Renata Binato

Instituto Nacional do Câncer

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Eliana Abdelhay

Instituto Nacional do Câncer

Eliana Abdelhay

Instituto Nacional do Câncer

Stephany Corrêa

Instituto Nacional do Câncer

Carolina Panis

Universidade Estadual de Londrina

Luciana Pizzatti

Universidade Federal do Rio de Janeiro

Bárbara Du Rocher

Fundação Oswaldo Cruz

André Luiz Mencalha

Universidade do Estado do Rio de Janeiro

Thomas Liehr

Friedrich Schiller University Jena

Gerson Ferreira

Instituto Nacional do Câncer

Everton Cruz dos Santos

Instituto Nacional do Câncer

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Instituto Nacional do Câncer

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Universidade Federal do Rio de Janeiro

Istituti di Ricovero e Cura a Carattere Scientifico

Universidade de São Paulo

Weatherford College

Inserm

Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale"

Universidad de Guadalajara

Instituto Nacional del Cáncer

Universidade do Estado do Rio de Janeiro

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LPA Induces Colon Cancer Cell Proliferation through a Cooperation between the ROCK and STAT-3 Pathways

PLoS ONE (2015)

Fernanda Leve Rubem J. Peres-Moreira Renata Binato Eliana Abdelhay José Andrés Morgado‐Díaz

Lysophosphatidic acid (LPA) plays a critical role in the proliferation and migration of colon cancer cells; however, the downstream signaling events underlying these processes remain poorly characterized. The aim of this study was to investigate the signaling pathways triggered by LPA to regulate the mechanisms involved in the progression of colorectal cancer (CRC). We have used three cell line models of CRC, and initially analyzed the expression profile of LPA receptors (LPAR). Then, we treated the cells with LPA and events related to their tumorigenic potential, such as migration, invasion, anchorage-independent growth, proliferation as well as apoptosis and cell cycle were evaluated. We used the Chip array technique to analyze the global gene expression profiling that occurs after LPA treatment, and we identified cell signaling pathways related to the cell cycle. The inhibition of these pathways verified the conclusions of the transcriptomic analysis. We found that the cell lines expressed LPAR1, -2 and -3 in a differential manner and that 10 μM LPA did not affect cell migration, invasion and anchorage-independent growth, but it did induce proliferation and cell cycle progression in HCT-116 cells. Although LPA in this concentration did not induce transcriptional activity of β-catenin, it promoted the activation of Rho and STAT-3. Moreover, ROCK and STAT-3 inhibitors prevented LPA-induced proliferation, but ROCK inhibition did not prevent STAT-3 activation. Finally, we observed that LPA regulates the expression of genes related to the cell cycle and that the combined inhibition of ROCK and STAT-3 prevented cell cycle progression and increased the LPA-induced expression of cyclins E1, A2 and B1 to a greater degree than either inhibitor alone. Overall, these results demonstrate that LPA increases the proliferative potential of colon adenocarcinoma HCT-116 cells through a mechanism involving cooperation between the Rho-ROCK and STAT3 pathways involved in cell cycle control.

10.1371/journal.pone.0139094

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Citations (34)

Abstract 608: Molecular features of breast cancer involved in classification and prognosis of a multi-country Latin American cohort: The US-LACRN-MPBCS breast cancer cohort

Cancer Research (2021)

Andrea S. Llera Eliana Abdelhay Osvaldo L. Podhajcer Nora Artagaveytia Adrián Daneri‐Navarro

