|
For:
|
Durand MKV, Bødker JS, Christensen A, Dupont DM, Hansen M, Jensen JK, Kjelgaard S, Mathiasen L, Pedersen KE, Skeldal S, Wind T, Andreasen PA. Plasminogen activator inhibitor-I and tumour growth, invasion, and metastasis. Thromb Haemost 2004;91:438-49. [PMID: 14983218 DOI: 10.1160/th03-12-0784] [Citation(s) in RCA: 109] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] |
Supplementary Information
The online version contains supplementary material available at 10.1186/s12964-022-00961-w.
Collapse
Affiliation(s)
| Number |
Cited by Other Article(s) |
|
1
|
Ibrahim AA, Fujimura T, Uno T, Terada T, Hirano KI, Hosokawa H, Ohta A, Miyata T, Ando K, Yahata T. Plasminogen activator inhibitor-1 promotes immune evasion in tumors by facilitating the expression of programmed cell death-ligand 1. Front Immunol 2024; 15:1365894. [PMID: 38779680 PMCID: PMC11109370 DOI: 10.3389/fimmu.2024.1365894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 04/23/2024] [Indexed: 05/25/2024] Open
Abstract
Background Increased levels of plasminogen activator inhibitor-1 (PAI-1) in tumors have been found to correlate with poor clinical outcomes in patients with cancer. Although abundant data support the involvement of PAI-1 in cancer progression, whether PAI-1 contributes to tumor immune surveillance remains unclear. The purposes of this study are to determine whether PAI-1 regulates the expression of immune checkpoint molecules to suppresses the immune response to cancer and demonstrate the potential of PAI-1 inhibition for cancer therapy. Methods The effects of PAI-1 on the expression of the immune checkpoint molecule programmed cell death ligand 1 (PD-L1) were investigated in several human and murine tumor cell lines. In addition, we generated tumor-bearing mice and evaluated the effects of a PAI-1 inhibitor on tumor progression or on the tumor infiltration of cells involved in tumor immunity either alone or in combination with immune checkpoint inhibitors. Results PAI-1 induces PD-L1 expression through the JAK/STAT signaling pathway in several types of tumor cells and surrounding cells. Blockade of PAI-1 impedes PD-L1 induction in tumor cells, significantly reducing the abundance of immunosuppressive cells at the tumor site and increasing cytotoxic T-cell infiltration, ultimately leading to tumor regression. The anti-tumor effect elicited by the PAI-1 inhibitor is abolished in immunodeficient mice, suggesting that PAI-1 blockade induces tumor regression by stimulating the immune system. Moreover, combining a PAI-1 inhibitor with an immune checkpoint inhibitor significantly increases tumor regression. Conclusions PAI-1 protects tumors from immune surveillance by increasing PD-L1 expression; hence, therapeutic PAI-1 blockade may prove valuable in treating malignant tumors.
Collapse
Affiliation(s)
- Abd Aziz Ibrahim
- Translational Molecular Therapeutics Laboratory, Division of Host Defense Mechanism, Tokai University School of Medicine, Kanagawa, Japan
| | - Taku Fujimura
- Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomoko Uno
- Department of Hematology and Oncology, Tokai University School of Medicine, Kanagawa, Japan
| | - Tomoya Terada
- Translational Molecular Therapeutics Laboratory, Division of Host Defense Mechanism, Tokai University School of Medicine, Kanagawa, Japan
| | - Ken-ichi Hirano
- Department of Immunology, Tokai University School of Medicine, Kanagawa, Japan
| | - Hiroyuki Hosokawa
- Department of Immunology, Tokai University School of Medicine, Kanagawa, Japan
| | - Akio Ohta
- Department of Immunology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan
| | - Toshio Miyata
- Department of Molecular Medicine and Therapy, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Kiyoshi Ando
- Department of Hematology and Oncology, Tokai University School of Medicine, Kanagawa, Japan
| | - Takashi Yahata
- Translational Molecular Therapeutics Laboratory, Division of Host Defense Mechanism, Tokai University School of Medicine, Kanagawa, Japan
| |
Collapse
|
|
2
|
Asumda FZ, Campbell NA, Hassan MA, Fathi R, Vasquez Rico DF, Kiem M, Vang EV, Kim YH, Luo X, O’Brien DR, Buhrow SA, Reid JM, Moore MJ, Ben-Yair VK, Levitt ML, Leiting JL, Abdelrahman AM, Zhu X, Lucien F, Truty MJ, Roberts LR. Combined Antitumor Effect of the Serine Protease Urokinase Inhibitor Upamostat and the Sphingosine Kinase 2 Inhibitor Opaganib on Cholangiocarcinoma Patient-Derived Xenografts. Cancers (Basel) 2024; 16:1050. [PMID: 38473407 PMCID: PMC10930726 DOI: 10.3390/cancers16051050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 02/16/2024] [Accepted: 02/18/2024] [Indexed: 03/14/2024] Open
Abstract
Upamostat is an orally available small-molecule serine protease inhibitor that is a highly potent inhibitor of trypsin 1, trypsin 2, trypsin 3 (PRSS1/2/3), and the urokinase-type plasminogen activator (uPA). These enzymes are expressed in many cancers, especially during tissue remodeling and subsequent tumor cell invasion. Opaganib (ABC294640), a novel, orally available small molecule is a selective inhibitor of the phosphorylation of sphingosine to sphingosine-1-phosphate (S-1-P) by sphingosine kinase 2 (SPHK2). Both sphingosine kinase 1 (SPHK1) and SPHK2 are known to regulate the proliferation-inducing compound S-1-P. However, SPHK2 is more critical in cancer pathogenesis. The goal of this project was to investigate the potential antitumor effects of upamostat and opaganib, individually and in combination, on cholangiocarcinoma (CCA) xenografts in nude mice. PAX165, a patient-derived xenograft (PDX) from a surgically resected CCA, expresses substantial levels of SPHK2, PRSS1, PRSS2, and PRSS3. Four groups of 18 mice each were treated with upamostat, opaganib, both, or vehicle. Mouse weights and PAX165 tumor volumes were measured. Tumor volumes in the upamostat, opaganib, and upamostat plus opaganib groups were significantly decreased compared to the control group.
Collapse
Affiliation(s)
- Faizal Z. Asumda
- Departments of Pediatrics and Pathology, Medical College of Georgia-Augusta University Medical Center, Augusta, GA 30912, USA;
| | - Nellie A. Campbell
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Mayo Clinic Cancer Center, Rochester, MN 55905, USA; (N.A.C.); (M.J.M.); (X.Z.)
| | | | - Reza Fathi
- RedHill Biopharma, Ltd., 21 Ha’arba’a St., Tel Aviv 6473921, Israel; (R.F.); (M.L.L.)
| | | | - Melanie Kiem
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Mayo Clinic Cancer Center, Rochester, MN 55905, USA; (N.A.C.); (M.J.M.); (X.Z.)
- Study of Human Medicine, Paracelsus Medical University, Strubergasse 21, 5020 Salzburg, Austria
| | - Ethan V. Vang
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Mayo Clinic Cancer Center, Rochester, MN 55905, USA; (N.A.C.); (M.J.M.); (X.Z.)
| | - Yo Han Kim
- Department of Urology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA; (Y.H.K.); (F.L.)
| | - Xin Luo
- Hepatic Surgery Center and Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Daniel R. O’Brien
- Department of Quantitative Health Sciences, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA;
| | - Sarah A. Buhrow
- Department of Oncology and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA; (S.A.B.); (J.M.R.)
| | - Joel M. Reid
- Department of Oncology and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA; (S.A.B.); (J.M.R.)
| | - Michael J. Moore
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Mayo Clinic Cancer Center, Rochester, MN 55905, USA; (N.A.C.); (M.J.M.); (X.Z.)
| | - Vered Katz Ben-Yair
- RedHill Biopharma, Ltd., 21 Ha’arba’a St., Tel Aviv 6473921, Israel; (R.F.); (M.L.L.)
| | - Mark L. Levitt
- RedHill Biopharma, Ltd., 21 Ha’arba’a St., Tel Aviv 6473921, Israel; (R.F.); (M.L.L.)
| | - Jennifer L. Leiting
- Division of Subspecialty General Surgery, Department of Surgery, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA;
| | - Amro M. Abdelrahman
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA; (A.M.A.); (M.J.T.)
| | - Xinli Zhu
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Mayo Clinic Cancer Center, Rochester, MN 55905, USA; (N.A.C.); (M.J.M.); (X.Z.)
- Department of Radiation Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310030, China
| | - Fabrice Lucien
- Department of Urology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA; (Y.H.K.); (F.L.)
| | - Mark J. Truty
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA; (A.M.A.); (M.J.T.)
| | - Lewis R. Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Mayo Clinic Cancer Center, Rochester, MN 55905, USA; (N.A.C.); (M.J.M.); (X.Z.)
| |
Collapse
|
|
3
|
Yagi T, Sawada K, Miyamoto M, Shimizu A, Oi Y, Toda A, Nakamura K, Kinose Y, Kodama M, Hashimoto K, Kimura T. Continuous Administration of Anti-VEGFA Antibody Upregulates PAI-1 Secretion from Ovarian Cancer Cells via miR-143-3p Downregulation. Mol Cancer Res 2023; 21:1093-1106. [PMID: 37327051 DOI: 10.1158/1541-7786.mcr-23-0015] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 05/06/2023] [Accepted: 06/14/2023] [Indexed: 06/17/2023]
Abstract
Although bevacizumab (BEV) plays a key role in ovarian cancer treatment, BEV resistance is often observed in clinical settings. This study aimed to identify the genes responsible for BEV resistance. C57BL/6 mice inoculated with ID-8 murine ovarian cancer cells were treated with anti-VEGFA antibody or IgG (control) twice weekly for 4 weeks. The mice were sacrificed, then, RNA was extracted from the disseminated tumors. qRT-PCR assays were performed to identify angiogenesis-related genes and miRNAs that were altered by anti-VEGFA treatment. SERPINE1/PAI-1 was found to be upregulated during BEV treatment. Therefore, we focused on miRNAs to elucidate the mechanism underlying the upregulation of PAI-1 during BEV treatment. Kaplan-Meier plotter analysis revealed that higher expression levels of SERPINE1/PAI-1 were associated with poor prognoses among BEV-treated patients, suggesting that SERPINE1/PAI may be involved in the acquisition of BEV resistance. miRNA microarray analysis followed by in silico and functional assays revealed that miR-143-3p targeted SERPINE1 and negatively regulated PAI-1 expression. The transfection of miR-143-3p suppressed PAI-1 secretion from ovarian cancer cells and inhibited in vitro angiogenesis in HUVECs. Next, miR-143-3p-overexpressing ES2 cells were intraperitoneally injected into BALB/c nude mice. ES2-miR-143-3p cells downregulated PAI-1 production, attenuated angiogenesis, and significantly inhibited intraperitoneal tumor growth following treatment with anti-VEGFA antibody. Continuous anti-VEGFA treatment downregulated miR-143-3p expression, which upregulated PAI-1 and activated an alternative angiogenic pathway in ovarian cancer. In conclusion, the substitution of this miRNA during BEV treatment may help overcome BEV resistance, and this may be used as a novel treatment strategy in clinical settings. IMPLICATIONS Continuous administration of VEGFA antibody upregulates SERPINE1/PAI-1 expression via the downregulation of miR-143-3p, which contributes to acquiring bevacizumab resistance in ovarian cancer.
