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Article ; Online: Evaluation of usability, adherence, and clinical efficacy of therapeutic footwear in persons with diabetes at moderate to high risk of diabetic foot ulcers: A multicenter prospective study.

López-Moral, Mateo / Molines-Barroso, Raúl J / Altonaga-Calvo, Borja J / Carrascosa-Romero, Elena / Cecilia-Matilla, Almudena / Dòria-Cervós, Montserrat / García-Martínez, María T / Ortiz-Nistal, Adrian / Palma-Bravo, Anabel / Pereira-Losada, Navor / Rivera-San Martin, Gabriel / Samaniego-Muñoz, Jordi / Villares-Tobajas, Marcos / Lázaro-Martínez, José Luis

Clinical rehabilitation

2024 Volume 38, Issue 5, Page(s) 612–622

Abstract: Objective: To evaluate therapeutic footwear expectations and usability of individuals with diabetes and foot complications.: Design: A prospective multicenter study was conducted on participants with a high risk of developing a diabetic foot ulcer.!## ...

Abstract	Objective: To evaluate therapeutic footwear expectations and usability of individuals with diabetes and foot complications. Design: A prospective multicenter study was conducted on participants with a high risk of developing a diabetic foot ulcer. Setting: Participants were enrolled in 11 different specialized diabetic foot units in Spain between March 2022 and June 2023. Subjects: Patients with diabetes at moderate to high risk of foot ulceration receiving first therapeutic footwear prescription. Interventions: All the patients included in the research were prescribed with their first pair of therapeutic footwear. Main measures: Primary outcome measures were MOS-pre and MOS-post questionnaires evaluating use and usability of prescribed therapeutic footwear. Secondary outcome measures aimed to evaluate footwear clinical efficacy as ulceration rate and self-reported perceived walking distance per day. Results: The use of therapeutic footwear exceeded the patient's pre-provision prediction of their anticipated use in 94% of people ( Conclusions: Diabetes patients at moderate to high risk of diabetic foot ulcer improved their perception of walking ability after therapeutic footwear prescription. Adherence to the therapeutic footwear prescription resulted in less ulcerations.
MeSH term(s)	Humans ; Diabetic Foot/diagnosis ; Diabetic Foot/etiology ; Diabetic Foot/therapy ; Prospective Studies ; Shoes ; Foot ; Treatment Outcome ; Diabetes Mellitus
Language	English
Publishing date	2024-01-09
Publishing country	England
Document type	Multicenter Study ; Journal Article
ZDB-ID	639276-3
ISSN	1477-0873 ; 0269-2155
ISSN (online)	1477-0873
ISSN	0269-2155
DOI	10.1177/02692155231225743
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Article: Protease-Activated Receptors and other G-Protein-Coupled Receptors: the Melanoma Connection.

Rosero, Rebecca A / Villares, Gabriel J / Bar-Eli, Menashe

Frontiers in genetics

2016 Volume 7, Page(s) 112

Abstract: The vast array of G-protein-coupled receptors (GPCRs) play crucial roles in both physiological and pathological processes, including vision, coagulation, inflammation, autophagy, and cell proliferation. GPCRs also affect processes that augment cell ... ...

Abstract	The vast array of G-protein-coupled receptors (GPCRs) play crucial roles in both physiological and pathological processes, including vision, coagulation, inflammation, autophagy, and cell proliferation. GPCRs also affect processes that augment cell proliferation and metastases in many cancers including melanoma. Melanoma is the deadliest form of skin cancer, yet limited therapeutic modalities are available to patients with metastatic melanoma. Studies have found that both chemokine receptors and protease-activated receptors, both of which are GPCRs, are central to the metastatic melanoma phenotype and may serve as potential targets in novel therapies against melanoma and other cancers.
Language	English
Publishing date	2016-06-15
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2016.00112
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Article ; Online: The emerging role of the thrombin receptor (PAR-1) in melanoma metastasis--a possible therapeutic target.

Villares, Gabriel J / Zigler, Maya / Bar-Eli, Menashe

Oncotarget

2011 Volume 2, Issue 1-2, Page(s) 8–17

Abstract: Melanoma remains as the deadliest form of skin cancer with limited and inefficient treatment options available for patients with metastatic disease. Within the last decade, the thrombin receptor, Protease Activated Receptor-1, has been described as an ... ...

