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1.
Histol Histopathol ; : 18464, 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35510512

RESUMO

Invasive micropapillary carcinoma has been reported in the adenocarcinoma of many organs including cervix, and many studies have proved it has more invasive biological behavior. This study, for the first time, reports cervical squamous carcinoma with invasive micropapillary like pattern and phenotype (IMLPP) and further investigates its clinicopathologic features. Cervical squamous carcinoma with IMLPP was selected by histological characteristics and immunohistochemical staining. All patients' clinical information and pathological parameters were collected. Based on histological characteristics and immunohistochemical staining results, 24 cases, out of 104 cases of cervical squamous carcinoma, were identified as having invasive micropapillary like pattern. The staining of all 24 cases with EMA and MUC-1 showed the feature of "reverse polarity like". Meanwhile, patient age at diagnosis (P=0.011), maximum invasion depth (P=0.001), maximum diameter (P=0.015), lymphvascular space invasion (P<0.001), pelvic lymph node metastasis (P<0.001), metastasis (P=0.020), death (P=0.025) and FIGO stages (P=0.001) were related to the existence of IMLPP, independently of the proportion of IMLPP to the whole tumor in size. Univariate and multivariate disease-free survival analyses (follow-up time >12 months) showed significant statistical difference between cervical squamous carcinoma with or without IMLPP (P=0.016, P=0.043). Results from our study suggested that IMLPP may be associated with aggressive biological behavior in cervical squamous carcinoma. Therefore, pathologists should pay attention to the existence of it, no matter its proportion with relation to the whole tumor, and bring it to the attention of clinicians.

2.
Adv Mater ; : e2201562, 2022 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-35576606

RESUMO

Proteins are essential elements for almost all life activities. The emergence of nanotechnology offers innovative strategies to create a diversity of nanoparticles with intrinsic capacities of mimicking the functions of proteins. These artificial mimics are produced in a cost-efficient and controllable manner, with their protein-mimicking performances comparable or superior to those of natural proteins. Moreover, they can be endowed with additional functionalities that are absent in natural proteins, such as cargo loading, active targeting, membrane penetrating and multi-stimuli responding. Therefore, protein-mimicking nanoparticles have been utilized more and more often in biosystems for a wide range of applications including detection, imaging, diagnosis and therapy. To highlight recent progresses in this broad field, we herein summarize representative protein-mimicking nanoparticles that fall into one of the four distinct categories: mimics of enzymes (nanozymes), mimics of fluorescent proteins, nanoparticles with high affinity binding to specific proteins or DNA sequences, and mimics of protein scaffolds. This review covers their sub-classifications, characteristic features, functioning mechanisms as well as the extensive exploitation of their great potential for biological and biomedical purposes. Finally, the challenges and prospects in future development of protein-mimicking nanoparticles are discussed. This article is protected by copyright. All rights reserved.

3.
J Biomed Nanotechnol ; 18(2): 293-318, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-35484759

RESUMO

The newly emerged cancer immunotherapy has shown a great potential in clinical trials. However, most immunotherapeutic strategies focus on restoring and/or enhancing the effector T cell responses, and only a small portion of malignancies respond favorably due to the lacking of T cell infiltration. Recently, the modulation of innate immune system has been applied as an alternative or combined strategy to improve host anti-tumor immunity. In this review, we summarize recent progress in nanotechnology-based innate immunomodulation for cancer therapy. Firstly, we present various types of nanodevices that serve to deliver or mimic the reactions of pathogen-associated molecular patterns (PAMPs), such as bacterial components, viral DNA or viral RNA, for the stimulation of type I interferons (IFNs) and pro-inflammatory cytokines. We also introduce nanodevice-mediated immunogenic cell death (ICD) for the generation of endogenous danger-associated molecular patterns (DAMPs) and improvement of immune responses. Moreover, targeted manipulation of specific types of innate immune cells by nanodevices are discussed. Lastly, we describe typical strategies of combining innate immunomodulatory nanodevices with immune checkpoint blockade to amplify the anti-tumor efficacy.