Collapse
Affiliation(s)
- Taro Yagi
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan
| | - Kenjiro Sawada
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan
| | - Mayuko Miyamoto
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan
| | - Aasa Shimizu
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan
| | - Yukako Oi
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan
| | - Aska Toda
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan
| | - Koji Nakamura
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan
| | - Yasuto Kinose
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan
| | - Michiko Kodama
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan
| | - Kae Hashimoto
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan
| | - Tadashi Kimura
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan
| |
Collapse
|
|
4
|
Mazurkiewicz J, Simiczyjew A, Dratkiewicz E, Kot M, Pietraszek-Gremplewicz K, Wilk D, Ziętek M, Matkowski R, Nowak D. Melanoma stimulates the proteolytic activity of HaCaT keratinocytes. Cell Commun Signal 2022; 20:146. [PMID: 36123693 PMCID: PMC9484146 DOI: 10.1186/s12964-022-00961-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 08/20/2022] [Indexed: 11/21/2022] Open
Abstract
Background Keratinocytes constitute a major part of the melanoma microenvironment, considering their protective role towards melanocytes in physiological conditions. However, their interactions with tumor cells following melanomagenesis are still unclear. Methods We used two in vitro models (melanoma-conditioned media and indirect co-culture of keratinocytes with melanoma cells on Transwell inserts) to activate immortalized keratinocytes towards cancer-associated ones. Western Blotting and qPCR were used to evaluate keratinocyte markers and mediators of cell invasiveness on protein and mRNA expression level respectively. The levels and activity of proteases and cytokines were analysed using gelatin-FITC staining, gelatin zymography, chemiluminescent enzymatic test, as well as protein arrays. Finally, to further study the functional changes influenced by melanoma we assessed the rate of proliferation of keratinocytes and their invasive abilities by employing wound healing assay and the Transwell filter invasion method. Results HaCaT keratinocytes activated through incubation with melanoma-conditioned medium or indirect co-culture exhibit properties of less differentiated cells (downregulation of cytokeratin 10), which also prefer to form connections with cancer cells rather than adjacent keratinocytes (decreased level of E-cadherin). While they express only a small number of cytokines, the variety of secreted proteases is quite prominent especially considering that several of them were never reported as a part of secretome of activated keratinocytes’ (e.g., matrix metalloproteinase 3 (MMP3), ADAM metallopeptidase with thrombospondin type 1 motif 1). Activated keratinocytes also seem to exhibit a high level of proteolytic activity mediated by MMP9 and MMP14, reduced expression of TIMPs (tissue inhibitor of metalloproteinases), upregulation of ERK activity and increased levels of MMP expression regulators-RUNX2 and galectin 3. Moreover, cancer-associated keratinocytes show slightly elevated migratory and invasive abilities, however only following co-culture with melanoma cells on Transwell inserts. Conclusions Our study offers a more in-depth view of keratinocytes residing in the melanoma niche, drawing attention to their unique secretome and mediators of invasive abilities, factors which could be used by cancer cells to support their invasion of surrounding tissues.
|
Video abstract
- Justyna Mazurkiewicz
- Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, 50-383, Wrocław, Poland.
| |
- Aleksandra Simiczyjew
- Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, 50-383, Wrocław, Poland
| |
- Ewelina Dratkiewicz
- Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, 50-383, Wrocław, Poland
| |
- Magdalena Kot
- Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, 50-383, Wrocław, Poland
| |
| |
- Dominika Wilk
- Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, 50-383, Wrocław, Poland
| |
- Marcin Ziętek
- Department of Oncology and Division of Surgical Oncology, Wroclaw Medical University, Plac Hirszfelda 12, 53-413, Wrocław, Poland.,Wroclaw Comprehensive Cancer Center, Plac Hirszfelda 12, 53-413, Wrocław, Poland
| |
- Rafał Matkowski
- Department of Oncology and Division of Surgical Oncology, Wroclaw Medical University, Plac Hirszfelda 12, 53-413, Wrocław, Poland.,Wroclaw Comprehensive Cancer Center, Plac Hirszfelda 12, 53-413, Wrocław, Poland
| |
- Dorota Nowak
- Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, 50-383, Wrocław, Poland
| |
Collapse
5
PAI-1 is a potential transcriptional silencer that supports bladder cancer cell activity.
Sci Rep 2022;
12:12186. [PMID:
35842542 PMCID:
PMC9288475 DOI:
10.1038/s41598-022-16518-3]
[Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 07/11/2022] [Indexed: 12/12/2022] Open
Abstract
The extracellular activity of Plasminogen activator inhibitor-1 (PAI-1) is well described, acting as an inhibitor of tissue plasminogen activator and urokinase-type plasminogen activator, impacting fibrinolysis. Recent studies have revealed a pro-tumorigenic role of PAI-1 in human cancers, via the regulation of angiogenesis and tumor cell survival. In this study, immunohistochemical staining of 939 human bladder cancer specimens showed that PAI-1 expression levels correlated with tumor grade, tumor stage and overall survival. The typical subcellular localization of PAI-1 is cytoplasmic, but in approximately a quarter of the cases, PAI-1 was observed to be localized to both the tumor cell cytoplasm and the nucleus. To investigate the potential function of nuclear PAI-1 in tumor biology we applied chromatin immunoprecipitation (ChIP)-sequencing, gene expression profiling, and rapid immunoprecipitation mass spectrometry to a pair of bladder cancer cell lines. ChIP-sequencing revealed that PAI-1 can bind DNA at distal intergenic regions, suggesting a role as a transcriptional coregulator. The downregulation of PAI-1 in bladder cancer cell lines caused the upregulation of numerous genes, and the integration of ChIP-sequence and RNA-sequence data identified 57 candidate genes subject to PAI-1 regulation. Taken together, the data suggest that nuclear PAI-1 can influence gene expression programs and support malignancy.
Collapse
6
Stokes SC, Kabagambe SK, Lee CJ, Wang A, Farmer DL, Kumar P. Impact of Gestational Age on Neuroprotective Function of Placenta-Derived Mesenchymal Stromal Cells.
J Surg Res 2022;
273:201-210. [PMID:
35093836 PMCID:
PMC9396930 DOI:
10.1016/j.jss.2021.12.039]
[Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 10/29/2021] [Accepted: 12/15/2021] [Indexed: 11/26/2022]
Abstract
INTRODUCTION
The Management of Myelomeningocele Study demonstrated that in utero repair of myelomeningocele improved motor outcomes compared with postnatal repair. However, even after in utero repair, many children were still unable to walk. We have previously demonstrated that augmentation of in utero repair with early-gestation placental mesenchymal stromal cells (PMSCs) improves motor outcomes in lambs compared with standard in utero repair. The neuroprotective potential of PMSCs of all gestational ages has not been evaluated previously.
METHODS
PMSCs were isolated from discarded first trimester (n = 3), second trimester (n = 3), and term (n = 3) placentas by explant culture. Cytokine array analysis was performed. Secretion of two neurotrophic factors, brain-derived neurotrophic factor and hepatocyte growth factor, was evaluated by enzyme-linked immunosorbent assay. An in vitro neuroprotective assay demonstrated to be associated with in vivo function was performed.
RESULTS
All cell lines secreted immunomodulatory and neuroprotective cytokines and secreted the neurotrophic factors evaluated. Increased neuroprotective capabilities relative to no PMSCs were demonstrated in two of the three first trimester cell lines (5.61, 4.96-6.85, P < 0.0001 and 2.67, 1.67-4.12, P = 0.0046), two of the three second trimester cell lines (2.82, 2.45-3.43, P = 0.0004 and 3.25, 2.62-3.93, P < 0.0001), and two of the three term cell lines (2.72, 2.32-2.92, P = 0.0033 and 2.57, 1.41-4.42, P = 0.0055).
CONCLUSIONS
We demonstrated variation in neuroprotective function between cell lines and found that some cell lines from each trimester had neuroprotective properties. This potentially expands the donor pool of PMSCs for clinical use. Further in-depth studies are needed to understand potential subtle differences in cell function at different gestational ages.
Collapse
7
PAI-1 in Diabetes: Pathophysiology and Role as a Therapeutic Target.
Int J Mol Sci 2021;
22:ijms22063170. [PMID:
33804680 PMCID:
PMC8003717 DOI:
10.3390/ijms22063170]
[Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/16/2021] [Accepted: 03/17/2021] [Indexed: 12/14/2022] Open
Abstract
Hypofibrinolysis is a key abnormality in diabetes and contributes to the adverse vascular outcome in this population. Plasminogen activator inhibitor (PAI)-1 is an important regulator of the fibrinolytic process and levels of this antifibrinolytic protein are elevated in diabetes and insulin resistant states. This review describes both the physiological and pathological role of PAI-1 in health and disease, focusing on the mechanism of action as well as protein abnormalities in vascular disease with special focus on diabetes. Attempts at inhibiting protein function, using different techniques, are also discussed including direct and indirect interference with production as well as inhibition of protein function. Developing PAI-1 inhibitors represents an alternative approach to managing hypofibrinolysis by targeting the pathological abnormality rather than current practice that relies on profound inhibition of the cellular and/or acellular arms of coagulation, and which can be associated with increased bleeding events. The review offers up-to-date knowledge on the mechanisms of action of PAI-1 together with the role of altering protein function to improve hypofirbinolysis. Developing PAI-1 inhibitors may form for the basis of future new class of antithrombotic agents that reduce vascular complications in diabetes.
Collapse
8
Chu Y, Bucci JC, Peterson CB. Dissecting molecular details and functional effects of the high-affinity copper binding site in plasminogen activator Inhibitor-1.
Protein Sci 2020;
30:597-612. [PMID:
33345392 DOI:
10.1002/pro.4017]
[Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 12/01/2020] [Accepted: 12/15/2020] [Indexed: 11/08/2022]
Abstract
Plasminogen activator inhibitor-1 (PAI-1) is the primary inhibitor for plasminogen activators, tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). As a unique member in the serine protease inhibitor (serpin) family, PAI-1 is metastable and converts to an inactive, latent structure with a half-life of 1-2 hr under physiological conditions. Unusual effects of metals on the rate of the latency conversion are incompletely understood. Previous work has identified two residues near the N-terminus, H2 and H3, which reside in a high-affinity copper-binding site in PAI-1 [Bucci JC, McClintock CS, Chu Y, Ware GL, McConnell KD, Emerson JP, Peterson CB (2017) J Biol Inorg Chem 22:1123-1,135]. In this study, neighboring residues, H10, E81, and H364, were tested as possible sites that participate in Cu(II) coordination at the high-affinity site. Kinetic methods, gel sensitivity assays, and isothermal titration calorimetry (ITC) revealed that E81 and H364 have different roles in coordinating metal and mediating the stability of PAI-1. H364 provides a third histidine in the metal-coordination sphere with H2 and H3. In contrast, E81 does not appear to be required for metal ligation along with histidines; contacts made by the side-chain carboxylate upon metal binding are perturbed and, in turn, influence dynamic fluctuations within the region encompassing helices D, E, and F and the W86 loop that are important in the pathway for the PAI-1 latency conversion. This investigation underscores a prominent role of protein dynamics, noncovalent bonding networks and ligand binding in controlling the stability of the active form of PAI-1.
Collapse
Affiliation(s)
- Yuzhuo Chu
- Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana, USA
| |
- Joel C Bucci
- Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana, USA
| |
- Cynthia B Peterson
- Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana, USA
| |
Collapse
9
Pouliquen DL, Boissard A, Coqueret O, Guette C. Biomarkers of tumor invasiveness in proteomics (Review).
Int J Oncol 2020;
57:409-432. [PMID:
32468071 PMCID:
PMC7307599 DOI:
10.3892/ijo.2020.5075]
[Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 05/07/2020] [Indexed: 12/13/2022] Open
Abstract
Over the past two decades, quantitative proteomics has emerged as an important tool for deciphering the complex molecular events involved in cancers. The number of references involving studies on the cancer metastatic process has doubled since 2010, while the last 5 years have seen the development of novel technologies combining deep proteome coverage capabilities with quantitative consistency and accuracy. To highlight key findings within this huge amount of information, the present review identified a list of tumor invasive biomarkers based on both the literature and data collected on a biocollection of experimental cell lines, tumor models of increasing invasiveness and tumor samples from patients with colorectal or breast cancer. Crossing these different data sources led to 76 proteins of interest out of 1,245 mentioned in the literature. Information on these proteins can potentially be translated into clinical prospects, since they represent potential targets for the development and evaluation of innovative therapies, alone or in combination. Herein, a systematical review of the biology of each of these proteins, including their specific subcellular/extracellular or multiple localizations is presented. Finally, as an important advantage of quantitative proteomics is the ability to provide data on all these molecules simultaneously in cell pellets, body fluids or paraffin‑embedded sections of tumors/invaded tissues, the significance of some of their interconnections is discussed.
