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Article ; Online: Autophagy Roles in the Modulation of DNA Repair Pathways.

Gomes, Luciana R / Menck, Carlos F M / Leandro, Giovana S

International journal of molecular sciences

2017 Volume 18, Issue 11

Abstract: Autophagy and DNA repair are biological processes vital for cellular homeostasis maintenance and when dysfunctional, they lead to several human disorders including premature aging, neurodegenerative diseases, and cancer. The interchange between these ... ...

Abstract	Autophagy and DNA repair are biological processes vital for cellular homeostasis maintenance and when dysfunctional, they lead to several human disorders including premature aging, neurodegenerative diseases, and cancer. The interchange between these pathways is complex and it may occur in both directions. Autophagy is activated in response to several DNA lesions types and it can regulate different mechanisms and molecules involved in DNA damage response (DDR), such as cell cycle checkpoints, cell death, and DNA repair. Thus, autophagy may modulate DNA repair pathways, the main focus of this review. In addition to the already well-documented autophagy positive effects on homologous recombination (HR), autophagy has also been implicated with other DNA repair mechanisms, such as base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR). Given the relevance of these cellular processes, the clinical applications of drugs targeting this autophagy-DNA repair interface emerge as potential therapeutic strategies for many diseases, especially cancer.
MeSH term(s)	Animals ; Autophagy/genetics ; Autophagy/physiology ; DNA End-Joining Repair/genetics ; DNA End-Joining Repair/physiology ; DNA Repair/genetics ; DNA Repair/physiology ; Homologous Recombination/genetics ; Homologous Recombination/physiology ; Humans
Language	English
Publishing date	2017-11-07
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms18112351
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Article ; Online: Chaperone-mediated autophagy prevents cellular transformation by regulating MYC proteasomal degradation.

Gomes, Luciana R / Menck, Carlos F M / Cuervo, Ana Maria

Autophagy

2017 Volume 13, Issue 5, Page(s) 928–940

Abstract: Chaperone-mediated autophagy (CMA), a selective form of protein lysosomal degradation, is maximally activated in stress situations to ensure maintenance of cellular homeostasis. CMA activity decreases with age and in several human chronic disorders, but ... ...

Abstract	Chaperone-mediated autophagy (CMA), a selective form of protein lysosomal degradation, is maximally activated in stress situations to ensure maintenance of cellular homeostasis. CMA activity decreases with age and in several human chronic disorders, but in contrast, in most cancer cells, CMA is upregulated and required for tumor growth. However, the role of CMA in malignant transformation remains unknown. In this study, we demonstrate that CMA inhibition in fibroblasts augments the efficiency of MYC/c-Myc-driven cellular transformation. CMA blockage contributes to the increase of total and nuclear MYC, leading to enhancement of cell proliferation and colony formation. Impaired CMA functionality accentuates tumorigenesis-related metabolic changes observed upon MYC-transformation. Although not a direct CMA substrate, we have found that CMA regulates cellular MYC levels by controlling its proteasomal degradation. CMA promotes MYC ubiquitination and degradation by regulating the degradation of C330027C09Rik/KIAA1524/CIP2A (referred to hereafter as CIP2A), responsible for MYC stabilization. Ubiquitination and proteasomal degradation of MYC requires dephosphorylation at Ser62, and CIP2A inhibits the phosphatase responsible for this dephosphorylation. Failure to degrade CIP2A upon CMA blockage leads to increased levels of phosphorylated MYC (Ser62) and to stabilization of this oncogene. We demonstrate that this phosphorylation is essential for the CMA-mediated effect, since specific mutation of this site (Ser62 to Ala62) is enough to normalize MYC levels in CMA-incompetent cells. Altogether these data demonstrate that CMA mitigates MYC oncogenic activity by promoting its proteasomal degradation and reveal a novel tumor suppressive role for CMA in nontumorigenic cells.
MeSH term(s)	Animals ; Autophagy/physiology ; Cell Proliferation/physiology ; Fibroblasts/metabolism ; Lysosomes/metabolism ; Mice ; Molecular Chaperones/metabolism ; Neoplasms/metabolism ; Proto-Oncogene Proteins c-myc/metabolism ; Ubiquitination/physiology
Chemical Substances	Molecular Chaperones ; Proto-Oncogene Proteins c-myc
Language	English
Publishing date	2017-03-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.1080/15548627.2017.1293767
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Article ; Online: Microenvironment and autophagy cross-talk: Implications in cancer therapy.

