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1.
Elife ; 82019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31309927

RESUMO

Autophagy defects are implicated in multiple late-onset neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS) and Alzheimer's, Huntington's, and Parkinson's diseases. Since aging is the most common shared risk factor in neurodegeneration, we assessed rates of autophagy in mammalian neurons during aging. We identified a significant decrease in the rate of constitutive autophagosome biogenesis during aging and observed pronounced morphological defects in autophagosomes in neurons from aged mice. While early stages of autophagosome formation were unaffected, we detected the frequent production of stalled LC3B-negative isolation membranes in neurons from aged mice. These stalled structures recruited the majority of the autophagy machinery, but failed to develop into LC3B-positive autophagosomes. Importantly, ectopically expressing WIPI2B effectively restored autophagosome biogenesis in aged neurons. This rescue is dependent on the phosphorylation state of WIPI2B at the isolation membrane, suggesting a novel therapeutic target in age-associated neurodegeneration.


Assuntos
Envelhecimento/patologia , Autofagossomos/metabolismo , Proteínas Relacionadas à Autofagia/biossíntese , Autofagia , Expressão Gênica , Neurônios/patologia , Proteínas de Ligação a Fosfato/biossíntese , Animais , Camundongos
2.
Mol Cell Biol ; 39(6)2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30602494

RESUMO

Autophagy is a process of lysosomal self-degradation of cellular components by forming autophagosomes. Autophagosome formation is an essential process in autophagy and is fine-tuned by various autophagy-related gene (ATG) products, including ATG5, ATG12, and ATG16. Although several reports have shown that numerous factors affect multiple levels of gene regulation to orchestrate cellular autophagy, the detailed mechanism of autophagosome formation still needs further investigation. In this study, we demonstrate that the RNA binding protein HuR (human antigen R) performs an essential function in autophagosome formation. We observe that HuR silencing leads to inhibition of autophagosome formation and autophagic flux in liver cells. Ribonucleoprotein immunoprecipitation (RIP) assay allows the identification of ATG5, ATG12, and ATG16 mRNAs as the direct targets of HuR. We further show that HuR mediates the translation of ATG5, ATG12, and ATG16 mRNAs by binding to their 3' untranslated regions (UTRs). In addition, we show that HuR expression positively correlates with the levels of ATG5 and ATG12 in hepatocellular carcinoma (HCC) cells. Collectively, our results suggest that HuR functions as a pivotal regulator of autophagosome formation by enhancing the translation of ATG5, ATG12, and ATG16 mRNAs and that augmented expression of HuR and ATGs may participate in the malfunction of autophagy in HCC cells.


Assuntos
Autofagossomos/metabolismo , Proteínas Relacionadas à Autofagia/biossíntese , Carcinoma Hepatocelular/metabolismo , Proteína Semelhante a ELAV 1/metabolismo , Neoplasias Hepáticas/metabolismo , Autofagia/genética , Autofagia/fisiologia , Proteína 12 Relacionada à Autofagia/genética , Proteína 12 Relacionada à Autofagia/metabolismo , Proteína 5 Relacionada à Autofagia/metabolismo , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Proteína Semelhante a ELAV 1/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Proteínas Associadas aos Microtúbulos/metabolismo , Fagossomos/metabolismo , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
3.
Histol Histopathol ; 34(1): 47-56, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29989143

RESUMO

BACKGROUND: Wilms' tumor treatment has achieved great success in the last decade. Nevertheless, some cases still fail to respond to the current multimodality therapy. These cases fall mainly in the unfavorable histology group with very few belonging to the favorable histology group. In recent years, autophagy manipulation whether inhibition or stimulation has been shown to affect cancer cell behavior and has emerged as a novel mechanism to improve cancer cell response to currently used therapeutic regimens. OBJECTIVE: The current study aimed to investigate the expression of autophagy related markers (ATG4B and Beclin1) in WT, its association with the different clinic-pathological parameters and its impact on patient survival. METHODS: Twenty-one formalin fixed paraffin embedded (FFPE) WT specimens were immunohistochemically stained using autophagy related markers; Beclin-1 and ATG4B. All clinical, radiological and follow up data were retrieved from the patient records. RESULTS: All specimens showed positive expression of both Beclin-1 and ATG4B. The staining score for Beclin1 varied between 50 and 300, and its expression was significantly associated with favorable histology (p=0.007). Similarly, ATG4B expression was significantly higher in favorable histology tumors compared to unfavorable histology (p=0.046). A statistically significant positive correlation between Beclin-1 and ATG4B expression was observed. The cumulative disease-free survival in patients with favorable histology was significantly higher compared to patients with unfavorable histology (p=0.0027). CONCLUSIONS: Beclin-1 and ATG4B expression were both found to be statistically significant discriminators of survival. Collectively these findings suggest that the expression of autophagy-related markers is associated with a favorable histology and could predict better survival in these patients.