Collapse
Affiliation(s)
| |
- Alice Boissard
- Paul Papin ICO Cancer Center, CRCINA, Inserm, Université d'Angers, F‑44000 Nantes, France
| |
| |
- Catherine Guette
- Paul Papin ICO Cancer Center, CRCINA, Inserm, Université d'Angers, F‑44000 Nantes, France
| |
Collapse
10
Ciebiera M, Jakiel G, Nowicka G, Laganà AS, Ghezzi F, Łoziński T, Wojtyła C, Włodarczyk M. The effect of ulipristal acetate on tumor necrosis factor α, insulin-like growth factor 1, and plasminogen activator inhibitor-1 serum levels in patients with symptomatic uterine fibroids.
Arch Med Sci 2020;
20:751-761. [PMID:
39050181 PMCID:
PMC11264157 DOI:
10.5114/aoms.2020.94296]
[Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Accepted: 01/02/2020] [Indexed: 07/27/2024] Open
Abstract
Introduction
Uterine fibroids (UFs) are benign tumors of the female reproductive system originating from the smooth muscle of the uterus. Currently, progesterone is known to play a key role in the differentiation of the myometrial tissue to form UFs and their abnormal growth. The mechanism of action of progesterone in UF tumorigenesis involves its effect on increasing the concentrations and dysregulation of selected growth factors.
Material and methods
A retrospective cohort study was performed to evaluate and compare tumor necrosis factor α (TNF-α), insulin-like growth factor 1 (IGF-1), plasminogen activator inhibitor-1 (PAI-1) serum concentrations in patients with UFs without prior hormonal treatment, patients with UFs treated with a 3-month standard ulipristal acetate (UPA - a type of selective progesterone receptor modulator) scheme (5 mg/day) and in control patients without UFs. A total of 120 patients were divided into 3 groups (controls, UFs with UPA treatment, UFs without UPA treatment).
Results
There were no significant differences in TNF-α serum concentrations between patients with UFs who underwent UPA treatment and patients who did not. Serum concentrations of IGF-1 and PAI-1 did not show significant intergroup differences.
Conclusions
No significant differences were found between TNF-α concentrations in the serum of patients with UFs treated with UPA, and patients without UPA treatment. In addition, our data analysis did not show significant differences in the concentrations of IGF-1 and PAI-1 between patients with UFs and the control group. Further studies on the dependence of specific symptoms on selected growth factors are mandatory.
Collapse
Affiliation(s)
- Michał Ciebiera
- II Department of Obstetrics and Gynecology, The Center of Postgraduate Medical Education, Warsaw, Poland
| |
- Grzegorz Jakiel
- I Department of Obstetrics and Gynecology, The Center of Postgraduate Medical Education, Warsaw, Poland
| |
- Grażyna Nowicka
- Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, Poland
| |
- Antonio Simone Laganà
- Department of Obstetrics and Gynecology, “Filippo Del Ponte” Hospital, University of Insubria, Varese, Italy
| |
- Fabio Ghezzi
- Department of Obstetrics and Gynecology, “Filippo Del Ponte” Hospital, University of Insubria, Varese, Italy
| |
| |
- Cezary Wojtyła
- European Observatory of Health Inequalities, State University of Applied Sciences, Kalisz, Poland
- Department of Gynecologic Oncology and Obstetrics, The Center of Postgraduate Medical Education, Warsaw, Poland
| |
- Marta Włodarczyk
- Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, Poland
| |
Collapse
11
Krämer M, Markart P, Drakopanagiotakis F, Mamazhakypov A, Schaefer L, Didiasova M, Wygrecka M. Pirfenidone inhibits motility of NSCLC cells by interfering with the urokinase system.
Cell Signal 2020;
65:109432. [DOI:
10.1016/j.cellsig.2019.109432]
[Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 09/26/2019] [Accepted: 09/27/2019] [Indexed: 12/26/2022]
12
Chu Y, Bucci JC, Peterson CB. Identification of a PAI-1-binding site within an intrinsically disordered region of vitronectin.
Protein Sci 2019;
29:494-508. [PMID:
31682300 DOI:
10.1002/pro.3770]
[Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 10/28/2019] [Indexed: 12/14/2022]
Abstract
The serine protease inhibitor, plasminogen activator inhibitor Type-1 (PAI-1) is a metastable protein that undergoes an unusual transition to an inactive conformation with a short half-life of only 1-2 hr. Circulating PAI-1 is bound to a cofactor vitronectin, which stabilizes PAI-1 by slowing this latency conversion. A well-characterized PAI-1-binding site on vitronectin is located within the somatomedin B (SMB) domain, corresponding to the first 44 residues of the protein. Another PAI-1 recognition site has been identified with an engineered form of vitronectin lacking the SMB domain, yet retaining PAI-1 binding capacity (Schar, Blouse, Minor, Peterson. J Biol Chem. 2008;283:28487-28496). This additional binding site is hypothesized to lie within an intrinsically disordered domain (IDD) of vitronectin. To localize the putative binding site, we constructed a truncated form of vitronectin containing 71 amino acids from the N-terminus, including the SMB domain and an additional 24 amino acids from the IDD region. This portion of the IDD is rich in acidic amino acids, which are hypothesized to be complementary to several basic residues identified within an extensive vitronectin-binding site mapped on PAI-1 (Schar, Jensen, Christensen, Blouse, Andreasen, Peterson. J Biol Chem. 2008;283:10297-10309). Steady-state and stopped-flow fluorescence measurements demonstrate that the truncated form of vitronectin exhibits the same rapid biphasic association as full-length vitronectin and that the IDD hosts the elusive second PAI-1 binding site that lies external to the SMB domain of vitronectin.
Collapse
Affiliation(s)
- Yuzhuo Chu
- Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana, United States
| |
- Joel C Bucci
- Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana, United States
| |
- Cynthia B Peterson
- Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana, United States
| |
Collapse
13
Shang L, Xue G, Gong L, Zhang Y, Peng S, Yuan C, Huang M. A novel ELISA for the detection of active form of plasminogen activator inhibitor-1 based on a highly specific trapping agent.
Anal Chim Acta 2019;
1053:98-104. [DOI:
10.1016/j.aca.2018.12.005]
[Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 11/26/2018] [Accepted: 12/08/2018] [Indexed: 10/27/2022]
14
Wach S, Brandl M, Borchardt H, Weigelt K, Lukat S, Nolte E, Al-Janabi O, Hart M, Grässer F, Giedl J, Jung R, Stöhr R, Hartmann A, Lieb V, Höbel S, Peters A, Stäubert C, Wullich B, Taubert H, Aigner A. Exploring the MIR143-UPAR Axis for the Inhibition of Human Prostate Cancer Cells In Vitro and In Vivo.
MOLECULAR THERAPY. NUCLEIC ACIDS 2019;
16:272-283. [PMID:
30933831 PMCID:
PMC6444223 DOI:
10.1016/j.omtn.2019.02.020]
[Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 01/16/2019] [Accepted: 02/21/2019] [Indexed: 01/12/2023]
Abstract
MIR143 is pathologically downregulated and may function as a tumor suppressor in prostate cancer. Likewise, the urokinase plasminogen activator receptor (UPAR) is overexpressed in prostate carcinoma, representing a negative prognostic marker and putative therapeutic target gene. In this paper, we establish UPAR as a new direct target of MIR143. Luciferase reporter gene constructs identify one of the two in silico-predicted binding sites as functionally relevant for direct MIR143 binding to the 3′ UTR, and, concomitantly, transfection of MIR143 reduces UPAR protein levels in prostate carcinoma cells in vitro. Inhibitory effects on cell proliferation and colony formation, spheroid growth and integrity, and cell viability are extensively analyzed, and they are compared to direct small interfering RNA (siRNA)-mediated uPAR knockdown or combined microRNA (miRNA)-siRNA treatment. Switching to a therapeutically more relevant in vivo model, we demonstrate tumor-inhibitory effects of MIR143 replacement therapy by systemic treatment of mice bearing subcutaneous PC-3 tumor xenografts with MIR143 formulated in polymeric nanoparticles. This efficient, nanoparticle-mediated delivery of intact MIR143 mediates the marked downregulation of uPAR protein, but not mRNA levels, thus indicating translational inhibition rather than mRNA degradation. In summary, we identify UPAR as a direct target gene of MIR143, and we establish the therapeutic anti-tumor potential of nanoparticle-based MIR143 replacement in prostate cancer.
Collapse
Affiliation(s)
- Sven Wach
- Department of Urology, Friedrich Alexander University Hospital Erlangen-Nürnberg, Erlangen, Germany
| |
- Madeleine Brandl
- Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, University of Leipzig, Leipzig, Germany
| |
- Hannes Borchardt
- Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, University of Leipzig, Leipzig, Germany
| |
- Katrin Weigelt
- Department of Urology, Friedrich Alexander University Hospital Erlangen-Nürnberg, Erlangen, Germany
| |
- Sabine Lukat
- Department of Urology, Friedrich Alexander University Hospital Erlangen-Nürnberg, Erlangen, Germany
| |
- Elke Nolte
- Department of Urology, Friedrich Alexander University Hospital Erlangen-Nürnberg, Erlangen, Germany
| |
- Omar Al-Janabi
- Department of Urology, Friedrich Alexander University Hospital Erlangen-Nürnberg, Erlangen, Germany
| |
- Martin Hart
- Institute of Virology, University of Saarland Medical School, Kirrbergerstrasse, Homburg/Saar, Germany
| |
- Friedrich Grässer
- Institute of Virology, University of Saarland Medical School, Kirrbergerstrasse, Homburg/Saar, Germany
| |
- Johannes Giedl
- Institute of Pathology, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany
| |
- Rudolf Jung
- Institute of Pathology, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany
| |
- Robert Stöhr
- Institute of Pathology, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany
| |
- Arndt Hartmann
- Institute of Pathology, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany
| |
- Verena Lieb
- Department of Urology, Friedrich Alexander University Hospital Erlangen-Nürnberg, Erlangen, Germany
| |
- Sabrina Höbel
- Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, University of Leipzig, Leipzig, Germany
| |
- Anna Peters
- Rudolf-Schönheimer-Institute for Biochemistry, University of Leipzig, Leipzig, Germany
| |
- Claudia Stäubert
- Rudolf-Schönheimer-Institute for Biochemistry, University of Leipzig, Leipzig, Germany
| |
- Bernd Wullich
- Department of Urology, Friedrich Alexander University Hospital Erlangen-Nürnberg, Erlangen, Germany
| |
- Helge Taubert
- Department of Urology, Friedrich Alexander University Hospital Erlangen-Nürnberg, Erlangen, Germany.
| |
- Achim Aigner
- Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, University of Leipzig, Leipzig, Germany
| |
Collapse
15
Humphries BA, Buschhaus JM, Chen YC, Haley HR, Qyli T, Chiang B, Shen N, Rajendran S, Cutter A, Cheng YH, Chen YT, Cong J, Spinosa PC, Yoon E, Luker KE, Luker GD. Plasminogen Activator Inhibitor 1 (PAI1) Promotes Actin Cytoskeleton Reorganization and Glycolytic Metabolism in Triple-Negative Breast Cancer.
Mol Cancer Res 2019;
17:1142-1154. [PMID:
30718260 DOI:
10.1158/1541-7786.mcr-18-0836]
[Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 10/22/2018] [Accepted: 01/29/2019] [Indexed: 11/16/2022]
Abstract
Migration and invasion of cancer cells constitute fundamental processes in tumor progression and metastasis. Migratory cancer cells commonly upregulate expression of plasminogen activator inhibitor 1 (PAI1), and PAI1 correlates with poor prognosis in breast cancer. However, mechanisms by which PAI1 promotes migration of cancer cells remain incompletely defined. Here we show that increased PAI1 drives rearrangement of the actin cytoskeleton, mitochondrial fragmentation, and glycolytic metabolism in triple-negative breast cancer (TNBC) cells. In two-dimensional environments, both stable expression of PAI1 and treatment with recombinant PAI1 increased migration, which could be blocked with the specific inhibitor tiplaxtinin. PAI1 also promoted invasion into the extracellular matrix from coculture spheroids with human mammary fibroblasts in fibrin gels. Elevated cellular PAI1 enhanced cytoskeletal features associated with migration, actin-rich migratory structures, and reduced actin stress fibers. In orthotopic tumor xenografts, we discovered that TNBC cells with elevated PAI1 show collagen fibers aligned perpendicular to the tumor margin, an established marker of invasive breast tumors. Further studies revealed that PAI1 activates ERK signaling, a central regulator of motility, and promotes mitochondrial fragmentation. Consistent with known effects of mitochondrial fragmentation on metabolism, fluorescence lifetime imaging microscopy of endogenous NADH showed that PAI1 promotes glycolysis in cell-based assays, orthotopic tumor xenografts, and lung metastases. Together, these data demonstrate for the first time that PAI1 regulates cancer cell metabolism and suggest targeting metabolism to block motility and tumor progression. IMPLICATIONS: We identified a novel mechanism through which cancer cells alter their metabolism to promote tumor progression.