Abstract Although gene expression-derived PAM50 intrinsic subtypes (LumA, LumB, HER2E and Basal) were reported in Latin American breast cancer, most studies did not adequately represent the unique and diverse genetic admixture of the Latin American population and/or included a small number of individuals. As a result of these limitations, confirmation of the prognostic value of available intrinsic subtype classification signatures in a diverse cohort of Latin American women is of utmost importance. We assessed the general distribution and prognostic performance of PAM50-based intrinsic and immunohistochemistry (IHC)-based surrogate subtype classifications in Latin American women included in the Molecular Profile of Breast Cancer Study (MPBCS), an initiative of the US-Latin America Cancer Research Network (US-LACRN) comprising institutions of Argentina, Brazil, Chile, Mexico and Uruguay. MPBCS focused on stage II-III breast cancer in Latin American women. Eligible enrolled patients (n=1300) were characterized clinically, pathologically and epidemiologically and followed-up for 5 years. IHC subtypes were assessed according to St Gallen's 2013 criteria, using Ki67 to discriminate LumB from LumA tumors. A total of 1071 tumors were characterized by gene-expression microarrays. PAM50 classification defined 45% of tumors as LumA, 19.7% as LumB, 13.8% as HER2E and 17.5% as Basal. Normal-like tumors (6.3%) were excluded from the analysis. The 5-year prognostic ability of PAM50 and IHC classifications, both at the cancer-specific (OS) and progression-free survival (PFS), was tested. The prognosis for LumA tumors was significantly better than for other subtypes, while Basal-like tumors had the worst prognosis. The prognostic power of IHC-based subtypes (C-index 0.698 for OS, 0.635 for PFS) was very similar to that of PAM50 (C-index 0.678 for OS, 0.639 for PFS), indicating that in US-LACRN-MPBCS, contrary to other cohorts, surrogate subtypes are as useful as PAM50 for discriminating recurrence risk. PAM50-derived risks of recurrence (RORs), in particular ROR-S (C-index 0.699 for OS, 0.649 for PFS), clearly discriminated risk into low, intermediate and high-risk groups. Transcriptomic pathway analysis showed high proliferation (i.e. cell cycle control and DNA damage repair) associated with LumB, HER2E and Basal tumors, and a strong dependency on the estrogen pathway for LumA. Overall, a general concordance of the molecular features of US-LACRN-MPBCS breast cancer tumors with those of other cohorts was confirmed. The shift towards non-luminal subtypes could be partly attributable to the recruitment bias towards advanced stages. Further refinement of analyses using molecular ancestry assignation may help to reveal more subtle differences in this heterogeneously admixed population. Citation Format: Andrea S. Llera, Eliana Abdelhay, Osvaldo Podhajcer, Nora Artagaveytia, Adrián Daneri-Navarro, Bettina Müller, Carlos Velázquez Contreras, Darío Rocha, Juan Martín Sendoya, Renata Binato, Elmer Fernández, Elsa Alcoba, Isabel Alonso, Alicia I. Bravo, Natalia Camejo, Dirce Carraro, Mónica Castro, Juan M. Castro-Cervantes, Sandra Cataldi, Alfonso Cayota, Mauricio Cerda, Susanne Crocamo, Raul Delgadillo-Cisterna, Lucía Delgado, Alicia del Toro Arreola, Marisa Dreyer Breitenbach, Jorge Fernández, Wanda Fernández, Ramon A. Franco-Topete, Fancy Gaete, Jorge Gómez, Gonzalo Greif, Marisol Guerrero, Marianne Marianne Henderson, Andres de J Moran-Mendoza, María Aparecida Nagai, Antonio Oceguera-Villanueva, Antonio Quintero-Ramos, Rui Reis, Javier Retamales, Robinson Rodríguez, Cristina Rosales, Efrain Salas-González, Laura Segovia, Araceli Silva-García, Vidya Vedham, Livia Zagame, The US-Latin American Cancer Research Network. Molecular features of breast cancer involved in classification and prognosis of a multi-country Latin American cohort: The US-LACRN-MPBCS breast cancer cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 608.

Tissue microarray

10.1158/1538-7445.am2021-608

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BCR–ABL-mediated upregulation of PRAME is responsible for knocking down TRAIL in CML patients

Oncogene (2010)

Daniel D. De Carvalho Renata Binato Welbert Oliveira Pereira Janine Marie Gisele Leroy M D Colassanti

breakpoint cluster region

10.1038/onc.2010.409

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Forkhead Box M1 (FoxM1) Gene Is a New STAT3 Transcriptional Factor Target and Is Essential for Proliferation, Survival and DNA Repair of K562 Cell Line

PLoS ONE (2012)

André Luiz Mencalha Renata Binato Gerson Ferreira Bárbara Du Rocher Eliana Abdelhay

The forkhead box (Fox) M1 gene belongs to a superfamily of evolutionarily conserved transcriptional regulators that are involved in a wide range of biological processes, and its deregulation has been implicated in cancer survival, proliferation and chemotherapy resistance. However, the role of FoxM1, the signaling involved in its activation and its role in leukemia are poorly known. Here, we demonstrate by gene promoter analysis, Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays that FoxM1 is a new target of the STAT3 transcriptional activator. Additionally, FoxM1 is transcriptionally dependent on STAT3 signaling activation. Furthermore, we verified that FoxM1 is crucial for K562 cell proliferation, cell cycle checkpoints and viability and could be related to chemotherapeutic resistance. By microarray analysis, we determined the signaling pathways related to FoxM1 expression and its role in DNA repair using K562 cells. Our results revealed new signaling involved in FoxM1 expression and its role in leukemic cells that elucidate cellular mechanisms associated with the development of leukemia and disease progression.