Gomes, Luciana R / Vessoni, Alexandre T / Menck, Carlos F M

Pharmacological research

2016 Volume 107, Page(s) 300–307

Abstract: There are many ongoing clinical trials to validate tumour microenvironment or autophagic pathway components as targets for anticancer therapies. Different components of the tumour microenvironment play important roles in tumour cell responses, directly ... ...

Abstract	There are many ongoing clinical trials to validate tumour microenvironment or autophagic pathway components as targets for anticancer therapies. Different components of the tumour microenvironment play important roles in tumour cell responses, directly affecting malignant transformation, drug resistance and metastasis. Autophagy is also related to chemotherapy responses by inducing tumour cell death or survival. Thus, the autophagy pathway may act as oncosuppressor, in addition to protecting cells from chemotherapy. The cross-talk between the microenvironment and autophagy is very complex and poorly understood. In a recent study using a three-dimensional (3D) cell culture model, the well-documented chemotherapy-mediated activation of autophagy was impaired in breast cancer cells, suggesting a context-dependent outcome for autophagy modulators, under the control of the p53 protein. A deeper understanding of this microenvironment/autophagy interplay may provide important clues for identifying differences in the tumour cell signalling network from in vitro basic research studies to the actual clinical context. In this work, we summarize the role of the microenvironment and autophagy in physiological and tumourigenic conditions, their interactions, and the challenges related to the use of drugs that target these pathways in cancer treatment protocols, emphasizing the potential use of 3D cell culture models in preclinical studies.
MeSH term(s)	Animals ; Antineoplastic Agents/therapeutic use ; Autophagy/drug effects ; Humans ; Neoplasms/drug therapy ; Tumor Microenvironment/drug effects
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2016
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	1003347-6
ISSN	1096-1186 ; 0031-6989 ; 1043-6618
ISSN (online)	1096-1186
ISSN	0031-6989 ; 1043-6618
DOI	10.1016/j.phrs.2016.03.031
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Zs.A 721: Show issues

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Article ; Online: A Three-Dimensional Lung Cell Model to Leptospira Virulence Investigations.

Campos, Camila L / Gomes, Luciana R / Covarrubias, Ambart E / Kato, Ellen E / Souza, Gisele G / Vasconcellos, Silvio A / Heinemann, Marcos B / Martins, Elizabeth A L / Ho, Paulo L / Da Costa, Renata M A / Da Silva, Josefa B

Current microbiology

2022 Volume 79, Issue 2, Page(s) 57

Abstract: Leptospirosis is a worldwide zoonosis and a serious public health threat in tropical and subtropical areas. The etiologic agents of leptospirosis are pathogenic spirochetes from the genus Leptospira. In severe cases, patients develop a pulmonary ... ...

Abstract	Leptospirosis is a worldwide zoonosis and a serious public health threat in tropical and subtropical areas. The etiologic agents of leptospirosis are pathogenic spirochetes from the genus Leptospira. In severe cases, patients develop a pulmonary hemorrhage that is associated with high fatality rates. Several animal models were established for leptospirosis studies, such as rodents, dogs, and monkeys. Although useful to study the relationship among Leptospira and its hosts, the animal models still exhibit economic and ethical limitation reasons and do not fully represent the human infection. As an attempt to bridge the gap between animal studies and clinical information from patients, we established a three-dimensional (3-D) human lung cell culture for Leptospira infection. We show that Leptospira is able to efficiently infect the cell lung spheroids and also to infiltrate in deeper areas of the cell aggregates. The ability to infect the 3-D lung cell aggregates was time-dependent. The 3-D spheroids infection occurred up to 120 h in studies with two serovars, Canicola and Copenhageni. We standardized the number of bacteria in the initial inoculum for infection of the spheroids and we also propose two alternative culture media conditions. This new approach was validated by assessing the expression of three genes of Leptospira related to virulence and motility. The transcripts of these genes increased in both culture conditions, however, in higher rates and earlier times in the 3-D culture. We also assessed the production of chemokines by the 3-D spheroids before and after Leptospira infection, confirming induction of two of them, mainly in the 3-D spheroids. Chemokine CCL2 was expressed only in the 3-D cell culture. Increasing of this chemokine was observed previously in infected animal models. This new approach provides an opportunity to study the interaction of Leptospira with the human lung epithelium in vitro.
MeSH term(s)	Animals ; Cell Culture Techniques, Three Dimensional ; Humans ; Leptospira ; Leptospirosis/veterinary ; Lung ; Virulence
Language	English
Publishing date	2022-01-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	134238-1
ISSN	1432-0991 ; 0343-8651
ISSN (online)	1432-0991
ISSN	0343-8651
DOI	10.1007/s00284-021-02720-5
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Zs.A 1446: Show issues

