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1.
Nat Commun ; 12(1): 2666, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976222

RESUMO

Tumor necrosis happens commonly in advanced solid tumors. We reported that necroptosis plays a major role in tumor necrosis. Although several key necroptosis regulators including receptor interacting protein kinase 1 (RIPK1) have been identified, the regulation of tumor necroptosis during tumor development remains elusive. Here, we report that Z-DNA-binding protein 1 (ZBP1), not RIPK1, mediates tumor necroptosis during tumor development in preclinical cancer models. We found that ZBP1 expression is dramatically elevated in necrotic tumors. Importantly, ZBP1, not RIPK1, deletion blocks tumor necroptosis during tumor development and inhibits metastasis. We showed that glucose deprivation triggers ZBP1-depedent necroptosis in tumor cells. Glucose deprivation causes mitochondrial DNA (mtDNA) release to the cytoplasm and the binding of mtDNA to ZBP1 to activate MLKL in a BCL-2 family protein, NOXA-dependent manner. Therefore, our study reveals ZBP1 as the key regulator of tumor necroptosis and provides a potential drug target for controlling tumor metastasis.


Assuntos
Neoplasias da Mama/genética , Necroptose/genética , Proteínas de Ligação a RNA/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Células HEK293 , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Knockout , Camundongos Nus , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Proteínas de Ligação a RNA/metabolismo , Terapêutica com RNAi/métodos , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
2.
Anticancer Res ; 41(5): 2321-2331, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952457

RESUMO

BACKGROUND/AIM: The mechanisms of galectin-1 in radioresistance may not only involve intracellular but also extracellular effects because galectin-1 can be secreted into the extracellular matrix. We, therefore, aimed to investigate the role of the galectin-1 tumor microenvironment on radiosensitivity in a murine tumor model. MATERIALS AND METHODS: Wild-type or stable galectin-1-down-regulated cancer cells (melanoma (B16F10) and lung cancer (LLC1)) were injected (subcutaneous injection) into wild-type or knockout (galectin-1, B cells, and T cells) mice that were subject to 0 or 8 Gy irradiation. RESULTS: Galectin-1-down-regulated B16F10 cells showed increased radiosensitivity when injected into galectin-1 knockout mice. Interestingly, radioresistance of wild-type LCC1 tumors was noted when injected into galectin-1 and B cell knockout mice. However, radiosensitization was observed in T cell knockout mice with wild-type LCC1 cells. CONCLUSION: The role of endogenous galectin-1 in radioresistance exists in cases without extracellular galectin-1. Extracellular galectin-1 requires endogenous galectin-1 to radiosensitize tumors in mice.


Assuntos
Galectina 1/genética , Neoplasias Experimentais/radioterapia , Tolerância a Radiação/genética , Microambiente Tumoral/efeitos da radiação , Animais , Linhagem Celular Tumoral , Galectina 1/metabolismo , Camundongos , Camundongos Knockout , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Análise de Sobrevida , Carga Tumoral/genética , Carga Tumoral/efeitos da radiação , Microambiente Tumoral/genética
3.
Nat Commun ; 12(1): 2288, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863883

RESUMO

Hypothalamic tanycytes in median eminence (ME) are emerging as a crucial cell population that regulates endocrine output, energy balance and the diffusion of blood-born molecules. Tanycytes have recently been considered as potential somatic stem cells in the adult mammalian brain, but their regenerative and tumorigenic capacities are largely unknown. Here we found that Rax+ tanycytes in ME of mice are largely quiescent but quickly enter the cell cycle upon neural injury for self-renewal and regeneration. Mechanistically, Igf1r signaling in tanycytes is required for tissue repair under injury conditions. Furthermore, Braf oncogenic activation is sufficient to transform Rax+ tanycytes into actively dividing tumor cells that eventually develop into a papillary craniopharyngioma-like tumor. Together, these findings uncover the regenerative and tumorigenic potential of tanycytes. Our study offers insights into the properties of tanycytes, which may help to manipulate tanycyte biology for regulating hypothalamic function and investigate the pathogenesis of clinically relevant tumors.