FOXM1

Chromatin immunoprecipitation

K562 cells

10.1371/journal.pone.0048160

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Citations (62)

AVALIAÇÃO PROTEÔMICA DO MECANISMO DE AÇÃO ANTINEOPLÁSICA DO DERIVADO TIOFENO SB-83 EM LINHAGEM LEUCEMICARESISTENTE

Anais do 5º Encontro Brasileiro para Inovação Terapêutica (2017)

LS Carvalho Mariana Senna Quirino Renata Binato Eliana Abdelhay Tiago Bento de Oliveira

RESUMO -Leucemias são um grupo heterogêneo de neoplasias hematológicas que tem como primeira linha de tratamento a quimioterapia.Sabe-se, porém, que os agentes quimioterápicos não agem exclusivamente em células neoplásicas, podendo levar a diferentes graus de toxicidade e inúmeros efeitos adversos.Além disso, não raro os clones neoplásicos exibem resistência aos quimioterápicos tornando o tratamento desafiador.Nesse sentido, a presente proposta buscou a elucidação do mecanismo de ação de um novo agente antineoplásico por meio de análise proteômica na linhagem leucêmica resistente a vários quimioterápicos, HL60-MX1.No estudo utilizamos um derivado tiofeno, SB-83, com atividade antileucêmica in vitro comprovada anteriormente pelo grupo.SB-83 exibiu valor de IC 50 de 7,96 µM para linhagem leucêmica e 34 µM em células saudáveis (PBMC) com índice de seletividade de 4,26 indicando-o como um agente antitumoral promissor.A avaliação do mecanismo de ação feita por proteômica gel free e label free utilizando cromatografia bidimensional acoplada à espectrometria de massas, identificou um total de 734 proteínas moduladas pelo derivado.Em nossa análise somente foram consideradas

10.17648/ebit-2017-85677

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An unusual T-cell childhood acute lymphoblastic leukemia harboring a yet unreported near-tetraploid karyotype

Molecular Cytogenetics (2011)

Daniela R. Ney Garcia Samarth Bhatt Marina Manvelyan Mariana Tavares de Souza Renata Binato

Abstract Background Near-tetraploid (model #81-103) and near-triploid (model #67-81) karyotypes are found in around 1% of childhood acute lymphoblastic leukemia. Due to its rarity, these two cytogenetic subgroups are generally included in the hyperdiploid group (model # > 51). Therefore separate informations about these two subgroups are limited to a few reports. Some studies found that near-tetraploidy is relatively more frequent in higher median ages and it is associated to Frech-American-British Classification subtype L2. Although the mechanisms by which leukemic blast cells divide is still unclear, studies have suggested that hyperdiploidy, near-triploidy and near-tetraploidy do not seem to share the same mechanism. Findings Herewith, we present a new childhood T-acute lymphoblastic leukemia case of near-tetraploid karyotype with loss of two p53-gene copies, characterized in detail by cytogenetic and molecular studies. Conclusion We suggest that p53 is a good target gene to be screened, once p53 is one of the main effectors of cell cycle checkpoints.

Human genetics

10.1186/1755-8166-4-20

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SUZ12 is a candidate target of the non‐canonical WNT pathway in the progression of chronic myeloid leukemia

Genes Chromosomes and Cancer (2009)

Luciana Pizzatti Renata Binato Jaime Cofré Bernadete Evangelho Gomes Jane Dobbin

Polycomb proteins form multiprotein complexes that repress target genes by chromatin remodeling. In this work, we report that the SUZ12 polycomb gene is over-expressed in bone marrow samples of patients at the blastic phase of chronic myeloid leukemia. We also found a direct interaction between polycomb group genes and the WNT signaling pathway in chronic myeloid leukemia transformation. Electrophoretic mobility shift assay (EMSA), Chromatin immunoprecipitation assay (ChIP), and mass spectrometry assays identified noncanonical WNT pathway members, such as WNT5A and WNT11, bound to the SUZ12 promoter. Immunohistochemistry and immunofluorescence with WNT5A and WNT11 antibodies confirmed nuclear localization. Knockdown of WNTs 1, 5A, and 11 with RNAi approaches showed that WNT members are capable of activating SUZ12 transcription with varying promoter affinities. Finally, we suggest that SUZ12 is blocking cellular differentiation, as SUZ12 knockdown release differentiation programs in chronic myeloid blastic phase (CML-BP) transformed cell line.

