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1.
Ugeskr Laeger ; 183(39)2021 Sep 27.
Artigo em Dinamarquês | MEDLINE | ID: mdl-34596511

RESUMO

About half of all Danish cancer patients are 70 years or older at diagnosis. The incidence is expected to increase further over the coming years because of an increasing longevity. Therefore, this review recommends that the Danish health care system develops and implement models to ensure optimal care for older adults with cancer. We are still in need of knowledge about the optimal treatment, rehabilitation, palliation and care for older adults with cancer. We encourage the Danish health authorities to formulate a national strategy for this area.

2.
Mol Cancer ; 20(1): 108, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34446021

RESUMO

BACKGROUND: Early recurrence is a major obstacle to prolonged postoperative survival in squamous cell lung carcinoma (SqCLC). The molecular mechanisms underlying early SqCLC recurrence remain unclear, and effective prognostic biomarkers for predicting early recurrence are needed. METHODS: We analyzed primary tumor samples of 20 SqCLC patients using quantitative proteomics to identify differentially-expressed proteins in patients who experienced early versus late disease recurrence. The expression and prognostic significance of DDX56 was evaluated using a SqCLC tumor tissue microarray and further verified using different online databases. We performed in vitro and in vivo experiments to obtain detailed molecular insight into the functional role of DDX56 in SqCLC. RESULTS: We found that DDX56 exhibited increased expression in tumors of patients who experienced early versus late disease recurrence. Increased DDX56 expression in SqCLC tumors was subsequently confirmed as an independent prognostic factor of poor recurrence-free survival in independent SqCLC cohorts. Functionally, DDX56 promotes SqCLC cell growth and migration in vitro, and xenograft tumor progression in vivo. Mechanistically, DDX56 post-transcriptionally promotes expression of multiple Wnt signaling pathway-related genes, including CTNNB1, WNT2B, and represses a subset of miRNAs, including miR-378a-3p, a known suppressor of Wnt signaling. Detailed analysis revealed that DDX56 facilitated degradation of primary miR-378a, leading to down-regulation of mature miR-378a-3p and thus derepression of the target gene WNT2B. CONCLUSION: We identified DDX56 as a novel independent prognostic biomarker that exerts its oncogenic effects through miRNA-mediated post-transcriptional regulation of Wnt signaling genes to promote early SqCLC recurrence. DDX56 may assist in identifying SqCLC patients at increased risk of early recurrence and who could benefit from Wnt signaling-targeted therapies.

4.
Nat Commun ; 12(1): 5112, 2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433817

RESUMO

CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy have shown impressive efficacy in estrogen receptor-positive advanced breast cancer. However, most patients will eventually experience disease progression on this combination, underscoring the need for effective subsequent treatments or better initial therapies. Here, we show that triple inhibition with fulvestrant, CDK4/6i and AKT inhibitor (AKTi) durably impairs growth of breast cancer cells, prevents progression and reduces metastasis of tumor xenografts resistant to CDK4/6i-fulvestrant combination or fulvestrant alone. Importantly, switching from combined fulvestrant and CDK4/6i upon resistance to dual combination with AKTi and fulvestrant does not prevent tumor progression. Furthermore, triple combination with AKTi significantly inhibits growth of patient-derived xenografts resistant to combined CDK4/6i and fulvestrant. Finally, high phospho-AKT levels in metastasis of breast cancer patients treated with a combination of CDK4/6i and endocrine therapy correlates with shorter progression-free survival. Our findings support the clinical development of ER, CDK4/6 and AKT co-targeting strategies following progression on CDK4/6i and endocrine therapy combination, and in tumors exhibiting high phospho-AKT levels, which are associated with worse clinical outcome.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Fulvestranto/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/metabolismo , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Quimioterapia Combinada , Feminino , Humanos , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas c-akt/genética
6.
Mol Oncol ; 2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34165921