Assuntos
Craniofaringioma/patologia , Células Ependimogliais/fisiologia , Eminência Mediana/fisiologia , Neoplasias Experimentais/patologia , Regeneração , Animais , Carcinogênese/patologia , Autorrenovação Celular/fisiologia , Craniofaringioma/induzido quimicamente , Craniofaringioma/genética , Proteínas do Olho/metabolismo , Feminino , Proteínas de Homeodomínio/metabolismo , Eminência Mediana/citologia , Camundongos , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/genética , Proteínas Proto-Oncogênicas B-raf/genética , RNA-Seq , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais , Análise de Célula Única , Fatores de Transcrição/metabolismo
4.
Int J Mol Sci ; 22(9)2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33924999

RESUMO

Pancreatic cancer (PC) is the seventh leading cause of cancer death worldwide, and remains one of our most recalcitrant and dismal diseases. In contrast to many other malignancies, there has not been a significant improvement in patient survival over the past decade. Despite advances in our understanding of the genetic alterations associated with this disease, an incomplete understanding of the underlying biology and lack of suitable animal models have hampered efforts to develop more effective therapies. LKB1 is a tumor suppressor that functions as a primary upstream kinase of adenine monophosphate-activated protein kinase (AMPK), which is an important mediator in the regulation of cell growth and epithelial polarity pathways. LKB1 is mutated in a significant number of Peutz-Jeghers syndrome (PJS) patients and in a small proportion of sporadic cancers, including PC; however, little is known about how LKB1 loss contributes to PC development. Here, we report that a reduction in Wnt/ß-catenin activity is associated with LKB1 tumor-suppressive properties in PC. Remarkably, in vivo functional analyses of ß-catenin in the Pdx-1-Cre LKB1L/L ß-cateninL/L mouse model compared to LKB1 loss-driven cystadenoma demonstrate that the loss of ß-catenin impairs cystadenoma development in the pancreas of Pdx-1Cre LKB1L/L mice and dramatically restores the normal development and functions of the pancreas. This study further determined the in vivo and in vitro therapeutic efficacy of the ß-catenin inhibitor FH535 in suppressing LKB1 loss-driven cystadenoma and reducing PC progression that delineates the potential roles of Wnt/ß-catenin signaling in PC harboring LKB1 deficiency.


Assuntos
Cistadenoma Mucinoso/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Serina-Treonina Quinases/deficiência , Sulfonamidas/farmacologia , beta Catenina/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Linhagem Celular Tumoral , Cistadenoma Mucinoso/etiologia , Cistadenoma Mucinoso/prevenção & controle , Feminino , Humanos , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mutação , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/prevenção & controle , Síndrome de Peutz-Jeghers/genética , Síndrome de Peutz-Jeghers/metabolismo , Proteínas Serina-Treonina Quinases/genética , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/genética
5.
Nat Commun ; 12(1): 1912, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33771989

RESUMO

Glioblastoma (GB) is a highly invasive type of brain cancer exhibiting poor prognosis. As such, its microenvironment plays a crucial role in its progression. Among the brain stromal cells, the microglia were shown to facilitate GB invasion and immunosuppression. However, the reciprocal mechanisms by which GB cells alter microglia/macrophages behavior are not fully understood. We propose that these mechanisms involve adhesion molecules such as the Selectins family. These proteins are involved in immune modulation and cancer immunity. We show that P-selectin mediates microglia-enhanced GB proliferation and invasion by altering microglia/macrophages activation state. We demonstrate these findings by pharmacological and molecular inhibition of P-selectin which leads to reduced tumor growth and increased survival in GB mouse models. Our work sheds light on tumor-associated microglia/macrophage function and the mechanisms by which GB cells suppress the immune system and invade the brain, paving the way to exploit P-selectin as a target for GB therapy.


Assuntos
Neoplasias Encefálicas/genética , Glioblastoma/genética , Macrófagos/metabolismo , Microglia/metabolismo , Selectina-P/genética , Animais , Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Células Cultivadas , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos SCID , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Selectina-P/antagonistas & inibidores , Selectina-P/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
6.
Mol Cell ; 81(6): 1216-1230.e9, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33606996