Collapse
Affiliation(s)
- Brock A Humphries
- Center for Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, Michigan
| |
- Johanna M Buschhaus
- Center for Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, Michigan.,Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| |
- Yu-Chih Chen
- Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, Michigan.,Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.,Forbes Institute for Cancer Discovery, University of Michigan, Ann Arbor, Michigan
| |
- Henry R Haley
- Center for Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, Michigan
| |
- Tonela Qyli
- Center for Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, Michigan
| |
- Benjamin Chiang
- Center for Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, Michigan
| |
- Nathan Shen
- Center for Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, Michigan
| |
- Shrila Rajendran
- Center for Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, Michigan
| |
- Alyssa Cutter
- Center for Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, Michigan
| |
- Yu-Heng Cheng
- Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, Michigan
| |
- Yu-Ting Chen
- Computer Science Department UCLA, Boelter Hall, Los Angeles, California
| |
- Jason Cong
- Computer Science Department UCLA, Boelter Hall, Los Angeles, California
| |
- Phillip C Spinosa
- Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan
| |
- Euisik Yoon
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan.,Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, Michigan
| |
- Kathryn E Luker
- Center for Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, Michigan
| |
- Gary D Luker
- Center for Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, Michigan. .,Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan.,Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan
| |
Collapse
16
Yan W, Zheng H, Dong J, Liu C, Zuo Z, Liu X. MicroRNA-30b is involved in the pathological process of diabetes mellitus induced by pancreatic cancer by regulating plasminogen activator inhibitor-1.
BIOTECHNOL BIOTEC EQ 2019. [DOI:
10.1080/13102818.2019.1698977]
[Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Affiliation(s)
- Wei Yan
- Department of Anatomy, Histology and Embryology, Guangxi Medical University, Nanning, P.R. China
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, P.R. China
| |
- He Zheng
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, P.R. China
| |
- Jun Dong
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, P.R. China
| |
- Chao Liu
- Department of Genetics, Jinzhou Medical University, Jinzhou, P.R. China
| |
- Zhongfu Zuo
- Department of Anatomy, Histology and Embryology, Guangxi Medical University, Nanning, P.R. China
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, P.R. China
| |
- Xuezheng Liu
- Department of Anatomy, Histology and Embryology, Guangxi Medical University, Nanning, P.R. China
- Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, P.R. China
| |
Collapse
17
Primed atypical ductal hyperplasia-associated fibroblasts promote cell growth and polarity changes of transformed epithelium-like breast cancer MCF-7 cells via miR-200b/c-IKKβ signaling.
Cell Death Dis 2018;
9:122. [PMID:
29374150 PMCID:
PMC5833401 DOI:
10.1038/s41419-017-0133-1]
[Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Revised: 10/24/2017] [Accepted: 11/07/2017] [Indexed: 12/11/2022]
Abstract
Cancer-associated fibroblasts (CAFs) support tumorigenesis by stimulating cancer cell proliferation, and invasion, but how the premalignant stromal fibroblasts trigger epithelial changes remain unclear. We demonstrate that atypical ductal hyperplasia-associated fibroblasts (AHFs) are one kind of activated fibroblasts and stimulate cell growth and polarity change of epithelium-like tumor cell MCF-7 as CAFs-like fibroblasts. Microarray shows miR-200b and miR-200c are downregulated during AHFs and CAFs, and contribute to stromal fibroblast activity. Additionally, miR-200b/c with target gene IKKβ (inhibitor of nuclear factor kappa-B kinase β) control PAI-1 (plasminogen activator inhibitor-1) expression to regulate growth and polarity changes of MCF-7 cells through NF-κB pathway. Exploring the difference of AHFs in premalignant transformation is crucial for understanding the pathobiology of breast cancer progression.
Collapse
18
Fang WF, Chen YM, Lin CY, Huang HL, Yeh H, Chang YT, Huang KT, Lin MC. Histone deacetylase 2 (HDAC2) attenuates lipopolysaccharide (LPS)-induced inflammation by regulating PAI-1 expression.
JOURNAL OF INFLAMMATION-LONDON 2018;
15:3. [PMID:
29344006 PMCID:
PMC5763578 DOI:
10.1186/s12950-018-0179-6]
[Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 01/04/2018] [Indexed: 12/22/2022]
Abstract
Background
Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection, and is primarily characterized by an uncontrolled systemic inflammatory response. In the present study, we developed an effective adjunct therapy mediated by a novel mechanism, to attenuate overt inflammation. LPS-treated macrophages were adopted as an in vitro model of endotoxin-induced inflammation during sepsis. Experiments were carried out using primary mouse peritoneal macrophages and the murine macrophage cell line RAW264.7, to elucidate the mechanisms by which HDAC2 modulates endotoxin-induced inflammation.
Results
Results revealed that PAI-1, TNF, and MIP-2 expression were inhibited by theophylline, an HDAC2 enhancer, in a RAW macrophage cell line, following LPS-induced inflammation. Thus, HDAC2 plays an important role in immune defense by regulating the expression of inflammatory genes via the c-Jun/PAI-1 pathway. During LPS-induced inflammation, overexpression of HDAC2 was found to inhibit PAI-1, TNF, and MIP-2 expression. Following LPS stimulation, HDAC2 knockdown increased nuclear translocation and DNA binding of c-Jun to the PAI-1 gene promoter, thereby activating PAI-1 gene transcription. Furthermore, inhibition of PAI-1 by TM5275 alone or in combination with theophylline notably suppressed TNF and MIP-2 expression.
Conclusion
HDAC2 can attenuate lipopolysaccharide-induced inflammation by regulating c-Jun and PAI-1 expression in macrophages.
Collapse
Affiliation(s)
- Wen-Feng Fang
- 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 833 Taiwan.,2Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta-Pei Rd, Niao-Sung Dist, Kaohsiung, 833 Taiwan.,3Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi, 813 Taiwan
| |
- Yu-Mu Chen
- 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 833 Taiwan
| |
- Chiung-Yu Lin
- 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 833 Taiwan
| |
- Hui-Lin Huang
- 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 833 Taiwan
| |
- Hua Yeh
- 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 833 Taiwan
| |
- Ya-Ting Chang
- 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 833 Taiwan
| |
- Kuo-Tung Huang
- 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 833 Taiwan
| |
- Meng-Chih Lin
- 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 833 Taiwan.,2Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta-Pei Rd, Niao-Sung Dist, Kaohsiung, 833 Taiwan
| |
Collapse
19
Fortenberry YM, Brandal SM, Carpentier G, Hemani M, Pathak AP. Intracellular Expression of PAI-1 Specific Aptamers Alters Breast Cancer Cell Migration, Invasion and Angiogenesis.
PLoS One 2016;
11:e0164288. [PMID:
27755560 PMCID:
PMC5068744 DOI:
10.1371/journal.pone.0164288]
[Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Accepted: 09/22/2016] [Indexed: 02/07/2023] Open
Abstract
Plasminogen activator inhibitor-1 (PAI-1) is elevated in various cancers, where it has been shown to effect cell migration and invasion and angiogenesis. While, PAI-1 is a secreted protein, its intercellular levels are increased in cancer cells. Consequently, intracellular PAI-1 could contribute to cancer progression. While various small molecule inhibitors of PAI-1 are currently being investigated, none specifically target intracellular PAI-1. A class of inhibitors, termed aptamers, has been used effectively in several clinical applications. We previously generated RNA aptamers that target PAI-1 and demonstrated their ability to inhibit extracellular PAI-1. In the current study we explored the effect of these aptamers on intracellular PAI-1. We transiently transfected the PAI-1 specific aptamers into both MDA-MB-231 human breast cancer cells, and human umbilical vein endothelial cells (HUVECs) and studied their effects on cell migration, invasion and angiogenesis. Aptamer expressing MDA-MB-231 cells exhibited a decrease in cell migration and invasion. Additionally, intracellular PAI-1 and urokinase plasminogen activator (uPA) protein levels decreased, while the PAI-1/uPA complex increased. Moreover, a significant decrease in endothelial tube formation in HUVECs transfected with the aptamers was observed. In contrast, conditioned media from aptamer transfected MDA-MB-231 cells displayed a slight pro-angiogenic effect. Collectively, our study shows that expressing functional aptamers inside breast and endothelial cells is feasible and may exhibit therapeutic potential.
Collapse
Affiliation(s)
- Yolanda M Fortenberry
- Department of Pediatric Hematology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.,Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| |
- Stephanie M Brandal
- Department of Pediatric Hematology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| |
- Gilles Carpentier
- Laboratoire CRRET, Faculté des Sciences et Technologie, Université Paris-Est Créteil, 61 avenue du général De Gaulle, 94010 Créteil, France
| |
- Malvi Hemani
- Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| |
- Arvind P Pathak
- Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| |
Collapse
20
Botla SK, Savant S, Jandaghi P, Bauer AS, Mücke O, Moskalev EA, Neoptolemos JP, Costello E, Greenhalf W, Scarpa A, Gaida MM, Büchler MW, Strobel O, Hackert T, Giese NA, Augustin HG, Hoheisel JD. Early Epigenetic Downregulation of microRNA-192 Expression Promotes Pancreatic Cancer Progression.
Cancer Res 2016;
76:4149-59. [PMID:
27216198 DOI:
10.1158/0008-5472.can-15-0390]
[Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2015] [Accepted: 04/22/2016] [Indexed: 12/27/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by very early metastasis, suggesting the hypothesis that metastasis-associated changes may occur prior to actual tumor formation. In this study, we identified miR-192 as an epigenetically regulated suppressor gene with predictive value in this disease. miR-192 was downregulated by promoter methylation in both PDAC and chronic pancreatitis, the latter of which is a major risk factor for the development of PDAC. Functional studies in vitro and in vivo in mouse models of PDAC showed that overexpression of miR-192 was sufficient to reduce cell proliferation and invasion. Mechanistic analyses correlated changes in miR-192 promoter methylation and expression with epithelial-mesenchymal transition. Cell proliferation and invasion were linked to altered expression of the miR-192 target gene SERPINE1 that is encoding the protein plasminogen activator inhibitor-1 (PAI-1), an established regulator of these properties in PDAC cells. Notably, our data suggested that invasive capacity was altered even before neoplastic transformation occurred, as triggered by miR-192 downregulation. Overall, our results highlighted a role for miR-192 in explaining the early metastatic behavior of PDAC and suggested its relevance as a target to develop for early diagnostics and therapy. Cancer Res; 76(14); 4149-59. ©2016 AACR.
Collapse
Affiliation(s)
- Sandeep K Botla
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| |
- Soniya Savant
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faulty Mannheim, Heidelberg University, Mannheim, Germany
| |
- Pouria Jandaghi
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| |
- Andrea S Bauer
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| |
- Oliver Mücke
- Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany
| |
- Evgeny A Moskalev
- Diagnostic Molecular Pathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| |
- John P Neoptolemos
- National Institute for Health Research, Liverpool Pancreas Biomedical Research Unit, Liverpool, UK
| |
- Eithne Costello
- National Institute for Health Research, Liverpool Pancreas Biomedical Research Unit, Liverpool, UK
| |
- William Greenhalf
- National Institute for Health Research, Liverpool Pancreas Biomedical Research Unit, Liverpool, UK
| |
- Aldo Scarpa
- Department of Pathology and Diagnostics, Università di Verona, Verona, Italy
| |
- Matthias M Gaida
- Department of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| |
- Markus W Büchler
- Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany
| |
- Oliver Strobel
- Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany
| |
- Thilo Hackert
- Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany
| |
- Nathalia A Giese
- Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany
| |
- Hellmut G Augustin
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faulty Mannheim, Heidelberg University, Mannheim, Germany. German Cancer Consortium, Heidelberg, Germany
| |
- Jörg D Hoheisel
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
| |
Collapse
21
Jin B, Choung PH. Recombinant Human Plasminogen Activator Inhibitor-1 Accelerates Odontoblastic Differentiation of Human Stem Cells from Apical Papilla.