Assuntos
Imunidade Inata , Neoplasias , Citocinas , Humanos , Imunomodulação , Neoplasias/tratamento farmacológico , Linfócitos T
4.
Dis Markers ; 2022: 3554100, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35186166

RESUMO

PURPOSE: The aim of this study was to investigate the expression of stathmin 1 (STMN1) in ovarian cancer and its effect on prognosis. The effect and mechanism of STMN1 on the proliferation and migration of ovarian cancer cells were also investigated. METHODS: Expression of STMN1 was measured by immunohistochemical staining in ovarian cancer tissues. The effects of STMN1 on the proliferation and migration capacity of ovarian cancer were evaluated using Cell Counting Kit-8 (CCK-8) assays, colony formation assays, immunofluorescence staining, wound healing assays, and Transwell assays. Transcription factors were predicted by bioinformatic analysis of TCGA database. RESULTS: STMN1 was upregulated in ovarian cancer tissues as compared to paracancerous tissues and associated with shorter overall survival. STMN1 expression significantly correlated with FIGO staging and tumor differentiation (P < 0.05). Furthermore, STMN1 promoted proliferation and migration in ovarian cancer cell lines. Bioinformatic analysis revealed that STMN1 was potentially regulated by E2F transcription factors. Then, we found that E2F1 regulated the expression of STMN1 and affected proliferation. CONCLUSION: STMN1 is overexpressed in ovarian cancer, and its high expression suggests a poor prognosis. STMN1 promotes the proliferation and migration of ovarian cancer and is regulated by E2F1. Thus, STMN1 may serve as a negative prognostic factor and possible target for the treatment of ovarian cancer patients.


Assuntos
Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Estatmina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Prognóstico , Taxa de Sobrevida
5.
Cell Prolif ; 55(3): e13192, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35084069

RESUMO

OBJECTIVES: Synthetic oligodeoxynucleotides (ODNs) that contain unmethylated cytosine-phosphate-guanine (CpG) motifs serve as immune adjuvants in disease treatment. However, the poor cell permeability and safety concerns limit their medical applications, and biocompatible strategies for efficient delivery of functional CpG ODNs are highly desirable. MATERIALS AND METHODS: Self-assembled, cell membrane-coated CpG nanoparticles (NP) are prepared, and their physicochemical properties are characterized. The uncoated and membrane-coated CpG NP are compared for their biocompatibility, cellular uptake kinetics, endocytic pathways, subcellular localization, and immunostimulatory activities in macrophages and microglia. RESULTS: Macrophage- or microglia-derived cell membrane camouflaging alters the endocytic pathways of CpG NP, promotes their targeted delivery to the cells with homologous membrane, ensures their endosomal localization, and enhances their immunomodulatory effects. CONCLUSIONS: We design a type of biomimetic NP consisting of self-assembled CpG NP core and cell membrane shell, and demonstrate its advantages in the modulation of peripheral and central immune cells. Our study provides a new strategy for the application of CpG ODNs.


Assuntos
Imunomodulação/imunologia , Macrófagos/imunologia , Nanopartículas/metabolismo , Oligodesoxirribonucleotídeos/imunologia , Animais , Citosina/metabolismo , Macrófagos/metabolismo , Oligodesoxirribonucleotídeos/metabolismo , Receptor Toll-Like 9/imunologia , Receptor Toll-Like 9/metabolismo
6.
Front Oncol ; 11: 756412, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34804948

RESUMO

The N6-methyladenosine (m6A) has been considered as a new layer of epitranscriptomic regulation on mRNA processing, stability, and translation. However, potential roles of m6A RNA methylation modification in tumor immune microenvironment (TIME) of breast cancer are yet fully understood. In this study, we comprehensively evaluated the genetic variations and transcript expressions of 15 m6A regulators in 1,079 breast cancer samples from the Cancer Genome Atlas (TCGA) database. We validated major regulators had significantly differential mRNA and protein expression in tumor tissue compared to normal tissues from 39 pairs of clinical breast cancer samples with different molecular subtypes, and especially high expression of m6A readers YTHDF1 and YTHDF3 predicted poor survival. Two clusters of breast cancer patients identified by the 15 m6A regulators' pattern showed distinct overall survival, immune activation status, and immune cell infiltration, and clinical samples confirmed the diversity of lymphocytic infiltration. The profiles of these two clusters accorded with that of two classical cancer-immune phenotypes, immune-excluded and immune-inflamed phenotypes, it suggested that m6A regulators-based patterns might serve as crucial mediators of TIME in breast cancer. Moreover, the m6A phenotype-related gene signatures could also be survival predictor in breast cancer. Therefore, comprehensive evaluation of tumor m6A modification pattern will contribute to enhance our understanding of the characterization of immune cell infiltration in the tumor microenvironment and promote the responsiveness of breast cancer to immunotherapy.