RESUMO

Interferon-γ (IFN-γ)-mediated adaptive resistance is one major barrier to improving immunotherapy in solid tumors. However, the mechanisms are not completely understood. Here, we report that IFN-γ promotes nuclear translocation and phase separation of YAP after anti-PD-1 therapy in tumor cells. Hydrophobic interactions of the YAP coiled-coil domain mediate droplet initiation, and weak interactions of the intrinsically disordered region in the C terminus promote droplet formation. YAP partitions with the transcription factor TEAD4, the histone acetyltransferase EP300, and Mediator1 and forms transcriptional hubs for maximizing target gene transcriptions, independent of the canonical STAT1-IRF1 transcription program. Disruption of YAP phase separation reduced tumor growth, enhanced immune response, and sensitized tumor cells to anti-PD-1 therapy. YAP activity is negatively correlated with patient outcome. Our study indicates that YAP mediates the IFN-γ pro-tumor effect through its nuclear phase separation and suggests that YAP can be used as a predictive biomarker and target of anti-PD-1 combination therapy.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Resistencia a Medicamentos Antineoplásicos , Imunoterapia , Interferon gama/metabolismo , Neoplasias Experimentais , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Células A549 , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Células HEK293 , Humanos , Interferon gama/genética , Camundongos , Camundongos Knockout , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Fatores de Transcrição/genética
7.
ACS Appl Mater Interfaces ; 13(5): 6043-6052, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33525876

RESUMO

DNA methylation is a kind of a crucial epigenetic marker orchestrating gene expression, molecular function, and cellular phenotype. However, manipulating the methylation status of specific genes remains challenging. Here, a clustered regularly interspaced palindromic repeats-Cas9-based near-infrared upconversion-activated DNA methylation editing system (CNAMS) was designed for the optogenetic editing of DNA methylation. The fusion proteins of photosensitive CRY2PHR, the catalytic domain of DNMT3A or TET1, and the fusion proteins for CIBN and catalytically inactive Cas9 (dCas9) were engineered. The CNAMS could control DNA methylation editing in response to blue light, thus allowing methylation editing in a spatiotemporal manner. Furthermore, after combination with upconversion nanoparticles, the spectral sensitivity of DNA methylation editing was extended from the blue light to near-infrared (NIR) light, providing the possibility for remote DNA methylation editing. These results demonstrated a meaningful step forward toward realizing the specific editing of DNA methylation, suggesting the wide utility of our CNAMS for functional studies on epigenetic regulation and potential therapeutic strategies for related diseases.


Assuntos
Proteína 9 Associada à CRISPR/genética , Sistemas CRISPR-Cas/genética , Edição de Genes , Técnicas Genéticas , Raios Infravermelhos , Neoplasias da Glândula Tireoide/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Apoptose/genética , Proteína 9 Associada à CRISPR/metabolismo , Sobrevivência Celular , Células Cultivadas , Metilação de DNA/genética , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Tamanho da Partícula , Propriedades de Superfície , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/terapia
8.
Nat Commun ; 12(1): 759, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536421

RESUMO

The malignancy of colorectal cancer (CRC) is connected with inflammation and tumor-associated macrophages (TAMs), but effective therapeutics for CRC are limited. To integrate therapeutic targeting with tumor microenvironment (TME) reprogramming, here we develop biocompatible, non-covalent channel-type nanoparticles (CNPs) that are fabricated through host-guest complexation and self-assemble of mannose-modified γ-cyclodextrin (M-γ-CD) with Regorafenib (RG), RG@M-γ-CD CNPs. In addition to its carrier role, M-γ-CD serves as a targeting device and participates in TME regulation. RG@M-γ-CD CNPs attenuate inflammation and inhibit TAM activation by targeting macrophages. They also improve RG's anti-tumor effect by potentiating kinase suppression. In vivo application shows that the channel-type formulation optimizes the pharmacokinetics and bio-distribution of RG. In colitis-associated cancer and CT26 mouse models, RG@M-γ-CD is proven to be a targeted, safe and effective anti-tumor nanomedicine that suppresses tumor cell proliferation, lesions neovascularization, and remodels TME. These findings indicate RG@M-γ-CD CNPs as a potential strategy for CRC treatment.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Nanopartículas/administração & dosagem , Neoplasias Experimentais/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , gama-Ciclodextrinas/administração & dosagem , Animais , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HT29 , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Manose/química , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nanopartículas/química , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Compostos de Fenilureia/química , Piridinas/química , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , gama-Ciclodextrinas/química
9.
Acta Biochim Biophys Sin (Shanghai) ; 53(3): 325-332, 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33501502

