molecular scissors" and aggravate the poor prognosis of sepsis. To better understand the roles of RECK and the related mechanisms, we make here a systematic and in-depth review of RECK. We first summarize the findings on structural characteristics of RECK protein and the regulation at the transcription, post-transcription, or protein level of RECK. Then, we discuss the roles of RECK in inflammation, infection, and vascular injury by focusing on the RECK function on ADAMs and MMPs, as well as the pathways of VEGF, WNT, angiopoietin, and notch signaling. In conclusion, RECK participation as a guardian in the development of sepsis provides insight into the strategies of precisely intervening in RECK dysregulationfor the treatment of sepsis.
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Affiliation(s)
- Yuting Qin
- Dongguan Key Laboratory of Sepsis Translational Medicine, The Intensive Care Unit, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, People’s Republic of China
| | - Shuanglin Liao
- Dongguan Key Laboratory of Sepsis Translational Medicine, The Intensive Care Unit, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, People’s Republic of China
| | - Jianbo Sun
- Dongguan Key Laboratory of Chronic Inflammatory Diseases, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, People’s Republic of China
| | - Huiyun Ye
- Dongguan Key Laboratory of Sepsis Translational Medicine, The Intensive Care Unit, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, People’s Republic of China
| | - Jiafu Li
- Dongguan Key Laboratory of Sepsis Translational Medicine, The Intensive Care Unit, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, People’s Republic of China
| | - Jiahui Pan
- Dongguan Key Laboratory of Sepsis Translational Medicine, The Intensive Care Unit, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, People’s Republic of China
| | - Junbing He
- The Key Laboratory of Organ Dysfunction and Protection Translational Medicine, Jieyang Medical Research Center, Jieyang People’s Hospital, Jieyang, Guangdong, People’s Republic of China
| | - Zhengyuan Xia
- Department of Anesthesiology and Perioperative Medicine, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, People’s Republic of China
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, People’s Republic of China
| | - Yiming Shao
- Dongguan Key Laboratory of Sepsis Translational Medicine, The Intensive Care Unit, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, People’s Republic of China
- The Key Laboratory of Sepsis Translational Medicine, Guangdong Medical University, Zhanjiang, Guangdong, People’s Republic of China
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Du S, Kretsch RC, Parres-Gold J, Pieri E, Cruzeiro VWD, Zhu M, Pinney MM, Yabukarski F, Schwans JP, Martínez TJ, Herschlag D. Conformational ensembles reveal the origins of serine protease catalysis. Science 2025; 387:eado5068. [PMID: 39946472 DOI: 10.1126/science.ado5068] [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] [Received: 02/29/2024] [Accepted: 11/22/2024] [Indexed: 04/23/2025]
Abstract
Enzymes exist in ensembles of states that encode the energetics underlying their catalysis. Conformational ensembles built from 1231 structures of 17 serine proteases revealed atomic-level changes across their reaction states. By comparing the enzymatic and solution reaction, we identified molecular features that provide catalysis and quantified their energetic contributions to catalysis. Serine proteases precisely position their reactants in destabilized conformers, creating a downhill energetic gradient that selectively favors the motions required for reaction while limiting off-pathway conformational states. The same catalytic features have repeatedly evolved in proteases and additional enzymes across multiple distinct structural folds. Our ensemble-function analyses revealed previously unknown catalytic features, provided quantitative models based on simple physical and chemical principles, and identified motifs recurrent in nature that may inspire enzyme design.
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Affiliation(s)
- Siyuan Du
- Department of Biochemistry, Stanford University, Stanford, CA, USA
- Department of Chemistry, Stanford University, Stanford, CA, USA
| | - Rachael C Kretsch
- Department of Biochemistry, Stanford University, Stanford, CA, USA
- Biophysics Program, Stanford University, Stanford, CA, USA
| | | | - Elisa Pieri
- Department of Chemistry, Stanford University, Stanford, CA, USA
- The PULSE Institute, Stanford University, Stanford, CA, USA
- SLAC National Accelerator Laboratory, Menlo Park, CA, USA
| | - Vinícius Wilian D Cruzeiro
- Department of Chemistry, Stanford University, Stanford, CA, USA
- The PULSE Institute, Stanford University, Stanford, CA, USA
- SLAC National Accelerator Laboratory, Menlo Park, CA, USA
| | - Mingning Zhu
- Department of Chemistry, Stanford University, Stanford, CA, USA
- The PULSE Institute, Stanford University, Stanford, CA, USA
- SLAC National Accelerator Laboratory, Menlo Park, CA, USA
| | - Margaux M Pinney
- Department of Biochemistry, Stanford University, Stanford, CA, USA
| | - Filip Yabukarski
- Department of Biochemistry, Stanford University, Stanford, CA, USA
| | - Jason P Schwans
- Department of Biochemistry, Stanford University, Stanford, CA, USA
| | - Todd J Martínez
- Department of Chemistry, Stanford University, Stanford, CA, USA
- The PULSE Institute, Stanford University, Stanford, CA, USA
- SLAC National Accelerator Laboratory, Menlo Park, CA, USA
| | - Daniel Herschlag
- Department of Biochemistry, Stanford University, Stanford, CA, USA
- Department of Chemical Engineering, Stanford University, Stanford, CA, USA
- Stanford ChEM-H, Stanford University, Stanford, CA, USA
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Ma ZH, Ma XN, Zhu HW, Cheng L, Gou LZ, Zhang DK. Clinical significance of peripheral blood DDR1 and CtBP gene methylation detection in patients with acute pancreatitis. Epigenetics 2024; 19:2421631. [PMID: 39485950 PMCID: PMC11540100 DOI: 10.1080/15592294.2024.2421631] [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: 06/20/2024] [Revised: 09/03/2024] [Accepted: 10/22/2024] [Indexed: 11/03/2024] Open
Abstract
To investigate the clinical value of methylation levels of peripheral blood DDR1 and CtBP genes in evaluating the severity of acute pancreatitis (AP). Collect 90 blood samples from AP patients and healthy volunteers, and test methylation levels of SPINK1, STAT3, KIT, CFTR, DDR1, CtBP1, CtBP2 genes by bisulfite amplicon sequencing (BSAS). The gene methylation and clinical predictors of SAP early prediction were determined by univariate and multifactorial analysis, respectively. (1) The methylation level of CtBP1 gene and MCTSI score were independent predictors of SAP, with AUC values of 0.723 and 0.8895, respectively. (2) The methylation levels of DDR1, CtBP2, CFTR and SPINK1 genes were statistically significant in HC group vs AP group, HC group vs MAP group, and HC group vs SAP group. (3) The combined detection of CtBP1 gene methylation level and MCTSI score predicted the sensitivity, specificity, AUC, and 95%CI of SAP were 0.750, 0.957, 0.902, and 0.816-0.989, respectively. (1) The methylation level of CtBP1 gene in peripheral blood is an independent risk factor for predicting SAP and is a potentially good predictor of SAP, and the combined testing with the MCTSI score does not further significantly improve the early predictive value for SAP. (2) The methylation levels of DDR1, SPINK1, CtBP2, and CFTR genes were potential indicators for recognizing AP.
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Affiliation(s)
- Zeng-Hui Ma
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- Key laboratory of Digestive Diseases, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Xue-Ni Ma
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- Key laboratory of Digestive Diseases, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Hong-Wen Zhu
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- Key laboratory of Digestive Diseases, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Long Cheng
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- Key laboratory of Digestive Diseases, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Ling-Zhu Gou
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- Key laboratory of Digestive Diseases, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - De-Kui Zhang
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- Key laboratory of Digestive Diseases, Lanzhou University Second Hospital, Lanzhou, Gansu, China
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Gukovskaya AS, Lerch MM, Mayerle J, Sendler M, Ji B, Saluja AK, Gorelick FS, Gukovsky I. Trypsin in pancreatitis: The culprit, a mediator, or epiphenomenon? World J Gastroenterol 2024; 30:4417-4438. [PMID: 39534420 PMCID: PMC11551668 DOI: 10.3748/wjg.v30.i41.4417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 06/19/2024] [Accepted: 07/16/2024] [Indexed: 10/23/2024] Open
Abstract
Pancreatitis is a common, life-threatening inflammatory disease of the exocrine pancreas. Its pathogenesis remains obscure, and no specific or effective treatment is available. Gallstones and alcohol excess are major etiologies of pancreatitis; in a small portion of patients the disease is hereditary. Pancreatitis is believed to be initiated by injured acinar cells (the main exocrine pancreas cell type), leading to parenchymal necrosis and local and systemic inflammation. The primary function of these cells is to produce, store, and secrete a variety of enzymes that break down all categories of nutrients. Most digestive enzymes, including all proteases, are secreted by acinar cells as inactive proforms (zymogens) and in physiological conditions are only activated when reaching the intestine. The generation of trypsin from inactive trypsinogen in the intestine plays a critical role in physiological activation of other zymogens. It was proposed that pancreatitis results from proteolytic autodigestion of the gland, mediated by premature/inappropriate trypsinogen activation within acinar cells. The intra-acinar trypsinogen activation is observed in experimental models of acute and chronic pancreatitis, and in human disease. On the basis of these observations, it has been considered the central pathogenic mechanism of pancreatitis - a concept with a century-old history. This review summarizes the data on trypsinogen activation in experimental and genetic rodent models of pancreatitis, particularly the more recent genetically engineered mouse models that mimic mutations associated with hereditary pancreatitis; analyzes the mechanisms mediating trypsinogen activation and protecting the pancreas against its' damaging effects; discusses the gaps in our knowledge, potential therapeutic approaches, and directions for future research. We conclude that trypsin is not the culprit in the disease pathogenesis but, at most, a mediator of some pancreatitis responses. Therefore, the search for effective therapies should focus on approaches to prevent or normalize other intra-acinar pathologic processes, such as defective autophagy leading to parenchymal cell death and unrelenting inflammation.
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Affiliation(s)
- Anna S Gukovskaya
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90073, United States
- Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, United States
| | - Markus M Lerch
- Department of Medicine, Ludwig Maximilian University Hospital, Munich 81377, Germany
| | - Julia Mayerle
- Department of Medicine II, Ludwig Maximilian University of Munich, Munich 81377, Germany
| | - Matthias Sendler
- Department of Medicine A, University of Greifswald, Greifswald 17475, Germany
| | - Baoan Ji
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, United States
| | - Ashok K Saluja
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, United States
| | - Fred S Gorelick
- Departments of Cell Biology and Internal Medicine, Yale University School of Medicine and VA West Haven, New Haven, CT 06519, United States
| | - Ilya Gukovsky
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90073, United States
- Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, United States
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Daneva GN, Tsiakanikas P, Adamopoulos PG, Scorilas A. Kallikrein-related peptidases: mechanistic understanding for potential therapeutic targeting in cancer. Expert Opin Ther Targets 2024; 28:875-894. [PMID: 39431595 DOI: 10.1080/14728222.2024.2415014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 09/18/2024] [Accepted: 10/07/2024] [Indexed: 10/22/2024]
Abstract
INTRODUCTION Human kallikrein-related peptidases (KLKs) represent a subgroup of 15 serine endopeptidases involved in various physiological processes and pathologies, including cancer. AREAS COVERED This review aims to provide a comprehensive overview of the KLK family, highlighting their genomic structure, expression profiles and substrate specificity. We explore the role of KLKs in tumorigenesis, emphasizing their potential as biomarkers and therapeutic targets in cancer treatment. The dysregulated activity of KLKs has been linked to various malignancies, making them promising candidates for cancer diagnostics and therapy. EXPERT OPINION : Recent advancements in understanding the mechanistic pathways of KLK-related tumorigenesis offer new prospects for developing targeted cancer treatments. Expert opinion suggests that while significant progress has been made, further research is necessary to fully exploit KLKs' potential in clinical applications.
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Affiliation(s)
- Glykeria N Daneva
- Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Tsiakanikas
- Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis G Adamopoulos
- Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Andreas Scorilas
- Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece
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Shao S, Liu K, Du J, Yin C, Wang M, Wang Y. Functional characterization of serine proteinase inhibitor Kazal-Type in the red claw crayfish Cherax quadricarinatus. FISH & SHELLFISH IMMUNOLOGY 2024; 148:109525. [PMID: 38537926 DOI: 10.1016/j.fsi.2024.109525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 03/09/2024] [Accepted: 03/24/2024] [Indexed: 04/09/2024]
Abstract
Serine protease inhibitors Kazal type (SPINKs) function in physiological and immunological processes across multicellular organisms. In the present study, we identified a SPINK gene, designated as CqSPINK, in the red claw crayfish Cherax quadricarinatus, which is the ortholog of human SPINK5. The deduced CqSPINK contains two Kazal domains consisting of 45 amino acid residues with a typical signature motif C-X3-C-X5-PVCG-X5-Y-X3-C-X6-C-X12-14-C. Each Kazal domain contains six conserved cysteine residues forming three pairs of disulfide bonds, segmenting the structure into three rings. Phylogenetic analysis revealed CqSPINK as a homolog of human SPINK5. CqSPINK expression was detected exclusively in hepatopancreas and epithelium, with rapid up-regulation in hepatopancreas upon Vibrio parahaemolyticus E1 challenge. Recombinant CqSPINK protein (rCqSPINK) was heterologously expressed in Escherichia coli and purified for further study. Proteinase inhibition assays demonstrated that rCqSPINK could potently inhibit proteinase K and subtilisin A, weakly inhibit α-chymotrypsin and elastase, but extremely weak inhibit trypsin. Furthermore, CqSPINK inhibited bacterial secretory proteinase activity from Bacillus subtilis, E. coli, and Staphylococcus aureus, and inhibited B. subtilis growth. These findings suggest CqSPINK's involvement in antibacterial immunity through direct inhibition of bacterial proteases, contributing to resistance against pathogen invasion.