Tissue Eng Part A 2016;
22:721-32. [PMID:
27046084 DOI:
10.1089/ten.tea.2015.0273]
[Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Dental caries, the most prevalent oral disease in dental patients, involves the phases of demineralization and destruction of tooth hard tissues like enamel, dentin, and cementum. Dentin is a major component of the root and is also the innermost layer that protects the tooth nerve, exposure of which results in pain. In this study, we used human stem cells from apical papilla (hSCAP), which are early progenitor cells, to examine the effects of recombinant human plasminogen activator inhibitor-1 (rhPAI-1) on odontogenic differentiation in vitro and in vivo. We demonstrated that rhPAI-1 promoted the proliferation and odontogenic differentiation of hSCAP and increased the expression levels of odontoblast-associated markers. We also observed that rhPAI-1 upregulated the expression of Smad4, nuclear factor I-C (NFI-C), Runx2, and osterix (OSX) during odontogenic differentiation. Notably, transplantation of rhPAI-1-treated hSCAP effectively induced odontoblastic differentiation and dentinal formation. And the differentiated odontoblast-like cells showed numerous odontoblast processes inserted in dentin tubules and arranged collagen fibers. Furthermore, odontoblast-associated markers were more highly expressed in the rhPAI-1-induced differentiated odontoblast-like cells compared with the control group. These markers were also more highly expressed in the newly formed dentin-like tissue of the rhPAI-1-treated group compared with the control group. Consistent with our in vitro results, the expression levels of Smad4, NFI-C, and OSX were also increased in the rhPAI-1-treated group compared with the control group. Taken together, these results suggest that rhPAI-1 promotes odontoblast differentiation and dentin formation of hSCAP, and Smad4/NFI-C/OSX may play critical roles in the rhPAI-1-induced odontogenic differentiation. Thus, dental stem cells from apical papilla combined with rhPAI-1 could lead to dentin regeneration in clinical implications.
Collapse
Affiliation(s)
- Bin Jin
- Department of Oral and Maxillofacial Surgery, Tooth Bioengineering Laboratory, Dental Research Institute, School of Dentistry, National University , Seoul, Korea
| |
- Pill-Hoon Choung
- Department of Oral and Maxillofacial Surgery, Tooth Bioengineering Laboratory, Dental Research Institute, School of Dentistry, National University , Seoul, Korea
| |
Collapse
22
Inflammation as a Keystone of Bone Marrow Stroma Alterations in Primary Myelofibrosis.
Mediators Inflamm 2015;
2015:415024. [PMID:
26640324 PMCID:
PMC4660030 DOI:
10.1155/2015/415024]
[Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 10/08/2015] [Accepted: 10/15/2015] [Indexed: 01/11/2023] Open
Abstract
Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm where severity as well as treatment complexity is mainly attributed to a long lasting disease and presence of bone marrow stroma alterations as evidenced by myelofibrosis, neoangiogenesis, and osteosclerosis. While recent understanding of mutations role in hematopoietic cells provides an explanation for pathological myeloproliferation, functional involvement of stromal cells in the disease pathogenesis remains poorly understood. The current dogma is that stromal changes are secondary to the cytokine “storm” produced by the hematopoietic clone cells. However, despite therapies targeting the myeloproliferation-sustaining clones, PMF is still regarded as an incurable disease except for patients, who are successful recipients of allogeneic stem cell transplantation. Although the clinical benefits of these inhibitors have been correlated with a marked reduction in serum proinflammatory cytokines produced by the hematopoietic clones, further demonstrating the importance of inflammation in the pathological process, these treatments do not address the role of the altered bone marrow stroma in the pathological process. In this review, we propose hypotheses suggesting that the stroma is inflammatory-imprinted by clonal hematopoietic cells up to a point where it becomes “independent” of hematopoietic cell stimulation, resulting in an inflammatory vicious circle requiring combined stroma targeted therapies.
Collapse
23
Jackson DP, Joshi AD, Elferink CJ. Ah Receptor Pathway Intricacies; Signaling Through Diverse Protein Partners and DNA-Motifs.
Toxicol Res (Camb) 2015;
4:1143-1158. [PMID:
26783425 PMCID:
PMC4714567 DOI:
10.1039/c4tx00236a]
[Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The Ah receptor is a transcription factor that modulates gene expression via interactions with multiple protein partners; these are reviewed, including the novel NC-XRE pathway involving KLF6.
Collapse
24
Pan XY, Wang Y, Su J, Huang GX, Cao DM, Qu S, Lu J. The mechanism and significance of synergistic induction of the expression of plasminogen activator inhibitor-1 by glucocorticoid and transforming growth factor beta in human ovarian cancer cells.
Mol Cell Endocrinol 2015;
407:37-45. [PMID:
25770462 DOI:
10.1016/j.mce.2015.03.005]
[Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Revised: 03/05/2015] [Accepted: 03/06/2015] [Indexed: 11/17/2022]
Abstract
Plasminogen activator inhibitor-1 (PAI-1) plays a key role in tissue remodeling and tumor development by suppression of plasminogen activator function. Glucocorticoids (GCs) and transforming growth factor beta (TGF-β) signal pathways cross-talk to regulate gene expression, but the mechanism is poorly understood. Here we investigated the mechanism and significance of co-regulation of PAI-1 by TGF-β and dexamethasone (DEX), a synthetic glucocorticoid in ovarian cancer cells. We found that TGF-β and DEX showed rapidly synergistic induction of PAI-1 expression, which contributed to the early pro-adhesion effects. The synergistic induction effect was accomplished by several signal pathways, including GC receptor (GR) pathway and TGF-β-activated p38MAPK, ERK and Smad3 pathways. TGF-β-activated p38MAPK and ERK pathways cross-talked with GR pathway to augment the expression of PAI-1 through enhancing DEX-induced GR phosphorylation at Ser211 in ovarian cancer cells. These findings reveal possible novel mechanisms by which TGF-β pathways cooperatively cross-talk with GR pathway to regulate gene expression.
Collapse
Affiliation(s)
- Xiao-yu Pan
- Department of Endocrinology, Shanghai 10th People's Hospital, Tongji University, Shanghai 200072, China
| |
- Yan Wang
- Department of Pathophysiology, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China
| |
- Jie Su
- Department of Pathophysiology, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China
| |
- Gao-xiang Huang
- Department of Pathophysiology, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China
| |
- Dong-mei Cao
- Department of Pathophysiology, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China
| |
- Shen Qu
- Department of Endocrinology, Shanghai 10th People's Hospital, Tongji University, Shanghai 200072, China
| |
- Jian Lu
- Department of Pathophysiology, The Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China.
| |
Collapse
25
Lankford L, Selby T, Becker J, Ryzhuk V, Long C, Farmer D, Wang A. Early gestation chorionic villi-derived stromal cells for fetal tissue engineering.
World J Stem Cells 2015;
7:195-207. [PMID:
25621120 PMCID:
PMC4300931 DOI:
10.4252/wjsc.v7.i1.195]
[Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Revised: 11/04/2014] [Accepted: 11/07/2014] [Indexed: 02/06/2023] Open
Abstract
AIM
To investigate the potential for early gestation placenta-derived mesenchymal stromal cells (PMSCs) for fetal tissue engineering.
METHODS
PMSCs were isolated from early gestation chorionic villus tissue by explant culture. Chorionic villus sampling (CVS)-size tissue samples (mean = 35.93 mg) were used to test the feasibility of obtaining large cell numbers from CVS within a clinically relevant timeframe. We characterized PMSCs isolated from 6 donor placentas by flow cytometry immunophenotyping, multipotency assays, and through immunofluorescent staining. Protein secretion from PMSCs was examined using two cytokine array assays capable of probing for over 70 factors in total. Delivery vehicle compatibility of PMSCs was determined using three common scaffold systems: fibrin glue, collagen hydrogel, and biodegradable nanofibrous scaffolds made from a combination of polylactic acid (PLA) and poly(lactic-co-glycolic acid) (PLGA). Viral transduction of PMSCs was performed using a Luciferase-GFP-containing lentiviral vector and efficiency of transduction was tested by fluorescent microscopy and flow cytometry analysis.
RESULTS
We determined that an average of 2.09 × 10(6) (SD ± 8.59 × 10(5)) PMSCs could be obtained from CVS-size tissue samples within 30 d (mean = 27 d, SD ± 2.28), indicating that therapeutic numbers of cells can be rapidly expanded from very limited masses of tissue. Immunophenotyping by flow cytometry demonstrated that PMSCs were positive for MSC markers CD105, CD90, CD73, CD44, and CD29, and were negative for hematopoietic and endothelial markers CD45, CD34, and CD31. PMSCs displayed trilineage differentiation capability, and were found to express developmental transcription factors Sox10 and Sox17 as well as neural-related structural proteins NFM, Nestin, and S100β. Cytokine arrays revealed a robust and extensive profile of PMSC-secreted cytokines and growth factors, and detected 34 factors with spot density values exceeding 10(3). Detected factors had widely diverse functions that include modulation of angiogenesis and immune response, cell chemotaxis, cell proliferation, blood vessel maturation and homeostasis, modulation of insulin-like growth factor activity, neuroprotection, extracellular matrix degradation and even blood coagulation. Importantly, PMSCs were also determined to be compatible with both biological and synthetic material-based delivery vehicles such as collagen and fibrin hydrogels, and biodegradable nanofiber scaffolds made from a combination of PLA and PLGA. Finally, we demonstrated that PMSCs can be efficiently transduced (> 95%) with a Luciferase-GFP-containing lentiviral vector for future in vivo cell tracking after transplantation.
CONCLUSION
Our findings indicate that PMSCs represent a unique source of cells that can be effectively utilized for in utero cell therapy and tissue engineering.
Collapse
Affiliation(s)
- Lee Lankford
- Lee Lankford, Taryn Selby, James Becker, Volodymyr Ryzhuk, Connor Long, Diana Farmer, Aijun Wang, Department of Surgery, University of California, Davis Health System, Sacramento, CA 95817, United States
| |
- Taryn Selby
- Lee Lankford, Taryn Selby, James Becker, Volodymyr Ryzhuk, Connor Long, Diana Farmer, Aijun Wang, Department of Surgery, University of California, Davis Health System, Sacramento, CA 95817, United States
| |
- James Becker
- Lee Lankford, Taryn Selby, James Becker, Volodymyr Ryzhuk, Connor Long, Diana Farmer, Aijun Wang, Department of Surgery, University of California, Davis Health System, Sacramento, CA 95817, United States
| |
- Volodymyr Ryzhuk
- Lee Lankford, Taryn Selby, James Becker, Volodymyr Ryzhuk, Connor Long, Diana Farmer, Aijun Wang, Department of Surgery, University of California, Davis Health System, Sacramento, CA 95817, United States
| |
- Connor Long
- Lee Lankford, Taryn Selby, James Becker, Volodymyr Ryzhuk, Connor Long, Diana Farmer, Aijun Wang, Department of Surgery, University of California, Davis Health System, Sacramento, CA 95817, United States
| |
- Diana Farmer
- Lee Lankford, Taryn Selby, James Becker, Volodymyr Ryzhuk, Connor Long, Diana Farmer, Aijun Wang, Department of Surgery, University of California, Davis Health System, Sacramento, CA 95817, United States
| |
- Aijun Wang
- Lee Lankford, Taryn Selby, James Becker, Volodymyr Ryzhuk, Connor Long, Diana Farmer, Aijun Wang, Department of Surgery, University of California, Davis Health System, Sacramento, CA 95817, United States
| |
Collapse
26
Rouch A, Vanucci-Bacqué C, Bedos-Belval F, Baltas M. Small molecules inhibitors of plasminogen activator inhibitor-1 - an overview.