RESUMO

Glioma is one of the most pervasive and invasive primary malignancies in the central nervous system. Due to its abnormal proliferation, glioma remains hard to cure at present. Protein tyrosine phosphatase 1B (PTP1B) has been proved to be involved in the process of proliferation in many malignancies. However, whether PTP1B is involved in the proliferation of glioma and how it acts are still unclear. In this study, the PTP1B expressions in glioma tissues and cells were determined by quantitative real-time PCR and western blot analysis. The effects of PTP1B on the proliferation characteristics of glioma were explored using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation assay, and tumor xenografts in mice. We found that the protein and mRNA levels of PTP1B in glioma tissues were significantly higher than those in paired nontumor tissues. MTT and clone formation assays showed that PTP1B is closely related to human glioma cell proliferation. In addition, TargetScan revealed that miR-34c regulates PTP1B. Mechanistically, we proved that miR-34c negatively regulates PTP1B and then participates in the regulation of glioma cell proliferation in vivo. Collectively, these results suggested that miR-34c inhibits the proliferation of human glioma cells by targeting PTP1B, which will provide a potential target for the treatment of glioma.


Assuntos
Proliferação de Células , Glioma/metabolismo , MicroRNAs/metabolismo , Proteínas de Neoplasias/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , RNA Neoplásico/metabolismo , Animais , Linhagem Celular Tumoral , Glioma/genética , Glioma/patologia , Humanos , Camundongos , MicroRNAs/genética , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , RNA Neoplásico/genética
10.
Mol Cell ; 81(4): 767-783.e11, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33333017

RESUMO

Chromatin is a barrier to efficient DNA repair, as it hinders access and processing of certain DNA lesions. ALC1/CHD1L is a nucleosome-remodeling enzyme that responds to DNA damage, but its precise function in DNA repair remains unknown. Here we report that loss of ALC1 confers sensitivity to PARP inhibitors, methyl-methanesulfonate, and uracil misincorporation, which reflects the need to remodel nucleosomes following base excision by DNA glycosylases but prior to handover to APEX1. Using CRISPR screens, we establish that ALC1 loss is synthetic lethal with homologous recombination deficiency (HRD), which we attribute to chromosome instability caused by unrepaired DNA gaps at replication forks. In the absence of ALC1 or APEX1, incomplete processing of BER intermediates results in post-replicative DNA gaps and a critical dependence on HR for repair. Hence, targeting ALC1 alone or as a PARP inhibitor sensitizer could be employed to augment existing therapeutic strategies for HRD cancers.


Assuntos
Montagem e Desmontagem da Cromatina , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Experimentais/metabolismo , Nucleossomos/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Animais , DNA Helicases/genética , Replicação do DNA/efeitos dos fármacos , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Proteínas de Ligação a DNA/genética , Recombinação Homóloga/efeitos dos fármacos , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Neoplasias Experimentais/genética , Nucleossomos/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/genética
11.
JCI Insight ; 6(3)2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33351788

RESUMO

Human lung adenocarcinoma (LUAD) in current or former smokers exhibits a high tumor mutational burden (TMB) and distinct mutational signatures. Syngeneic mouse models of clinically relevant smoking-related LUAD are lacking. We established and characterized a tobacco-associated, transplantable murine LUAD cell line, designated FVBW-17, from a LUAD induced by the tobacco carcinogen 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone in the FVB/N mouse strain. Whole-exome sequencing of FVBW-17 cells identified tobacco-associated KrasG12D and Trp53 mutations and a similar mutation profile to that of classic alkylating agents with a TMB greater than 500. FVBW-17 cells transplanted subcutaneously, via tail vein, and orthotopically generated tumors that were histologically similar to human LUAD in FVB/N mice. FVBW-17 tumors expressed programmed death ligand 1 (PD-L1), were infiltrated with CD8+ T cells, and were responsive to anti-PD-L1 therapy. FVBW-17 cells were also engineered to express green fluorescent protein and luciferase to facilitate detection and quantification of tumor growth. Distant metastases to lung, spleen, liver, and kidney were observed from subcutaneously transplanted tumors. This potentially novel cell line is a robust representation of human smoking-related LUAD biology and provides a much needed preclinical model in which to test promising new agents and combinations, including immune-based therapies.