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Affiliation(s)
- Shuoru Shao
- MOE Key Laboratory of Marine Genetics and Breeding (Qingdao 266003), and Key Laboratory of Tropical Aquatic Germplasm of Hainan Province of Sanya Oceanographic Institution (Sanya 572024), Ocean University of China, China
| | - Kexin Liu
- MOE Key Laboratory of Marine Genetics and Breeding (Qingdao 266003), and Key Laboratory of Tropical Aquatic Germplasm of Hainan Province of Sanya Oceanographic Institution (Sanya 572024), Ocean University of China, China
| | - Jiansen Du
- Qingdao International Travel Healthcare Center, Qingdao Customs District PR China, Qingdao, 266000, China
| | - Chenlin Yin
- MOE Key Laboratory of Marine Genetics and Breeding (Qingdao 266003), and Key Laboratory of Tropical Aquatic Germplasm of Hainan Province of Sanya Oceanographic Institution (Sanya 572024), Ocean University of China, China
| | - Mengqiang Wang
- MOE Key Laboratory of Marine Genetics and Breeding (Qingdao 266003), and Key Laboratory of Tropical Aquatic Germplasm of Hainan Province of Sanya Oceanographic Institution (Sanya 572024), Ocean University of China, China; Hainan Yazhou Bay Seed Laboratory, Sanya, 572024, China.
| | - Yan Wang
- Zhanjiang Experimental Station, Chinese Academy of Tropical Agricultural Sciences, Zhanjiang, 524013, China; Sanya Research Institute of Chinese Academy of Tropical Agricultural Sciences, Sanya, 572025, China; Hainan Yazhou Bay Seed Laboratory, Sanya, 572024, China.
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Chen D, Shi Z, Gao X, Yang Y, Lei X, Hu Y. SPINK1 is a Potential Diagnostic and Prognostic Biomarker for Sepsis. Infect Drug Resist 2024; 17:875-884. [PMID: 38476769 PMCID: PMC10929552 DOI: 10.2147/idr.s440117] [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: 10/08/2023] [Accepted: 02/19/2024] [Indexed: 03/14/2024] Open
Abstract
Purpose There are no satisfactory diagnostic biomarkers for sepsis. Accordingly, this study screened biomarkers valuable for sepsis diagnosis and prognosis using data-independent acquisition (DIA) combined with clinical data analysis. Patients and Methods Serine protease inhibitor Kazal-type 1 (SPINK1) is a differentially expressed protein that was screened using DIA and bioinformatics in sepsis patients (n = 22) and healthy controls (n = 10). The plasma SPINK1 levels were detected using an enzyme-linked immunosorbent assay (ELISA) in an expanded population (sepsis patients, n = 52; healthy controls, n = 10). The diagnostic value of SPINK1 in sepsis was evaluated using receiver operating characteristic (ROC) curve analysis based on clinical data. The prognostic value of SPINK1 for sepsis was evaluated using correlation and survival analyses. Results DIA quality control identified 78 differential proteins (72 upregulated and six downregulated), among which SPINK1 was highly expressed in sepsis. The ELISA results suggested that SPINK1 expression was significantly elevated in the sepsis group (P < 0.05). ROC analysis of SPINK1 yielded an area under the curve (AUC) of 0.9096. Combining SPINK1 with procalcitonin (PCT) for ROC analysis yielded an AUC of 1. SPINK1 expression was positively correlated with the Sequential Organ Failure Assessment (SOFA) score (r = 3497, P = 0.0053) and APACHE II score (r = 3223, P = 0.0106). High plasma SPINK1 protein expression was negatively correlated with the 28-day survival rate of patients with sepsis (P = 0.0149). Conclusion The plasma of sepsis patients contained increased SPINK1 protein expression. Combining SPINK1 with PCT might have a high diagnostic value for sepsis. SPINK1 was associated with the SOFA score, APACHE II score, and the 28-day survival rate in patients with sepsis.
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Affiliation(s)
- Dexiu Chen
- Department of Critical Care Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China
| | - Zhangjing Shi
- Department of Critical Care Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China
| | - Xiaolan Gao
- Department of Critical Care Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China
| | - Yuxiang Yang
- Department of Critical Care Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China
| | - Xianying Lei
- Department of Critical Care Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China
| | - Yingchun Hu
- Department of Emergency Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China
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Al Bashir S, Alorjani MS, Kheirallah K, Al Hamad M, Haddad HK, Al-Dwairy A, Bani-Fawwaz BA, Aldaoud N, Halalsheh O, Amawi S, Matalka II. PTEN, ERG, SPINK1, and TFF3 Status and Relationship in a Prostate Cancer Cohort from Jordanian Arab Population. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:174. [PMID: 38256434 PMCID: PMC10821453 DOI: 10.3390/medicina60010174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 01/11/2024] [Accepted: 01/16/2024] [Indexed: 01/24/2024]
Abstract
Background and Objectives: Prognostic biomarkers in prostate cancer (PCa) include PTEN, ERG, SPINK1, and TFF3. Their relationships and patterns of expression in PCa in developing countries, including Jordan, have not yet been investigated. Materials and Methods: A tissue microarray (TMA) of PCa patients was taken from paraffin-embedded tissue blocks for 130 patients. PTEN, ERG, SPINK1, and TFF3 expression profiles were examined using immunohistochemistry (IHC) and correlated with each other and other clinicopathological factors. Results: PTEN loss of any degree was observed in 42.9% of PCa cases. ERG and TFF3 were expressed in 59.3% and 46.5% of PCa cases, respectively. SPINK1 expression was observed in 6 out of 104 PCa cases (5.4%). Among all PCa cases (n = 104), 3.8% (n = 4) showed SPINK1+/ERG+ phenotype, 1.9% (n = 2) showed SPINK1+/ERG- phenotype, 56.7% (n = 59) showed SPINK1-/ERG+ phenotype, and 37.5% showed SPINK1-/ERG- phenotype (n = 39). Among ERG positive cases (n = 63), 6.3% were SPINK1 positive. Among SPINK1 positive cases (n = 6), 66.7% were ERG positive. SPINK1 expression was predominantly observed in a subgroup of cancers that expressed TFF3 (6/6). Additionally, a statistically significant loss of PTEN expression was observed from Gleason Score 6 (GS6) (Grade Group 1 (GG1)) to GS9-10 (GG5); (p-value 0.019). Conclusions: This is the first study to look at the status of the PTEN, ERG, SPINK1, and TFF3 genes in a Jordanian Arab population. Loss of PTEN has been linked to more aggressive prostate cancer with high GSs/GGs. SPINK1 expression was predominantly observed in a subgroup of cancers that expressed TFF3. Our results call for screening these biomarkers for grading and molecular subtyping of the disease.
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Affiliation(s)
- Samir Al Bashir
- Department of Pathology and Microbiology, Faculty of Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan; (M.S.A.); (N.A.); (I.I.M.)
| | - Mohammed S. Alorjani
- Department of Pathology and Microbiology, Faculty of Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan; (M.S.A.); (N.A.); (I.I.M.)
| | - Khalid Kheirallah
- Department of Public Health and Community Medicine, Faculty of Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan;
| | - Mohammad Al Hamad
- Department of Pathology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia;
| | - Husam K. Haddad
- Department of Pathology and Laboratory Medicine, Ministry of Health, Amman 11118, Jordan;
| | - Ahmad Al-Dwairy
- Medstar-Georgetown Washington Hospital Center, Georgetown University, Washington, DC 20057, USA;
| | - Baha A. Bani-Fawwaz
- Gastroenterology and Hepatology Department, Adventhealth, Orlando, FL 32804, USA;
| | - Najla Aldaoud
- Department of Pathology and Microbiology, Faculty of Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan; (M.S.A.); (N.A.); (I.I.M.)
| | - Omar Halalsheh
- Department of General Surgery and Urology, Faculty of Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan;
| | - Saddam Amawi
- Johns Hopkins Aramco Health Centre, Al Mubarraz 36423, Saudi Arabia;
| | - Ismail I. Matalka
- Department of Pathology and Microbiology, Faculty of Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan; (M.S.A.); (N.A.); (I.I.M.)
- College of Medicine, Ras Al-Khaimah (RAK) Medical and Health Sciences University, Ras Al-Khaimah 11172, United Arab Emirates
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Yi S, Zhang C, Li M, Qu T, Wang J. Machine learning and experiments identifies SPINK1 as a candidate diagnostic and prognostic biomarker for hepatocellular carcinoma. Discov Oncol 2023; 14:231. [PMID: 38093163 PMCID: PMC10719188 DOI: 10.1007/s12672-023-00849-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 12/08/2023] [Indexed: 12/17/2023] Open
Abstract
Machine learning techniques have been widely used in predicting disease prognosis, including cancer prognosis. One of the major challenges in cancer prognosis is to accurately classify cancer types and stages to optimize early screening and detection, and machine learning techniques have proven to be very useful in this regard. In this study, we aimed at identifying critical genes for diagnosis and outcomes of hepatocellular carcinoma (HCC) patients using machine learning. The HCC expression dataset was downloaded from GSE65372 datasets and TCGA datasets. Differentially expressed genes (DEGs) were identified between 39 HCC and 15 normal samples. For the purpose of locating potential biomarkers, the LASSO and the SVM-RFE assays were performed. The ssGSEA method was used to analyze the TCGA to determine whether there was an association between SPINK1 and tumor immune infiltrates. RT-PCR was applied to examine the expression of SPINK1 in HCC specimens and cells. A series of functional assays were applied to examine the function of SPINK1 knockdown on the proliferation of HCC cells. In this study, 103 DEGs were obtained. Based on LASSO and SVM-RFE analysis, we identified nine critical diagnostic genes, including C10orf113, SPINK1, CNTLN, NRG3, HIST1H2AI, GPRIN3, SCTR, C2orf40 and PITX1. Importantly, we confirmed SPINK1 as a prognostic gene in HCC. Multivariate analysis confirmed that SPINK1 was an independent prognostic factor for overall survivals of HCC patients. We also found that SPINK1 level was positively associated with Macrophages, B cells, TFH, T cells, Th2 cells, iDC, NK CD56bright cells, Th1 cells, aDC, while negatively associated with Tcm and Eosinophils. Finally, we demonstrated that SPINK1 expression was distinctly increased in HCC specimens and cells. Functionally, silence of SPINK1 distinctly suppressed the proliferation of HCC cells via regulating Wnt/β-catenin pathway. The evidence provided suggested that SPINK1 may possess oncogenic properties by inducing dysregulated immune infiltration in HCC. Additionally, SPINK1 was identified as a novel biomarker and therapeutic target for HCC.
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Affiliation(s)
- Shiming Yi
- Department of Hepatobiliary Surgery, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China
| | - Chunlei Zhang
- Department of Colorectal and Anus Surgery, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China
| | - Ming Li
- Department of Gastroenterology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China
| | - Tianyi Qu
- Emergency Department, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China
| | - Jiafeng Wang
- Department of Hepatobiliary Surgery, the Affiliated Taian City Central Hospital of Qingdao University, Taian, China.
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10
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Nomura K, Okamoto R, Maki Y, Hayashibara A, Takao T, Fukuoka T, Miyoshi E, Pentelute BL, Kajihara Y. Rapid Chemical Synthesis of Serine Protease Inhibitor Kazal-type 13 (SPINK13) Glycoform by a Combined Method with Glycan Insertion Strategy and Fast-Flow Fmoc SPPS. Chemistry 2023; 29:e202300646. [PMID: 37294165 DOI: 10.1002/chem.202300646] [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: 02/28/2023] [Indexed: 06/10/2023]
Abstract
Serine protease inhibitor Kazal type 13 (SPINK13) is a secreted protein that has been recently studied as a therapeutic drug and an interesting biomarker for cancer cells. Although SPINK13 has a consensus sequence (Pro-Asn-Val-Thr) for N-glycosylation, the existence of N-glycosylation and its functions are still unclear. In addition to this, the preparation of glycosylated SPINK 13 has not been examined by both the cell expression method and chemical synthesis. Herein we report the chemical synthesis of the scarce N-glycosylated form of SPINK13 by a rapid synthetic method combined with the chemical glycan insertion strategy and a fast-flow SPPS method. Glycosylated asparagine thioacid was designed to chemoselectively be inserted between two peptide segments where is the sterically bulky Pro-Asn(N-glycan)-Val junction by two coupling reactions which consist of diacyl disulfide coupling (DDC) and thioacid capture ligation (TCL). This insertion strategy successfully afforded the full-length polypeptide of SPINK13 within two steps from glycosylated asparagine thioacid. Because the two peptides used for this synthesis were prepared by a fast-flow SPPS, the total synthetic time of glycoprotein was considerably shortened. This synthetic concept enables us to repetitively synthesize a target glycoprotein easily. Folding experiments afforded well-folded structure confirmed by CD and disulfide bond map. Invasion assays of glycosylated SPINK13 and non-glycosylated SPINK13 with pancreatic cancer cells showed that non-glycosylated SPINK-13 was more potent than that of glycosylated SPINK13.