Assuntos
Proteínas Relacionadas à Autofagia/biossíntese , Proteína Beclina-1/biossíntese , Biomarcadores Tumorais/análise , Cisteína Endopeptidases/biossíntese , Neoplasias Renais/patologia , Tumor de Wilms/patologia , Autofagia , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Neoplasias Renais/mortalidade , Masculino , Prognóstico , Estudos Retrospectivos , Tumor de Wilms/mortalidade
4.
Biomed Pharmacother ; 109: 716-725, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30551524

RESUMO

OBJECTIVE: Coronary heart disease is a common cause of death and disability worldwide and mainly results from myocardial ischemia-reperfusion (I/R) injury. This study aimed to elucidate the roles and possible mechanism of long noncoding RNA Component Of Mitochondrial RNA Processing Endoribonuclease (RMRP) in protecting against ischemic myocardial injury. MATERIAL AND METHODS: The H9c2 cardiomyocytes were cultured under hypoxia condition to induce myocardial injury. The RMRP expression under hypoxia condition was determined, followed by investigation of the effects of RMRP dysregulation on hypoxia-induced injury in H9c2 cells. In addition, the regulatory relationship between RMRP and miR-206 was detected, and the potential target of miR-206 was identified. Besides, the association of RMRP and activation of PI3K/AKT/mTOR signaling pathway was explored. Furthermore, an in vivo rat model of myocardial I/R injury was established by subjection to 60 min ischemia and subsequently 24 h reperfusion for validation of the role of RMRP in regulating myocardial I/R injury in vivo. RESULTS: The results showed that overexpression of RMRP aggravated hypoxia-induced injury in H9c2 cells. Moreover, miR-206 was negatively regulated by RMRP and overexpression of RMRP aggravated hypoxia injury by downregulation of miR-206. Furthermore, ATG3 was a target of miR-206, and he effects of miR-206 on hypoxia injury were through targeting ATG3. Besides, overexpression of RMRP activated PI3K/AKT/mTOR pathway in hypoxia-treated H9c2 cells, which were reversed by miR-206 overexpression at the same time. Furthermore, in an in vivo rat model of myocardial I/R injury, suppression of RMPR improved cardiac function and inhibited apoptosis after myocardial I/R injury. CONCLUSIONS: Our findings reveal that upregulation of RMRP may aggravate myocardial I/R injury possible by downregulation of miR-206 and subsequently upregulation of ATG3. Activation of PI3K/Akt/mTOR pathway may be a key downstream mechanism mediating the cardioprotection of RMPR/miR-206/ATG3 axis against myocardial I/R injury.


Assuntos
Proteínas Relacionadas à Autofagia/biossíntese , MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Peptídeo Sintases/biossíntese , RNA Longo não Codificante/biossíntese , Regulação para Cima/fisiologia , Animais , Proteínas Relacionadas à Autofagia/genética , Linhagem Celular , Expressão Gênica , Marcação de Genes/métodos , Masculino , MicroRNAs/genética , Traumatismo por Reperfusão Miocárdica/genética , Peptídeo Sintases/genética , RNA Longo não Codificante/genética , Ratos , Ratos Sprague-Dawley
5.
J Neuroimmune Pharmacol ; 13(3): 383-395, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29790105