7.
Biosens Bioelectron ; 194: 113611, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34500229

RESUMO

The high toxicity of dicofol (DICO) to nontarget organisms has resulted in the contamination of food materials and caused a threat to human health. Developing a rapid and sensitive detection method of DICO in food samples is essential and still pursued. Fluorescent nanomaterials have been widely applied in biosensors to improve the sensitivity of detection. Herein, glutathione-capped Au-Ag bimetallic nanoclusters (Au-Ag NCs) exhibited the outstanding fluorescence characteristic with the average fluorescence lifetime of 1971.08 ns and photoluminescence quantum yield of 9.84% when the molar ratio of Au to Ag was 5:1. Polyethyleneimine modified gold nanoparticles (PEI-Au NPs) with the positive charge were prepared to generate a strong colorimetric signal. A dual-model colorimetric/fluorescent immune probe based on the Au-Ag NCs and PEI-Au NPs was successfully constructed by electrostatic force, and could be applied in both ic-ELISA and LFIA methods for rapid and ultrasensitive detection of DICO. In the ic-ELISA method, the introduction of fluorescence signal significantly increased the sensitivity of detection with the limit of detection (LOD) of 0.62 ng/mL and exhibited an excellent linear relationship within the range of 1.36 ng/mL-19.92 ng/mL. In the LFIA method, the fluorescence signal of Au-Ag NCs was accumulated on the test line and control line for the fluorescence model detection with a quantitative LOD at the level of 1.59 ng/mL. Such a dual-model colorimetric/fluorescent immunoassay serves as a promising candidate to develop new approaches in field detection.


Assuntos
Técnicas Biossensoriais , Nanopartículas Metálicas , Colorimetria , Dicofol , Ouro , Humanos , Imunoensaio , Prata
8.
iScience ; 24(8): 102819, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34381963

RESUMO

The endoplasmic reticulum (ER)-resident transmembrane protein kinase/RNase Ire1 is a conserved sensor of the cellular unfolded protein response and has been implicated in lipid homeostasis, including lipid synthesis and transport, across species. Here we report a novel catabolic role of Ire1 in regulating lipid mobilization in Drosophila. We found that Ire1 is activated by nutrient deprivation, and, importantly, fat body-specific Ire1 deficiency leads to increased lipid mobilization and sensitizes flies to starvation, whereas fat body Ire1 overexpression results in the opposite phenotypes. Genetic interaction and biochemical analyses revealed that Ire1 regulates lipid mobilization by promoting Xbp1s-associated FoxO degradation and suppressing FoxO-dependent lipolytic programs. Our results demonstrate that Ire1 is a catabolic sensor and acts through the Xbp1s-FoxO axis to hamper the lipolytic response during chronic food deprivation. These findings offer new insights into the conserved Ire1 regulation of lipid homeostasis.

9.
ACS Appl Mater Interfaces ; 13(27): 31331-31336, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34227383

RESUMO

The distinct physical and chemical properties of nanoparticles (NPs) offer great opportunities to develop new strategies for diagnostic and therapeutic purposes. Whereas NPs often serve as inert nanocarriers, their inherent "biological" activities have recently been extensively unveiled and explored. These protein-mimicking NPs (dubbed protmins) have been reported to modulate a cellular homeostasis without displaying a general toxicity, which may act as potential nanomedicines to provide a monotherapy or combination therapy in a disease treatment. In the meanwhile, the unexpected behaviors of protmins in complex biological systems also raise new concerns on the biosafety issue. Herein, we summarize several categories of the protmin-based regulation of cellular homeostasis and discuss their broad effects on cell functions and behaviors.


Assuntos
Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Homeostase , Nanopartículas/química , Proteínas/metabolismo , Animais , Humanos
10.
Nano Lett ; 21(10): 4394-4402, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-33998787

RESUMO

The high demand for acute kidney injury (AKI) therapy calls the development of multifunctional nanomedicine for renal management with programmable pharmacokinetics. Here, we developed a renal-accumulating DNA nanodevice with exclusive kidney retention for longitudinal protection of AKI in different stages in a renal ischemia-reperfusion (I/R) model. Due to the prolonged kidney retention time (>12 h), the ROS-sensitive nucleic acids of the nanodevice could effectively alleviate oxidative stress by scavenging ROS in stage I, and then the anticomplement component 5a (aC5a) aptamer loaded nanodevice could sequentially suppress the inflammatory responses by blocking C5a in stage II, which is directly related to the cytokine storm. This sequential therapy provides durable and pathogenic treatment of kidney dysfunction based on successive pathophysiological events induced by I/R, which holds great promise for renal management and the suppression of the cytokine storm in more broad settings including COVID-19.