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Article: A Three-Dimensional Lung Cell Model to Leptospira Virulence Investigations

Campos, Camila L. / Gomes, Luciana R. / Covarrubias, Ambart E. / Kato, Ellen E. / Souza, Gisele G. / Vasconcellos, Silvio A. / Heinemann, Marcos B. / Martins, Elizabeth A. L. / Ho, Paulo L. / Da Costa, Renata M. A. / Da Silva, Josefa B.

Current microbiology. 2022 Feb., v. 79, no. 2

2022

Abstract	Leptospirosis is a worldwide zoonosis and a serious public health threat in tropical and subtropical areas. The etiologic agents of leptospirosis are pathogenic spirochetes from the genus Leptospira. In severe cases, patients develop a pulmonary hemorrhage that is associated with high fatality rates. Several animal models were established for leptospirosis studies, such as rodents, dogs, and monkeys. Although useful to study the relationship among Leptospira and its hosts, the animal models still exhibit economic and ethical limitation reasons and do not fully represent the human infection. As an attempt to bridge the gap between animal studies and clinical information from patients, we established a three-dimensional (3-D) human lung cell culture for Leptospira infection. We show that Leptospira is able to efficiently infect the cell lung spheroids and also to infiltrate in deeper areas of the cell aggregates. The ability to infect the 3-D lung cell aggregates was time-dependent. The 3-D spheroids infection occurred up to 120 h in studies with two serovars, Canicola and Copenhageni. We standardized the number of bacteria in the initial inoculum for infection of the spheroids and we also propose two alternative culture media conditions. This new approach was validated by assessing the expression of three genes of Leptospira related to virulence and motility. The transcripts of these genes increased in both culture conditions, however, in higher rates and earlier times in the 3-D culture. We also assessed the production of chemokines by the 3-D spheroids before and after Leptospira infection, confirming induction of two of them, mainly in the 3-D spheroids. Chemokine CCL2 was expressed only in the 3-D cell culture. Increasing of this chemokine was observed previously in infected animal models. This new approach provides an opportunity to study the interaction of Leptospira with the human lung epithelium in vitro.
Keywords	Leptospira ; cell culture ; chemokine CCL2 ; death ; epithelium ; ethics ; hemorrhage ; humans ; inoculum ; leptospirosis ; lungs ; public health ; serotypes ; virulence ; zoonoses
Language	English
Dates of publication	2022-02
Size	p. 57.
Publishing place	Springer US
Document type	Article
ZDB-ID	134238-1
ISSN	1432-0991 ; 0343-8651
ISSN (online)	1432-0991
ISSN	0343-8651
DOI	10.1007/s00284-021-02720-5
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Article ; Online: RECK is not an independent prognostic marker for breast cancer.

Gomes, Luciana R / Fujita, André / Mott, Joni D / Soares, Fernando A / Labriola, Leticia / Sogayar, Mari C

BMC cancer

2015 Volume 15, Page(s) 660

Abstract: Background: The REversion-inducing Cysteine-rich protein with Kazal motif (RECK) is a well-known inhibitor of matrix metalloproteinases (MMPs) and cellular invasion. Although high expression levels of RECK have already been correlated with a better ... ...