Eur J Med Chem 2015;
92:619-36. [PMID:
25615797 DOI:
10.1016/j.ejmech.2015.01.010]
[Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Revised: 01/05/2015] [Accepted: 01/07/2015] [Indexed: 12/14/2022]
Abstract
PAI-1, a glycoprotein from the serpin family and the main inhibitor of tPA and uPA, plays an essential role in the regulation of intra and extravascular fibrinolysis by inhibiting the formation of plasmin from plasminogen. PAI-1 is also involved in pathological processes such as thromboembolic diseases, atherosclerosis, fibrosis and cancer. The inhibition of PAI-1 activity by small organic molecules has been observed in vitro and with some in vivo models. Based on these findings, PAI-1 appears as a potential therapeutic target for several pathological conditions. Over the past decades, many efforts have therefore been devoted to developing PAI-1 inhibitors. This article provides an overview of the publishing activity on small organic molecules used as PAI-1 inhibitors. The chemical synthesis of the most potent inhibitors as well as their biological and biochemical evaluations is also presented.
Collapse
Affiliation(s)
- Anne Rouch
- Université Paul Sabatier Toulouse III, UMR 5068, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France; CNRS, UMR 5068, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France
| |
- Corinne Vanucci-Bacqué
- Université Paul Sabatier Toulouse III, UMR 5068, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France; CNRS, UMR 5068, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France
| |
- Florence Bedos-Belval
- Université Paul Sabatier Toulouse III, UMR 5068, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France; CNRS, UMR 5068, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France.
| |
- Michel Baltas
- Université Paul Sabatier Toulouse III, UMR 5068, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France; CNRS, UMR 5068, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France.
| |
Collapse
27
Functional stability of plasminogen activator inhibitor-1.
ScientificWorldJournal 2014;
2014:858293. [PMID:
25386620 PMCID:
PMC4214104 DOI:
10.1155/2014/858293]
[Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 09/17/2014] [Indexed: 12/23/2022] Open
Abstract
Plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of plasminogen activators, such as tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), and a major regulator of the fibrinolytic system. PAI-1 plays a pivotal role in acute thrombotic events such as deep vein thrombosis (DVT) and myocardial infarction (MI). The biological effects of PAI-1 extend far beyond thrombosis including its critical role in fibrotic disorders, atherosclerosis, renal and pulmonary fibrosis, type-2 diabetes, and cancer. The conversion of PAI-1 from the active to the latent conformation appears to be unique among serpins in that it occurs spontaneously at a relatively rapid rate. Latency transition is believed to represent a regulatory mechanism, reducing the risk of thrombosis from a prolonged antifibrinolytic action of PAI-1. Thus, relying solely on plasma concentrations of PAI-1 without assessing its function may be misleading in interpreting the role of PAI-1 in many complex diseases. Environmental conditions, interaction with other proteins, mutations, and glycosylation are the main factors that have a significant impact on the stability of the PAI-1 structure. This review provides an overview on the current knowledge on PAI-1 especially importance of PAI-1 level and stability and highlights the potential use of PAI-1 inhibitors for treating cardiovascular disease.
Collapse
28
Thapa B, Koo BH, Kim YH, Kwon HJ, Kim DS. Plasminogen activator inhibitor-1 regulates infiltration of macrophages into melanoma via phosphorylation of FAK-Tyr⁹²⁵.
Biochem Biophys Res Commun 2014;
450:1696-701. [PMID:
25063025 DOI:
10.1016/j.bbrc.2014.07.070]
[Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2014] [Accepted: 07/15/2014] [Indexed: 12/22/2022]
Abstract
Tumor-infiltrating macrophages are potential candidates for cancer immunotherapy. However, the detailed molecular mechanism underlying macrophage infiltration into tumors is poorly understood. Based on our previous finding that plasminogen activator inhibitor-1 (PAI-1) enhances vitronectin-dependent migration of macrophages, we investigated the potential role of PAI-1 in macrophage invasion into melanoma. Experimental evidence obtained from spheroid confrontation assay clearly showed that PAI-1 overexpression significantly enhanced the invasion of RAW 264.7 cells into B16F10 melanoma. We further demonstrated that PAI-1 induces phosphorylation of focal adhesion kinase (FAK) at Tyr(925), which, in turn, mediated the invasion of macrophages into the melanoma. This work further illustrates that low-density lipoprotein receptor related-protein 1 (LRP1) is essential for PAI-1-mediated FAK phosphorylation and macrophage invasion into melanoma. In conclusion, our study demonstrates a novel role of PAI-1 in macrophage invasion into melanoma and provides insights into the underlying molecular mechanism.
Collapse
Affiliation(s)
- Bikash Thapa
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 134 Sinchon-Dong, Seodaemun-Gu, 120-749 Seoul, Republic of Korea
| |
- Bon-Hun Koo
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 134 Sinchon-Dong, Seodaemun-Gu, 120-749 Seoul, Republic of Korea
| |
- Yeon Hyang Kim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 134 Sinchon-Dong, Seodaemun-Gu, 120-749 Seoul, Republic of Korea
| |
- Hyung-Joo Kwon
- Department of Microbiology, College of Medicine, Hallym University, Gangwon-do 200-702, Republic of Korea
| |
- Doo-Sik Kim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 134 Sinchon-Dong, Seodaemun-Gu, 120-749 Seoul, Republic of Korea.
| |
Collapse
29
Damare J, Brandal S, Fortenberry YM. Inhibition of PAI-1 antiproteolytic activity against tPA by RNA aptamers.
Nucleic Acid Ther 2014;
24:239-49. [PMID:
24922319 DOI:
10.1089/nat.2013.0475]
[Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Plasminogen activator inhibitor-1 (PAI-1; SERPINE1) inhibits the plasminogen activators: tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). Elevated levels of PAI-1 have been correlated with an increased risk for cardiovascular disease. Pharmacologically suppressing PAI-1 might prevent, or successfully treat PAI-1 related vascular diseases. This can potentially be accomplished by using small RNA molecules (aptamers). This study's goal is to develop RNA aptamers to a region of PAI-1 that will prevent the ability of PAI-1 to interact with the plasminogen activators. The aptamers were generated through a systematic evolution of ligands via exponential enrichment approach that ensures the creation of RNA molecules that bind to our target protein, PAI-1. In vitro assays were used to determine the effect of these aptamers on PAI-1's inhibitory activity. Three aptamers that bind to PAI-1 with affinities in the nanomolar range were isolated. The aptamer clones R10-4 and R10-2 inhibited PAI-1's antiproteolytic activity against tPA and disrupted PAI-1's ability to form a stable covalent complex with tPA. Increasing aptamer concentrations correlated positively with an increase in cleaved PAI-1. To the best of our knowledge, this is the first report of RNA molecules that inhibit the antiproteolytic activity of PAI-1.
Collapse
Affiliation(s)
- Jared Damare
- 1 Department of Pediatric Hematology, Johns Hopkins University School of Medicine , Baltimore, Maryland
| |
| |
| |
Collapse
30
Chen F, Zhang G, Hong Z, Lin Z, Lei M, Huang M, Hu L. Design, synthesis, and SAR of embelin analogues as the inhibitors of PAI-1 (plasminogen activator inhibitor-1).
Bioorg Med Chem Lett 2014;
24:2379-82. [DOI:
10.1016/j.bmcl.2014.03.045]
[Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Revised: 03/12/2014] [Accepted: 03/15/2014] [Indexed: 02/01/2023]
31
Thapa B, Kim YH, Kwon HJ, Kim DS. The LRP1-independent mechanism of PAI-1-induced migration in CpG-ODN activated macrophages.
Int J Biochem Cell Biol 2014;
49:17-25. [PMID:
24440681 DOI:
10.1016/j.biocel.2014.01.008]
[Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Revised: 12/10/2013] [Accepted: 01/07/2014] [Indexed: 12/24/2022]
Abstract
CpG-oligodeoxynucleotides (CpG-ODNs) induces plasminogen activator inhibitor type-1 (PAI-1) expression in macrophages, leading to enhanced migration through vitronectin. However, the precise role of low-density lipoprotein receptor-related protein 1 (LRP1) in PAI-1 induced migration of macrophages in the inflammatory environment is not known. In this study, we elucidated a novel mechanism describing the altered role of LRP1 in macrophage migration depending on the activation state of the cells. Experimental evidence clearly shows that the blocking of LRP1 function inhibited the PAI-induced migration of resting RAW 264.7 cells through vitronectin but exerted a pro-migratory effect on CpG-ODN-activated cells. We also demonstrate that CpG-ODN downregulates the protein and mRNA levels of LRP1 both in vivo and in vitro, a function that depends on the NF-κB signaling pathway, resulting in reduced internalization of PAI-1. This work illustrates the distinct mechanism that PAI-1-induced migration of CpG-ODN-activated cells through vitronectin depends on the interaction of PAI-1 with vitronectin but not LRP1 unlike in the resting cells, where the migration is LRP1 dependent and vitronectin independent. In conclusion, our experimental results demonstrate the altered function of LRP1 in the migration of resting and activated macrophages in the context of microenvironmental extracellular matrix components.
Collapse
Affiliation(s)
- Bikash Thapa
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 134 Sinchon-Dong Seodaemun-Gu, 120-749 Seoul, Republic of Korea
| |
- Yeon Hyang Kim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 134 Sinchon-Dong Seodaemun-Gu, 120-749 Seoul, Republic of Korea
| |
- Hyung-Joo Kwon
- Department of Microbiology, College of Medicine, Hallym University, Gangwon-do 200-702, Republic of Korea
| |
- Doo-Sik Kim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 134 Sinchon-Dong Seodaemun-Gu, 120-749 Seoul, Republic of Korea.
| |
Collapse
32
Mengele K, Napieralski R, Magdolen V, Reuning U, Gkazepis A, Sweep F, Brünner N, Foekens J, Harbeck N, Schmitt M. Characteristics of the level-of-evidence-1 disease forecast cancer biomarkers uPA and its inhibitor PAI-1.
Expert Rev Mol Diagn 2014;
10:947-62. [DOI:
10.1586/erm.10.73]
[Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
33
Du F, Zhang X, Li S, Wang Y, Zheng M, Wang Y, Zhao S, Wu J, Gui L, Zhao M, Peng S. Mechanism of forming trimer, self-assembling nano-particle and inhibiting tumor growth of small molecule CIPPCT.
MEDCHEMCOMM 2014. [DOI:
10.1039/c4md00158c]
[Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The mechanism whereby CIPPCT forms nanoparticles capable of delivery in circulation and adhering on cancer cells is presented.
Collapse
Affiliation(s)
- Fengxiang Du
- College of Pharmaceutical Sciences
- Capital Medical University
- Beijing 100069, P.R. China
| |
- Xiaoyi Zhang
- College of Pharmaceutical Sciences
- Capital Medical University
- Beijing 100069, P.R. China
| |
- Shan Li
- College of Pharmaceutical Sciences
- Capital Medical University
- Beijing 100069, P.R. China
| |
- Yaonan Wang
- College of Pharmaceutical Sciences
- Capital Medical University
- Beijing 100069, P.R. China
| |
- Meiqing Zheng
- College of Pharmaceutical Sciences
- Capital Medical University
- Beijing 100069, P.R. China
| |
- Yuji Wang
- College of Pharmaceutical Sciences
- Capital Medical University
- Beijing 100069, P.R. China
| |
- Shurui Zhao
- College of Pharmaceutical Sciences
- Capital Medical University
- Beijing 100069, P.R. China
| |
- Jianhui Wu
- College of Pharmaceutical Sciences
- Capital Medical University
- Beijing 100069, P.R. China
| |
- Lin Gui
- College of Pharmaceutical Sciences
- Capital Medical University
- Beijing 100069, P.R. China
| |
- Ming Zhao
- College of Pharmaceutical Sciences
- Capital Medical University
- Beijing 100069, P.R. China
- Department of Biomedical Science and Environmental Biology
- Kaohsiung Medical University
| |
- Shiqi Peng
- College of Pharmaceutical Sciences
- Capital Medical University
- Beijing 100069, P.R. China
| |
Collapse
34
MRIOUAH JIHANE, BOURA CÉDRIC, GARGOURI MYRIEM, PLÉNAT FRANÇOIS, FAIVRE BÉATRICE. PTEN expression is involved in the invasive properties of HNSCC: A key protein to consider in locoregional recurrence.