Assuntos
Injúria Renal Aguda , COVID-19 , Traumatismo por Reperfusão , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/metabolismo , Humanos , Rim/metabolismo , Estresse Oxidativo , Traumatismo por Reperfusão/tratamento farmacológico , SARS-CoV-2
11.
Adv Mater ; 33(18): e2100949, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33792093

RESUMO

The induced expansion of tumor-initiating cells (T-ICs) upon repeated exposure of tumors to chemotherapeutic drugs forms a major cause for chemoresistance and cancer metastasis. Here, a tumor-microenvironment-responsive hydrogel patch is designed to modulate the plasticity of T-ICs in triple-negative breast cancer (TNBC), which is insensitive to hormone- and HER2-targeting. The on-site formation of the hydrogel network patches tumors in a chemoresistant TNBC murine model and senses intratumoral reactive oxygen species for linker cleavage and payload release. Patch-mediated inhibition of the histone demethylase lysine-specific demethylase 1 (LSD1) epigenetically regulates the switch of T-ICs from self-renewal to differentiation, rehabilitating their chemosensitivity. Moreover, the hydrogel patch enhances tumor immunogenicity and increases T-cell infiltration via epigenetic activation of innate immunity. A single-dose of the hydrogel patch harboring LSD1 inhibitor and chemotherapy agent efficiently suppresses tumor growth, postsurgical relapse, and metastasis. The superior efficacy against multidrug resistance further reveals the broad applicability of epigenetic remodeling hydrogel patches.


Assuntos
Epigênese Genética , Hidrogéis , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral/genética , Animais , Linhagem Celular Tumoral , Humanos , Camundongos
12.
Cell Prolif ; 54(5): e13038, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33793020

RESUMO

OBJECTIVES: Organic Selenium (Se) compounds such as L-Se-methylselenocysteine (L-SeMC/SeMC) have been employed as a class of anti-oxidant to protect normal tissues and organs from chemotherapy-induced systemic toxicity. However, their comprehensive effects on cancer cell proliferation and tumour progression remain elusive. MATERIALS AND METHODS: CCK-8 assays were conducted to determine the viabilities of cancer cells after exposure to SeMC, chemotherapeutics or combined treatment. Intracellular reactive oxygen species (ROS) levels and lipid peroxidation levels were assessed via fluorescence staining. The efficacy of free drugs or drug-loaded hydrogel against tumour growth was evaluated in a xenograft mouse model. RESULTS: Among tested cancer cells and normal cells, the A549 lung adenocarcinoma cells showed higher sensitivity to SeMC exposure. In addition, combined treatments with several types of chemotherapeutics induced synergistic lethality. SeMC promoted lipid peroxidation in A549 cells and thereby increased ROS generation. Significantly, the in vivo efficacy of combination therapy was largely potentiated by hydrogel-mediate drug delivery. CONCLUSIONS: Our study reveals the selectivity of SeMC in the inhibition of cancer cell proliferation and develops an efficient strategy for local combination therapy.


Assuntos
Proliferação de Células/efeitos dos fármacos , Selenocisteína/análogos & derivados , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/química , Feminino , Humanos , Hidrogéis/química , Peroxidação de Lipídeos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Espécies Reativas de Oxigênio/metabolismo , Selenocisteína/química , Selenocisteína/farmacologia , Selenocisteína/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Adv Mater ; 32(45): e2003708, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33015921

RESUMO

The development of nanozymes has made active impact in diagnosis and therapeutics. However, understanding of the full effects of these nanozymes on biochemical pathways and metabolic homeostasis remains elusive. Here, it is found that iron oxide nanoparticles (Fe3 O4 NPs), a type of well-established nanozyme, can locally regulate the energy sensor adenosine 5'-monophosphate-activated protein kinase (AMPK) via their peroxidase-like activity in the acidic lysosomal compartment, thereby promoting glucose metabolism and insulin response. Fe3 O4 NPs induce AMPK activation and enhance glucose uptake in a variety of metabolically active cells as well as in insulin resistant cell models. Dietary Fe3 O4 NPs display therapeutic effects on hyperglycemia and hyperinsulinemia in Drosophila models of diabetes induced by genetic manipulation or high-sugar diet. More importantly, intraperitoneal administration of Fe3 O4 NPs stimulates AMPK activities in metabolic tissues, reduces blood glucose levels, and improves glucose tolerance and insulin sensitivity in diabetic ob/ob mice. The study reveals intrinsic organelle-specific properties of Fe3 O4 NPs in AMPK activation, glycemic control, and insulin-resistance improvement, suggesting their potential efficacy in diabetes care.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Nanopartículas de Magnetita/uso terapêutico , Organelas/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Açúcares da Dieta/efeitos adversos , Modelos Animais de Doenças , Drosophila melanogaster , Ativação Enzimática/efeitos dos fármacos , Nanomedicina , Organelas/efeitos dos fármacos
14.
Biomed Res Int ; 2020: 9512793, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32775453