RESUMO

Tissue damage and pathogen invasion during surgical trauma have been identified as contributing factors leading to neuroinflammation in the hippocampus, which can be protected by stimulation of the cholinergic anti-inflammatory pathway using the acetylcholinesterase inhibitor physostigmine. Macroautophagy, an intracellular degradation pathway used to recycle and eliminate damaged proteins and organelles by lysosomal digestion, seems to be important for cell survival under stress conditions. This study aimed to examine the role of autophagy in physostigmine-mediated hippocampal cell protection in a rat model of surgery stress. In the presence or absence of physostigmine, adult Wistar rats underwent surgery in combination with lipopolysaccharide (LPS). Activated microglia, apoptosis-, autophagy-, and anti-inflammatory-related genes and -proteins in the hippocampus were determined by Real-Time PCR, Western blot and fluorescence microscopy after 1 h, 24 h and 3 d. Surgery combined with LPS-treatment led to microglia activation after 1 h and 24 h which was accompanied by apoptotic cell death after 24 h in the hippocampus. Furthermore, it led to a decreased expression of ATG-3 after 24 h and an increased expression of p62/ SQSTM1 after 1 h and 24 h. Administration of physostigmine significantly increased autophagy related markers and restored the autophagic flux after surgery stress, detected by increased degradation of p62/ SQSTM1 in the hippocampus after 1 h and 24 h. Furthermore, physostigmine reduced activated microglia and apoptosis relevant proteins and elevated the increased expression of TGF-beta1 and MFG-E8 after surgery stress. In conclusion, activation of autophagy may be essential in physostigmine-induced neuroprotection against surgery stress.


Assuntos
Autofagia/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Lipopolissacarídeos/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Fisostigmina/farmacologia , Estresse Fisiológico , Animais , Apoptose/efeitos dos fármacos , Proteínas Relacionadas à Autofagia/biossíntese , Proteína Beclina-1/metabolismo , Inflamação/genética , Inflamação/patologia , Inflamação/psicologia , Lipopolissacarídeos/toxicidade , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Microglia/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , Peptídeo Sintases/biossíntese , Período Pós-Operatório , Ratos , Ratos Wistar , Proteína Sequestossoma-1/biossíntese
6.
Oxid Med Cell Longev ; 2018: 1471682, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30622661

RESUMO

ROS and oxidative stress may promote autophagy; on the other hand, autophagy may help reduce oxidative damages. According to the known interplay of ROS, autophagy, and melanoma onset, we hypothesized that autophagy-related genes (ARGs) may represent useful melanoma biomarkers. We therefore analyzed the gene and protein expression of 222 ARGs in human melanoma samples, from 5 independent expression databases (overall 572 patients). Gene expression was first evaluated in the GEO database. Forty-two genes showed extremely high ability to discriminate melanoma from nevi (63 samples) according to ROC (AUC ≥ 0.85) and Mann-Whitney (p < 0.0001) analyses. The 9 genes never related to melanoma before were then in silico validated in the IST online database. BAG1, CHMP2B, PEX3, and WIPI1 confirmed a strong differential gene expression, in 355 samples. A second-round validation performed on the Human Protein Atlas database showed strong differential protein expression for BAG1, PEX3, and WIPI1 in melanoma vs control samples, according to the image analysis of 80 human histological sections. WIPI1 gene expression also showed a significant prognostic value (p < 0.0001) according to 102 melanoma patients' survival data. We finally addressed in Oncomine database whether WIPI1 overexpression is melanoma-specific. Within more than 20 cancer types, the most relevant WIPI1 expression change (p = 0.00002; fold change = 3.1) was observed in melanoma. Molecular/functional relationships of the investigated molecules with melanoma and their molecular/functional network were analyzed via Chilibot software, STRING analysis, and gene ontology enrichment analysis. We conclude that WIPI1 (AUC = 0.99), BAG1 (AUC = 1), and PEX3 (AUC = 0.93) are relevant novel melanoma markers at both gene and protein levels.