RESUMO

RAS-MAPK signaling promotes immune evasion and cancer cell survival, and MAPK inhibitors (MAPKis) are frequently used as cancer therapies. Despite progress elucidating the direct effects of MAPKi on immune cells, their indirect effect on the tumor microenvironment (TME) through changes in tumor cells remains incompletely understood. Here, we present evidence of a rapid compensatory response to MAPKi that is driven by sustained p38 MAPK signaling and by which cancer cells can upregulate the immunosuppressive protein CD73 to reduce the antitumor immune response. This compensatory response also results in decreased sensitivity toward MAPKi, and, accordingly, combining anti-CD73 antibodies and MAPKi significantly enhances the antitumor effect compared to single-agent treatment in vivo. Combining MAPKi and anti-CD73 was accompanied by significant alterations in intratumor immune cell composition, supporting the effect of MAPKi-induced CD73 expression on the TME. We show that high CD73 expression significantly correlates with worse outcome in MAPKi-treated colorectal cancer patients, highlighting the potential clinical importance of increased CD73 expression following MAPKi treatment. Our findings may explain the diminished effect of MAPKi in cancer patients and provides further rationale for combined anti-CD73 and MAPKi treatment.

8.
Methods Mol Biol ; 2282: 43-56, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33928569

RESUMO

Small interfering RNAs (siRNAs) are RNA molecules with promising therapeutic potential as a result of their selective mRNA cleavage. However, despite recent progress, low stability in the bloodstream is an impediment to successful administration in vivo. Thus, the availability of flexible and rapid methods for studying siRNA stability and vehicles is crucial for future novel siRNA-based therapeutics. Herein, we report a fast Förster resonance energy transfer (FRET) method based on agarose gel electrophoresis to evaluate the stability of siRNA in serum as well as siRNA interaction with serum proteins and enzymes.


Assuntos
Proteínas Sanguíneas/metabolismo , Eletroforese em Gel de Ágar , Transferência Ressonante de Energia de Fluorescência , Interferência de RNA , Estabilidade de RNA , RNA Interferente Pequeno/metabolismo , Imagem Individual de Molécula , Cinética , Medições Luminescentes , RNA Interferente Pequeno/genética , Projetos de Pesquisa , Fluxo de Trabalho
9.
Methods Mol Biol ; 2282: 353-376, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33928584

RESUMO

SiRNAs may act as selective and potent therapeutics, but poor deliverability in vivo is a limitation. Among the recently proposed vectors, cell-penetrating peptides (CPPs), also referred as protein transduction domains (PTDs), allow siRNA stabilization and increased cellular uptake. This chapter aims to guide scientists in the preparation and characterization of CPP-siRNA complexes, particularly the evaluation of novel CPPs variants for siRNA encapsulation and delivery. Herein, we present a collection of methods to determine CPP-siRNA interaction, encapsulation, stability, conformation, transfection, and silencing efficiency.


Assuntos
Peptídeos Penetradores de Células/química , Interferência de RNA , RNA Interferente Pequeno/genética , Transfecção , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular , Peptídeos Penetradores de Células/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Humanos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Células MCF-7 , RNA Interferente Pequeno/química , RNA Interferente Pequeno/metabolismo , Projetos de Pesquisa , Fluxo de Trabalho
10.
Life Sci ; 276: 119431, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33785332