RESUMO

MicroRNAs (miRNAs) have been identified as negative posttranscriptional regulators of target genes and are involved directly in the pathological processes of tumors, including drug resistance. However, the exact function of miR-520h in breast cancer remains poorly understood. The aim of this study was to investigate the molecular mechanisms of miR-520h in paclitaxel resistance in the MCF-7 breast cancer cell line. Ectopic expression of miR-520h could promote the proliferation of breast cancer cells and inhibit paclitaxel-induced cell apoptosis. Inhibiting the expression of miR-520h could enhance the sensitivity to paclitaxel in paclitaxel-resistant MCF-7/Taxol cells. Furthermore, luciferase reporter assays showed that OTUD3 was a direct target of miR-520h. OTUD3 plays a necessary role in the paclitaxel resistance effect of miR-520h, and cotreatment with a miR-520h inhibitor and OTUD3 overexpression significantly enhanced MCF-7 cell sensitivity to paclitaxel. Moreover, miR-520h substantially inhibited the protein expression of PTEN via OTUD3 and subsequently affected downstream p-AKT pathway activity. In a clinical study, we also found that high miR-520h expression was associated with more aggressive pathological characteristic and poor prognosis. Therefore, our findings showed that miR-520h targeted the OTUD3-PTEN axis to drive paclitaxel resistance, and this miR might be an important potential target for breast cancer treatment.


Assuntos
Neoplasias da Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Paclitaxel , RNA Neoplásico/metabolismo , Proteases Específicas de Ubiquitina/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , Células MCF-7 , MicroRNAs/genética , PTEN Fosfo-Hidrolase/genética , RNA Neoplásico/genética , Proteases Específicas de Ubiquitina/genética
15.
Nano Lett ; 20(7): 5228-5235, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32510963

RESUMO

Cell-membrane-camouflaged nanoparticles (CMC-NPs) have been increasingly exploited to develop various therapeutic tools due to their high biocompatibility and cell-type-specific tumor-targeting properties. However, the molecular mechanism of CMC-NPs for homotypic targeting remains elusive. Here, we develop a plasmonic imaging method by coating gold nanoparticles (AuNPs) with cancer cell membranes and perform plasmonic imaging of the interactions between CMC-NPs and living cells at the single-cell level. Quantitative analysis of CMC-NPs in a different clustering status reveals that the presence of cell membranes on CMC-NPs results in a 7-fold increase in homotypic cell delivery and nearly 2 orders of magnitude acceleration of the intracellular agglomeration process. Significantly, we identify that integrin αvß3, a cell surface receptor abundantly expressed in tumor cells, is critical for the selective cell recognition of CMC-NPs. We thus establish a single-cell plasmonic imaging platform for probing NP-cell interactions, which sheds new light on the therapeutic applications of CMC-NPs.


Assuntos
Nanopartículas Metálicas , Nanopartículas , Linhagem Celular Tumoral , Membrana Celular , Ouro , Integrina alfaVbeta3
16.
Cell Death Dis ; 11(2): 150, 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32094323

RESUMO

Since online publication of this article, the authors noticed that some of the fly stocks were mislabelled in the methods and in Supplementary Figure 5. The corrected methods text is provided below.