Assuntos
Adenocarcinoma de Pulmão/induzido quimicamente , Antígeno B7-H1/metabolismo , Carcinógenos/toxicidade , Neoplasias Pulmonares/induzido quimicamente , Nitrosaminas/toxicidade , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Animais , Antígeno B7-H1/antagonistas & inibidores , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Masculino , Camundongos , Mutação , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/genética , Neoplasias Experimentais/imunologia , Fumaça/efeitos adversos , Tabaco/toxicidade , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
12.
Int J Cancer ; 148(1): 226-237, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32700769

RESUMO

Hepatocellular carcinoma (HCC) is highly resistant to anticancer therapy and novel therapeutic strategies are needed. Chronotherapy may become a promising approach because it may improve the efficacy of antimitotic radiation and chemotherapy by considering timing of treatment. To date little is known about time-of-day dependent changes of proliferation and DNA damage in HCC. Using transgenic c-myc/transforming growth factor (TGFα) mice as HCC animal model, we immunohistochemically demonstrated Ki67 as marker for proliferation and γ-H2AX as marker for DNA damage in HCC and surrounding healthy liver (HL). Core clock genes (Per1, Per2, Cry1, Cry2, Bmal 1, Rev-erbα and Clock) were examined by qPCR. Data were obtained from samples collected ex vivo at four different time points and from organotypic slice cultures (OSC). Significant differences were found between HCC and HL. In HCC, the number of Ki67 immunoreactive cells showed two peaks (ex vivo: ZT06 middle of day and ZT18 middle of night; OSC: CT04 and CT16). In ex vivo samples, the number of γ-H2AX positive cells in HCC peaked at ZT18 (middle of the night), while in OSC their number remained high during subjective day and night. In both HCC and HL, clock gene expression showed a time-of-day dependent expression ex vivo but no changes in OSC. The expression of Per2 and Cry1 was significantly lower in HCC than in HL. Our data support the concept of chronotherapy of HCC. OSC may become useful to test novel cancer therapies.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Neoplasias Experimentais/genética , Proteínas Circadianas Period/genética , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Proliferação de Células/genética , Cloretos/administração & dosagem , Cloretos/toxicidade , Cronoterapia , Dano ao DNA , Regulação Neoplásica da Expressão Gênica , Humanos , Fígado/patologia , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Camundongos , Camundongos Transgênicos , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/terapia , Fotoperíodo , Proteínas Proto-Oncogênicas c-myc/genética , Fator de Crescimento Transformador alfa/genética , Células Tumorais Cultivadas , Compostos de Zinco/administração & dosagem , Compostos de Zinco/toxicidade
13.
Pharm Res ; 37(10): 196, 2020 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-32944844

RESUMO

PURPOSE: Hypoxia-inducible factor (HIF) is one of the critical components of the tumor microenvironment that is involved in tumor development. HIF-1α functionally and physically interacts with CDK1, 2, and 5 and stimulates the cell cycle progression and Cyclin-Dependent Kinase (CDK) expression. Therefore, hypoxic tumor microenvironment and CDK overexpression lead to increased cell cycle progression and tumor expansion. Therefore, we decided to suppress cancer cell expansion by blocking HIF-1α and CDK molecules. METHODS: In the present study, we used the carboxylated graphene oxide (CGO) conjugated with trimethyl chitosan (TMC) and hyaluronate (HA) nanoparticles (NPs) loaded with HIF-1α-siRNA and Dinaciclib, the CDK inhibitor, for silencing HIF-1α and blockade of CDKs in CD44-expressing cancer cells and evaluated the impact of combination therapy on proliferation, metastasis, apoptosis, and tumor growth. RESULTS: The results indicated that the manufactured NPs had conceivable physicochemical properties, high cellular uptake, and low toxicity. Moreover, combination therapy of cancer cells using CGO-TMC-HA NPs loaded with HIF-1α siRNA and Dinaciclib (SCH 727965) significantly suppressed the CDKs/HIF-1α and consequently, decreased the proliferation, migration, angiogenesis, and colony formation in tumor cells. CONCLUSIONS: These results indicate the ability of CGO-TMC-HA NPs for dual drug/gene delivery in cancer treatment. Furthermore, the simultaneous inhibition of CDKs/HIF-1α can be considered as a novel anti-cancer treatment strategy; however, further research is needed to confirm this treatment in vivo. Graphical Abstract The suppression of HIF-1α and CDKs inhibits cancer growth. HIF-1α is overexpressed by the cells present in the tumor microenvironment. The hypoxic environment elevates mitochondrial ROS production and increases p38 MAP kinase, JAK/STAT, ERK, JNK, and Akt/PI3K signaling, resulting in cyclin accumulation and aberrant cell cycle progression. Furthermore, the overexpression of HIF-1α/CDK results in increased expression of genes such as BCL2, Bcl-xl, Ki-67, TGFß, VEGF, FGF, MMP2, MMP9, and, HIF-1α and consequently raise the survival, proliferation, angiogenesis, metastasis, and invasion of tumor cells. In conclusion, HIF-1α-siRNA/Dinaciclib-loaded CGO-TMC-HA NPs can inhibit the tumor expansion by blockage of CDKs and HIF-1α (JAK: Janus kinase, STAT: Signal transducer and activator of transcription, MAPK: mitogen-activated protein kinase, ERK: extracellular signal-regulated kinase, JNK: c-Jun N-terminal kinase, PI3K: phosphatidylinositol 3-kinase).