Assuntos
Proteínas Relacionadas à Autofagia/genética , Proteínas de Ligação a DNA/genética , Lipoproteínas/genética , Melanoma/genética , Proteínas de Membrana/genética , Peroxinas/genética , Fatores de Transcrição/genética , Autofagia/genética , Proteínas Relacionadas à Autofagia/biossíntese , Proteínas Relacionadas à Autofagia/metabolismo , Proteínas de Ligação a DNA/metabolismo , Bases de Dados Genéticas , Expressão Gênica , Humanos , Lipoproteínas/metabolismo , Melanoma/metabolismo , Melanoma/patologia , Proteínas de Membrana/biossíntese , Proteínas de Membrana/metabolismo , Peroxinas/metabolismo , Prognóstico , Fatores de Transcrição/metabolismo
7.
Cancer Lett ; 409: 81-90, 2017 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-28889000

RESUMO

Considerable evidences have shown that both heat shock transcription factor 1 (HSF1) and autophagy can attenuate the sensitivity of hepatocellular carcinoma (HCC) cells to chemotherapeutic reagents. However, it is still little known whether HSF1 is associated with autophagy in regulating the chemosensitivity of HCC cells. In this study, we for the first time demonstrated that HSF1 markedly attenuated the killing effect of epirubicin (EPI) to HCC cells via enhancing the EPI-induced protective autophagy. Mechanistically, HSF1 upregulated autophagy related 4B (ATG4B) in HCC cells, which enhanced the EPI-triggered protective autophagy. Reporter assay showed that HSF1 increased the transcriptional activity of ATG4B gene promoter, and chromatin immunoprecipitation assay verified that HSF1 bound to the site (-1429 to -1417) in ATG4B gene promoter region. The experiments in nude mice showed that knockdown of HSF1 or ATG4B strengthened the anti-HCC effect of EPI in vivo. Collectively, these results revealed that HSF1 elevates ATG4B via promoting its transcription, which alleviates the sensitivity of EPI in HCC cells through enhancing protective autophagy, suggesting that the "HSF1/ATG4B/protective autophagy" pathway may be a novel target for developing sensitizing strategy to HCC chemotherapy.


Assuntos
Proteínas Relacionadas à Autofagia/biossíntese , Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Cisteína Endopeptidases/biossíntese , Proteínas de Ligação a DNA/metabolismo , Epirubicina/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Fatores de Transcrição/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Antibióticos Antineoplásicos/farmacologia , Proteínas Relacionadas à Autofagia/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Cloroquina/farmacologia , Cisteína Endopeptidases/metabolismo , Proteínas de Ligação a DNA/genética , Sinergismo Farmacológico , Fatores de Transcrição de Choque Térmico , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Nus , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição/genética , Transfecção , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Tumour Biol ; 39(6): 1010428317709676, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28639909

RESUMO

NRAGE has been reported to be overexpressed in cancer cells, especially in lung cancer cells. To determine the role of NRAGE in non-small-cell lung cancer cells, we investigated the effects of NRAGE on autophagy in non-small-cell lung cancer cells. Human A549 and H1299 cells were transfected with NRAGE-specific small-interfering RNA. The Cell Counting Kit-8 and plate clone assay showed that downregulation of NRAGE could induce the proliferation in A549 and H1299 cells. In addition, our data suggested that downregulation of NRAGE enhances autophagosome formation by immunofluorescence. We found that knockdown of NRAGE induced autophagy, together with downregulation of P62 and upregulation of LC3-II protein. Furthermore, to elucidate the mechanism of NRAGE in suppressing autophagy, the protein expressions of AMPK, Ulk1, and Atg13 were assessed. Collectively, these results demonstrate the effective anti-autophagic of NRAGE in non-small-cell lung cancer cells through AMPK/Ulk1/Atg13 autophagy signaling pathways. Therefore, NRAGE could be used as a potential therapeutic target for lung cancer.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Antígenos de Neoplasias/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Proteínas Relacionadas à Autofagia/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Neoplasias/genética , Células A549 , Proteínas Quinases Ativadas por AMP/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/biossíntese , Proteínas Relacionadas à Autofagia/biossíntese , Carcinoma Pulmonar de Células não Pequenas/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Proteínas de Neoplasias/antagonistas & inibidores , Fosforilação , RNA Interferente Pequeno , Transdução de Sinais
9.
Oncotarget ; 8(13): 21692-21709, 2017 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-28423511