Abstract	Melanoma remains as the deadliest form of skin cancer with limited and inefficient treatment options available for patients with metastatic disease. Within the last decade, the thrombin receptor, Protease Activated Receptor-1, has been described as an essential gene involved in the progression of human melanoma. PAR-1 is known to activate adhesive, invasive and angiogenic factors to promote melanoma metastasis. It is overexpressed not only in metastatic melanoma cell lines but is also highly expressed in metastatic lesions as compared to primary nevi and normal skin. Recently, PAR-1 has been described to regulate the gap junction protein Connexin 43 and the tumor suppressor gene Maspin to promote the metastatic melanoma phenotype. Herein, we review the role of PAR-1 in the progression of melanoma as well as utilizing PAR-1-regulated genes as potential therapeutic targets for melanoma treatment.
MeSH term(s)	Disease Progression ; Gene Expression Regulation, Neoplastic ; Humans ; Melanoma/drug therapy ; Melanoma/genetics ; Melanoma/metabolism ; Melanoma/pathology ; Molecular Targeted Therapy ; Neoplasm Metastasis ; Receptor, PAR-1/genetics ; Receptor, PAR-1/metabolism ; Receptor, PAR-1/physiology ; Skin Neoplasms/drug therapy ; Skin Neoplasms/genetics ; Skin Neoplasms/metabolism ; Skin Neoplasms/pathology
Chemical Substances	Receptor, PAR-1
Language	English
Publishing date	2011-03-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.211
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Article ; Online: Carbon nanotube capsules enhance the in vivo efficacy of cisplatin.

Guven, Adem / Villares, Gabriel J / Hilsenbeck, Susan G / Lewis, Alaina / Landua, John D / Dobrolecki, Lacey E / Wilson, Lon J / Lewis, Michael T

Acta biomaterialia

2017 Volume 58, Page(s) 466–478

Abstract: Over the past few years, numerous nanotechnology-based drug delivery systems have been developed in an effort to maximize therapeutic effectiveness of conventional drug delivery, while limiting undesirable side effects. Among these, carbon nanotubes ( ... ...

Abstract	Over the past few years, numerous nanotechnology-based drug delivery systems have been developed in an effort to maximize therapeutic effectiveness of conventional drug delivery, while limiting undesirable side effects. Among these, carbon nanotubes (CNTs) are of special interest as potential drug delivery agents due to their numerous unique and advantageous physical and chemical properties. Here, we show in vivo favorable biodistribution and enhanced therapeutic efficacy of cisplatin (CDDP) encapsulated within ultra-short single-walled carbon nanotube capsules (CDDP@US-tubes) using three different human breast cancer xenograft models. In general, the CDDP@US-tubes demonstrated greater efficacy in suppressing tumor growth than free CDDP in both MCF-7 cell line xenograft and BCM-4272 patient-derived xenograft (PDX) models. The CDDP@US-tubes also demonstrated a prolonged circulation time compared to free CDDP which enhanced permeability and retention (EPR) effects resulting in significantly more CDDP accumulation in tumors, as determined by platinum (Pt) analysis via inductively-coupled plasma mass spectrometry (ICP-MS). Statement of significance: Over the past decade, drug-loaded nanocarriers have been widely fabricated and studied to enhance tumor specific delivery. Among the diverse classes of nanomaterials, carbon nanotubes (CNTs), or more specifically ultra-short single-walled carbon nanocapsules (US-tubes), have been shown to be a popular, new platform for the delivery of various medical agents for both imaging and therapeutic purposes. Here, for the first time, we have shown that US-tubes can be utilized as a drug delivery platform in vivo to deliver the chemotherapeutic drug, cisplatin (CDDP) as CDDP@US-tubes. The studies have demonstrated the ability of the US-tube platform to promote the delivery of encapsulated CDDP by increasing the accumulation of drug in breast cancer resistance cells, which reveals how CDDP@US-tubes help overcome CDDP resistance.
MeSH term(s)	Animals ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cisplatin/chemistry ; Cisplatin/pharmacology ; Humans ; MCF-7 Cells ; Mice ; Nanocapsules/chemistry ; Nanocapsules/therapeutic use ; Nanotubes, Carbon/chemistry ; Neoplasms, Experimental/drug therapy ; Neoplasms, Experimental/metabolism ; Neoplasms, Experimental/pathology ; Xenograft Model Antitumor Assays
Chemical Substances	Antineoplastic Agents ; Nanocapsules ; Nanotubes, Carbon ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2017-05-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2173841-5
ISSN	1878-7568 ; 1742-7061
ISSN (online)	1878-7568
ISSN	1742-7061
DOI	10.1016/j.actbio.2017.04.035
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Article: Emerging roles of PAR-1 and PAFR in melanoma metastasis.