RESUMO

MicroRNAs (miRNAs) have the ability to regulate gene expression programs in cells. Hence, altered expression of miRNAs significantly contributes to breast cancer development and progression. Here, we demonstrate that the miRNA miR-142-3p directly targets the 3' untranslated region of HMGA2, which encodes an onco-embryonic protein that is overexpressed in most cancers, including breast cancer. Down regulation of miR-142-3p predicting poor patient survival in grade 3 breast cancer (P-value = 0.045). MiR-142-3p downregulates HMGA2 mRNA and protein levels. Higher miR-142-3p and lower HMGA2 expressed are found in breast cancer versus normal breast tissue (P-value<0.05), and their levels inversely correlate in breast cancers (P-value = 1.46 × 10-4). We demonstrate that miR-142-3p induces apoptosis and G2/M cell cycle arrest in breast cancer cells. In addition, it inhibits breast cancer stem cell properties and decreases SOX2, NANOG, ALDH and c-Myc expression. MiR-142-3p also decreases cell proliferation through inhibition of the ERK/AKT/STAT3 signaling pathways. Finally, pathway analyses of patient samples suggest that these mechanisms also acting in the tumors of breast cancer patients. Thus, our work identifies HMGA2 as a direct miR-142-3p target and indicates that miR-142-3p is an important suppressor of breast cancer oncogenesis. This identifies miR-142-3p may candidate as a therapeutic molecule for breast cancer treatment.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Regulação Neoplásica da Expressão Gênica , Proteína HMGA2/metabolismo , MicroRNAs/genética , Apoptose , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Ciclo Celular , Movimento Celular , Proliferação de Células , Feminino , Proteína HMGA2/genética , Humanos , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas
11.
Genes (Basel) ; 12(2)2021 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-33668453

RESUMO

The high mobility group protein 2 (HMGA2) regulates gene expression by binding to AT-rich regions of DNA. Akin to other DNA architectural proteins, HMGA2 is highly expressed in embryonic stem cells during embryogenesis, while its expression is more limited at later stages of development and in adulthood. Importantly, HMGA2 is re-expressed in nearly all human malignancies, where it promotes tumorigenesis by multiple mechanisms. HMGA2 increases cancer cell proliferation by promoting cell cycle entry and inhibition of apoptosis. In addition, HMGA2 influences different DNA repair mechanisms and promotes epithelial-to-mesenchymal transition by activating signaling via the MAPK/ERK, TGFß/Smad, PI3K/AKT/mTOR, NFkB, and STAT3 pathways. Moreover, HMGA2 supports a cancer stem cell phenotype and renders cancer cells resistant to chemotherapeutic agents. In this review, we discuss these oncogenic roles of HMGA2 in different types of cancers and propose that HMGA2 may be used for cancer diagnostic, prognostic, and therapeutic purposes.


Assuntos
Proliferação de Células/genética , Proteínas de Ligação a DNA/genética , Proteína HMGA2/genética , Neoplasias/genética , Apoptose/genética , Movimento Celular/genética , Reparo do DNA/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias/patologia
12.
Breast Cancer Res ; 23(1): 26, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33602273

RESUMO

BACKGROUND: Resistance to endocrine treatment in metastatic breast cancer is a major clinical challenge. Clinical tools to predict both drug resistance and possible treatment combination approaches to overcome it are lacking. This unmet need is mainly due to the heterogeneity underlying both the mechanisms involved in resistance development and breast cancer itself. METHODS: To study the complexity of the mechanisms involved in the resistance to the selective estrogen receptor degrader (SERD) fulvestrant, we performed comprehensive biomarker analyses using several in vitro models that recapitulate the heterogeneity of developed resistance. We further corroborated our findings in tissue samples from patients treated with fulvestrant. RESULTS: We found that different in vitro models of fulvestrant resistance show variable stability in their phenotypes, which corresponded with distinct genomic alterations. Notably, the studied models presented adaptation at different cell cycle nodes to facilitate progression through the cell cycle and responded differently to CDK inhibitors. Cyclin E2 overexpression was identified as a biomarker of a persistent fulvestrant-resistant phenotype. Comparison of pre- and post-treatment paired tumor biopsies from patients treated with fulvestrant revealed an upregulation of cyclin E2 upon development of resistance. Moreover, overexpression of this cyclin was found to be a prognostic factor determining resistance to fulvestrant and shorter progression-free survival. CONCLUSIONS: These data highlight the complexity of estrogen receptor positive breast cancer and suggest that the development of diverse resistance mechanisms dictate levels of ER independence and potentially cross-resistance to CDK inhibitors.