RESUMO

The efficacy of Ataxia-Telangiectasia Mutated (ATM) kinase signalling inhibition in cancer therapy is tempered by the identification of new emerging functions of ATM, which suggests that the role of this protein in cancer progression is complex. We recently demonstrated that this tumor suppressor gene could act as tumor promoting factor in HER2 (Human Epidermal Growth Factor Receptor 2) positive breast cancer. Herein we put in evidence that ATM expression sustains the proportion of cells with a stem-like phenotype, measured as the capability to form mammospheres, independently of HER2 expression levels. Transcriptomic analyses revealed that, in mammospheres, ATM modulates the expression of cell cycle-, DNA repair- and autophagy-related genes. Among these, the silencing of the autophagic gene, autophagy related 4C cysteine peptidase (ATG4C), impairs mammosphere formation similarly to ATM depletion. Conversely, ATG4C ectopic expression in cells silenced for ATM expression, rescues mammospheres growth. Finally, tumor array analyses, performed using public data, identify a significant correlation between ATM and ATG4C expression levels in all human breast cancer subtypes, except for the basal-like one.Overall, we uncover a new connection between ATM kinase and autophagy regulation in breast cancer. We demonstrate that, in breast cancer cells, ATM and ATG4C are essential drivers of mammosphere formation, suggesting that their targeting may improve current approaches to eradicate breast cancer cells with a stem-like phenotype.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteínas Relacionadas à Autofagia/biossíntese , Autofagia , Neoplasias da Mama/patologia , Cisteína Endopeptidases/biossíntese , Células-Tronco Neoplásicas/patologia , Autofagia/fisiologia , Western Blotting , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Imunofluorescência , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Células-Tronco Neoplásicas/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase
10.
Gene ; 594(2): 268-271, 2016 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-27613142

RESUMO

Protein expression can be controlled via AUG sequences located upstream to the initiation codon in the 5' end untranslated region (5' UTR). Our study was focused on the effect of distance between the initiation codon and the first upstream AUG. An inhibitory effect on protein expression was established when AUG exists in 5' UTR, and this effect is increased when multiple AUG sequences occur there. The study was performed with ATG16L2, a non-lethal gene with no introns or upstream AUG sequence to avoid any interference. New mutations were generated at different locations within the promoter region of ATG16L2 gene and added to a plasmid construct containing a luciferase gene reporter gene. The results show a clear relationship between the distance of the novel AUGs from initiation codon and protein expression. The inhibitory effect was even stronger when multiple AUG sequences were present in 5' UTR.


Assuntos
Regiões 5' não Traduzidas , Códon de Iniciação , Regulação da Expressão Gênica , Mutação , Regiões Promotoras Genéticas , Animais , Proteínas Relacionadas à Autofagia/biossíntese , Proteínas Relacionadas à Autofagia/genética , Códon de Iniciação/genética , Códon de Iniciação/metabolismo , Humanos
11.
Oncotarget ; 7(41): 66970-66988, 2016 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-27556700

RESUMO

Autophagy, a lysosome-mediated degradation and recycling process, functions in advanced malignancies to promote cancer cell survival and contribute to cancer progression and drug resistance. While various autophagy inhibition strategies are under investigation for cancer treatment, corresponding patient selection criteria for these autophagy inhibitors need to be developed. Due to its central roles in the autophagy process, the cysteine protease ATG4B is one of the autophagy proteins being pursued as a potential therapeutic target. In this study, we investigated the expression of ATG4B in breast cancer, a heterogeneous disease comprised of several molecular subtypes. We examined a panel of breast cancer cell lines, xenograft tumors, and breast cancer patient specimens for the protein expression of ATG4B, and found a positive association between HER2 and ATG4B protein expression. We showed that HER2-positive cells, but not HER2-negative breast cancer cells, require ATG4B to survive under stress. In HER2-positive cells, cytoprotective autophagy was dependent on ATG4B under both starvation and HER2 inhibition conditions. Combined knockdown of ATG4B and HER2 by siRNA resulted in a significant decrease in cell viability, and the combination of ATG4B knockdown with trastuzumab resulted in a greater reduction in cell viability compared to trastuzumab treatment alone, in both trastuzumab-sensitive and -resistant HER2 overexpressing breast cancer cells. Together these results demonstrate a novel association of ATG4B positive expression with HER2 positive breast cancers and indicate that this subtype is suitable for emerging ATG4B inhibition strategies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas Relacionadas à Autofagia/biossíntese , Autofagia/fisiologia , Neoplasias da Mama/metabolismo , Cisteína Endopeptidases/biossíntese , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Adulto , Idoso , Animais , Autofagia/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Feminino , Xenoenxertos , Humanos , Camundongos , Pessoa de Meia-Idade , Receptor ErbB-2/biossíntese , Trastuzumab/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Int J Cancer ; 139(7): 1564-73, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27225307