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Affiliation(s)
- Kota Nomura
- Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka, 560-0043, Japan
| | - Ryo Okamoto
- Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka, 560-0043, Japan
- Forefront Research Center, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka, 560-0043, Japan
| | - Yuta Maki
- Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka, 560-0043, Japan
- Forefront Research Center, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka, 560-0043, Japan
| | - Ayumu Hayashibara
- Department of Molecular Biochemistry and Clinical Investigation, Graduate School of Medicine, Osaka University, 1-7 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Toshifumi Takao
- Institute of Protein Research, Osaka University, 3-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Tomoya Fukuoka
- Department of Molecular Biochemistry and Clinical Investigation, Graduate School of Medicine, Osaka University, 1-7 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Eiji Miyoshi
- Department of Molecular Biochemistry and Clinical Investigation, Graduate School of Medicine, Osaka University, 1-7 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Bradley L Pentelute
- Department of Chemistry, Massachusetts Institute of Technology B18, R596, 77 Massachusetts Ave., Cambridge, MA 02139, USA
| | - Yasuhiro Kajihara
- Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka, 560-0043, Japan
- Forefront Research Center, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka, 560-0043, Japan
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11
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Barresi V, Di Bella V, Lo Nigro L, Privitera AP, Bonaccorso P, Scuderi C, Condorelli DF. Temporary serine protease inhibition and the role of SPINK2 in human bone marrow. iScience 2023; 26:106949. [PMID: 37378330 PMCID: PMC10291479 DOI: 10.1016/j.isci.2023.106949] [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: 11/11/2022] [Revised: 03/23/2023] [Accepted: 05/20/2023] [Indexed: 06/29/2023] Open
Abstract
Protease temporary inhibitors are true substrates that bind the catalytic site with high affinity but are slowly degraded, thus acting as inhibitor for a defined time window. Serine peptidase inhibitor Kazal type (SPINK) family is endowed with such functional property whose physiological meaning is poorly explored. High expression of SPINK2 in some hematopoietic malignancies prompted us to investigate its role in adult human bone marrow. We report here the physiological expression of SPINK2 in hematopoietic stem and progenitor cells (HSPCs) and mobilized cluster differentiation 34 (CD34)+ cells. We determined the SPINK2 degradation constant and derived a mathematical relationship predicting the zone of inhibited target protease activity surrounding the SPINK2-secreting HSPCs. Analysis of putative target proteases for SPINK2 revealed the expression of PRSS2 and PRSS57 in HSPCs. Our combined results suggest that SPINK2 and its target serine proteases might play a role in the intercellular communication within the hematopoietic stem cell niche.
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Affiliation(s)
- Vincenza Barresi
- Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, 95123 Catania, Italy
| | - Virginia Di Bella
- Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, 95123 Catania, Italy
| | - Luca Lo Nigro
- Cytogenetic-Cytofluorimetric-Molecular Biology Lab, 95123 Catania, Italy
- Center of Pediatric Hematology-Oncology, Azienda Policlinico – San Marco, 95123 Catania, Italy
| | - Anna Provvidenza Privitera
- Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, 95123 Catania, Italy
| | - Paola Bonaccorso
- Cytogenetic-Cytofluorimetric-Molecular Biology Lab, 95123 Catania, Italy
- Center of Pediatric Hematology-Oncology, Azienda Policlinico – San Marco, 95123 Catania, Italy
| | - Chiara Scuderi
- Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, 95123 Catania, Italy
| | - Daniele Filippo Condorelli
- Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, 95123 Catania, Italy
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12
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Shen C, Zhang M, Liang H, He J, Zhang B, Liang B. Gene cloning and functional study of PmKSPI from Pinctada fucata martensii. FISH & SHELLFISH IMMUNOLOGY 2022; 131:1157-1165. [PMID: 36400373 DOI: 10.1016/j.fsi.2022.11.021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 09/28/2022] [Accepted: 11/11/2022] [Indexed: 06/16/2023]
Abstract
Kunitz-type serine protease inhibitors (KSPI) are a family of serine protease inhibitors (SPIs) and are extensively found in animals, plants, and microbes. SPI can inhibit proteases that may be harmful or unwanted to its cells. Here, a four-domain Kunitz-type SPI, PmKSPI, was cloned by RACE in the pearl oyster Pinctada fucata martensii. The full-length cDNA sequence of PmKSPI was 1318 bp, including the 5' UTR (25 bp), the 3' UTR (96 bp) and ORF (1197 bp). Homology analysis indicated that PmKSPI had the highest resemblance (30.14%) with its homolog in Crassostrea gigas. Phylogenetic analysis revealed that PmKSPI clustered with homologs in other molluscs. We found that PmKSPI mRNA expression in P. f. martensii was distributed in all six tissues, with the highest level in the mantle, and almost no expression in other tissues. After PAMPs challenge, expression of PmKSPI mRNA in the mantle was significantly up-regulated. The recombinant protein rPmKSPI significantly inhibited the growth of 5 kinds of Gram-negative bacteria but had little effect on Gram-positive bacterial activity. Transmission electron microscopy showed that plasmolysis occurred in two Gram-negative bacteria species when treated with rPmKSPI. rPmKSPI may thus have a bactericidal effect by destroying the bacterial cell membrane or cell walls and releasing its contents. Therefore, our results suggest that PmKSPI is tightly associated with the immunological defence of P. f. martensii.
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Affiliation(s)
- Chenghao Shen
- Fisheries College of Guangdong Ocean University, Zhanjiang, Guangdong, 524088, China
| | - Meizhen Zhang
- Fisheries College of Guangdong Ocean University, Zhanjiang, Guangdong, 524088, China
| | - Haiying Liang
- Fisheries College of Guangdong Ocean University, Zhanjiang, Guangdong, 524088, China; Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture, Zhanjiang, Guangdong, 524088, China.
| | - Junjun He
- Fisheries College of Guangdong Ocean University, Zhanjiang, Guangdong, 524088, China
| | - Bin Zhang
- Fisheries College of Guangdong Ocean University, Zhanjiang, Guangdong, 524088, China
| | - Bidan Liang
- Fisheries College of Guangdong Ocean University, Zhanjiang, Guangdong, 524088, China
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13
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Chen YT, Tseng TT, Tsai HP, Kuo SH, Huang MY, Wang JY, Chai CY. Serine protease inhibitor Kazal type 1 (SPINK1) promotes proliferation, migration, invasion and radiation resistance in rectal cancer patients receiving concurrent chemoradiotherapy: a potential target for precision medicine. Hum Cell 2022; 35:1912-1927. [PMID: 36053457 PMCID: PMC9515043 DOI: 10.1007/s13577-022-00776-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 08/23/2022] [Indexed: 12/24/2022]
Abstract
Serine peptidase inhibitor Kazal type-1 (SPINK1), a trypsin kinase inhibitor, is known to be associated with inflammation and pathogenesis. The aim in this study was to demonstrate the clinicopathological role and progression of SPINK1 in rectal cancer (RC) patients undergoing concurrent chemoradiotherapy (CCRT). Immunohistochemical staining for SPINK1 protein expression in 111 RC cases revealed high SPINK1 expression was significantly associated with perineural invasion and poor CCRT response in pre-CCRT specimens. In addition, multivariable analyses showed that pre-CCRT SPINK1 expression was a significant prognostic marker of both overall and disease-free survival in RC patients receiving pre-operative CCRT; furthermore, in vitro studies demonstrated SPINK1 interacted with EGFR to promote the abilities of proliferation, migration and invasion attenuated by SPINK1 si-RNA via ERK, p38, and JNK pathways. SPINK1 was also found to regulate radio-resistance in CRC cell lines. In conclusion, SPINK1 expression is an independent prognostic marker in patients receiving pre-operative CCRT, and SPINK1 regulates proliferation, migration and invasion via EGFR-downstream ERK, p38 and JNK pathways. The phenotypes of radiosensitivity that could be reversed with attenuation of SPINK1 levels suggest that targeting SPINK1 might offer a strategy for optimal precision medicine.
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Affiliation(s)
- Yi-Ting Chen
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100, Tzyou 1st Road, Kaohsiung, 807, Taiwan
- Department of Pathology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tzu-Ting Tseng
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100, Tzyou 1st Road, Kaohsiung, 807, Taiwan
| | - Hung-Pei Tsai
- Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Shih-Hsun Kuo
- Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Yii Huang
- Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Radiation Oncology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jaw-Yuan Wang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chee-Yin Chai
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100, Tzyou 1st Road, Kaohsiung, 807, Taiwan.
- Department of Pathology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
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14
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A Kazal-type serine protease inhibitor mediates innate immunity in wild silkworm Actias selene Hübner. J Biosci 2022. [DOI: 10.1007/s12038-022-00272-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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15
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Scaffold stability and P14' residue steric hindrance in the differential inhibition of FXIIa by Aedes aegypti trypsin inhibitor versus Infestin-4. Biosci Rep 2022; 42:231253. [PMID: 35485437 PMCID: PMC9112662 DOI: 10.1042/bsr20220421] [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: 02/20/2022] [Revised: 04/07/2022] [Accepted: 04/29/2022] [Indexed: 11/17/2022] Open
Abstract
Kazal-type protease inhibitors strictly regulate Factor XIIa (FXIIa), a blood-clotting serine protease. However, when negatively-charged surface of prosthetic device come into contact with FXII, it undergoes conformational change and auto-activation, leading to thrombus formation. Some research suggests that Kazal-type protease inhibitor specificity against FXIIa is governed solely by the reactive-site loop sequence, as this sequence makes most-if not all-of the direct contacts with FXIIa. Here, we sought to compare the inhibitory properties of two Kazal-type inhibitors, Infestin-4 (Inf4), a potent inhibitor of FXIIa, and Aedes aegypti trypsin inhibitor (AaTI), which does not inhibit FXIIa, to better understand Kazal-type protease specificity and determine the structural components responsible for inhibition. There are only 3 residue differences in the reactive-site loop between AaTI and Inf4. Through site-directed mutagenesis, we show that the reactive-site loop is only partially responsible for the inhibitory specificity of these proteases. The protein scaffold of AaTI is unstable due to an elongated C5C6 region. Through chimeric study, we show that swapping the protease-binding loop and the C5C6 region from Inf4 with that of AaTI can partially enhance the inhibitory activity of the AaTI_Inf4 chimera. Furthermore, the additional substitution of Asn at the P14' position of AaTI with Gly (Gly27 in Inf4) absolves the steric clashing between AaTI and the surface 140-loop of FXIIa, and increases the inhibition of the chimeric AaTI to match that of wild-type Inf4. Our findings suggest that ancillary regions in addition to the reactive-site loop sequence are important factors driving Kazal-type inhibitor specificity.
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16
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Liao C, Wang Q, An J, Zhang M, Chen J, Li X, Xiao L, Wang J, Long Q, Liu J, Guan X. SPINKs in Tumors: Potential Therapeutic Targets. Front Oncol 2022; 12:833741. [PMID: 35223512 PMCID: PMC8873584 DOI: 10.3389/fonc.2022.833741] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 01/14/2022] [Indexed: 12/14/2022] Open
Abstract
The serine protease inhibitor Kazal type (SPINK) family includes SPINK1-14 and is the largest branch in the serine protease inhibitor family. SPINKs play an important role in pancreatic physiology and disease, sperm maturation and capacitation, Nager syndrome, inflammation and the skin barrier. Evidence shows that the unregulated expression of SPINK1, 2, 4, 5, 6, 7, and 13 is closely related to human tumors. Different SPINKs exhibit various regulatory modes in different tumors and can be used as tumor prognostic markers. This article reviews the role of SPINK1, 2, 4, 5, 6, 7, and 13 in different human cancer processes and helps to identify new cancer treatment targets.
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Affiliation(s)
- Chengcheng Liao
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
| | - Qian Wang
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
- Microbial Resources and Drug Development Key Laboratory of Guizhou Tertiary Institution, Life Sciences Institute, Zunyi Medical University, Zunyi, China
| | - Jiaxing An
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Minglin Zhang
- Department of Gastroenterology, Affiliated Baiyun Hospital of Guizhou Medical University, Guiyang, China
| | - Jie Chen
- Department of Urology, The Third Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Xiaolan Li
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
- Microbial Resources and Drug Development Key Laboratory of Guizhou Tertiary Institution, Life Sciences Institute, Zunyi Medical University, Zunyi, China
| | - Linlin Xiao
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
| | - Jiajia Wang
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China
| | - Qian Long
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
- *Correspondence: Qian Long, ; Xiaoyan Guan, ; Jianguo Liu,
| | - Jianguo Liu
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
- *Correspondence: Qian Long, ; Xiaoyan Guan, ; Jianguo Liu,
| | - Xiaoyan Guan
- Department of Orthodontics II, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi, China
- *Correspondence: Qian Long, ; Xiaoyan Guan, ; Jianguo Liu,
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17
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Walvekar VA, Ramesh K, Jobichen C, Kannan M, Sivaraman J, Kini RM, Mok YK. Crystal structure of Aedes aegypti trypsin inhibitor in complex with μ-plasmin reveals role for scaffold stability in Kazal-type serine protease inhibitor. Protein Sci 2022; 31:470-484. [PMID: 34800067 PMCID: PMC8820117 DOI: 10.1002/pro.4245] [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] [Received: 08/11/2021] [Revised: 11/11/2021] [Accepted: 11/12/2021] [Indexed: 02/03/2023]
Abstract
Kazal-type protease inhibitor specificity is believed to be determined by sequence of the reactive-site loop that make most, if not all, contacts with the serine protease. Here, we determined the complex crystal structure of Aedes aegypti trypsin inhibitor (AaTI) with μ-plasmin, and compared its reactivities with other Kazal-type inhibitors, infestin-1 and infestin-4. We show that the shortened 99-loop of plasmin creates an S2 pocket, which is filled by phenylalanine at the P2 position of the reactive-site loop of infestin-4. In contrast, AaTI and infestin-1 retain a proline at P2, rendering the S2 pocket unfilled, which leads to lower plasmin inhibitions. Furthermore, the protein scaffold of AaTI is unstable, due to an elongated Cys-V to Cys-VI region leading to a less compact hydrophobic core. Chimeric study shows that the stability of the scaffold can be modified by swapping of this Cys-V to Cys-VI region between AaTI and infestin-4. The scaffold instability causes steric clashing of the bulky P2 residue, leading to significantly reduced inhibition of plasmin by AaTI or infestin-4 chimera. Our findings suggest that surface loops of protease and scaffold stability of Kazal-type inhibitor are both necessary for specific protease inhibition, in addition to reactive site loop sequence. PDB ID code: 7E50.