Abstract	Background: The REversion-inducing Cysteine-rich protein with Kazal motif (RECK) is a well-known inhibitor of matrix metalloproteinases (MMPs) and cellular invasion. Although high expression levels of RECK have already been correlated with a better clinical outcome for several tumor types, its main function, as well as its potential prognostic value for breast cancer patients, remain unclear. Methods: The RECK expression profile was investigated in a panel of human breast cell lines with distinct aggressiveness potential. RECK functional analysis was undertaken using RNA interference methodology. RECK protein levels were also analyzed in 1040 cases of breast cancer using immunohistochemistry and tissue microarrays (TMAs). The association between RECK expression and different clinico-pathological parameters, as well as the overall (OS) and disease-free (DFS) survival rates, were evaluated. Results: Higher RECK protein expression levels were detected in more aggressive breast cancer cell lines (T4-2, MDA-MB-231 and Hs578T) than in non-invasive (MCF-7 and T47D) and non-tumorigenic (S1) cell lines. Indeed, silencing RECK in MDA-MB-231 cells resulted in elevated levels of pro-MMP-9 and increased invasion compared with scrambled (control) cells, without any effect on cell proliferation. Surprisingly, by RECK immunoreactivity analysis on TMAs, we found no association between RECK positivity and survival (OS and DFS) in breast cancer patients. Even considering the different tumor subtypes (luminal A, luminal B, Her2 type and basal-like) or lymph node status, RECK remained ineffective for predicting the disease outcome. Moreover, by multivariate Cox regression analysis, we found that RECK has no prognostic impact for OS and DFS, relative to standard clinical variables. Conclusions: Although it continues to serve as an invasion and MMP inhibitor in breast cancer, RECK expression analysis is not useful for prognosis of these patients.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/mortality ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Cell Movement/genetics ; Cell Proliferation ; Female ; GPI-Linked Proteins/genetics ; GPI-Linked Proteins/metabolism ; Gene Expression ; Humans ; Kaplan-Meier Estimate ; Matrix Metalloproteinase 9/metabolism ; Middle Aged ; Neoplasm Grading ; Prognosis ; Proportional Hazards Models ; Risk Factors ; Tumor Burden
Chemical Substances	Biomarkers, Tumor ; GPI-Linked Proteins ; RECK protein, human ; Matrix Metalloproteinase 9 (EC 3.4.24.35)
Language	English
Publishing date	2015-10-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1471-2407
ISSN (online)	1471-2407
DOI	10.1186/s12885-015-1666-2
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Article ; Online: TGF-β1 modulates the homeostasis between MMPs and MMP inhibitors through p38 MAPK and ERK1/2 in highly invasive breast cancer cells

Gomes Luciana R / Terra Letícia F / Wailemann Rosângela AM / Labriola Leticia / Sogayar Mari C

BMC Cancer, Vol 12, Iss 1, p

2012 Volume 26

Abstract: Abstract Background Metastasis is the main factor responsible for death in breast cancer patients. Matrix metalloproteinases (MMPs) and their inhibitors, known as tissue inhibitors of MMPs (TIMPs), and the membrane-associated MMP inhibitor (RECK), are ... ...

Abstract	Abstract Background Metastasis is the main factor responsible for death in breast cancer patients. Matrix metalloproteinases (MMPs) and their inhibitors, known as tissue inhibitors of MMPs (TIMPs), and the membrane-associated MMP inhibitor (RECK), are essential for the metastatic process. We have previously shown a positive correlation between MMPs and their inhibitors expression during breast cancer progression; however, the molecular mechanisms underlying this coordinate regulation remain unknown. In this report, we investigated whether TGF-β1 could be a common regulator for MMPs, TIMPs and RECK in human breast cancer cell models. Methods The mRNA expression levels of TGF-β isoforms and their receptors were analyzed by qRT-PCR in a panel of five human breast cancer cell lines displaying different degrees of invasiveness and metastatic potential. The highly invasive MDA-MB-231 cell line was treated with different concentrations of recombinant TGF-β1 and also with pharmacological inhibitors of p38 MAPK and ERK1/2. The migratory and invasive potential of these treated cells were examined in vitro by transwell assays. Results In general, TGF-β2, TβRI and TβRII are over-expressed in more aggressive cells, except for TβRI, which was also highly expressed in ZR-75-1 cells. In addition, TGF-β1-treated MDA-MB-231 cells presented significantly increased mRNA expression of MMP-2, MMP-9, MMP-14, TIMP-2 and RECK. TGF-β1 also increased TIMP-2, MMP-2 and MMP-9 protein levels but downregulated RECK expression. Furthermore, we analyzed the involvement of p38 MAPK and ERK1/2, representing two well established Smad-independent pathways, in the proposed mechanism. Inhibition of p38MAPK blocked TGF-β1-increased mRNA expression of all MMPs and MMP inhibitors analyzed, and prevented TGF-β1 upregulation of TIMP-2 and MMP-2 proteins. Moreover, ERK1/2 inhibition increased RECK and prevented the TGF-β1 induction of pro-MMP-9 and TIMP-2 proteins. TGF-β1-enhanced migration and invasion capacities were blocked by p38MAPK, ERK1/2 and MMP inhibitors. Conclusion Altogether, our results support that TGF-β1 modulates the mRNA and protein levels of MMPs (MMP-2 and MMP-9) as much as their inhibitors (TIMP-2 and RECK). Therefore, this cytokine plays a crucial role in breast cancer progression by modulating key elements of ECM homeostasis control. Thus, although the complexity of this signaling network, TGF-β1 still remains a promising target for breast cancer treatment.
Keywords	Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Oncology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	616
Language	English
Publishing date	2012-01-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
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Article ; Online: DUOX1 Silencing in Mammary Cell Alters the Response to Genotoxic Stress.