13.
Stem Cells ; 39(2): 133-143, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33211379

RESUMO

Since the discovery of breast cancer stem cells (CSCs), a significant effort has been made to identify and characterize these cells. It is a generally believe that CSCs play an important role in cancer initiation, therapy resistance, and progression of triple-negative breast cancer (TNBC), an aggressive breast cancer subtype with poor prognosis. Thus, therapies targeting these cells would be a valuable addition to standard treatments that primarily target more differentiated, rapidly dividing TNBC cells. Although several cell surface and intracellular proteins have been described as biomarkers for CSCs, none of these are specific to this population of cells. Recent research is moving toward cellular signaling pathways as targets and biomarkers for CSCs. The WNT pathway, the nuclear factor-kappa B (NF-κB) pathway, and the cholesterol biosynthesis pathway have recently been identified to play a key role in proliferation, survival, and differentiation of CSCs, including those of breast cancer. In this review, we assess recent findings related to these three pathways in breast CSC, with particular focus on TNBC CSCs, and discuss how targeting these pathways, in combination with current standard of care, might prove effective and improve the prognosis of TNBC patients.

14.
Nat Commun ; 11(1): 5878, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33208750

RESUMO

HER2-targeted therapy has yielded a significant clinical benefit in patients with HER2+ breast cancer, yet disease relapse due to intrinsic or acquired resistance remains a significant challenge in the clinic. Here, we show that the protein phosphatase 2A (PP2A) regulatory subunit PPP2R2B is a crucial determinant of anti-HER2 response. PPP2R2B is downregulated in a substantial subset of HER2+ breast cancers, which correlates with poor clinical outcome and resistance to HER2-targeted therapies. EZH2-mediated histone modification accounts for the PPP2R2B downregulation, resulting in sustained phosphorylation of PP2A targets p70S6K and 4EBP1 which leads to resistance to inhibition by anti-HER2 treatments. Genetic depletion or inhibition of EZH2 by a clinically-available EZH2 inhibitor restores PPP2R2B expression, abolishes the residual phosphorylation of p70S6K and 4EBP1, and resensitizes HER2+ breast cancer cells to anti-HER2 treatments both in vitro and in vivo. Furthermore, the same epigenetic mechanism also contributes to the development of acquired resistance through clonal selection. These findings identify EZH2-dependent PPP2R2B suppression as an epigenetic control of anti-HER2 resistance, potentially providing an opportunity to mitigate anti-HER2 resistance with EZH2 inhibitors.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteína Fosfatase 2/metabolismo , Receptor ErbB-2/metabolismo , Animais , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Humanos , Camundongos , Camundongos Nus , Proteínas do Tecido Nervoso/genética , Proteína Fosfatase 2/genética , Quinazolinas/administração & dosagem , Receptor ErbB-2/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo
15.
Expert Opin Ther Targets ; : 1-11, 2020 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-32172636

RESUMO

Despite improved therapeutic strategies for early-stage breast cancer, the most common cancer type in women, relapse remains common and the underlying mechanisms for this progression remain poorly understood. To gain more insight, we studied the DNA-binding protein HMGA2 in breast cancer development and stemness. We demonstrated that HMGA2 is overexpressed in breast cancer tissues at the mRNA and protein levels (P value <0.0001). HMGA2 knockdown and overexpression in breast cancer cells revealed that HMGA2 promotes cell proliferation and protects against apoptosis via the intrinsic pathway. HMGA2 knockdown also causes cell cycle arrest in G2/M phase. In addition, we found that HMGA2 increases breast cancer cell migration and invasion (P value <0.001) and promotes the acquisition of cancer stem cell features, both in vitro, in colony formation (P value <0.01) and spheroid assays, and in breast cancer tissues. Overexpression of HMGA2 in breast cancer spurs the acquisition of several hallmarks of cancer, including increased cell proliferation, migration, invasion and stemness, and decreased apoptosis. Thus, targeting HMGA2 could represent an effective strategy to block breast cancer progression.