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Affiliation(s)
| | - Karthik Ramesh
- Department of Biological SciencesNational University of SingaporeSingapore,Present address:
Department of Biophysics and BiochemistryUT Southwestern Medical CentreDallasTXUSA
| | - Chacko Jobichen
- Department of Biological SciencesNational University of SingaporeSingapore
| | - Muthu Kannan
- Department of Biological SciencesNational University of SingaporeSingapore
| | - J. Sivaraman
- Department of Biological SciencesNational University of SingaporeSingapore
| | - R. Manjunatha Kini
- Department of Biological SciencesNational University of SingaporeSingapore,Department of PharmacologyYong Loo Lin School of Medicine, National University of SingaporeSingapore
| | - Yu Keung Mok
- Department of Biological SciencesNational University of SingaporeSingapore
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18
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Sun S, Zhao S, Yang H, Wang F. microRNA 21 Promotes the Proliferation and Metastasis of Oral Squamous Cell Carcinoma by Targeting RECK. J HARD TISSUE BIOL 2022. [DOI: 10.2485/jhtb.31.257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Shuntao Sun
- Department of Stomatology, Tongde Hospital of Zhejiang Province
| | - Shanshan Zhao
- Department of Stomatology, Tongde Hospital of Zhejiang Province
| | - Hongyu Yang
- Department of Stomatology, Shenzhen Hospital, Peking University
| | - Feng Wang
- Department of Stomatology, Shenzhen Hospital, Peking University
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19
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Dong Z, An L, Lu M, Tang M, Chen H, Huang X, Hou Y, Shen G, Zhang X, Zhang Y, Xia Q, Zhao P. SPINK7 Recognizes Fungi and Initiates Hemocyte-Mediated Immune Defense Against Fungal Infections. Front Immunol 2021; 12:735497. [PMID: 34603317 PMCID: PMC8484702 DOI: 10.3389/fimmu.2021.735497] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 08/30/2021] [Indexed: 12/02/2022] Open
Abstract
Serine protease inhibitors of Kazal-type (SPINKs) were widely identified in vertebrates and invertebrates, and played regulatory roles in digestion, coagulation, and fibrinolysis. In this study, we reported the important role of SPINK7 in regulating immune defense of silkworm, Bombyx mori. SPINK7 contains three Kazal domains and has 6 conserved cysteine residues in each domain. Quantitative real-time PCR analyses revealed that SPINK7 was exclusively expressed in hemocytes and was upregulated after infection with two fungi, Saccharomyces cerevisiae and Candida albicans. Enzyme activity inhibition test showed that SPINK7 significantly inhibited the activity of proteinase K from C. albicans. Additionally, SPINK7 inhibited the growth of three fungal spores, including S. cerevisiae, C. albicans, and Beauveria bassiana. The pathogen-associated molecular patterns (PAMP) binding assays suggested that SPINK7 could bind to β-D-glucan and agglutinate B. bassiana and C. albicans. In vitro assays were performed using SPINK7-coated agarose beads, and indicated that SPINK7 promoted encapsulation and melanization of agarose beads by B. mori hemocytes. Furthermore, co-localization studies using immunofluorescence revealed that SPINK7 induced hemocytes to aggregate and entrap the fungi spores of B. bassiana and C. albicans. Our study revealed that SPINK7 could recognize fungal PAMP and induce the aggregation, melanization, and encapsulation of hemocytes, and provided valuable clues for understanding the innate immunity and cellular immunity in insects.
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Affiliation(s)
- Zhaoming Dong
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.,Biological Science Research Center, Southwest University, Chongqing, China.,Chongqing Key laboratory of Sericultural Science, Chongqing Engineering and Technology Research Center for Novel Silk Materials, Southwest University, Chongqing, China
| | - Lingna An
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.,Biological Science Research Center, Southwest University, Chongqing, China.,Chongqing Key laboratory of Sericultural Science, Chongqing Engineering and Technology Research Center for Novel Silk Materials, Southwest University, Chongqing, China
| | - Mengyao Lu
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.,Biological Science Research Center, Southwest University, Chongqing, China.,Chongqing Key laboratory of Sericultural Science, Chongqing Engineering and Technology Research Center for Novel Silk Materials, Southwest University, Chongqing, China
| | - Muya Tang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.,Biological Science Research Center, Southwest University, Chongqing, China.,Chongqing Key laboratory of Sericultural Science, Chongqing Engineering and Technology Research Center for Novel Silk Materials, Southwest University, Chongqing, China
| | - Haiqin Chen
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.,Biological Science Research Center, Southwest University, Chongqing, China.,Chongqing Key laboratory of Sericultural Science, Chongqing Engineering and Technology Research Center for Novel Silk Materials, Southwest University, Chongqing, China
| | - Xuan Huang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.,Biological Science Research Center, Southwest University, Chongqing, China.,Chongqing Key laboratory of Sericultural Science, Chongqing Engineering and Technology Research Center for Novel Silk Materials, Southwest University, Chongqing, China
| | - Yong Hou
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.,Biological Science Research Center, Southwest University, Chongqing, China.,Chongqing Key laboratory of Sericultural Science, Chongqing Engineering and Technology Research Center for Novel Silk Materials, Southwest University, Chongqing, China
| | - Guanwang Shen
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.,Biological Science Research Center, Southwest University, Chongqing, China.,Chongqing Key laboratory of Sericultural Science, Chongqing Engineering and Technology Research Center for Novel Silk Materials, Southwest University, Chongqing, China
| | - Xiaolu Zhang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.,Biological Science Research Center, Southwest University, Chongqing, China.,Chongqing Key laboratory of Sericultural Science, Chongqing Engineering and Technology Research Center for Novel Silk Materials, Southwest University, Chongqing, China
| | - Yan Zhang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.,Biological Science Research Center, Southwest University, Chongqing, China.,Chongqing Key laboratory of Sericultural Science, Chongqing Engineering and Technology Research Center for Novel Silk Materials, Southwest University, Chongqing, China
| | - Qingyou Xia
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.,Biological Science Research Center, Southwest University, Chongqing, China.,Chongqing Key laboratory of Sericultural Science, Chongqing Engineering and Technology Research Center for Novel Silk Materials, Southwest University, Chongqing, China
| | - Ping Zhao
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.,Biological Science Research Center, Southwest University, Chongqing, China.,Chongqing Key laboratory of Sericultural Science, Chongqing Engineering and Technology Research Center for Novel Silk Materials, Southwest University, Chongqing, China
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20
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Vancheri C, Morini E, Prandi FR, Alkhoury E, Celotto R, Romeo F, Novelli G, Amati F. Two RECK Splice Variants (Long and Short) Are Differentially Expressed in Patients with Stable and Unstable Coronary Artery Disease: A Pilot Study. Genes (Basel) 2021; 12:genes12060939. [PMID: 34205376 PMCID: PMC8234100 DOI: 10.3390/genes12060939] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/10/2021] [Accepted: 06/15/2021] [Indexed: 12/12/2022] Open
Abstract
Primary prevention is crucial for coronary heart disease (CAD) and the identification of new reliable biomarkers might help risk stratification or predict adverse coronary events. Alternative splicing (AS) is a less investigated genetic factors implicated in CAD etiology. We performed an RNA-seq study on PBMCs from CAD patients and control subjects (CTR) and observed 113 differentially regulated AS events (24 up and 89 downregulated) in 86 genes. The RECK (Reversion-inducing-cysteine-rich protein with Kazal motifs) gene was further analyzed in a larger case study (24 CTR subjects, 72 CAD and 32 AMI patients) for its Splicing-Index FC (FC = −2.64; p = 0.0217), the AS event involving an exon (exon 18), and its role in vascular inflammation and remodeling. We observed a significant downregulation of Long RECK splice variant (containing exon 18) in PBMCs of AMI compared to CTR subjects (FC = −3.3; p < 0.005). Interestingly, the Short RECK splice variant (lacking exon 18) was under-expressed in AMI compared to both CTR (FC = −4.5; p < 0.0001) and CAD patients (FC = −4.2; p < 0.0001). A ROC curve, constructed combining Long and Short RECK expression data, shows an AUC = 0.81 (p < 0.001) to distinguish AMI from stable CAD patients. A significant negative correlation between Long RECK and triglycerides in CTR group and a positive correlation in the AMI group was found. The combined evaluation of Long and Short RECK expression levels is a potential genomic biomarker for the discrimination of AMI from CAD patients. Our results underline the relevance of deeper studies on the expression of these two splice variants to elucidate their functional role in CAD development and progression.
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Affiliation(s)
- Chiara Vancheri
- Genetics Unit, Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, 00133 Rome, Italy; (C.V.); (E.M.); (G.N.)
| | - Elena Morini
- Genetics Unit, Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, 00133 Rome, Italy; (C.V.); (E.M.); (G.N.)
| | - Francesca Romana Prandi
- Unit of Cardiology, University Hospital “Tor Vergata”, 00133 Rome, Italy; (F.R.P.); (E.A.); (R.C.); (F.R.)
| | - Elie Alkhoury
- Unit of Cardiology, University Hospital “Tor Vergata”, 00133 Rome, Italy; (F.R.P.); (E.A.); (R.C.); (F.R.)
| | - Roberto Celotto
- Unit of Cardiology, University Hospital “Tor Vergata”, 00133 Rome, Italy; (F.R.P.); (E.A.); (R.C.); (F.R.)
| | - Francesco Romeo
- Unit of Cardiology, University Hospital “Tor Vergata”, 00133 Rome, Italy; (F.R.P.); (E.A.); (R.C.); (F.R.)
- Unicamillus International Medical University, 00131 Rome, Italy
| | - Giuseppe Novelli
- Genetics Unit, Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, 00133 Rome, Italy; (C.V.); (E.M.); (G.N.)
- Medical Genetics Laboratories, Tor Vergata University Hospital, PTV, 00133 Rome, Italy
- Neuromed IRCCS Institute, 86077 Pozzilli, Italy
- School of Medicine, Reno University of Nevada, Reno, NV 1664, USA
| | - Francesca Amati
- Genetics Unit, Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, 00133 Rome, Italy; (C.V.); (E.M.); (G.N.)
- Department for the Promotion of Human Science and Quality of Life, University San Raffaele, 00166 Rome, Italy
- Correspondence:
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21
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Lin TC. Functional Roles of SPINK1 in Cancers. Int J Mol Sci 2021; 22:ijms22083814. [PMID: 33916984 PMCID: PMC8067593 DOI: 10.3390/ijms22083814] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/04/2021] [Accepted: 04/04/2021] [Indexed: 12/15/2022] Open
Abstract
Serine Peptidase Inhibitor Kazal Type 1 (SPINK1) is a secreted protein known as a protease inhibitor of trypsin in the pancreas. However, emerging evidence shows its function in promoting cancer progression in various types of cancer. SPINK1 modulated tumor malignancies and induced the activation of the downstream signaling of epidermal growth factor receptor (EGFR) in cancer cells, due to the structural similarity with epidermal growth factor (EGF). The discoverable SPINK1 somatic mutations, expressional signatures, and prognostic significances in various types of cancer have attracted attention as a cancer biomarker in clinical applications. Emerging findings further clarify the direct and indirect biological effects of SPINK1 in regulating cancer proliferation, metastasis, drug resistance, transdifferentiation, and cancer stemness, warranting the exploration of the SPINK1-mediated molecular mechanism to identify a therapeutic strategy. In this review article, we first integrate the transcriptomic data of different types of cancer with clinical information and recent findings of SPINK1-mediated malignant phenotypes. In addition, a comprehensive summary of SPINK1 expression in a pan-cancer panel and individual cell types of specific organs at the single-cell level is presented to indicate the potential sites of tumorigenesis, which has not yet been reported. This review aims to shed light on the roles of SPINK1 in cancer and provide guidance and potential directions for scientists in this field.
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Affiliation(s)
- Tsung-Chieh Lin
- Genomic Medicine Core Laboratory, Department of Medical Research and Development, Chang Gung Memorial Hospital, Linkou 333, Taoyuan City, Taiwan
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22
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Wang Y, Wang B, Liu M, Jiang K, Wang M, Wang L. Characterization and function analysis of a Kazal-type serine proteinase inhibitor in the red claw crayfish Cherax quadricarinatus. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2021; 114:103871. [PMID: 32946920 DOI: 10.1016/j.dci.2020.103871] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 09/11/2020] [Accepted: 09/11/2020] [Indexed: 06/11/2023]
Abstract
Kazal-type serine proteinase inhibitors (KPIs) function in physiological and immunological processes requiring proteinase action. In the present study, the first Cherax quadricarinatus KPI gene (designated CqKPI) was identified and characterized. The open reading frame of CqKPI contains 405 nucleotides and encodes a protein of 134 amino acids. CqKPI has two Kazal domains comprising 44 amino acid residues with the conserved amino acid sequence C-X3-C-X7-C-X6-Y-X3-C-X6-C-X12-C. Each Kazal domain has six conserved cysteine residues, which can form a structural conformation of three pairs of disulfide bonds stabilizing the Kazal domain. CqKPI exhibited high similarity with previously identified KPIs from crayfish hemocytes. The results of tissue distribution showed that CqKPI had the highest expression level in hemocytes, and this was in agreement with phylogenic relationships. Recombinant CqKPI (rCqKPI) was heterologously expressed in Escherichia coli and purified for further study. The proteinase inhibition assays suggested that rCqKPI could potently inhibit elastase and weakly inhibit trypsin, subtilisin A, and proteinase K, but not α-chymotrypsin. It can firmly bind to Bacillus hwajinpoensis, Staphylococcus aureus, and Vibrio parahaemolyticus, with weak binding to Candida albicans. In addition, CqKPI inhibited bacterial secretory proteinase activity and inhibited the growth of B. hwajinpoensis and C. albicans. These data suggest that CqKPI might be involved in anti-bacterial immunity, acting as an inhibitor of the proteinase cascade in the resistance to invasion of pathogens.