Int J Oncol 2013;
44:709-16. [DOI:
10.3892/ijo.2013.2219]
[Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Accepted: 10/11/2013] [Indexed: 11/06/2022] Open
35
Taubert H, Magdolen V, Kotzsch M. Impact of expression of the uPA system in sarcomas.
Biomark Med 2013;
7:473-80. [PMID:
23734810 DOI:
10.2217/bmm.12.105]
[Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The uPA system mainly comprises the urokinase-type plasminogen activator uPA, the cell-surface receptor uPA receptor and the inhibitor PAI-1. Its clinical and prognostic impact especially in breast cancer is well investigated. In this short report, we summarize the published data describing expression of uPA, PAI-1 and uPA receptor and their relevance to clinical and survival data in sarcomas underlining their impact as tumor biomarkers in this tumor type as well.
Collapse
Affiliation(s)
- Helge Taubert
- Clinic of Urology, Division of Molecular Urology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
| |
| |
| |
Collapse
36
Kasza A. Signal-dependent Elk-1 target genes involved in transcript processing and cell migration.
BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2013;
1829:1026-33. [PMID:
23711433 DOI:
10.1016/j.bbagrm.2013.05.004]
[Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Revised: 05/16/2013] [Accepted: 05/17/2013] [Indexed: 11/25/2022]
Abstract
Elk-1 was regarded as a transcription factor engaged mainly in the regulation of cell growth, differentiation, and survival. Recent findings show the engagement of Elk-1 in the control of expression of genes encoding proteins involved in transcript turnover, such as MCPIP1/ZC3H12A and tristetraprolin (TTP/ZFP36). Thus, Elk-1 plays an important role in the control of gene expression not only through the stimulation of expression of transcription factors, but also through regulation of transcript half-live. Moreover, Elk-1 is engaged in the regulation of expression of genes encoding proteins that control proteolytic activity, such as inhibitor of plasminogen activator-1 (PAI-1) and metalloproteinases-2 and -9 (MMP-2 and MMP-9). This review summarizes the biological roles of proteins with expression regulated by Elk-1, involved in transcripts turnover or in cell migration. The broad range of function of these proteins illustrates the complex role of Elk-1 in the regulation of cancer and inflammation.
Collapse
Affiliation(s)
- Aneta Kasza
- Department of Cell Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland.
| |
Collapse
37
Hagelgans A, Menschikowski M, Fuessel S, Nacke B, Arneth BM, Wirth MP, Siegert G. Deregulated expression of urokinase and its inhibitor type 1 in prostate cancer cells: role of epigenetic mechanisms.
Exp Mol Pathol 2013;
94:458-65. [PMID:
23541763 DOI:
10.1016/j.yexmp.2013.03.006]
[Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2013] [Revised: 03/01/2013] [Accepted: 03/19/2013] [Indexed: 10/27/2022]
Abstract
Plasminogen activator inhibitor-1 (PAI-1) and urokinase-type plasminogen activator (uPA) play a crucial role in cancer progression. In the present study we examined the regulation of PAI-1 and uPA expressions in normal prostate epithelial cells (PrEC) and the prostate cancer cell lines LNCaP, DU-145, and PC-3. The antigen and mRNA levels of PAI-1 were down-regulated in cancer cells, especially in LNCaP and DU-145. In the presence of proinflammatory cytokines, an increase of PAI-1 mRNA levels was observed in PrEC, LNCaP and PC-3, but not in DU-145 cells. Treatment with demethylating agent, 5-aza-2'-deoxycytidine increased the level of PAI-1 transcript in DU-145 cells and restored the inducing effect of cytokines on PAI-1 expression. An aberrant methylation of PAI-1 promoter in DU-145 and LNCaP cells was shown by methylation-sensitive high resolution melting (MS-HRM) analysis. PAI-1 methylation was also significantly increased in tumor samples (23.2±1.7%) in comparison to adjacent non-tumor tissue (6.0±0.8%). Furthermore, the expression of uPA was increased in high invasive cell lines DU-145 and PC-3 in comparison to PrEC and low invasive LNCaP cells. MS-HRM analysis revealed aberrant methylation of uPA promoter in LNCaP cells, but not in PrEC, DU-145 and PC-3 cells, as well as in normal and prostate cancer tissue samples. In conclusion, the study shows that PAI-1 and uPA expressions were changed in opposite directions in high invasive prostate cancer cell lines resulting in a strong decrease of PAI-1/uPA ratio, which may indicate a shift towards proteolytic activities. Methylation of the PAI-1 gene is suggested as one of the molecular mechanisms involved in the cancer-associated down-regulation of the PAI-1 expression.
Collapse
Affiliation(s)
- Albert Hagelgans
- Institute of Clinical Chemistry and Laboratory Medicine of Technical University of Dresden, Medical Faculty Carl Gustav Carus, Dresden, Germany.
| |
| |
| |
| |
| |
| |
| |
Collapse
38
Yang H, Li G, Wu JJ, Wang L, Uhler M, Simeone DM. Protein kinase A modulates transforming growth factor-β signaling through a direct interaction with Smad4 protein.
J Biol Chem 2013;
288:8737-8749. [PMID:
23362281 PMCID:
PMC3605691 DOI:
10.1074/jbc.m113.455675]
[Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2013] [Indexed: 12/21/2022] Open
Abstract
Transforming growth factor β (TGFβ) signaling normally functions to regulate embryonic development and cellular homeostasis. It is increasingly recognized that TGFβ signaling is regulated by cross-talk with other signaling pathways. We previously reported that TGFβ activates protein kinase A (PKA) independent of cAMP through an interaction of an activated Smad3-Smad4 complex and the regulatory subunit of the PKA holoenzyme (PKA-R). Here we define the interaction domains of Smad4 and PKA-R and the functional consequences of this interaction. Using a series of Smad4 and PKA-R truncation mutants, we identified amino acids 290-300 of the Smad4 linker region as critical for the specific interaction of Smad4 and PKA-R. Co-immunoprecipitation assays showed that the B cAMP binding domain of PKA-R was sufficient for interaction with Smad4. Targeting of B domain regions conserved among all PKA-R isoforms and exposed on the molecular surface demonstrated that amino acids 281-285 and 320-329 were required for complex formation with Smad4. Interactions of these specific regions of Smad4 and PKA-R were necessary for TGFβ-mediated increases in PKA activity, CREB (cAMP-response element-binding protein) phosphorylation, induction of p21, and growth inhibition. Moreover, this Smad4-PKA interaction was required for TGFβ-induced epithelial mesenchymal transition, invasion of pancreatic tumor cells, and regulation of tumor growth in vivo.
Collapse
Affiliation(s)
- Huibin Yang
- Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109
| |
- Gangyong Li
- Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109
| |
- Jing-Jiang Wu
- Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109
| |
- Lidong Wang
- Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109
| |
- Michael Uhler
- Department of Biochemistry, University of Michigan, Ann Arbor, Michigan 48109
| |
- Diane M Simeone
- Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109; Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109; Translational Oncology Program, University of Michigan, Ann Arbor, Michigan 48109.
| |
Collapse
39
Sánchez-Tilló E, de Barrios O, Siles L, Amendola PG, Darling DS, Cuatrecasas M, Castells A, Postigo A. ZEB1 Promotes invasiveness of colorectal carcinoma cells through the opposing regulation of uPA and PAI-1.
Clin Cancer Res 2013;
19:1071-82. [PMID:
23340304 DOI:
10.1158/1078-0432.ccr-12-2675]
[Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE
Carcinoma cells enhance their invasive capacity through dedifferentiation and dissolution of intercellular adhesions. A key activator of this process is the ZEB1 transcription factor, which is induced in invading cancer cells by canonical Wnt signaling (β-catenin/TCF4). Tumor invasiveness also entails proteolytic remodeling of the peritumoral stroma. This study aimed to investigate the potential regulation by ZEB1 of the plasminogen proteolytic system constituted by the urokinase plasminogen activator (uPA), and its inhibitor, plasminogen activator inhibitor-1 (PAI-1).
EXPERIMENTAL DESIGN
Through multiple experimental approaches, colorectal carcinoma (CRC) cell lines and samples from human primary CRC and ZEB1 (-/-) mice were used to examine ZEB1-mediated regulation of uPA and PAI-1 at the protein, mRNA, and transcriptional level.
RESULTS
ZEB1 regulates uPA and PAI-1 in opposite directions: induces uPA and inhibits PAI-1. In vivo expression of uPA depends on ZEB1 as it is severely reduced in the developing intestine of ZEB1 null (-/-) mice. Optimal induction of uPA by Wnt signaling requires ZEB1 expression. ZEB1 binds to the uPA promoter and activates its transcription through a mechanism implicating the histone acetyltransferase p300. In contrast, inhibition of PAI-1 by ZEB1 does not involve transcriptional repression but rather downregulation of mRNA stability. ZEB1-mediated tumor cell migration and invasion depend on its induction of uPA. ZEB1 coexpresses with uPA in cancer cells at the invasive front of CRCs.
CONCLUSIONS
ZEB1 promotes tumor invasiveness not only via induction in cancer cells of a motile dedifferentiated phenotype but also by differential regulation of genes involved in stroma remodeling.
Collapse
Affiliation(s)
- Ester Sánchez-Tilló
- Group of Transcriptional Regulation of Gene Expression, Department of Oncology and Hematology, IDIBAPS, Barcelona, Spain
| |
| |
| |
| |
| |
| |
| |
| |
Collapse
40
Lee JH, Kim Y, Choi JW, Kim YS. Clinicopathological significance of plasminogen activator inhibitor-1 promoter 4G/5G polymorphism in breast cancer: a meta-analysis.
Arch Med Res 2013;
44:39-45. [PMID:
23291383 DOI:
10.1016/j.arcmed.2012.12.002]
[Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2012] [Accepted: 12/05/2012] [Indexed: 01/01/2023]
Abstract
BACKGROUND AND AIMS
Plasminogen activator inhibitor type 1 (PAI-1) is associated with poor prognosis in breast cancer. Transcriptional expression of the PAI-1 can be controlled by PAI-1 promoter 4G/5G polymorphism. However, the significance of PAI-1 promoter 4G/5G polymorphism in breast cancer patients is contentious. To address this controversy, we conducted a meta-analysis for the relationships between PAI-1 promoter polymorphism and clinicopathological characteristics of breast cancer.
METHODS
Relevant published studies were identified using a search of PubMed, Embase, and the ISI Web of Science. The effect sizes of PAI-1 promoter 4G/5G polymorphism on breast cancer risk, lymph node metastasis, histologic grade, and overall survival were calculated by odds ratio (OR) or hazard ratio. The effect sizes were combined using a random-effects model.
RESULTS
Individuals with 4G/4G genotype had a higher risk of breast cancer than those with the combined 4G/5G and 5G/5G genotypes (OR = 1.388; p = 0.031). Breast cancer patients with the 5G/5G genotype displayed lymph node metastasis more than patients with either the combined other genotypes (OR = 1.495; p = 0.027) or with the 4G/4G genotype (OR = 1.623; p = 0.018). However, the PAI-1 promoter 4G/5G polymorphism was not associated with histological grade or overall survival.
CONCLUSIONS
PAI-1 promoter 4G/5G polymorphism is associated with a relatively increased risk of breast cancer development and lymph node metastasis.
Collapse
Affiliation(s)
- Ju-Han Lee
- Department of Pathology, Korea University Ansan Hospital, Ansan, Republic of Korea
| |
| |
| |
| |
Collapse
41
Pernodet N, Hermetet F, Adami P, Vejux A, Descotes F, Borg C, Adams M, Pallandre JR, Viennet G, Esnard F, Jouvenot M, Despouy G. High expression of QSOX1 reduces tumorogenesis, and is associated with a better outcome for breast cancer patients.
Breast Cancer Res 2012;
14:R136. [PMID:
23098186 PMCID:
PMC4053115 DOI:
10.1186/bcr3341]
[Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2012] [Accepted: 10/24/2012] [Indexed: 11/18/2022] Open
Abstract
Introduction
The gene quiescin/sulfhydryl oxidase 1, QSOX1, encodes an enzyme directed to the secretory pathway and excreted into the extracellular space. QSOX1 participates in the folding and stability of proteins and thus could regulate the biological activity of its substrates in the secretory pathway and/or outside the cell. The involvement of QSOX1 in oncogenesis has been studied primarily in terms of its differential expression in systemic studies. QSOX1 is overexpressed in prostate cancers and in pancreatic adenocarcinoma. In contrast, QSOX1 gene expression is repressed in endothelial tumors. In the present study, we investigated the role of QSOX1 in breast cancer.