16.
ACS Med Chem Lett ; 11(2): 195-202, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32071688

RESUMO

Small interfering RNAs (siRNAs) are potent therapeutic molecules, but despite recent progress, their administration in vivo remains challenging due to their low stability in the bloodstream. Thus, techniques for investigating the stability of siRNA are fundamental for the development of efficient siRNA delivery systems. We designed a simple FRET electrophoresis method to dynamically evaluate serum siRNA stability in parallel with its interaction with the serum components. Each strand of the siRNA was labeled with the fluorophore carboxyfluorescein (FAM) at the 5'-end and the quencher carboxytetramethylrhodamine (TAMRA) at the 3'-end. After incubation in serum, molecular stability was proportional to the FRET efficiency that could be quantified in-gel by ImageJ analysis. Compared to the usual gel-shift and other plate-based FRET assays, this method is more sensitive and allows investigation of the stability of serum siRNA and siRNA-based nanoparticles, as well as the extrapolation of degradation kinetics in parallel with interaction analysis.

17.
Cell Death Dis ; 11(2): 110, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034120

RESUMO

p53-mutated tumors often exhibit increased resistance to standard chemotherapy and enhanced metastatic potential. Here we demonstrate that inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme of the de novo pyrimidine synthesis pathway, effectively decreases proliferation of cancer cells via induction of replication and ribosomal stress in a p53- and checkpoint kinase 1 (Chk1)-dependent manner. Mechanistically, a block in replication and ribosomal biogenesis result in p53 activation paralleled by accumulation of replication forks that activate the ataxia telangiectasia and Rad3-related kinase/Chk1 pathway, both of which lead to cell cycle arrest. Since in the absence of functional p53 the cell cycle arrest fully depends on Chk1, combined DHODH/Chk1 inhibition in p53-dysfunctional cancer cells induces aberrant cell cycle re-entry and erroneous mitosis, resulting in massive cell death. Combined DHODH/Chk1 inhibition effectively suppresses p53-mutated tumors and their metastasis, and therefore presents a promising therapeutic strategy for p53-mutated cancers.


Assuntos
Neoplasias da Mama/metabolismo , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Pirimidinas/biossíntese , Ribossomos/metabolismo , Proteína Supressora de Tumor p53/deficiência , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Quinase 1 do Ponto de Checagem/genética , Quinase 1 do Ponto de Checagem/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Genes erbB-2 , Células HCT116 , Humanos , Leflunomida/farmacologia , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Ribossomos/genética , Transdução de Sinais , Proteína Supressora de Tumor p53/genética
18.
J Thorac Oncol ; 15(6): 973-999, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32018052

RESUMO

INTRODUCTION: Acquired cancer therapy resistance evolves under selection pressure of immune surveillance and favors mechanisms that promote drug resistance through cell survival and immune evasion. AXL receptor tyrosine kinase is a mediator of cancer cell phenotypic plasticity and suppression of tumor immunity, and AXL expression is associated with drug resistance and diminished long-term survival in a wide range of malignancies, including NSCLC. METHODS: We aimed to investigate the mechanisms underlying AXL-mediated acquired resistance to first- and third-generation small molecule EGFR tyrosine kinase inhibitors (EGFRi) in NSCLC. RESULTS: We found that EGFRi resistance was mediated by up-regulation of AXL, and targeting AXL reduced reactivation of the MAPK pathway and blocked onset of acquired resistance to long-term EGFRi treatment in vivo. AXL-expressing EGFRi-resistant cells revealed phenotypic and cell signaling heterogeneity incompatible with a simple bypass signaling mechanism, and were characterized by an increased autophagic flux. AXL kinase inhibition by the small molecule inhibitor bemcentinib or siRNA mediated AXL gene silencing was reported to inhibit the autophagic flux in vitro, bemcentinib treatment blocked clonogenicity and induced immunogenic cell death in drug-resistant NSCLC in vitro, and abrogated the transcription of autophagy-associated genes in vivo. Furthermore, we found a positive correlation between AXL expression and autophagy-associated gene signatures in a large cohort of human NSCLC (n = 1018). CONCLUSION: Our results indicate that AXL signaling supports a drug-resistant persister cell phenotype through a novel autophagy-dependent mechanism and reveals a unique immunogenic effect of AXL inhibition on drug-resistant NSCLC cells.