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Affiliation(s)
- Yan Wang
- CAS Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Baojie Wang
- CAS Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China
| | - Mei Liu
- CAS Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China
| | - Keyong Jiang
- CAS Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China
| | - Mengqiang Wang
- MOE Key Laboratory of Marine Genetics and Breeding, Ocean University of China, Qingdao, 266003, China; The Laboratory of Tropical Marine Germplasm Resources and Breeding Engineering, SANYA Oceanographic Institution of the Ocean University of China, Sanya, 572024, China; Center for Marine Molecular Biotechnology, National Laboratory for Marine Science and Technology, Qingdao, 266237, China.
| | - Lei Wang
- CAS Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China; Laboratory for Marine Biology and Biotechnology, National Laboratory for Marine Science and Technology, Qingdao, 266237, China; CAS Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao, 266400, China.
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23
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Jones TE, Bellin MD, Yadav D, Freeman ML, Schwarzenberg SJ, Slivka A, Chennat JS, Beilman GJ, Chinnakotla S, Pruett TL, Kirchner V, Humar A, Wijkstrom M, Zureikat AH, Nikiforova MN, Wald AI, Whitcomb DC, Singhi AD. The histopathology of SPINK1-associated chronic pancreatitis. Pancreatology 2020; 20:1648-1655. [PMID: 33097431 PMCID: PMC7704661 DOI: 10.1016/j.pan.2020.10.030] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 09/20/2020] [Accepted: 10/08/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND The identification of genetic risk factors for chronic pancreatitis, such as PRSS1, CFTR and SPINK1, provides the opportunity to define key pathologic hallmarks and etiologic-specific changes. For example, pancreata from PRSS1 and CFTR patients exhibit progressive lipomatous atrophy without significant fibrosis. Considering the pathology of SPINK1-associated pancreatitis is ill-defined, we examined the pancreata of SPINK1 patients with chronic pancreatitis. METHODS Histologic sections after total pancreatectomy with islet autotransplantation and associated clinicopathologic data were collected from 28 patients with SPINK1 germline alterations. Clinical findings, germline data, anatomic anomalies and pathologic findings were descriptively evaluated. RESULTS Patients ranged in age from 5 to 48 years (median, 21.6 years) with abdominal pain between 2 and 25 years (median, 5.8 years). Most patients were SPINK1 heterozygous and 14 (50%) had co-occurring CFTR (n = 12) and CTRC (n = 2) mutations. Other pancreatitis risk factors included anatomic anomalies (n = 9) and tobacco use (n = 1). Overall, 24 (86%) patients had additional pancreatitis-associated germline alterations, SPINK1 homozygosity, anatomic anomalies or environmental factors. Examination of pancreata revealed a sequential pattern of exocrine parenchymal loss and replacement by prominent fibrosis, dependent on the duration of abdominal pain. No malignancies were identified, but low-grade pancreatic intraepithelial neoplasia was present for 2 cases. CONCLUSIONS Within this descriptive study, SPINK1-associated pancreatitis is characterized by parenchymal fibrosis and suggests divergent pathophysiologic mechanisms from PRSS1 and CFTR-associated pancreatitis. Moreover, SPINK1 patients frequently had additional etiologic factors that did not impact the development of pancreatic fibrosis and may implicate SPINK1 as a disease modifier gene.
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Affiliation(s)
- Terrell E Jones
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Melena D Bellin
- Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA; Department of Surgery, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Dhiraj Yadav
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Martin L Freeman
- Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Sarah J Schwarzenberg
- Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Adam Slivka
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Jennifer S Chennat
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Gregory J Beilman
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Srinath Chinnakotla
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Timothy L Pruett
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Varvara Kirchner
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Abhinav Humar
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Martin Wijkstrom
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Amer H Zureikat
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Marina N Nikiforova
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Abigail I Wald
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - David C Whitcomb
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Aatur D Singhi
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
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24
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Analysis of the inhibiting activity of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) on matrix metalloproteinases. Sci Rep 2020; 10:6317. [PMID: 32286475 PMCID: PMC7156630 DOI: 10.1038/s41598-020-63338-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 03/30/2020] [Indexed: 12/26/2022] Open
Abstract
Matrix metalloproteinases (MMPs) occur in 23 human paralogues with key functions in physiology, and their activity is controlled by protein inhibitors. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), which is essential for embryogenesis and tumour suppression, has been reported to inhibit MMPs. Here, we developed eukaryotic and bacterial expression systems for different RECK variants and analysed their inhibitory capacity against representative MMPs in vitro. We could not detect any significant inhibition. Instead, we found that partially purified RECK from the conditioned medium of transfected Expi293F cells but not that of ExpiCHO-S or Drosophila Schneider cells contained a contaminant with proteolytic activity. The contaminant was removed through treatment with a small-molecule serine peptidase inhibitor and additional chromatographic purification. A tantamount contaminant was further detected in an equivalent expression system of the N-terminal fragment of the proteoglycan testican 3, but not in those of two other proteins. These results indicate that previous reports of inhibitory activity of recombinant RECK on MMPs, which were performed with partially purified samples, were probably masked by a coeluting contaminant present in the supernatant of HEK293-derived cells. Thus, RECK is probably not a direct inhibitor of MMP catalytic activity but may still regulate MMPs through other mechanisms.
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25
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Singh R, Balasubramanian I, Zhang L, Gao N. Metaplastic Paneth Cells in Extra-Intestinal Mucosal Niche Indicate a Link to Microbiome and Inflammation. Front Physiol 2020; 11:280. [PMID: 32296343 PMCID: PMC7138011 DOI: 10.3389/fphys.2020.00280] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 03/12/2020] [Indexed: 12/12/2022] Open
Abstract
Paneth cells are residents of the intestinal epithelium. Abnormal appearance of Paneth cells has been widely documented in non-intestinal tissues within the digestive tract and even observed in non-gastrointestinal organs. Although metaplastic Paneth cells are part of the overarching pathology of intestinal metaplasia (IM), only a fraction of intestinal metaplastic lesions contain Paneth cells. We survey literature documenting metaplastic Paneth cells to gain insights into mechanism underlying their etiologic development as well as their potential relevance to human health. A synthesized view from this study suggests that the emergence of metaplastic Paneth cells at extra-intestinal mucosal sites likely represents a protective, anti-bacterial, and inflammatory response evoked by an altered microbial activity.
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Affiliation(s)
- Rajbir Singh
- Department of Biological Sciences, Rutgers University, Newark, NJ, United States
| | | | - Lanjing Zhang
- Department of Biological Sciences, Rutgers University, Newark, NJ, United States.,Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, United States.,Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States.,Department of Pathology, Princeton Medical Center, Plainsboro, NJ, United States
| | - Nan Gao
- Department of Biological Sciences, Rutgers University, Newark, NJ, United States.,Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States
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26
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Huang K, Xie W, Wang S, Li Q, Wei X, Chen B, Hua Y, Li S, Peng B, Shen S. High SPINK1 Expression Predicts Poor Prognosis and Promotes Cell Proliferation and Metastasis of Hepatocellular Carcinoma. J INVEST SURG 2020; 34:1011-1020. [PMID: 32066292 DOI: 10.1080/08941939.2020.1728443] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Serine protease inhibitor Kazal type I (SPINK1) is highly expressed and promotes tumor progress in different cancers. This study aimed to evaluate SPINK1's prognostic value and its role in hepatocellular carcinoma (HCC) progress. METHODS We use tissue micro-arrays containing 273 tumor and paired para-tumor tissues to evaluate SPINK1's prognostic value in HCC. CCK8 cell proliferation assay, wound healing assays, transwell migration and invasion assays were performed to explore the effect of SPINIK1 on HCC cells. The Cancer Genome Atlas (TCGA) database and Gene set enrichment analysis (GSEA) were used to verify the prognosis value of SPINK1 in HCC and explore the underlying mechanisms. RESULTS SPINK1 expression was significantly higher in tumor tissues than paired para-tumor tissues (P < 0.001). Higher SPINK1 expression in tumor was significantly associated with portal vein tumor thrombus formation (P = 0.019) and shorter overall survival (P = 0.029). SPINK1 expression in tumor tissue was an independent predictor for overall survival. SPINK1 increased proliferation (P < 0.001), enhanced migration and invasion ability of HCC cell lines (P < 0.001). GSEA revealed that glycine, serine, threonine and bile acid metabolism may be the underlying mechanism of SPINK1 in HCC. CONCLUSIONS In conclusion, high SPINK1 expression is associated with poor prognosis of HCC. SPINK1 promotes proliferation, migration and invasion ability of HCC cells.
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Affiliation(s)
- Kaijun Huang
- Department of Hepatic Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.,Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Wenxuan Xie
- Department of Hepatic Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Shutong Wang
- Department of Hepatic Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Qiao Li
- Department of Hepatic Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.,Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xiangling Wei
- Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Bin Chen
- Department of Hepatic Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Yunpeng Hua
- Department of Hepatic Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Shaoqiang Li
- Department of Hepatic Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Baogang Peng
- Department of Hepatic Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Shunli Shen
- Department of Hepatic Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
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27
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Playford RJ, Marchbank T. Pancreatic secretory trypsin inhibitor reduces multi-organ injury caused by gut ischemia/reperfusion in mice. PLoS One 2020; 15:e0227059. [PMID: 31923181 PMCID: PMC6953855 DOI: 10.1371/journal.pone.0227059] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 12/10/2019] [Indexed: 11/18/2022] Open
Abstract
Intestinal ischemia/reperfusion (I/R) injury occurs during transplantation, mesenteric arterial occlusion, trauma and shock, causing systemic inflammation, multiple organ dysfunction and high mortality. Pancreatic secretory trypsin inhibitor (PSTI), a serine protease inhibitor expressed in gut mucosa may function as a mucosal protective/repair peptide. We examined whether PSTI affected mesenteric I/R-induced injury. Hypoxia/normoxia (H/N) caused 50% drop in cell viability of AGS, RIE1 and Caco-2 cells but PSTI (10 μg/ml) given prior- or during-hypoxic period improved survival by 50% (p<0.01). Similarly, Caco-2 monolayers exposed to H/N had 300% increase in transepithelial permeability, PSTI truncated this by 50% (p<0.01). Mice underwent mesenteric I/R by clamping jejunum, causing severe mucosal injury, increased apoptotic markers and 3-fold increases in plasma IL-6, IL1β, TNFα, and tissue lipid peroxidation (MDA) and inflammatory infiltration (MPO) levels. Lungs showed similar significant injury and inflammatory infiltrate markers. Smaller increases in MDA and MPO were seen in kidney & liver. PSTI (20 mg/kg) reduced all injury markers by 50–80% (p<0.01). In vitro and in vivo studies showed PSTI reduced pro-apoptotic Caspase 3, 9 and Baxα levels, normalised Bcl2 and caused additional increases in HIF1α, VEGF and Hsp70 above rises caused by I/R alone (all p<0.01). PSTI also prevented reduction of tight junction molecules ZO1 and Claudin1 (all p<0.01) but did not affect increased ICAM-1 caused by I/R in gut or lung. PSTI may be a useful clinical target to prevent I/R injury.
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Affiliation(s)
- Raymond J. Playford
- Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, United Kingdom
| | - Tania Marchbank
- Centre of Immunobiology, Blizard Institute, Barts and The London School of Medicine, Queen Mary, University of London, London, United Kingdom
- * E-mail:
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28
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Tazarotene-Induced Gene 1 (TIG1) Interacts with Serine Protease Inhibitor Kazal-Type 2 (SPINK2) to Inhibit Cellular Invasion of Testicular Carcinoma Cells. BIOMED RESEARCH INTERNATIONAL 2019; 2019:6171065. [PMID: 31886233 PMCID: PMC6899300 DOI: 10.1155/2019/6171065] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 07/23/2019] [Accepted: 08/05/2019] [Indexed: 01/04/2023]
Abstract
Tazarotene-induced gene 1 (TIG1) encodes a protein that is a retinoid-regulated tumor suppressor. TIG1 is expressed in most normal tissues, and downregulation of TIG1 expression in multiple cancers is caused by promoter hypermethylation. Kazal-type serine protease inhibitor-2 (SPINK2) is a serine protease inhibitor, and the SPINK protein family has been shown to inhibit the expression of urokinase-type plasminogen activator (uPA). In addition, increased levels of uPA and the uPA receptor were observed in testicular cancer tissues. This study demonstrated that TIG1 interacts with SPINK2 in NT2/D1 testicular carcinoma cells. TIG1 and SPINK2 were highly expressed in normal testis tissues, while low expression levels of TIG1 and SPINK2 were found in testicular cancer tissues. TIG1 inhibited cell invasion, migration, and epithelial-mesenchymal transition (EMT) of NT2/D1 cells. SPINK2 enhanced TIG1-regulated uPA activity and EMT suppression, while silencing SPINK2 alleviated TIG1-mediated EMT regulation, cell migration, and invasion. Therefore, the results suggest that the interaction between TIG1 and SPINK2 plays an important role in the inhibition of testicular cancer cell EMT, and suppression is mediated through downregulation of the uPA/uPAR signaling pathway.
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29
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Thélie A, Rehault-Godbert S, Poirier JC, Govoroun M, Fouchécourt S, Blesbois E. The seminal acrosin-inhibitor ClTI1/SPINK2 is a fertility-associated marker in the chicken. Mol Reprod Dev 2019; 86:762-775. [PMID: 31033055 PMCID: PMC6767445 DOI: 10.1002/mrd.23153] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 03/23/2019] [Accepted: 03/31/2019] [Indexed: 12/11/2022]
Abstract
The seminal plasma is a very complex fluid, which surrounds sperm in semen. It contains numerous proteins including proteases and protease inhibitors that regulate proteolytic processes associated with protein activation and degradation. We previously identified a seminal protein, chicken liver trypsin inhibitor 1 (ClTI-1) over expressed in semen of roosters with high fertility, suggesting a role in male fertility. In the present study, we showed that ClTI-1 gene is actually SPINK2. Using normal healthy adult roosters, we showed that SPINK2 amount in seminal plasma was positively correlated with male fertility in chicken lines with highly contrasted genetic backgrounds (broiler and layer lines). Using affinity chromatography combined to mass spectrometry analysis and kinetic assays, we demonstrated for the first time that two chicken acrosin isoforms (acrosin and acrosin-like proteins) are the physiological serine protease targets of SPINK2 inhibitor. SPINK2 transcript was overexpressed all along the male tract, and the protein was present in the lumen as expected for secreted proteins. Altogether, these data emphasize the role of seminal SPINK2 Kazal-type inhibitor as an important actor of fertility in birds through its inhibitory action on acrosin isoforms proteins.