Melnikova, Vladislava O / Villares, Gabriel J / Bar-Eli, Menashe

Cancer microenvironment : official journal of the International Cancer Microenvironment Society

2008 Volume 1, Issue 1, Page(s) 103–111

Abstract: Melanoma growth, angiogenesis and metastatic progression are strongly promoted by the inflammatory tumor microenvironment due to high levels of cytokine and chemokine secretion by the recruited inflammatory and stromal cells. In addition, platelets and ... ...

Abstract	Melanoma growth, angiogenesis and metastatic progression are strongly promoted by the inflammatory tumor microenvironment due to high levels of cytokine and chemokine secretion by the recruited inflammatory and stromal cells. In addition, platelets and molecular components of procoagulant pathways have been recently emerging as critical players of tumor growth and metastasis. In particular, thrombin, through the activity of its receptor protease-activated receptor-1 (PAR-1), regulates tumor cell adhesion to platelets and endothelial cells, stimulates tumor angiogenesis, and promotes tumor growth and metastasis. Notably, in many tumor types including melanoma, PAR-1 expression directly correlates with their metastatic phenotype and is directly responsible for the expression of interleukin-8, matrix metalloproteinase-2 (MMP-2), vascular endothelial growth factor, platelet-derived growth factor, and integrins. Another proinflammatory receptor-ligand pair, platelet-activating factor (PAF) and its receptor (PAFR), have been shown to act as important modulators of tumor cell adhesion to endothelial cells, angiogenesis, tumor growth and metastasis. PAF is a bioactive lipid produced by a variety of cells from membrane glycerophospholipids in the same reaction that releases arachidonic acid, and can be secreted by platelets, inflammatory cells, keratinocytes and endothelial cells. We have demonstrated that in metastatic melanoma cells, PAF stimulates the phosphorylation of cyclic adenosine monophosphate response element-binding protein (CREB) and activating transcription factor 1 (ATF-1), which results in overexpression of MMP-2 and membrane type 1-MMP (membrane type 1-MMP). Since only metastatic melanoma cells overexpress CREB/ATF-1, we propose that metastatic melanoma cells are better equipped than their non-metastatic counterparts to respond to PAF within the tumor microenvironment. The evidence supporting the hypothesis that the two G-protein coupled receptors, PAR-1 and PAFR, contribute to the acquisition of the metastatic phenotype of melanoma is presented and discussed.
Language	English
Publishing date	2008-02-20
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2422345-1
ISSN	1875-2284 ; 1875-2292
ISSN (online)	1875-2284
ISSN	1875-2292
DOI	10.1007/s12307-008-0002-7
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Article ; Online: PAR-1 and thrombin: the ties that bind the microenvironment to melanoma metastasis.

Zigler, Maya / Kamiya, Takafumi / Brantley, Emily C / Villares, Gabriel J / Bar-Eli, Menashe

Cancer research

2011 Volume 71, Issue 21, Page(s) 6561–6566

Abstract: Progression of melanoma is dependent on cross-talk between tumor cells and the adjacent microenvironment. The thrombin receptor, protease-activated receptor-1 (PAR-1), plays a key role in exerting this function during melanoma progression. PAR-1 and its ... ...

Abstract	Progression of melanoma is dependent on cross-talk between tumor cells and the adjacent microenvironment. The thrombin receptor, protease-activated receptor-1 (PAR-1), plays a key role in exerting this function during melanoma progression. PAR-1 and its activating factors, which are expressed on tumor cells and the surrounding stroma, induce not only coagulation but also cell signaling, which promotes the metastatic phenotype. Several adhesion molecules, cytokines, growth factors, and proteases have recently been identified as downstream targets of PAR-1 and have been shown to modulate interactions between tumor cells and the microenvironment in the process of melanoma growth and metastasis. Inhibiting such interactions by targeting PAR-1 could potentially be a useful therapeutic modality for melanoma patients.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Blood Coagulation ; Cell Adhesion ; Cell Movement ; Disease Progression ; Endothelial Cells/pathology ; Gene Expression Regulation, Neoplastic ; Humans ; Lung Neoplasms/secondary ; Lung Neoplasms/therapy ; Melanoma/blood ; Melanoma/pathology ; Melanoma/secondary ; Melanoma, Experimental/secondary ; Melanoma, Experimental/therapy ; Mice ; Molecular Targeted Therapy ; Neoplasm Proteins/biosynthesis ; Neoplasm Proteins/genetics ; Neoplasm Proteins/physiology ; Neoplastic Cells, Circulating ; Phenotype ; RNA, Small Interfering/therapeutic use ; Receptor, PAR-1/biosynthesis ; Receptor, PAR-1/genetics ; Receptor, PAR-1/physiology ; Signal Transduction/physiology ; Stromal Cells/physiology ; Thrombin/physiology ; Tumor Microenvironment/physiology ; Xenograft Model Antitumor Assays
Chemical Substances	Antineoplastic Agents ; Neoplasm Proteins ; RNA, Small Interfering ; Receptor, PAR-1 ; Thrombin (EC 3.4.21.5)
Language	English
Publishing date	2011-10-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-11-1432
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Article ; Online: Transcriptional control of melanoma metastasis: the importance of the tumor microenvironment.