Assuntos
Neoplasias Pulmonares , Preparações Farmacêuticas , Autofagia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB , Humanos , Morte Celular Imunogênica , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia
19.
Acta Oncol ; 59(1): 40-47, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31478407

RESUMO

Background: Little is known about the biological factors influencing ovarian cancer (OC) patient outcome, especially in older patients who are often underrepresented in clinical trials. We examined alterations in the transcriptomic profile of primary high-grade serous carcinoma (HGSC) samples from older OC patients (>70 years) receiving first-line platinum-based treatment to identify potential biomarkers for prediction of response to this therapy.Material and methods: Tumor samples from 50 HGSC patients were identified from a retrospective cohort, analyzed by gene expression array. The protein expression of selected biomarkers was examined using immunohistochemistry (IHC).Results: Gene expression profiling revealed 81 genes with significantly altered expression in patients experiencing progression after first-line platinum-based treatment within 6 months versus those who progressed later than 12 months. Expression of ankyrin repeat and PH domain 1 (ARAP1) was significantly lower in the group with early versus late progression (p ≤ .01). Correlation between ARAP1 expression and outcome was further confirmed by IHC staining in the discovery cohort (χ2-test, p = .004) and in independent validation cohorts. The sensitivity of ARAP1 allowed identification of 64.7% of patients with early progression in the discovery population, with a specificity of 78.6% and a negative predictive value of 78.6%. Multivariate regression analysis identified ARAP1 as an independent prognostic factor.Conclusions: This hypothesis generating study suggests that low expression of ARAP1 is an independent prognostic biomarker of shorter RFS in older patients with HGSC receiving first-line platinum-based antineoplastic therapy, which could be used to identify patients who should receive more intensive treatment and closer surveillance.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas de Transporte/metabolismo , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proteínas de Transporte/genética , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Feminino , Proteínas Ativadoras de GTPase/genética , Perfilação da Expressão Gênica , Humanos , Gradação de Tumores , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
20.
Cell Death Dis ; 10(11): 841, 2019 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-31695025

RESUMO

The senescence response to oncogenes is believed to be a barrier to oncogenic transformation in premalignant lesions, and describing the mechanisms by which tumor cells evade this response is important for early diagnosis and treatment. The male germ cell-associated protein SSX2 is ectopically expressed in many types of cancer and is functionally involved in regulating chromatin structure and supporting cell proliferation. Similar to many well-characterized oncogenes, SSX2 has the ability to induce senescence in cells. In this study, we performed a functional genetic screen to identify proteins implicated in SSX2-induced senescence and identified several subunits of the Mediator complex, which is central in regulating RNA polymerase-mediated transcription. Further experiments showed that reduced levels of MED1, MED4, and MED14 perturbed the development of senescence in SSX2-expressing cells. In contrast, knockdown of MED1 did not prevent development of B-Raf- and Epirubicin-induced senescence, suggesting that Mediator may be specifically linked to the cellular functions of SSX2 that may lead to development of senescence or be central in a SSX2-specific senescence response. Indeed, immunostaining of melanoma tumors, which often express SSX proteins, exhibited altered levels of MED1 compared to benign nevi. Similarly, RNA-seq analysis suggested that MED1, MED4, and MED14 were downregulated in some tumors, while upregulated in others. In conclusion, our study reveals the Mediator complex as essential for SSX2-induced senescence and suggests that changes in Mediator activity could be instrumental for tumorigenesis.


Assuntos
Senescência Celular/genética , Melanoma/genética , Proteínas de Neoplasias/genética , Proteínas Repressoras/genética , Linhagem Celular Tumoral , Núcleo Celular/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Complexo Mediador/genética , Subunidade 1 do Complexo Mediador/genética , Melanoma/patologia , Proteínas Quinases/genética , Sarcoma Sinovial/genética , Sarcoma Sinovial/patologia , Fatores de Transcrição/genética , Transcrição Genética , Ativação Transcricional/genética
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