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Affiliation(s)
- Aurore Thélie
- PRC, INRA, CNRS, IFCE, Université de Tours, Nouzilly, France
| | | | | | - Marina Govoroun
- PRC, INRA, CNRS, IFCE, Université de Tours, Nouzilly, France
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Chen F, Long Q, Fu D, Zhu D, Ji Y, Han L, Zhang B, Xu Q, Liu B, Li Y, Wu S, Yang C, Qian M, Xu J, Liu S, Cao L, Chin YE, Lam EWF, Coppé JP, Sun Y. Targeting SPINK1 in the damaged tumour microenvironment alleviates therapeutic resistance. Nat Commun 2018; 9:4315. [PMID: 30333494 PMCID: PMC6193001 DOI: 10.1038/s41467-018-06860-4] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 09/18/2018] [Indexed: 12/19/2022] Open
Abstract
Chemotherapy and radiation not only trigger cancer cell apoptosis but also damage stromal cells in the tumour microenvironment (TME), inducing a senescence-associated secretory phenotype (SASP) characterized by chronic secretion of diverse soluble factors. Here we report serine protease inhibitor Kazal type I (SPINK1), a SASP factor produced in human stromal cells after genotoxic treatment. DNA damage causes SPINK1 expression by engaging NF-κB and C/EBP, while paracrine SPINK1 promotes cancer cell aggressiveness particularly chemoresistance. Strikingly, SPINK1 reprograms the expression profile of cancer cells, causing prominent epithelial-endothelial transition (EET), a phenotypic switch mediated by EGFR signaling but hitherto rarely reported for a SASP factor. In vivo, SPINK1 is expressed in the stroma of solid tumours and is routinely detectable in peripheral blood of cancer patients after chemotherapy. Our study substantiates SPINK1 as both a targetable SASP factor and a novel noninvasive biomarker of therapeutically damaged TME for disease control and clinical surveillance.
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Affiliation(s)
- Fei Chen
- Key Laboratory of Tissue Microenvironment and Tumour, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Qilai Long
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Da Fu
- Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Dexiang Zhu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yan Ji
- Key Laboratory of Tissue Microenvironment and Tumour, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Liu Han
- Key Laboratory of Tissue Microenvironment and Tumour, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Boyi Zhang
- Key Laboratory of Tissue Microenvironment and Tumour, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Qixia Xu
- Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Bingjie Liu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Shanghai Medical College, Key Laboratory of Breast Cancer in Shanghai, Innovation Center for Cell Signaling Network, Cancer Institutes, Fudan University, Shanghai, 200032, China
| | - Yan Li
- Key Laboratory of Tissue Microenvironment and Tumour, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Shanshan Wu
- Key Laboratory of Tissue Microenvironment and Tumour, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Chen Yang
- Key Laboratory of Tissue Microenvironment and Tumour, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Min Qian
- Key Laboratory of Tissue Microenvironment and Tumour, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Jianmin Xu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Suling Liu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Shanghai Medical College, Key Laboratory of Breast Cancer in Shanghai, Innovation Center for Cell Signaling Network, Cancer Institutes, Fudan University, Shanghai, 200032, China
| | - Liu Cao
- Key Laboratory of Medical Cell Biology, China Medical University, Shenyang, 110122, China
| | - Y Eugene Chin
- Institute of Biology and Medical Sciences, Soochow University Medical College, 199 Renai Road, Suzhou, 215123, Jiangsu, China
| | - Eric W-F Lam
- Department of Surgery and Cancer, Imperial College London, London, W12 0NN, UK
| | - Jean-Philippe Coppé
- Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, 94115, USA
| | - Yu Sun
- Key Laboratory of Tissue Microenvironment and Tumour, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
- Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
- Department of Medicine, VAPSHCS, University of Washington, Seattle, WA, 98195, USA.
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Kwon H, Yang H, Lee S, Nilojan J, Bathige SDNK, Nam BH, Wan Q, Lee J. Characterization of a Kazal-type serine protease inhibitor from black rockfish Sebastes schlegelii and its possible role in hepatic immune response. FISH & SHELLFISH IMMUNOLOGY 2018; 74:485-490. [PMID: 29305992 DOI: 10.1016/j.fsi.2017.12.068] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 12/26/2017] [Accepted: 12/31/2017] [Indexed: 06/07/2023]
Abstract
Kazal-type serine protease inhibitors (KSPIs) play important roles in the regulation of endogenous proteases, cell development, blood coagulation, and immune response. In this study, we identified and characterized a KSPI homologue (SsKSPI) in black rockfish, Sebastes schlegelii. The full-length cDNA sequence of SsKSPI was 532 base pairs (bp), including an open reading frame (ORF) of 330 bp, which encodes a polypeptide of 110 amino acids with a signal peptide of 21 amino acids. The greatest value for identity (42.9%) and similarity (50.9%) was observed with Channa striata KSPI. We purified the recombinant protein of SsKSPI and performed protease inhibitory assays using three common serine proteases. The recombinant SsKSPI exhibited specific inhibitory activity against subtilisin A in a dose-dependent manner. Tissue distribution of SsKSPI mRNA has been examined amongst 10 important tissues in healthy rockfish and the liver was found to be the predominant expression organ of SsKSPI. The modulation of SsKSPI expression under immune challenges was also investigated in the liver. The SsKSPI mRNA expression was significantly up-regulated in response to both bacterial (Streptococcus iniae and lipopolysaccharide) and viral (polyinosinic:polycytidylic acid) challenges. Overall, we propose that SsKSPI is potentially involved in the hepatic immune response against bacterial and viral infections in black rockfish.
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Affiliation(s)
- Hyukjae Kwon
- Department of Marine Life Sciences & Fish Vaccine Research Center, Jeju National University, Jeju Self-Governing Province 63243, Republic of Korea
| | - Hyerim Yang
- Department of Marine Life Sciences & Fish Vaccine Research Center, Jeju National University, Jeju Self-Governing Province 63243, Republic of Korea
| | - Seongdo Lee
- Department of Marine Life Sciences & Fish Vaccine Research Center, Jeju National University, Jeju Self-Governing Province 63243, Republic of Korea
| | - Jehanathan Nilojan
- Department of Marine Life Sciences & Fish Vaccine Research Center, Jeju National University, Jeju Self-Governing Province 63243, Republic of Korea
| | - S D N K Bathige
- Department of Marine Life Sciences & Fish Vaccine Research Center, Jeju National University, Jeju Self-Governing Province 63243, Republic of Korea
| | - Bo-Hye Nam
- Biotechnology Research Division, National Institute of Fisheries Science, 408-1 Sirang-ri, Gijang-up, Gijang-gun, Busan, 46083 Republic of Korea
| | - Qiang Wan
- Department of Marine Life Sciences & Fish Vaccine Research Center, Jeju National University, Jeju Self-Governing Province 63243, Republic of Korea.
| | - Jehee Lee
- Department of Marine Life Sciences & Fish Vaccine Research Center, Jeju National University, Jeju Self-Governing Province 63243, Republic of Korea.
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Yu Q, Yang D, Wang Q, Zhang Y, Cong M, Wu H, Ji C, Li F, Zhao J. Molecular characterization, expression and functional analysis of two Kazal-type serine protease inhibitors from Venerupis philippinarum. FISH & SHELLFISH IMMUNOLOGY 2017; 70:156-163. [PMID: 28882790 DOI: 10.1016/j.fsi.2017.09.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2017] [Revised: 08/28/2017] [Accepted: 09/03/2017] [Indexed: 06/07/2023]
Abstract
Kazal-type serine protease inhibitors (KSPIs) act as negative regulators in immune signaling pathway by controlling the extent of serine protease (SP) activities. In this study, the full-length cDNA of two KSPIs (designed as VpKSPI-1 and VpKSPI-2) were identified from Venerupis philippinarum by rapid amplification of cDNA ends (RACE) approaches. The open reading frame (ORF) of VpKSPI-1 and VpKSPI-2 was of 552 bp and 402 bp, encoding a polypeptide of 183 and 133 amino acids, respectively. The transcripts of VpKSPI-1 and VpKSPI-2 were ubiquitously expressed in all tissues tested with the highest expression level in hepatopancreas. After Vibrio anguillarum challenge, the relative mRNA expression of VpKSPI-1 and VpKSPI-2 in hepatopancreas was both up-regulated within 96 h. The recombinant VpKSPI-1 (rVpKSPI-1) displayed weak activities towards chymotrypsin, moderate inhibitory activity to trypsin, while rVpKSPI-2 showed significant inhibitory activities against chymotrypsin and trypsin. When the molar ratio of rVpKSPI-2 to chymotrypsin and trypsin reached 1:4 and 1:2, the protease activities could be almost entirely inhibited. All these results suggested that both VpKSPI-1 and VpKSPI-2 perhaps play a vital role in the innate immunity of V. philippinarum.
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Affiliation(s)
- Qian Yu
- Key Laboratory of Coastal Environmental Processes and Ecological Remediation, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Dinglong Yang
- Key Laboratory of Coastal Environmental Processes and Ecological Remediation, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Qing Wang
- Key Laboratory of Coastal Environmental Processes and Ecological Remediation, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, PR China
| | - Yingying Zhang
- Key Laboratory of Coastal Environmental Processes and Ecological Remediation, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China
| | - Ming Cong
- Key Laboratory of Coastal Environmental Processes and Ecological Remediation, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, PR China
| | - Huifeng Wu
- Key Laboratory of Coastal Environmental Processes and Ecological Remediation, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, PR China
| | - Chenglong Ji
- Key Laboratory of Coastal Environmental Processes and Ecological Remediation, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, PR China
| | - Fei Li
- Key Laboratory of Coastal Environmental Processes and Ecological Remediation, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, PR China
| | - Jianmin Zhao
- Key Laboratory of Coastal Environmental Processes and Ecological Remediation, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, PR China; Muping Coastal Environment Research Station, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, PR China.
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Di Leo M, Bianco M, Zuppardo RA, Guslandi M, Calabrese F, Mannucci A, Neri TM, Testoni PA, Leandro G, Cavestro GM. Meta-analysis of the impact of SPINK1 p.N34S gene variation in Caucasic patients with chronic pancreatitis. An update. Dig Liver Dis 2017; 49:847-853. [PMID: 28546062 DOI: 10.1016/j.dld.2017.04.023] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 04/24/2017] [Accepted: 04/26/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND SPINK1 p.N34S gene variation is one of the endogenous factors which seem to be associated with chronic pancreatitis (CP). However, in literature there is no clear agreement regarding its contribution in different ethnicity and CP etiologies. AIM To investigate the role of SPINK1 p.N34S gene variation in CP patients with European origin by means of meta-analysis. METHODS Literature search was conducted and case-control studies evaluating Caucasian population, published between May 2007 and May 2015, were included. We also included Caucasian selected studies analyzed in previous meta-analysis. We carried out meta-analysis including all selected studies. After that, we performed two additional meta-analyses considering the incidence of SPINK1 p.N34S gene variation in alcoholic or in idiopathic CP patients vs control group. RESULTS Twenty-five studies were included and the total number of subjects was 8800 (2981 cases and 5819 controls). The presence of p.N34S variation increased nine times the overall CP risk in population of European origin [OR 9.695 (CI 95% 7.931-11.851)]. Also, the contribution of SPINK1 in idiopathic pancreatitis [OR 13.640 (CI 95% 8.858-21.002)] was found to be higher than in alcoholic CP [5.283 (CI 95% 3.449-8.092)]. CONCLUSION The association between SPINK1 p.N34S gene variation and CP is confirmed. Also, we confirmed that the idiopathic etiology needs a better definition by means of genetic analysis.