Methods
We analyzed QSOX1 mRNA expression in a cohort of 217 invasive ductal carcinomas of the breast. Moreover, we investigated QSOX1's potential role in regulating tumor growth and metastasis using cellular models in which we overexpressed or extinguished QSOX1 and xenograft experiments.
Results
We showed that the QSOX1 expression level is inversely correlated to the aggressiveness of breast tumors. Our results show that QSOX1 leads to a decrease in cell proliferation, clonogenic capacities and promotes adhesion to the extracellular matrix. QSOX1 also reduces the invasive potential of cells by reducing cell migration and decreases the activity of the matrix metalloproteinase, MMP-2, involved in these mechanisms. Moreover, in vivo experiments show that QSOX1 drastically reduces the tumor development.
Conclusions
Together, these results suggest that QSOX1 could be posited as a new biomarker of good prognosis in breast cancer and demonstrate that QSOX1 inhibits human breast cancer tumorogenesis.
Collapse
42
Humbert L, Lebrun JJ. TGF-beta inhibits human cutaneous melanoma cell migration and invasion through regulation of the plasminogen activator system.
Cell Signal 2012;
25:490-500. [PMID:
23085456 DOI:
10.1016/j.cellsig.2012.10.011]
[Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2012] [Revised: 10/09/2012] [Accepted: 10/16/2012] [Indexed: 11/24/2022]
Abstract
Over the past decades, the incidence of cutaneous melanoma in developed countries has increased faster than any other cancer. Although most patients have localized disease at the time of diagnosis and are cured by surgical excision of the primary tumor, melanoma can be highly malignant and the survival dramatically decreases for advanced stage melanomas. It is thus necessary to understand the progression of this disease. Cell migration and invasion promote tumor metastasis, the major cause of melanoma cancer morbidity and death. In this study, we investigated the role of the TGFβ/Smad signaling pathway in melanoma tumor progression and found TGFβ to potently inhibit both cell migration and invasion in human melanoma cell lines, established from different patients. Furthermore, we elucidated the molecular mechanisms by which TGFβ exerts its effects and found the plasminogen activation system (PAS) to play a central role in the regulation of these effects. We found TGFβ to strongly up-regulate the Plasminogen Activator Inhibitor-1 (PAI-1) in melanoma cells, leading to reduced plasmin generation and activity and, in turn to inhibition of cell migration and invasion. Together, our results define TGFβ as a potent suppressor of tumor progression in cutaneous melanoma, inhibiting both cell migration and invasion.
Collapse
Affiliation(s)
- Laure Humbert
- Division of Medical Oncology, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada
| |
| |
Collapse
43
Van De Craen B, Declerck PJ, Gils A. The Biochemistry, Physiology and Pathological roles of PAI-1 and the requirements for PAI-1 inhibition in vivo.
Thromb Res 2012;
130:576-85. [DOI:
10.1016/j.thromres.2012.06.023]
[Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2012] [Revised: 06/12/2012] [Accepted: 06/27/2012] [Indexed: 12/16/2022]
44
Ma X, Zhang QY. Protein Microarrays for Quantitative Detection of PAI-1 in Serum.
Chin J Cancer Res 2012;
24:220-5. [PMID:
23358703 PMCID:
PMC3555280 DOI:
10.1007/s11670-012-0220-x]
[Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2011] [Accepted: 01/18/2012] [Indexed: 10/28/2022] Open
Abstract
OBJECTIVE
Plasminogen activator inhibitor-1 (PAI-1), one crucial component of the plasminogen activator system, is a major player in the pathogenesis of many vascular diseases as well as in cancer. High levels of PAI-1 in breast cancer tissue are associated with poor prognosis. The aim of this study is to evaluate rigorously the potential of serum PAI-1 concentration functioning as a general screening test in diagnostic or prognostic assays.
METHODS
A protein-microarray-based sandwich fluorescence immunoassay (FIA) was developed to detect PAI-1 in serum. Several conditions of this microarray-based FIA were optimized to establish an efficacious method. Serum specimens of 84 healthy women and 285 women with breast cancer were analyzed using the optimized FIA microarray.
RESULTS
The median serum PAI-1 level of breast cancer patients was higher than that of healthy women (109.7 ng/ml vs. 63.4 ng/ml). Analysis of covariance revealed that PAI-1 levels of the two groups were significantly different (P<0.001) when controlling for an age effect on PAI-1 levels. However, PAI-1 values in TNM stage I-IV patients respectively were not significantly different from each other.
CONCLUSION
This microarray-based sandwich FIA holds potential for quantitative analysis of tumor markers such as PAI-1.
Collapse
Affiliation(s)
- Xu Ma
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Clinical Laboratory, Peking University Cancer Hospital & Institute, Beijing 100142, China
| |
| |
Collapse
45
Gilabert-Estellés J, Ramón LA, Braza-Boïls A, Gilabert J, Chirivella M, España F, Estellés A. Plasminogen activator inhibitor-1 (PAI-1) 4 G/5 G polymorphism and endometrial cancer. Influence of PAI-1 polymorphism on tissue PAI-1 antigen and mRNA expression and tumor severity.
Thromb Res 2012;
130:242-7. [DOI:
10.1016/j.thromres.2011.10.007]
[Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2011] [Revised: 09/16/2011] [Accepted: 10/10/2011] [Indexed: 01/08/2023]
46
Hsiao CJ, Hsiao SH, Chen WL, Guh JH, Hsiao G, Chan YJ, Lee TH, Chung CL. Pycnidione, a fungus-derived agent, induces cell cycle arrest and apoptosis in A549 human lung cancer cells.
Chem Biol Interact 2012;
197:23-30. [PMID:
22450442 DOI:
10.1016/j.cbi.2012.03.004]
[Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2011] [Revised: 03/03/2012] [Accepted: 03/07/2012] [Indexed: 11/24/2022]
Abstract
Pycnidione, a small tropolone first isolated from the fermented broth of Theissenia rogersii 92031201, exhibits antitumor activities through an undefined mechanism. The present study evaluated the effects and mechanisms of pycnidione on the growth and death of A549 human lung cancer cells. Pycnidione significantly inhibited the proliferation of A549 cells in a concentration-dependent manner, with a 50% growth inhibition (GI(50)) value of approximately 9.3nM at 48h. Pycnidione significantly decreased the expression of cyclins D1 and E and induced G(1)-phase cell cycle arrest and a subsequent increase in the sub-G(1) phase population. Pycnidione also markedly reduced the expression of survivin and activated caspase-8 and -3, increased reactive oxygen species (ROS) generation, caused the collapse of the mitochondrial membrane potential (MMP), and enhanced PAI-1 production, thus triggering apoptosis in the A549 cells. Taken together, pycnidione exerts anti-proliferative effects on human lung cancer cells through the induction of cell cycle arrest and apoptosis. Therefore, testing of its effects in vivo is warranted to evaluate its potential as a therapeutic agent against lung cancer.
Collapse
Affiliation(s)
- Che-Jen Hsiao
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan
| |
| |
| |
| |
| |
| |
| |
| |
Collapse
47
Glait-Santar C, Pasmanik-Chor M, Oron-Karni V, Benayahu D. Molecular profiling of functional interactions between pre-osteoblastic and breast carcinoma cells.
Genes Cells 2012;
17:302-15. [DOI:
10.1111/j.1365-2443.2012.01590.x]
[Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
48
Huang G, Elferink CJ. A novel nonconsensus xenobiotic response element capable of mediating aryl hydrocarbon receptor-dependent gene expression.
Mol Pharmacol 2012;
81:338-47. [PMID:
22113079 PMCID:
PMC3286297 DOI:
10.1124/mol.111.075952]
[Citation(s) in RCA: 86] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2011] [Accepted: 11/23/2011] [Indexed: 12/17/2022] Open
Abstract
The aryl hydrocarbon receptor (AhR) is a mediator of xenobiotic toxicity, best recognized for conveying the deleterious effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure. The AhR functions as a ligand-activated transcription factor that binds to a canonical xenobiotic response element (XRE) in association with the heterodimerization partner, the AhR nuclear translocator (Arnt) protein. However, within the repertoire of AhR target genes identified in recent years, many lack a clearly defined XRE highlighting the growing realization that AhR-mediated gene expression seems to involve additional mechanisms distinct from the well characterized process involving the XRE. The present study characterized a novel nonconsensus XRE (NC-XRE) in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene that recruits a novel protein-DNA complex responsible for TCDD-inducible expression. DNA binding studies and reporter assays identified key residues in the NC-XRE necessary for protein-DNA binding and function, respectively. Functional studies with AhR expression constructs confirm that TCDD-inducibility is AhR-dependent and requires direct AhR-DNA binding to the NC-XRE. Chromatin immunoprecipitation and RNA interference studies reveal that the Arnt protein is not a component of the NC-XRE-bound AhR complex, suggesting that in contrast to the XRE, AhR-dependent gene expression mediated through the NC-XRE may involve a new DNA binding partner.
Collapse
Affiliation(s)
- Gengming Huang
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555-0654, USA
| |
| |
Collapse
49
Complex Regulation of the Pericellular Proteolytic Microenvironment during Tumor Progression and Wound Repair: Functional Interactions between the Serine Protease and Matrix Metalloproteinase Cascades.
Biochem Res Int 2012;
2012:454368. [PMID:
22454771 PMCID:
PMC3290807 DOI:
10.1155/2012/454368]
[Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2011] [Accepted: 11/21/2011] [Indexed: 01/08/2023] Open
Abstract
Spatial and temporal regulation of the pericellular proteolytic environment by local growth factors, such as EGF and TGF-β, initiates a wide repertoire of cellular responses coupled to a plasmin/matrix metalloproteinase (MMP) dependent stromal-remodeling axis. Cell motility and invasion, tumor metastasis, wound healing, and organ fibrosis, for example, represent diverse events controlled by expression of a subset of genes that encode various classes of tissue remodeling proteins. These include members of the serine protease and MMP families that functionally constitute a complex system of interacting protease cascades and titrated by their respective inhibitors. Several structural components of the extracellular matrix are upregulated by TGF-β as are matrix-active proteases (e.g., urokinase (uPA), plasmin, MMP-1, -3, -9, -10, -11, -13, -14). Stringent controls on serine protease/MMP expression and their topographic activity are essential for maintaining tissue homeostasis. Targeting individual elements in this highly interactive network may lead to novel therapeutic approaches for the treatment of cancer, fibrotic diseases, and chronic wounds.
Collapse
50
Nishioka N, Matsuoka T, Yashiro M, Hirakawa K, Olden K, Roberts JD. Plasminogen activator inhibitor 1 RNAi suppresses gastric cancer metastasis in vivo.
Cancer Sci 2012;
103:228-32. [PMID:
22098548 DOI:
10.1111/j.1349-7006.2011.02155.x]
[Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Cancer metastasis remains the primary cause of pain, suffering, and death in cancer patients, and even the most current therapeutic strategies have not been highly successful in preventing or inhibiting metastasis. In most patients with scirrhous gastric cancer (one of the most aggressive of diffuse-type gastric cancer), recurrence occurs even after potentially curative resection, most frequently in the form of peritoneal metastasis. Given that the occurrence of diffuse-type gastric cancers has been increasing, the development of new strategies to combat metastasis of this disease is critically important. Plasminogen activator inhibitor-1 (PAI-1) is a critical factor in cancer progression; thus, PAI-1 RNAi may be an effective therapy against cancer metastasis. In the present study, we used an RNAi technique to reduce PAI-1 expression in an in vivo model system for gastric cancer metastasis. Ex vivo plasmid transfection and adenovirus infection were tested as mechanisms to incorporate specific PAI-1 RNAi vectors into human gastric carcinoma cells. Both approaches significantly decreased peritoneal tumor growth and the formation of bloody ascites in the mouse model, suggesting that this approach may provide a new, effective strategy for inhibiting cancer metastasis.
Collapse
Affiliation(s)
- Nobuaki Nishioka
- Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA
| |
| |
| |
| |
| |
| |
Collapse