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Experimentais/terapia , Compostos de Piridínio/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Quitosana/química , Grafite/química , Ácido Hialurônico/química , Camundongos , Nanopartículas/química , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Compostos de Piridínio/química , Compostos de Piridínio/farmacocinética , RNA Interferente Pequeno/química , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacocinética
14.
PLoS Pathog ; 16(6): e1008589, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32603362

RESUMO

Kaposi's sarcoma (KS), is an AIDS-associated neoplasm caused by the KS herpesvirus (KSHV/ HHV-8). KSHV-induced sarcomagenesis is the consequence of oncogenic viral gene expression as well as host genetic and epigenetic alterations. Although KSHV is found in all KS-lesions, the percentage of KSHV-infected (LANA+) spindle-cells of the lesion is variable, suggesting the existence of KS-spindle cells that have lost KSHV and proliferate autonomously or via paracrine mechanisms. A mouse model of KSHVBac36-driven tumorigenesis allowed us to induce KSHV-episome loss before and after tumor development. Although infected cells that lose the KSHV-episome prior to tumor formation lose their tumorigenicity, explanted tumor cells that lost the KSHV-episome remained tumorigenic. This pointed to the existence of virally-induced irreversible oncogenic alterations occurring during KSHV tumorigenesis supporting the possibility of hit and run viral-sarcomagenesis. RNA-sequencing and CpG-methylation analysis were performed on KSHV-positive and KSHV-negative tumors that developed following KSHV-episome loss from explanted tumor cells. When KSHV-positive cells form KSHV-driven tumors, along with viral-gene upregulation there is a tendency for hypo-methylation in genes from oncogenic and differentiation pathways. In contrast, KSHV-negative tumors formed after KSHV-episome loss, show a tendency towards gene hyper-methylation when compared to KSHV-positive tumors. Regarding occurrence of host-mutations, we found the same set of innate-immunity related mutations undetected in KSHV-infected cells but present in all KSHV-positive tumors occurring en exactly the same position, indicating that pre-existing host mutations that provide an in vivo growth advantage are clonally-selected and contribute to KSHV-tumorigenesis. In addition, KSHV-negative tumors display de novo mutations related to cell proliferation that, together with the PDGFRAD842V and other proposed mechanism, could be responsible for driving tumorigenesis in the absence of KSHV-episomes. KSHV-induced irreversible genetic and epigenetic oncogenic alterations support the possibility of "hit and run" KSHV-sarcomagenesis and point to the existence of selectable KSHV-induced host mutations that may impact AIDS-KS treatment.


Assuntos
Transformação Celular Viral , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Regulação Viral da Expressão Gênica , Herpesvirus Humano 8 , Neoplasias Experimentais , Plasmídeos , Sarcoma de Kaposi , Animais , Linhagem Celular , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Camundongos , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neoplasias Experimentais/virologia , Plasmídeos/genética , Plasmídeos/metabolismo , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/metabolismo , Sarcoma de Kaposi/patologia , Sarcoma de Kaposi/virologia
15.
Nat Commun ; 11(1): 2978, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32532977

RESUMO

The interplay between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) promotes progression of glioblastoma multiforme (GBM). However, the detailed molecular mechanisms underlying the relationship between these two cell types remain unclear. Here, we demonstrate that ARS2 (arsenite-resistance protein 2), a zinc finger protein that is essential for early mammalian development, plays critical roles in GSC maintenance and M2-like TAM polarization. ARS2 directly activates its novel transcriptional target MGLL, encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicity of GSCs through production of prostaglandin E2 (PGE2), which stimulates ß-catenin activation of GSC and M2-like TAM polarization. We identify M2-like signature downregulated by which MAGL-specific inhibitor, JZL184, increased survival rate significantly in the mouse xenograft model by blocking PGE2 production. Taken together, our results suggest that blocking the interplay between GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially novel therapeutic option for GBM patients.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Macrófagos/metabolismo , Monoacilglicerol Lipases/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Nucleares/metabolismo , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Autorrenovação Celular/genética , Células Cultivadas , Feminino , Glioblastoma/genética , Glioblastoma/terapia , Células HEK293 , Humanos , Estimativa de Kaplan-Meier , Ativação de Macrófagos/genética , Camundongos Endogâmicos BALB C , Camundongos Nus , Monoacilglicerol Lipases/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Células-Tronco Neoplásicas/patologia , Proteínas Nucleares/genética , Interferência de RNA , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
16.
Sci Rep ; 10(1): 7375, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32355198