Braeuer, Russell R / Zigler, Maya / Villares, Gabriel J / Dobroff, Andrey S / Bar-Eli, Menashe

Seminars in cancer biology

2010 Volume 21, Issue 2, Page(s) 83–88

Abstract: The molecular changes associated with the transition of melanoma cells from radial growth phase (RGP) to vertical growth phase (VGP) and the metastatic phenotype are not very well defined. However, some of the genes involved in this process and their ... ...

Abstract	The molecular changes associated with the transition of melanoma cells from radial growth phase (RGP) to vertical growth phase (VGP) and the metastatic phenotype are not very well defined. However, some of the genes involved in this process and their transcriptional regulation are beginning to be elucidated. For example, the switch from RGP to VGP and the metastatic phenotype is associated with loss of the AP-2α transcription factor. AP-2α regulates the expression of c-KIT, MMP-2, VEGF, and the adhesion molecule MCAM/MUC18. Recently, we reported that AP-2α also regulates two G-protein coupled receptors (GPCRs) PAR-1 and PAFR. In turn, the thrombin receptor, PAR-1, regulates the expression of the gap junction protein Connexin-43 and the tumor suppressor gene Maspin. Activation of PAR-1 also leads to overexpression and secretion of proangiogenic factors such as IL-8, uPA, VEGF, PDGF, as well certain integrins. PAR-1 also cooperates with PAFR to regulate the expression of the MCAM/MUC18 via phosphorylation of CREB. The ligands for these GPCRs, thrombin and PAF, are secreted by stromal cells, emphasizing the importance of the tumor microenvironment in melanoma metastasis. The metastatic phenotype of melanoma is also associated with overexpression and function of CREB/ATF-1. Loss of AP-2α and overexpression of CREB/ATF-1 results in the overexpression of MCAM/MUC18 which by itself contributes to melanoma metastasis by regulating the inhibitor of DNA binding-1 (Id-1). CREB/ATF-1 also regulates the angiogenic factor CYR-61. Our recent data indicate that CREB/ATF-1 regulates the expression of AP-2α, thus, supporting the notion that CREB is an important "master switch" in melanoma progression.
MeSH term(s)	Animals ; Cell Adhesion Molecules/metabolism ; Cyclic AMP Response Element-Binding Protein/metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Melanoma/genetics ; Melanoma/pathology ; Melanoma/secondary ; Neoplasm Metastasis ; Receptors, G-Protein-Coupled/metabolism ; Transcription Factor AP-2/genetics ; Transcription Factor AP-2/metabolism ; Tumor Microenvironment
Chemical Substances	Cell Adhesion Molecules ; Cyclic AMP Response Element-Binding Protein ; Receptors, G-Protein-Coupled ; Transcription Factor AP-2
Language	English
Publishing date	2010-12-13
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1033980-2
ISSN	1096-3650 ; 1044-579X
ISSN (online)	1096-3650
ISSN	1044-579X
DOI	10.1016/j.semcancer.2010.12.007
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Zs.A 2922: Show issues

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Article ; Online: NFAT1 Directly Regulates IL8 and MMP3 to Promote Melanoma Tumor Growth and Metastasis.

Shoshan, Einav / Braeuer, Russell R / Kamiya, Takafumi / Mobley, Aaron K / Huang, Li / Vasquez, Mayra E / Velazquez-Torres, Guermarie / Chakravarti, Nitin / Ivan, Cristina / Prieto, Victor / Villares, Gabriel J / Bar-Eli, Menashe

Cancer research

2016 Volume 76, Issue 11, Page(s) 3145–3155

Abstract: Nuclear factor of activated T cell (NFAT1, NFATC2) is a transcription factor that binds and positively regulates IL2 expression during T-cell activation. NFAT1 has important roles in both innate and adaptive immune responses, but its involvement in ... ...