Fortunato, Rodrigo S / Gomes, Luciana R / Munford, Veridiana / Pessoa, Carolina Fittipaldi / Quinet, Annabel / Hecht, Fabio / Kajitani, Gustavo S / Milito, Cristiane Bedran / Carvalho, Denise P / Menck, Carlos Frederico Martins

Oxidative medicine and cellular longevity

2018 Volume 2018, Page(s) 3570526

Abstract: DUOX1 is an ... ...

Abstract	DUOX1 is an H
MeSH term(s)	Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Cell Movement/genetics ; Cell Proliferation/genetics ; DNA Damage/drug effects ; DNA Damage/genetics ; Down-Regulation ; Doxorubicin/pharmacology ; Dual Oxidases/biosynthesis ; Dual Oxidases/genetics ; Female ; Gene Knockdown Techniques ; Gene Silencing ; Humans ; Hydrogen Peroxide/metabolism ; Interleukin-6/metabolism ; Interleukin-8/metabolism ; Tumor Cells, Cultured
Chemical Substances	IL6 protein, human ; Interleukin-6 ; Interleukin-8 ; Doxorubicin (80168379AG) ; Hydrogen Peroxide (BBX060AN9V) ; Dual Oxidases (EC 1.11.1.-) ; DUOX1 protein, human (EC 1.6.3.1)
Language	English
Publishing date	2018-04-19
Publishing country	United States
Document type	Journal Article
ISSN	1942-0994
ISSN (online)	1942-0994
DOI	10.1155/2018/3570526
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Article ; Online: TGF-β1 modulates the homeostasis between MMPs and MMP inhibitors through p38 MAPK and ERK1/2 in highly invasive breast cancer cells.

Gomes, Luciana R / Terra, Letícia F / Wailemann, Rosângela Am / Labriola, Leticia / Sogayar, Mari C

BMC cancer

2012 Volume 12, Page(s) 26

Abstract: Background: Metastasis is the main factor responsible for death in breast cancer patients. Matrix metalloproteinases (MMPs) and their inhibitors, known as tissue inhibitors of MMPs (TIMPs), and the membrane-associated MMP inhibitor (RECK), are essential ...