RESUMO

Secreted animal lectins of the galectin family are key players in cancer growth and metastasis. Here we show that galectin-8 (gal-8) induces the expression and secretion of cytokines and chemokines such as SDF-1 and MCP-1 in a number of cell types. This involves gal-8 binding to a uPAR/LRP1/integrin complex that activates JNK and the NFkB pathway. Cytokine and chemokine secretion, induced by gal-8, promotes migration of cancer cells toward cells treated with this lectin. Indeed, immune-competent gal-8 knockout (KO) mice express systemic lower levels of cytokines and chemokines while the opposite is true for gal-8 transgenic animals. Accordingly, gal-8 KO mice experience reduced tumor size and smaller and fewer metastatic lesions when injected with cancer cells. These results suggest the existence of a 'vicious cycle' whereby gal-8 secreted by the tumor microenvironment, promotes secretion of chemoattractants at the metastatic niche that promote further recruitment of tumor cells to that site. This study further implicate gal-8 in control of cancer progression and metastasis through its effects on the production of immunoregulatory cytokines.


Assuntos
Movimento Celular , Quimiocina CXCL12/metabolismo , Galectinas/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Experimentais/metabolismo , Animais , Quimiocina CCL2/genética , Quimiocina CXCL12/genética , Galectinas/genética , Camundongos , Camundongos Knockout , Metástase Neoplásica , Proteínas de Neoplasias/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia
17.
Sci Rep ; 10(1): 7376, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32355214

RESUMO

Radiation therapy has been shown to enhance the efficacy of various T cell-targeted immunotherapies that improve antigen-specific T cell expansion, T regulatory cell depletion, or effector T cell function. Additionally, radiation therapy has been proposed as a means to recruit T cells to the treatment site and modulate cancer cells as effector T cell targets. The significance of these features remains unclear. We set out to determine, in checkpoint inhibitor resistant models, which components of radiation are primarily responsible for overcoming this resistance. In order to model the vaccination effect of radiation, we used a Listeria monocytogenes based vaccine to generate a large population of tumor antigen specific T cells but found that the presence of cells with cytotoxic capacity was unable to replicate the efficacy of radiation with combination checkpoint blockade. Instead, we demonstrated that a major role of radiation was to increase the susceptibility of surviving cancer cells to CD8+ T cell-mediated control through enhanced MHC-I expression. We observed a novel mechanism of genetic induction of MHC-I in cancer cells through upregulation of the MHC-I transactivator NLRC5. These data support the critical role of local modulation of tumors by radiation to improve tumor control with combination immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Imunidade Celular , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Proteínas de Membrana/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias Experimentais/imunologia , Transcrição Genética/imunologia , Regulação para Cima/imunologia , Animais , Linfócitos T CD8-Positivos/patologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Antígenos de Histocompatibilidade Classe I/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Proteínas de Neoplasias/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/terapia , Radioterapia
18.
Exp Hematol ; 85: 13-19, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32437911

RESUMO

Rearrangements involving the mixed lineage leukemia gene (MLL) are found in the majority of leukemias that develop within the first year of age, known as infant leukemias, and likely originate during prenatal life. MLL rearrangements are also present in about 10% of other pediatric and adult acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). These translocations and others occurring in early life are associated with a dismal prognosis compared with adult leukemias carrying the same translocations. This observation suggests that infant and adult leukemias are biologically distinct but the underlying molecular mechanisms for these differences are not understood. In this work, we induced the same MLL chromosomal translocation in the embryo at the time of fetal liver hematopoiesis and in the adult hematopoietic tissues to develop disease models in mice that recapitulate human infant and adult leukemias, respectively. We successfully obtained myeloid leukemia in adult mice after MLL-ENL recombination induction using the interferon inducible Mx1-Cre line. Using this same Cre line, we generated embryonic MLL-ENL leukemias, which were more aggressive than the corresponding adult leukemias. In conclusion, we have developed a novel MLL-ENL embryonic leukemia model in mice that can be used to study some aspects of infant leukemia ontogeny.