17.
Cell Death Dis ; 10(11): 800, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31641108

RESUMO

Abnormal aggregation of misfolded pathological proteins in neurons is a prominent feature of neurodegenerative disorders including Parkinson's disease (PD). Perturbations of proteostasis at the endoplasmic reticulum (ER) triggers ER stress, activating the unfolded protein response (UPR). Chronic ER stress is thought to underlie the death of neurons during the neurodegenerative progression, but the precise mechanism by which the UPR pathways regulate neuronal cell fate remains incompletely understood. Here we report a critical neurodegenerative role for inositol-requiring enzyme 1 (IRE1), the evolutionarily conserved ER stress sensor, in a Drosophila model of PD. We found that IRE1 was hyperactivated upon accumulation of α-synuclein in the fly photoreceptor neurons. Ectopic overexpression of IRE1 was sufficient to trigger autophagy-dependent neuron death in an XBP1-independent, JNK-dependent manner. Furthermore, IRE1 was able to promote dopaminergic neuron loss, progressive locomotor impairment, and shorter lifespan, whereas blocking IRE1 or ATG7 expression remarkably ameliorated the progression of α-synuclein-caused Parkinson's disease. These results provide in vivo evidence demonstrating that the IRE1 pathway drives PD progression through coupling ER stress to autophagy-dependent neuron death.


Assuntos
Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , alfa-Sinucleína/metabolismo , Animais , Animais Geneticamente Modificados , Autofagia/fisiologia , Modelos Animais de Doenças , Proteínas de Drosophila , Drosophila melanogaster , Estresse do Retículo Endoplasmático , Endorribonucleases , Humanos , Neurônios/patologia , Doença de Parkinson/genética , Transdução de Sinais , alfa-Sinucleína/biossíntese , alfa-Sinucleína/genética
18.
Cell Prolif ; 52(5): e12656, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31264309

RESUMO

OBJECTIVES: Cell migration has a key role in cancer metastasis, which contributes to drug resistance and tumour recurrence. Better understanding of the mechanisms involved in this process will potentially reveal new drug targets for cancer therapy. Fer is a non-receptor protein tyrosine kinase aberrantly expressed in various human cancers, whereas its role in tumour progression remains elusive. MATERIALS AND METHODS: Transgenic flies and epigenetic analysis were employed to investigate the role of Drosophila Fer (FER) in cell migration and underlying mechanisms. Co-immunoprecipitation assay was used to monitor the interaction between FER and Drosophila JNK (Bsk). The conservation of Fer in regulating JNK signalling was explored in mammalian cancer and non-cancer cells. RESULTS: Overexpression of FER triggered cell migration and activated JNK signalling in the Drosophila wing disc. Upregulation and downregulation in the basal activity of Bsk exacerbated and eliminated FER-mediated migration, respectively. In addition, loss of FER blocked signal transduction of the JNK pathway. Specifically, FER interacted with and promoted the activity of Bsk, which required both the kinase domain and the C-terminal of Bsk. Lastly, Fer regulated JNK activities in mammalian cells. CONCLUSIONS: Our study reveals FER as a positive regulator of JNK-mediated cell migration and suggests its potential role as a therapeutic target for cancer metastasis.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteínas Tirosina Quinases/metabolismo , Animais , Animais Geneticamente Modificados/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proteínas de Drosophila/química , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/química , Metaloproteinase 1 da Matriz/metabolismo , Domínios Proteicos , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Interferência de RNA , RNA Interferente Pequeno , Transdução de Sinais , Asas de Animais/metabolismo
20.
Cell Prolif ; 52(1): e12529, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30328653

RESUMO

OBJECTIVES: Over the past decade an intriguing connection between cell polarity and tumorigenesis has emerged. Multiple core components of the junction complexes that help to form and maintain cell polarity display both pro- and anti-tumorigenic functions in a context-dependent manner, with the underlying mechanisms poorly understood. MATERIALS AND METHODS: With transgenic fly lines that overexpress or knock down specific signalling components, we perform genetic analysis to investigate the precise role of the polarity protein Canoe (Cno) in tumorigenesis and the downstream pathways. RESULTS: We show that overexpression of cno simultaneously activates JNK and Ras-MEK-ERK signalling, resulting in mixed phenotypes of both overproliferation and cell death in the Drosophila wing disc. Moderate alleviation of JNK activation eliminates the effect of Cno on cell death, leading to organ overgrowth and cell migration that mimic the formation and invasion of tumours. In addition, we find that the Hippo pathway acts downstream of JNK and Ras signalling to mediate the effect of Cno on cell proliferation. CONCLUSIONS: Our work reveals an oncogenic role of Cno and creates a new type of Drosophila tumour model for cancer research.


Assuntos
Polaridade Celular/fisiologia , Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteínas ras/metabolismo , Animais , Carcinogênese/genética , Morte Celular/genética , Proliferação de Células/genética , Drosophila/embriologia , Drosophila/genética , Proteínas de Drosophila/genética , Técnicas de Silenciamento de Genes , Neoplasias/genética , Neoplasias/patologia , Asas de Animais/embriologia
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