Abstract	Nuclear factor of activated T cell (NFAT1, NFATC2) is a transcription factor that binds and positively regulates IL2 expression during T-cell activation. NFAT1 has important roles in both innate and adaptive immune responses, but its involvement in cancer is not completely understood. We previously demonstrated that NFAT1 contributes to melanoma growth and metastasis by regulating the autotaxin gene (Enpp2). Here, we report a strong correlation between NFAT1 expression and metastatic potential in melanoma cell lines and tumor specimens. To elucidate the mechanisms underlying NFAT1 overexpression during melanoma progression, we conducted a microarray on a highly metastatic melanoma cell line in which NFAT1 expression was stably silenced. We identified and validated two downstream targets of NFAT1, IL8, and MMP3. Accordingly, NFAT1 depletion in metastatic melanoma cell lines was associated with reduced IL8 and MMP3 expression, whereas NFAT1 overexpression in a weakly metastatic cell line induced expression of these targets. Restoration of NFAT1 expression recovered IL8 and MMP3 expression levels back to baseline, indicating that both are direct targets of NFAT1. Moreover, in vivo studies demonstrated that NFAT1 and MMP3 promoted melanoma tumor growth and lung metastasis. Collectively, our findings assign a new role for NFAT1 in melanoma progression, underscoring the multifaceted functions that immunomodulatory factors may acquire in an unpredictable tumor microenvironment. Cancer Res; 76(11); 3145-55. ©2016 AACR.
MeSH term(s)	Animals ; Apoptosis ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Blotting, Western ; Cell Proliferation ; Female ; Humans ; Immunoenzyme Techniques ; Interleukin-8/genetics ; Interleukin-8/metabolism ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Lung Neoplasms/secondary ; Matrix Metalloproteinase 3/genetics ; Matrix Metalloproteinase 3/metabolism ; Melanoma/genetics ; Melanoma/metabolism ; Melanoma/pathology ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; NFATC Transcription Factors/genetics ; NFATC Transcription Factors/metabolism ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Neoplasm Staging ; Prognosis ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Survival Rate ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
Chemical Substances	Biomarkers, Tumor ; CXCL8 protein, human ; Interleukin-8 ; NFATC Transcription Factors ; NFATC2 protein, human ; RNA, Messenger ; MMP3 protein, human (EC 3.4.24.17) ; Matrix Metalloproteinase 3 (EC 3.4.24.17)
Language	English
Publishing date	2016-03-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-15-2511
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Article: Tumor immunotherapy in melanoma: strategies for overcoming mechanisms of resistance and escape.

Zigler, Maya / Villares, Gabriel J / Lev, Dina C / Melnikova, Vladislava O / Bar-Eli, Menashe

American journal of clinical dermatology

2008 Volume 9, Issue 5, Page(s) 307–311

Abstract: The incidence of melanoma has been steadily increasing over the last 3 decades. Currently, there are several approved treatments for metastatic melanoma, including chemotherapy and biologic therapy as both single treatments and in combination, but none ... ...