Assuntos
Proteínas de Ligação a DNA , Embrião de Mamíferos , Histona-Lisina N-Metiltransferase , Leucemia Mieloide Aguda , Proteína de Leucina Linfoide-Mieloide , Neoplasias Experimentais , Proteínas de Fusão Oncogênica , Leucemia-Linfoma Linfoblástico de Células Precursoras , Fatores de Transcrição , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Embrião de Mamíferos/embriologia , Embrião de Mamíferos/patologia , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Leucemia Mieloide Aguda/embriologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Transgênicos , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Neoplasias Experimentais/embriologia , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/embriologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
19.
Pediatr Blood Cancer ; 67(8): e28372, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32459399

RESUMO

BACKGROUND: Neurofibromatosis type 1 (NF1) is a common genetic disorder characterized by plexiform neurofibromas (pNF), which are thought to be congenital tumors that arise in utero and enlarge throughout life. Genetic studies in murine models delineated an indispensable role for the stem cell factor (SCF)/c-kit pathway in pNF initiation and progression. A subsequent phase 2 clinical trial using imatinib mesylate to inhibit SCF/c-kit demonstrated tumor shrinkage in a subset of preexisting pNF; however, imatinib's role on preventing pNF development has yet to be explored. PROCEDURE: We evaluated the effect of imatinib dosed at 10-100 mg/kg/day for 12 weeks to one-month-old Nf1flox/flox ;PostnCre(+) mice, prior to onset of pNF formation. To determine durability of response, we then monitored for pNF growth at later time points, comparing imatinib- with vehicle-treated mice. We assessed gross and histopathological analysis of tumor burden. RESULTS: Imatinib administered preventatively led to a significant decrease in pNF number, even at doses as low as 10 mg/kg/day. Tumor development continued to be significantly inhibited after cessation of imatinib dosed at 50 and 100 mg/kg/day. In the cohort of treated mice that underwent prolonged follow-up, the size of residual tumors was significantly reduced as compared with age-matched littermates that received vehicle control. CONCLUSIONS: Early administration of imatinib inhibits pNF genesis in vivo, and effects are sustained after discontinuation of therapy. These findings may guide clinical use of imatinib in young NF1 patients prior to the substantial development of pNF.


Assuntos
Mesilato de Imatinib/administração & dosagem , Neoplasias Experimentais/prevenção & controle , Neurofibroma Plexiforme/prevenção & controle , Neurofibromatose 1/prevenção & controle , Animais , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neurofibroma Plexiforme/genética , Neurofibroma Plexiforme/metabolismo , Neurofibroma Plexiforme/patologia , Neurofibromatose 1/genética , Neurofibromatose 1/metabolismo , Neurofibromatose 1/patologia
20.
Cancer Cell ; 37(3): 308-323.e12, 2020 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-32142668

RESUMO

Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors for which there is currently no effective treatment. Some of these tumors combine gain-of-function mutations in ACVR1, PIK3CA, and histone H3-encoding genes. The oncogenic mechanisms of action of ACVR1 mutations are currently unknown. Using mouse models, we demonstrate that Acvr1G328V arrests the differentiation of oligodendroglial lineage cells, and cooperates with Hist1h3bK27M and Pik3caH1047R to generate high-grade diffuse gliomas. Mechanistically, Acvr1G328V upregulates transcription factors which control differentiation and DIPG cell fitness. Furthermore, we characterize E6201 as a dual inhibitor of ACVR1 and MEK1/2, and demonstrate its efficacy toward tumor cells in vivo. Collectively, our results describe an oncogenic mechanism of action for ACVR1 mutations, and suggest therapeutic strategies for DIPGs.


Assuntos
Receptores de Ativinas Tipo I/química , Receptores de Ativinas Tipo I/genética , Neoplasias Encefálicas/patologia , Glioma/patologia , Mutação , Receptores de Ativinas Tipo I/antagonistas & inibidores , Receptores de Ativinas Tipo I/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Feminino , Glioma/tratamento farmacológico , Glioma/genética , Histonas/genética , Histonas/metabolismo , Humanos , Lactonas/farmacologia , Masculino , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neuroglia/metabolismo , Neuroglia/patologia , Oligodendroglia/patologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Fatores de Transcrição SOXC/genética , Fatores de Transcrição SOXC/metabolismo
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