Non canonical

10.1002/gcc.20722

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Citations (30)

SLPI overexpression in hMSCs could be implicated in the HSC gene expression profile in AML

Scientific Reports (2024)

Pedro Azevedo Simone Maradei Ricardo de Sá Bigni Jordana S. R. Aragao Eliana Abdelhay

Abstract Acute myeloid leukaemia (AML) is a severe haematological neoplasm that originates from the transformation of haematopoietic stem cells (HSCs) into leukaemic stem cells (LSCs). The bone marrow (BM) microenvironment, particularly that of mesenchymal stromal cells (hMSCs), plays a crucial role in the maintenance of HSCs. In this context, we explored whether alterations in the secretome of hMSCs derived from AML patients (hMSC-AML) could impact HSC gene expression. Proteomic analysis revealed that the secretome of coculture assays with hMSC-AMLs and HSC from healthy donor is altered, with increased levels of secretory leukocyte protease inhibitor (SLPI), a protein associated with important processes for maintenance of the haematopoietic niche that has already been described to be altered in several tumours. Increased SLPI expression was also observed in the BM plasma of AML patients. Transcriptome analysis of HSCs cocultured with hMSC-AML in comparison with HSCs cocultured with hMSC-HD revealed altered expression of SLPI target genes associated with the cell cycle, proliferation, and apoptosis. Important changes were identified, such as increased expression levels of CCNA2, CCNE2, CCND2, CD133 and CDK1 and decreased levels of CDKN2A and IGFBP3, among others. Overall, these findings suggest that the altered secretome of coculture assays with hMSC-AMLs and HSC from healthy donor, particularly increased SLPI expression, can contribute to gene expression changes in HSCs, potentially influencing important molecular mechanisms related to AML development and progression.

10.1038/s41598-024-66400-7

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Twist1 Influences the Expression of Leading Members of the IL-17 Signaling Pathway in HER2-Positive Breast Cancer Cells

International Journal of Molecular Sciences (2021)

Bruno Ricardo Barreto Pires Renata Binato Gerson Ferreira Stephany Corrêa Bárbara Du Rocher

Breast cancer (BC) is a heterogeneous disease composed of multiple subtypes with different molecular characteristics and clinical outcomes. The metastatic process in BC depends on the transcription factors (TFs) related to epithelial-mesenchymal transition (EMT), including the master regulator Twist1. However, its role beyond EMT in BC subtypes remains unclear. Our study aimed to investigate the role of Twist1, beyond EMT, in the molecular subtypes of BC. In patients, we observed the overexpression of TWIST1 in the HER2+ group. The silencing of TWIST1 in HER2+ BC cells resulted in the upregulation of 138 genes and the downregulation of 174 genes compared to control cells in a microarray assay. In silico analysis revealed correlations between Twist1 and important biological processes such as the Th17-mediated immune response, suggesting that Twist1 could be relevant for IL-17 signaling in HER2+ BC. IL-17 signaling was then examined, and it was shown that TWIST1 knockdown caused the downregulation of leading members of IL-17 signaling pathway. Taken together, our findings suggest that Twist1 plays a role on IL-17 signaling in HER2+ BC.

Twist transcription factor

10.3390/ijms222212144

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Citations (6)

LLL-3, a STAT3 inhibitor, represses BCR-ABL-positive cell proliferation, activates apoptosis and improves the effects of Imatinib mesylate

Cancer Chemotherapy and Pharmacology (2009)

André Luiz Mencalha Bárbara Du Rocher Daniela C. Salles Renata Binato Eliana Abdelhay

Viability assay

Imatinib Mesylate

K562 cells

Annexin A5

10.1007/s00280-009-1109-3

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Citations (27)