RESUMO

The aim of this article was to evaluate whether genetic variants in autophagy-related genes affect the overall survival (OS) of non-small cell lung cancer (NSCLC) patients. We analyzed 14 single nucleotide polymorphisms (SNPs) in core autophagy-related genes for OS in 1,001 NSCLC patients. Three promising SNPs in ATG10 were subsequently annotated by the expression quantitative trait loci (eQTL) and methylation quantitative trait loci (meQTL) analyses based on Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. We observed that the variants of rs10514231, rs1864182 and rs1864183 were associated with poor lung cancer survival (HR = 1.33, 95% CI = 1.07-1.65; HR = 1.43, 95% CI = 1.13-1.81; HR = 1.38, 95% CI = 1.14-1.68, respectively) and positively correlated with ATG10 expression (all p < 0.05) from GTEx and TCGA datasets. The elevated expression of ATG10 may predict shorter survival time in lung cancer patients in TCGA dataset (HR = 2.10, 95% CI = 1.33-3.29). Moreover, the variants of rs10514231 and rs1864182 were associated with the increased methylation levels of cg17942617 (meQTL), which in turn contributed to the elevated ATG10 expression and decreased survival time. Further functional assays revealed that ATG10 facilitated lung cancer cell proliferation and migration. Our findings suggest that eQTL/meQTL variations of ATG10 could influence lung cancer survival through regulating ATG10 expression.


Assuntos
Proteínas Relacionadas à Autofagia/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Locos de Características Quantitativas , Proteínas de Transporte Vesicular/genética , Autofagia/genética , Proteínas Relacionadas à Autofagia/biossíntese , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Linhagem Celular Tumoral , Metilação de DNA , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Polimorfismo de Nucleotídeo Único , Prognóstico , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Taxa de Sobrevida , Proteínas de Transporte Vesicular/biossíntese
13.
BMC Cancer ; 16: 207, 2016 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-26965179

RESUMO

BACKGROUND: Autophagy, a cellular degradation process, has complex roles in tumourigenesis and resistance to cancer treatment in humans. The aim of this study was to explore the expression levels of autophagy-related proteins in patients with rectal cancer and evaluate their clinical role in the neoadjuvant chemoradiotherapy setting. METHODS: All specimens evaluated were obtained from 101 patients with colorectal cancer who had undergone neoadjuvant chemoradiotherapy and curative surgery. The primary outcomes measured were the expression levels of two autophagy-related proteins (microtubule-associated protein 1 light chain 3 beta (LC3ß) and beclin-1) by immunohistochemistry and their association with clinicopathological parameters and patient survival. RESULTS: Among the 101 patients, the frequency of high expression of beclin-1 was 31.7% (32/101) and that of LC3ß was 46.5% (47/101). A pathologic complete response was inversely associated with LC3ß expression (P = 0.003) and alterations in the expression of autophagy-related proteins (P = 0.046). In the multivariate analysis, however, autophagy-related protein expression did not show prognostic significance for relapse-free survival or overall survival. CONCLUSIONS: High expression of autophagy-related proteins shows a strong negative association with the efficacy of neoadjuvant chemoradiotherapy in patients with rectal cancer. Autophagy has clear implications as a therapeutic target with which to improve the efficacy of neoadjuvant chemoradiotherapy.


Assuntos
Proteína Beclina-1/biossíntese , Proteínas Associadas aos Microtúbulos/biossíntese , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/radioterapia , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autofagia/efeitos dos fármacos , Autofagia/genética , Autofagia/efeitos da radiação , Proteínas Relacionadas à Autofagia/biossíntese , Proteínas Relacionadas à Autofagia/genética , Proteína Beclina-1/genética , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Quimiorradioterapia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Masculino , Proteínas Associadas aos Microtúbulos/genética , Pessoa de Meia-Idade , Terapia Neoadjuvante , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Neoplasias Retais/genética , Neoplasias Retais/patologia
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