Abstract	The incidence of melanoma has been steadily increasing over the last 3 decades. Currently, there are several approved treatments for metastatic melanoma, including chemotherapy and biologic therapy as both single treatments and in combination, but none is associated with a significant increase in survival. The chemotherapeutic agent dacarbazine is the standard treatment for metastatic melanoma, with a response rate of 15-20%, although most responses are not sustained. One of the main problems with melanoma treatment is chemotherapeutic resistance. The mechanisms of resistance of melanoma cells to chemotherapy have yet to be elucidated. Following treatment with dacarbazine, melanoma cells activate the extracellular signal-regulated kinase pathway, which results in over-expression and secretion of interleukin (IL)-8 and vascular endothelial growth factor. Melanoma cells utilize this mechanism to escape from the cytotoxic effect of the drug. We have previously reported on the development of fully human neutralizing antibodies against IL-8 (anti-IL-8-monoclonal-antibody [ABX-IL8]). In preclinical studies, ABX-IL8 inhibited tumor growth, angiogenesis, and metastasis of human melanoma in vivo. We propose that combination treatment with dacarbazine and IL-8 will potentiate the cytotoxic effect of the drug. Furthermore, formation of metastasis is a multistep process that includes melanoma cell adhesion to endothelial cells. Melanoma cell adhesion molecule (MUC18) mediates these processes in melanoma and is therefore a good target for eliminating metastasis. We have developed a fully human antibody against MUC18 that has shown promising results in preclinical studies. Since resistance is one of the major obstacles in the treatment of melanoma, we propose that utilization of antibodies against IL-8 or MUC18 alone, or as part of a 'cocktail' in combination with dacarbazine, may be a new treatment modality for metastatic melanoma that overcomes resistance of the disease to chemotherapy and significantly improves survival of patients.
MeSH term(s)	Antibodies, Monoclonal/therapeutic use ; Antineoplastic Agents/therapeutic use ; CD146 Antigen/immunology ; Dacarbazine/therapeutic use ; Disease Progression ; Drug Resistance, Neoplasm ; Humans ; Immunotherapy/methods ; Interleukin-8/immunology ; Melanoma/immunology ; Melanoma/pathology ; Melanoma/therapy ; Neoplasm Metastasis/prevention & control ; Skin Neoplasms/immunology ; Skin Neoplasms/pathology ; Skin Neoplasms/therapy
Chemical Substances	Antibodies, Monoclonal ; Antineoplastic Agents ; CD146 Antigen ; Interleukin-8 ; MCAM protein, human ; Dacarbazine (7GR28W0FJI)
Language	English
Publishing date	2008-08-16
Publishing country	New Zealand
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1502476-3
ISSN	1179-1888 ; 1175-0561
ISSN (online)	1179-1888
ISSN	1175-0561
DOI	10.2165/00128071-200809050-00004
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Zs.A 5639: Show issues

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Article ; Online: CREB inhibits AP-2alpha expression to regulate the malignant phenotype of melanoma.

Melnikova, Vladislava O / Dobroff, Andrey S / Zigler, Maya / Villares, Gabriel J / Braeuer, Russell R / Wang, Hua / Huang, Li / Bar-Eli, Menashe

PloS one

2010 Volume 5, Issue 8, Page(s) e12452

Abstract: Background: The loss of AP-2alpha and increased activity of cAMP-responsive element binding (CREB) protein are two hallmarks of malignant progression of cutaneous melanoma. However, the molecular mechanism responsible for the loss of AP-2alpha during ... ...

Abstract	Background: The loss of AP-2alpha and increased activity of cAMP-responsive element binding (CREB) protein are two hallmarks of malignant progression of cutaneous melanoma. However, the molecular mechanism responsible for the loss of AP-2alpha during melanoma progression remains unknown. Methodology/principal findings: Herein, we demonstrate that both inhibition of PKA-dependent CREB phosphorylation, as well as silencing of CREB expression by shRNA, restored AP-2alpha protein expression in two metastatic melanoma cell lines. Moreover, rescue of CREB expression in CREB-silenced cell lines downregulates expression of AP-2alpha. Loss of AP-2alpha expression in metastatic melanoma occurs via a dual mechanism involving binding of CREB to the AP-2alpha promoter and CREB-induced overexpression of another oncogenic transcription factor, E2F-1. Upregulation of AP-2alpha expression following CREB silencing increases endogenous p21(Waf1) and decreases MCAM/MUC18, both known to be downstream target genes of AP-2alpha involved in melanoma progression. Conclusions/significance: Since AP-2alpha regulates several genes associated with the metastatic potential of melanoma including c-KIT, VEGF, PAR-1, MCAM/MUC18, and p21(Waf1), our data identified CREB as a major regulator of the malignant melanoma phenotype.
MeSH term(s)	Animals ; CD146 Antigen/metabolism ; Cell Line, Tumor ; Cyclic AMP Response Element-Binding Protein/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Disease Progression ; E2F1 Transcription Factor/metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Melanoma/genetics ; Melanoma/metabolism ; Melanoma/pathology ; Neoplasm Metastasis ; Phosphorylation ; Promoter Regions, Genetic/genetics ; Transcription Factor AP-2/genetics ; Transcription Factor AP-2/metabolism ; Transcription, Genetic ; Up-Regulation
Chemical Substances	CD146 Antigen ; Cyclic AMP Response Element-Binding Protein ; Cyclin-Dependent Kinase Inhibitor p21 ; E2F1 Transcription Factor ; E2F1 protein, human ; MCAM protein, human ; Transcription Factor AP-2
Language	English
Publishing date	2010-08-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0012452
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