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Affiliation(s)
- Milena Di Leo
- Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy.
| | - Margherita Bianco
- Gastroenterology Unit 1, Gastroenterological Hospital 'S. De Bellis' IRCCS, Castellana Grotte, BA, Italy
| | - Raffaella Alessia Zuppardo
- Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Mario Guslandi
- Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Federica Calabrese
- Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Alessandro Mannucci
- Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Tauro Maria Neri
- Unit of Medical Genetics, Laboratory of Molecular Genetics, Diagnostic Department, University Hospital of Parma, Parma, Italy
| | - Pier Alberto Testoni
- Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Gioacchino Leandro
- Gastroenterology Unit 1, Gastroenterological Hospital 'S. De Bellis' IRCCS, Castellana Grotte, BA, Italy; Institute for Digestive and Liver Health, University College, London, UK
| | - Giulia Martina Cavestro
- Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
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Masurier N, Arama DP, El Amri C, Lisowski V. Inhibitors of kallikrein-related peptidases: An overview. Med Res Rev 2017; 38:655-683. [DOI: 10.1002/med.21451] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 04/24/2017] [Accepted: 05/16/2017] [Indexed: 12/11/2022]
Affiliation(s)
- Nicolas Masurier
- Institut des Biomolécules Max Mousseron, UMR 5247, CNRS; Université de Montpellier, ENSCM, UFR des Sciences Pharmaceutiques et Biologiques; Montpellier Cedex France
| | - Dominique P. Arama
- Institut des Biomolécules Max Mousseron, UMR 5247, CNRS; Université de Montpellier, ENSCM, UFR des Sciences Pharmaceutiques et Biologiques; Montpellier Cedex France
| | - Chahrazade El Amri
- Sorbonne Universités, UPMC Univ Paris 06, UMR 8256; Biological Adaptation and Ageing, Integrated Cellular Ageing and Inflammation, Molecular & Functional Enzymology; Paris France
| | - Vincent Lisowski
- Institut des Biomolécules Max Mousseron, UMR 5247, CNRS; Université de Montpellier, ENSCM, UFR des Sciences Pharmaceutiques et Biologiques; Montpellier Cedex France
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Lai Y, Li B, Liu W, Wang G, Du C, Ombati R, Lai R, Long C, Li H. Purification and Characterization of a Novel Kazal-Type Trypsin Inhibitor from the Leech of Hirudinaria manillensis. Toxins (Basel) 2016; 8:toxins8080229. [PMID: 27455325 PMCID: PMC4999845 DOI: 10.3390/toxins8080229] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Revised: 07/11/2016] [Accepted: 07/18/2016] [Indexed: 01/03/2023] Open
Abstract
Kazal-type serine proteinase inhibitors are found in a large number of living organisms and play crucial roles in various biological and physiological processes. Although some Kazal-type serine protease inhibitors have been identified in leeches, none has been reported from Hirudinaria manillensis, which is a medically important leech. In this study, a novel Kazal-type trypsin inhibitor was isolated from leech H. manillensis, purified and named as bdellin-HM based on the sequence similarity with bdellin-KL and bdellin B-3. Structural analysis revealed that bdellin-HM was a 17,432.8 Da protein and comprised of 149 amino acid residues with six cysteines forming three intra-molecular disulfide bonds. Bdellin-HM showed similarity with the Kazal-type domain and may belong to the group of “non-classical” Kazal inhibitors according to its CysI-CysII disulfide bridge position. Bdellin-HM had no inhibitory effect on elastase, chymotrypsin, kallikrein, Factor (F) XIIa, FXIa, FXa, thrombin and plasmin, but it showed a potent ability to inhibit trypsin with an inhibition constant (Ki) of (8.12 ± 0.18) × 10−9 M. These results suggest that bdellin-HM from the leech of H. manillensis plays a potent and specific inhibitory role towards trypsin.
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Affiliation(s)
- Yanmei Lai
- Department of Endocrine and breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
| | - Bowen Li
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming 650223, China.
| | - Weihui Liu
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming 650223, China.
| | - Gan Wang
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming 650223, China.
| | - Canwei Du
- Life Sciences College, Nanjing Agricultural University, Nanjing 210095, China.
| | - Rose Ombati
- Sino-Africa Joint Research Center, Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming 650223, Yunnan, China.
- Institute of Primate Research, P.O Box 24481, Nairobi, Kenya.
| | - Ren Lai
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming 650223, China.
- Sino-Africa Joint Research Center, Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming 650223, Yunnan, China.
| | - Chengbo Long
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming 650223, China.
| | - Hongyuan Li
- Department of Endocrine and breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
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Fernández J, Gutiérrez JM, Calvete JJ, Sanz L, Lomonte B. Characterization of a novel snake venom component: Kazal-type inhibitor-like protein from the arboreal pitviper Bothriechis schlegelii. Biochimie 2016; 125:83-90. [DOI: 10.1016/j.biochi.2016.03.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Accepted: 03/08/2016] [Indexed: 01/30/2023]
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Chen YT, Tsao SC, Tsai HP, Wang JY, Chai CY. Serine protease inhibitor Kazal type 1 (SPINK1) as a prognostic marker in stage IV colon cancer patients receiving cetuximab based targeted therapy. J Clin Pathol 2016; 69:jclinpath-2016-203638. [PMID: 27107100 DOI: 10.1136/jclinpath-2016-203638] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 04/03/2016] [Indexed: 11/04/2022]
Abstract
BACKGROUND Serine peptidase inhibitor Kazal type-1 (SPINK1), a trypsin kinase inhibitor, has well established associations with inflammation, cancer cell proliferation and carcinogenesis. However, the role of SPINK1 has not been investigated in stage IV colorectal cancer (CRC) patients receiving cetuximab based targeted therapy. The aim of this study was to evaluate the use of SPINK1 as a biomarker for predicting how patients with end stage CRC respond to anti-epidermal growth factor receptor (EGFR) therapies. METHODS Immunohistochemical staining was used for semiquantitative analysis of SPINK1 protein expression in 51 CRC cases. Expression of SPINK1 protein was then analysed to identify correlations with clinicopathological variables. RESULTS High SPINK1 expression was significantly associated with males (p=0.018). Kaplan-Meier analyses also showed that patients with high SPINK1 expression had significantly longer overall survival compared with controls (p=0.004). Multivariable analyses showed that SPINK1 expression and tumour size were significantly associated with prognosis (HR 0.416 and 0.437; 95% CI 0.217 to 0.797 and 0.236 to 0.810; p=0.008 and p=0.009, respectively) in these stage IV CRC cases. CONCLUSIONS High SPINK1 expression is associated with a good prognosis in stage IV CRC cases receiving cetuximab based targeted therapy. As SPINK1 expression is also an independent prognostic marker in these patients, it has potential use as a biomarker for clinical decision making and for designing personalised targeted therapies.
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Affiliation(s)
- Yi-Ting Chen
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shu-Chuan Tsao
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hung-Pei Tsai
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jaw-Yuan Wang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Department of Surgery, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Division of Gastroenterology and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Taiwan Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chee-Yin Chai
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Department of Pathology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
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Serine protease inhibitor Kazal type 1 and epidermal growth factor receptor are expressed in pancreatic tubular adenocarcinoma, intraductal papillary mucinous neoplasm, and pancreatic intraepithelial neoplasia. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2016; 20:620-7. [PMID: 23475261 DOI: 10.1007/s00534-012-0587-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
BACKGROUND Serine protease inhibitor Kazal type 1 (SPINK1) is expressed in normal human pancreatic acinar cells and in a variety of tumors, and binds to the epidermal growth factor receptor (EGFR), mediating cell proliferation through the mitogen-activated protein kinase cascade in pancreatic cancer cell lines. Here, we aimed to assess SPINK1 and EGFR expression in various neoplastic lesions, including tissues demonstrating precancerous changes. METHODS Surgical specimens of pancreatic ductal adenocarcinoma (n = 23), intraductal papillary mucinous neoplasm (IPMN;n = 21), pancreatic neoplasms other than ductal adenocarcinoma (n = 8), chronic pancreatitis (n = 11), and pancreatic intraepithelial neoplasia (PanIN) lesions within the resected specimens were analyzed immunohistochemically for SPINK1 and EGFR expression. RESULTS Sixty-five PanIN-1A, 32 PanIN-1B, 17 PanIN-2, and 6 PanIN-3 were identified. Both SPINK1 and EGFR were expressed in almost all PanIN lesions. All tubular ductal adenocarcinoma, IPMN, and mucinous cystadenocarcinoma samples (neoplasms of ductal origin) expressed SPINK1, whereas acinar cell carcinoma, anaplastic carcinoma, adenosquamous carcinoma, insulinoma, and islet cell carcinoma did not. EGFR was expressed in 87 % of tubular adenocarcinoma and 48 % of IPMN lesions. Among IPMN lesions, malignant lesions (IPMC) expressed EGFR more often than benign lesions (IPMA) did. Scattered expression of EGFR was observed in normal pancreatic ducts and within the tubular complex within chronic pancreatitis lesions. CONCLUSIONS These results indicate that SPINK1 plays a role as a growth factor, signaling through the EGFR pathway in pancreatic ductal adenocarcinoma and neoplasms, and that the EGFR is involved in the malignant transformation of IPMN.
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SPINK1 promotes colorectal cancer progression by downregulating Metallothioneins expression. Oncogenesis 2015; 4:e162. [PMID: 26258891 PMCID: PMC4632074 DOI: 10.1038/oncsis.2015.23] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 06/29/2015] [Indexed: 12/18/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer in the world, and second leading cause of cancer deaths in the US. Although, anti-EGFR therapy is commonly prescribed for CRC, patients harboring mutations in KRAS or BRAF show poor treatment response, indicating an ardent demand for new therapeutic targets discovery. SPINK1 (serine peptidase inhibitor, Kazal type 1) overexpression has been identified in many cancers including the colon, lung, breast and prostate. Our study demonstrates the functional significance of SPINK1 in CRC progression and metastases. Stable knockdown of SPINK1 significantly decreases cell proliferation, invasion and soft agar colony formation in the colon adenocarcinoma WiDr cells. Conversely, an increase in these oncogenic phenotypes was observed on stimulation with SPINK1-enriched conditioned media (CM) in multiple benign models such as murine colonic epithelial cell lines, MSIE and YAMC (SPINK3-negative). Mechanistically, SPINK1 promotes tumorigenic phenotype by activating phosphatidylinositol 3-kinase (PI3K/AKT) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathways, and the SPINK1-positive WiDr cells are sensitive to AKT and MEK inhibitors. Importantly, SPINK1 silencing mediated upregulation of various Metallothionein isoforms, considered as tumor suppressors in CRC, confer sensitivity to doxorubicin, which strengthens the rationale for using the combinatorial treatment approach for the SPINK1-positive CRC patients. Furthermore, in vivo studies using chicken chorioallantoic membrane assay, murine xenograft studies and metastasis models further suggest a pivotal role of SPINK1 in CRC progression and metastasis. Taken together, our study demonstrates an important role for the overexpressed SPINK1 in CRC disease progression, a phenomenon that needs careful evaluation towards effective therapeutic target development.
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40
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Qian C, Fang Q, Wang L, Ye GY. Molecular Cloning and Functional Studies of Two Kazal-Type Serine Protease Inhibitors Specifically Expressed by Nasonia vitripennis Venom Apparatus. Toxins (Basel) 2015; 7:2888-905. [PMID: 26248077 PMCID: PMC4549731 DOI: 10.3390/toxins7082888] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Revised: 06/29/2015] [Accepted: 07/27/2015] [Indexed: 12/21/2022] Open
Abstract
Two cDNA sequences of Kazal-type serine protease inhibitors (KSPIs) in Nasonia vitripennis, NvKSPI-1 and NvKSPI-2, were characterized and their open reading frames (ORFs) were 198 and 264 bp, respectively. Both NvKSPI-1 and NvKSPI-2 contained a typical Kazal-type domain. Real-time quantitative PCR (RT-qPCR) results revealed that NvKSPI-1 and NvKSPI-2 mRNAs were mostly detected specifically in the venom apparatus, while they were expressed at lower levels in the ovary and much lower levels in other tissues tested. In the venom apparatus, both NvKSPI-1 and NvKSPI-2 transcripts were highly expressed on the fourth day post eclosion and then declined gradually. The NvKSPI-1 and NvKSPI-2 genes were recombinantly expressed utilizing a pGEX-4T-2 vector, and the recombinant products fused with glutathione S-transferase were purified. Inhibition of recombinant GST-NvKSPI-1 and GST-NvKSPI-2 to three serine protease inhibitors (trypsin, chymotrypsin, and proteinase K) were tested and results showed that only NvKSPI-1 could inhibit the activity of trypsin. Meanwhile, we evaluated the influence of the recombinant GST-NvKSPI-1 and GST-NvKSPI-2 on the phenoloxidase (PO) activity and prophenoloxidase (PPO) activation of hemolymph from a host pupa, Musca domestica. Results showed PPO activation in host hemolymph was inhibited by both recombinant proteins; however, there was no significant inhibition on the PO activity. Our results suggested that NvKSPI-1 and NvKSPI-2 could inhibit PPO activation in host hemolymph and trypsin activity in vitro.
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Affiliation(s)
- Cen Qian
- College of Life Science, Anhui Agricultural University, Hefei 230036, China.
- State Key Laboratory of Rice Biology, Key Laboratory of Agricultural Entomology, Institute of Insect Sciences, Zhejiang University, Hangzhou 310058, China.
| | - Qi Fang
- State Key Laboratory of Rice Biology, Key Laboratory of Agricultural Entomology, Institute of Insect Sciences, Zhejiang University, Hangzhou 310058, China.
| | - Lei Wang
- College of Life Science, Anhui Agricultural University, Hefei 230036, China.
- State Key Laboratory of Rice Biology, Key Laboratory of Agricultural Entomology, Institute of Insect Sciences, Zhejiang University, Hangzhou 310058, China.
| | - Gong-Yin Ye
- State Key Laboratory of Rice Biology, Key Laboratory of Agricultural Entomology, Institute of Insect Sciences, Zhejiang University, Hangzhou 310058, China.
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Serine Protease Inhibitor Kazal Type 1 (SPINK1) Promotes Proliferation of Colorectal Cancer Through the Epidermal Growth Factor as a Prognostic Marker. Pathol Oncol Res 2015; 21:1201-8. [PMID: 26037168 DOI: 10.1007/s12253-015-9949-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Accepted: 05/08/2015] [Indexed: 10/23/2022]
Abstract
Serine protease inhibitor Kazal type-1 (SPINK1), a trypsin kinase inhibitor, is involved in inflammation, cell proliferation and carcinogenesis. The role and association between SPINK1, EGFR and Ki-67 in colorectal adenoma (CRA) and colorectal cancer (CRC) are still unknown. In this study, we used immunohistochemical stain to evaluate expression of SPINK1, EGFR and Ki-67 proteins in 30 CRA and 53 CRC patients semiquantitatively, and then analyzed their correlation with clinicopathologic parameters. Our results revealed that SPINK1 expression was noted in the upper and basal parts of the crypts in CRA and was more intensely related with cellular atypia. EGFR expression was found in 13 out of 30 adenomas, including 9 out of 15 adenomas with dysplasia or synchronous CRC (60 %), and 4 out of 15 adenomas without dysplasia (26.7 %). In CRC, high SPINK1 expression was significantly associated with males (p = 0.041) and advanced disease stage (p = 0.015). EGFR positivity was significantly correlated with higher T stage (p = 0.004) and disease stage (stage I-IV, p = 0.017; early vs. late, p = 0.015). Pearson's correlation showed positive correlation between the SPINK1 intensity and EGFR immunoreactivity (p = 0.011), and Ki-67 and SPINK1 intensity or percentage (p = 0.017 and p = 0.039 respectively). In Kaplan-Meier analyses, patients with high SPINK1 intensity tended to have shorter overall survival (p = 0.03). Concomitant expression of high SPINK1 intensity and EGFR was also identified as being associated with poor prognosis (p = 0.015). In conclusion, high SPINK1 expression is associated with advanced stage and poor prognosis. There is positive correlation between high SPINK1 expression, EGFR immunoreactivity, and high Ki-67 labeling index. The SPINK1 protein seems to play a role in tumor proliferation and malignant transformation through the EGFR pathway. SPINK1 may serve as a prognostic biomarker in therapeutic targeting in the future.