Abstract	Background: Metastasis is the main factor responsible for death in breast cancer patients. Matrix metalloproteinases (MMPs) and their inhibitors, known as tissue inhibitors of MMPs (TIMPs), and the membrane-associated MMP inhibitor (RECK), are essential for the metastatic process. We have previously shown a positive correlation between MMPs and their inhibitors expression during breast cancer progression; however, the molecular mechanisms underlying this coordinate regulation remain unknown. In this report, we investigated whether TGF-β1 could be a common regulator for MMPs, TIMPs and RECK in human breast cancer cell models. Methods: The mRNA expression levels of TGF-β isoforms and their receptors were analyzed by qRT-PCR in a panel of five human breast cancer cell lines displaying different degrees of invasiveness and metastatic potential. The highly invasive MDA-MB-231 cell line was treated with different concentrations of recombinant TGF-β1 and also with pharmacological inhibitors of p38 MAPK and ERK1/2. The migratory and invasive potential of these treated cells were examined in vitro by transwell assays. Results: In general, TGF-β2, TβRI and TβRII are over-expressed in more aggressive cells, except for TβRI, which was also highly expressed in ZR-75-1 cells. In addition, TGF-β1-treated MDA-MB-231 cells presented significantly increased mRNA expression of MMP-2, MMP-9, MMP-14, TIMP-2 and RECK. TGF-β1 also increased TIMP-2, MMP-2 and MMP-9 protein levels but downregulated RECK expression. Furthermore, we analyzed the involvement of p38 MAPK and ERK1/2, representing two well established Smad-independent pathways, in the proposed mechanism. Inhibition of p38MAPK blocked TGF-β1-increased mRNA expression of all MMPs and MMP inhibitors analyzed, and prevented TGF-β1 upregulation of TIMP-2 and MMP-2 proteins. Moreover, ERK1/2 inhibition increased RECK and prevented the TGF-β1 induction of pro-MMP-9 and TIMP-2 proteins. TGF-β1-enhanced migration and invasion capacities were blocked by p38MAPK, ERK1/2 and MMP inhibitors. Conclusion: Altogether, our results support that TGF-β1 modulates the mRNA and protein levels of MMPs (MMP-2 and MMP-9) as much as their inhibitors (TIMP-2 and RECK). Therefore, this cytokine plays a crucial role in breast cancer progression by modulating key elements of ECM homeostasis control. Thus, although the complexity of this signaling network, TGF-β1 still remains a promising target for breast cancer treatment.
MeSH term(s)	Blotting, Western ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Female ; Homeostasis/drug effects ; Humans ; MAP Kinase Signaling System/drug effects ; MAP Kinase Signaling System/physiology ; Matrix Metalloproteinase Inhibitors ; Matrix Metalloproteinases/metabolism ; Neoplasm Proteins/metabolism ; Polymerase Chain Reaction/methods ; RNA, Messenger/metabolism ; Tissue Inhibitor of Metalloproteinases/metabolism ; Transforming Growth Factor beta1/metabolism ; Transforming Growth Factor beta1/pharmacology ; p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors ; p38 Mitogen-Activated Protein Kinases/pharmacology
Chemical Substances	Matrix Metalloproteinase Inhibitors ; Neoplasm Proteins ; RNA, Messenger ; Tissue Inhibitor of Metalloproteinases ; Transforming Growth Factor beta1 ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Matrix Metalloproteinases (EC 3.4.24.-)
Language	English
Publishing date	2012-01-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1471-2407
ISSN (online)	1471-2407
DOI	10.1186/1471-2407-12-26
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Article ; Online: Correlation between MMPs and their inhibitors in breast cancer tumor tissue specimens and in cell lines with different metastatic potential

Silva Ismael DCG / Silva Fabricio C / Neto João S / Gomes Luciana R / Figueira Rita CS / Sogayar Mari C

BMC Cancer, Vol 9, Iss 1, p

2009 Volume 20

Abstract: Abstract Background The metastatic disease rather than the primary tumor itself is responsible for death in most solid tumors, including breast cancer. The role of matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs) and Reversion-inducing ...

Abstract	Abstract Background The metastatic disease rather than the primary tumor itself is responsible for death in most solid tumors, including breast cancer. The role of matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs) and Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) in the metastatic process has previously been established. However, in all published studies only a limited number of MMPs/MMP inhibitors was analyzed in a limited number of cell lines. Here, we propose a more comprehensive approach by analyzing the expression levels of several MMPs (MMP-2, MMP-9 and MMP-14) and MMP inhibitors (TIMP-1, TIMP-2 and RECK) in different models (five human breast cancer cell lines, 72 primary breast tumors and 30 adjacent normal tissues). Methods We analyzed the expression levels of MMP-2, MMP-9 and MMP-14 and their inhibitors (TIMP-1, TIMP-2 and RECK) by quantitative RT-PCR (qRT-PCR) in five human breast cancer cell lines presenting increased invasiveness and metastatic potential, 72 primary breast tumors and 30 adjacent normal tissues. Moreover, the role of cell-extracellular matrix elements interactions in the regulation of expression and activity of MMPs and their inhibitors was analyzed by culturing these cell lines on plastic or on artificial ECM (Matrigel). Results The results demonstrated that MMPs mRNA expression levels displayed a positive and statistically significant correlation with the transcriptional expression levels of their inhibitors both in the cell line models and in the tumor tissue samples. Furthermore, the expression of all MMP inhibitors was modulated by cell-Matrigel contact only in highly invasive and metastatic cell lines. The enzyme/inhibitor balance at the transcriptional level significantly favors the enzyme which is more evident in tumor than in adjacent non-tumor tissue samples. Conclusion Our results suggest that the expression of MMPs and their inhibitors, at least at the transcriptional level, might be regulated by common factors and signaling pathways. Therefore, the multi-factorial analysis of these molecules could provide new and independent prognostic information contributing to the determination of more adequate therapy strategies for each patient.
Keywords	Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Oncology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	616
Language	English
Publishing date	2009-01-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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