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42
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Negulescu H, Guo Y, Garner TP, Goodwin OY, Henderson G, Laine RA, Macnaughtan MA. A Kazal-Type Serine Protease Inhibitor from the Defense Gland Secretion of the Subterranean Termite Coptotermes formosanus Shiraki. PLoS One 2015; 10:e0125376. [PMID: 25978745 PMCID: PMC4433142 DOI: 10.1371/journal.pone.0125376] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Accepted: 03/24/2015] [Indexed: 11/28/2022] Open
Abstract
Coptotermes formosanus is an imported, subterranean termite species with the largest economic impact in the United States. The frontal glands of the soldier caste termites comprising one third of the body mass, contain a secretion expelled through a foramen in defense. The small molecule composition of the frontal gland secretion is well-characterized, but the proteins remain to be identified. Herein is reported the structure and function of one of several proteins found in the termite defense gland secretion. TFP4 is a 6.9 kDa, non-classical group 1 Kazal-type serine protease inhibitor with activity towards chymotrypsin and elastase, but not trypsin. The 3-dimensional solution structure of TFP4 was solved with nuclear magnetic resonance spectroscopy, and represents the first structure from the taxonomic family, Rhinotermitidae. Based on the structure of TFP4, the protease inhibitor active loop (Cys8 to Cys16) was identified.
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Affiliation(s)
- Horia Negulescu
- Department of Biological Sciences, Division of Biochemistry and Molecular Biology, Louisiana State University and A&M College, Baton Rouge, LA 70803, United States of America
| | - Youzhong Guo
- Currently at the Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, United States of America
| | - Thomas P Garner
- Currently at the Department of Biochemistry, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, United States of America
| | - Octavia Y Goodwin
- Department of Chemistry, Louisiana State University and A&M College, Baton Rouge, LA 70803, United States of America
| | - Gregg Henderson
- Department of Entomology, Louisiana State University Agricultural Center, Baton Rouge, LA 70803, United States of America
| | - Roger A Laine
- Department of Chemistry, Louisiana State University and A&M College, Baton Rouge, LA 70803, United States of America; Department of Biological Sciences, Division of Biochemistry and Molecular Biology, Louisiana State University and A&M College, Baton Rouge, LA 70803, United States of America
| | - Megan A Macnaughtan
- Department of Chemistry, Louisiana State University and A&M College, Baton Rouge, LA 70803, United States of America
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Ida S, Ozaki N, Araki K, Hirashima K, Zaitsu Y, Taki K, Sakamoto Y, Miyamoto Y, Oki E, Morita M, Watanabe M, Maehara Y, Yamamura KI, Baba H, Ohmuraya M. SPINK1 Status in Colorectal Cancer, Impact on Proliferation, and Role in Colitis-Associated Cancer. Mol Cancer Res 2015; 13:1130-8. [PMID: 25804623 DOI: 10.1158/1541-7786.mcr-14-0581] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Accepted: 03/05/2015] [Indexed: 11/16/2022]
Abstract
UNLABELLED Colorectal cancer is a major cause of deaths due to cancer; therefore, research into its etiology is urgently needed. Although it is clear that chronic inflammation is a risk factor for colorectal cancer, the details remain uncertain. Serine protease inhibitor, Kazal type 1 (SPINK1) is mainly produced in pancreatic acinar cells. However, SPINK1 is expressed in various cancers and in inflammatory states, such as colon cancer and inflammatory bowel disease. There are structural similarities between SPINK1 and epidermal growth factor (EGF). Hence, it was hypothesized that SPINK1 functions as a growth factor for tissue repair in inflammatory states, and if prolonged, acts as a promoter for cell proliferation in cancerous tissues. Here, immunohistochemical staining for SPINK1 was observed in a high percentage of colorectal cancer patient specimens and SPINK1 induced proliferation of human colon cancer cell lines. To clarify its role in colon cancer in vivo, a mouse model exposed to the colon carcinogen azoxymethane and nongenotoxic carcinogen dextran sodium sulfate revealed that Spink3 (mouse homolog of SPINK1) is overexpressed in cancerous tissues. In Spink3 heterozygous mice, tumor multiplicity and tumor volume were significantly decreased compared with wild-type mice. These results suggest that SPINK1/Spink3 stimulates the proliferation of colon cancer cells and is involved in colorectal cancer progression. IMPLICATIONS Evidence suggests that SPINK1 is an important growth factor that connects chronic inflammation and cancer.
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Affiliation(s)
- Satoshi Ida
- Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan. Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Nobuyuki Ozaki
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Kimi Araki
- Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan
| | - Kotaro Hirashima
- Department of Digestive and General Surgery, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Yoko Zaitsu
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Katsunobu Taki
- Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan. Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yasuo Sakamoto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yuji Miyamoto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masaru Morita
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masayuki Watanabe
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ken-Ichi Yamamura
- Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Masaki Ohmuraya
- Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan.
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Kumaresan V, Harikrishnan R, Arockiaraj J. A potential Kazal-type serine protease inhibitor involves in kinetics of protease inhibition and bacteriostatic activity. FISH & SHELLFISH IMMUNOLOGY 2015; 42:430-438. [PMID: 25433138 DOI: 10.1016/j.fsi.2014.11.027] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 10/31/2014] [Accepted: 11/21/2014] [Indexed: 06/04/2023]
Abstract
Kazal-type serine protease inhibitor (KSPI) is a pancreatic secretary trypsin inhibitor which involves in various cellular component regulations including development and defense process. In this study, we have characterized a KSPI cDNA sequence of freshwater striped murrel fish Channa striatus (Cs) at molecular level. Cellular location analysis predicted that the CsKSPI was an extracellular protein. The domain analysis showed that the CsKSPI contains a Kazal domain at 47-103 along with its family signature between 61 and 83. Phylogenetically, CsKSPI is closely related to KSPI from Maylandia zebra and formed a sister group with mammals. The 2D structure of CsKSPI showed three α-helical regions which are connected with random coils, one helix at signal sequence and two at the Kazal domain region. The relative gene expression showed that the CsKSPI was highly expressed in gills and its expression was induced upon fungus (Aphanomyces invadans), bacteria (Aeromonas hydrophila) and poly I:C (a viral analogue) challenge. The CsKSPI recombinant protein was produced to characterize and study the CsKSPI gene specific functions. The recombinant CsKSPI strongly inhibited trypsin compared to other tested proteases. The results of the kinetic activity of CsKSPI against trypsin was V(max)s = 1.62 nmol/min, K(M)s = 0.21 mM and K(i)s = 15.37 nM. Moreover, the recombinant CsKSPI inhibited the growth of Gram-negative bacteria A. hydrophila at 20 μM and Gram-positive bacteria Bacillus subtilis at the MIC50 of 15 μM. Overall, the study indicated that the CsKSPI was a potential trypsin inhibitor which involves in antimicrobial activity.
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Affiliation(s)
- Venkatesh Kumaresan
- Division of Fisheries Biotechnology & Molecular Biology, Department of Biotechnology, Faculty of Science and Humanities, SRM University, Kattankulathur, 603 203 Chennai, Tamil Nadu, India
| | - Ramaswamy Harikrishnan
- Department of Zoology, Pachaiyappa's College for Men, Kanchipuram 631 501, Tamil Nadu, India
| | - Jesu Arockiaraj
- Division of Fisheries Biotechnology & Molecular Biology, Department of Biotechnology, Faculty of Science and Humanities, SRM University, Kattankulathur, 603 203 Chennai, Tamil Nadu, India.
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45
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Ravi Kanth VV, Nageshwar Reddy D. Genetics of acute and chronic pancreatitis: An update. World J Gastrointest Pathophysiol 2014; 5:427-437. [PMID: 25400986 PMCID: PMC4231507 DOI: 10.4291/wjgp.v5.i4.427] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Revised: 10/01/2014] [Accepted: 10/14/2014] [Indexed: 02/06/2023] Open
Abstract
Progress made in identifying the genetic susceptibility underlying acute and chronic pancreatitis has benefitted the clinicians in understanding the pathogenesis of the disease in a better way. The identification of mutations in cationic trypsinogen gene (PRSS1 gene; functional gain mutations) and serine protease inhibitor kazal type 1 (SPINK1 gene; functional loss mutations) and other potential susceptibility factors in genes that play an important role in the pancreatic secretory functions or response to inflammation during pancreatic injury has changed the current concepts and understanding of a complex multifactorial disease like pancreatitis. An individual's susceptibility to the disease is governed by genetic factors in combination with environmental factors. Candidate gene and genetic linkage studies have identified polymorphisms in cationic trypsinogen (PRSS1), SPINK1, cystic fibrosis trans-membrane conductance regulator (CFTR), Chymotrypsinogen C (CTRC), Cathepsin B (CTSB) and calcium sensing receptor (CASR). Individuals with polymorphisms in the mentioned genes and other as yet identified genes are at an enhanced risk for the disease. Recently, polymorphisms in genes other than those involved in "intra-pancreatic trypsin regulatory mechanism" namely Claudin-2 (CLDN2) and Carboxypeptidase A1 (CPA1) gene have also been identified for their association with pancreatitis. With ever growing number of studies trying to identify the genetic susceptibility in the form of single nucleotide polymorphisms, this review is an attempt to compile the available information on the topic.
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Sakata K, Ohmuraya M, Araki K, Suzuki C, Ida S, Hashimoto D, Wang J, Uchiyama Y, Baba H, Yamamura KI. Generation and analysis of serine protease inhibitor kazal type 3-cre driver mice. Exp Anim 2014; 63:45-53. [PMID: 24521862 PMCID: PMC4160937 DOI: 10.1538/expanim.63.45] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Serine protease inhibitor Kazal type 1 (SPINK1; mouse homologue Spink3) was initially discovered as a trypsin-specific inhibitor in the pancreas. However, previous studies have suggested that SPINK1/Spink3 is expressed in a wide range of normal tissues and tumors, although precise characterization of its gene expression has not been described in adulthood. To further analyze Spink3 expression, we generated two mouse lines in which either lacZ or Cre recombinase genes were inserted into the Spink3 locus by Cre-loxP technology. In Spink3(lacZ) mice, β-galactosidase activity was found in acinar cells of the pancreas and kidney, as well as epithelial cells of the bronchus in the lung, but not in the gastrointestinal tract or liver. Spink3(cre) knock-in mice were crossed with Rosa26 reporter (R26R) mice to monitor Spink3 promoter activity. In Spink3(cre);R26R mice, β-galactosidase activity was found in acinar cells of the pancreas, kidney, lung, and a small proportion of cells in the gastrointestinal tract and liver. These data suggest that Spink3 is widely expressed in endoderm-derived tissues, and that Spink3(cre) knock-in mice are a useful tool for establishment of a conditional knockout mice to analyze Spink3 function not only in normal tissues, but also in tumors that express SPINK1/Spink3.
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Affiliation(s)
- Kazuya Sakata
- Institute of Resource Development and Analysis, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan
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Murao S, Sato S, Muto N. Isolation of Alkaline Protease Inhibitor Producing Microorganisms. ACTA ACUST UNITED AC 2014. [DOI: 10.1080/00021369.1972.10860474] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
- Sawao Murao
- Department of Agricultural Chemistry, College of Agriculture,University of Osaka Prefecture
| | - Sakae Sato
- Department of Agricultural Chemistry, College of Agriculture,University of Osaka Prefecture
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Itkonen O, Stenman UH. TATI as a biomarker. Clin Chim Acta 2014; 431:260-9. [DOI: 10.1016/j.cca.2014.02.014] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 02/14/2014] [Accepted: 02/18/2014] [Indexed: 12/22/2022]
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Ling S, Feng T, Jia K, Tian Y, Li Y. Inflammation to cancer: The molecular biology in the pancreas (Review). Oncol Lett 2014; 7:1747-1754. [PMID: 24932227 PMCID: PMC4049733 DOI: 10.3892/ol.2014.2003] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2013] [Accepted: 03/11/2014] [Indexed: 02/07/2023] Open
Abstract
Inflammatory responses are known to be correlated with cancer initiation and progression, and exploration of the route from inflammation to cancer makes a great contribution in elucidating the mechanisms underlying cancer development. Pancreatic cancer (PC) is a lethal disease with a low radical-resection rate and a poor prognosis. As chronic pancreatitis is considered to be a significant etiological factor for PC development, the current review aims to describe the molecular pathways from inflammation to pancreatic carcinogenesis, in support of the strategies for the prevention, diagnosis and treatment of PC.
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Affiliation(s)
- Sunbin Ling
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
| | - Tingting Feng
- Department of Medical Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
| | - Kaiqi Jia
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
| | - Yu Tian
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
| | - Yan Li
- Institute of Cancer Stem Cells, Dalian Medical University, Dalian, Liaoning 116044, P.R. China ; College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
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50
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Ozaki N, Fukuchi Y, Tomiyoshi SR, Uehara H, Ida S, Wang J, Araki K, Sibilia M, Baba H, Yamamura KI, Ohmuraya M. Autophagy regulation in pancreatic acinar cells is independent of epidermal growth factor receptor signaling. Biochem Biophys Res Commun 2014; 446:224-30. [DOI: 10.1016/j.bbrc.2014.02.111] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Accepted: 02/21/2014] [Indexed: 01/20/2023]
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