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1.
J Biol Regul Homeost Agents ; 35(1): 117-129, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33593046

RESUMO

Peptidyl arginine deiminase 4 (PADI4), an enzyme that converts arginine residues to citrulline residues in the presence of calcium ions, affects the biochemical activities of proteins. The biological function of PADI4 as well as its mechanism in nasopharyngeal carcinoma (NPC) necessitates further investigation. PADI4 expression in NPC tissues and cells was detected using Western blot. qRT-PCR was used to determine the expression of miR-335-5p and PADI4 mRNA in NPC tissues and cells. BrdU assay and CCK-8 assay were employed to detect cell proliferation. Cell migration and invasion were evaluated using Transwell assay. NPC cells were exposed to different doses of radiation in vitro, and then colony formation assays were used to detect colony survival. The target relationship between miR-335-5p and PADI4 was verified using Western blot, qRT-PCR, and dual-luciferase reporter gene assays. Compared with normal mucosal epithelial tissues and cell lines, the expression level of PADI4 in NPC tissues and cells was significantly up-regulated. PADI4 overexpression promoted the proliferation, migration, and invasion of NPC cells. Under radiation, NPC cell survival was significantly promoted by the up-regulation of PADI4. Conversely, knock-down of PADI4 suppressed the above-mentioned malignant phenotypes. MiR-335-5p could bind with the 3' UTR of PADI4 mRNA, and suppressed the expression of PADI4. PADI4 down-regulated the expression of p21 and activated the mTOR signaling pathway. PADI4, which is negatively regulated by miR-335-5p, promotes the proliferation, migration, invasion and radioresistance of NPC cells by regulating the p21 and mTOR signaling pathways.


Assuntos
MicroRNAs/provisão & distribução , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/radioterapia , Proteína-Arginina Desiminase do Tipo 4 , Tolerância a Radiação/genética
2.
Crit Rev Oncol Hematol ; 157: 103183, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33310279

RESUMO

Radioresistance remains as an obstacle in cancer treatment. This systematic review and meta-analysis aimed to evaluate the association between the expression of miRNAs and responses to radiotherapy and the prognosis of different tumors. In total, 77 miRNAs in 19 cancer types were studied, in which 24 miRNAs were upregulated and 58 miRNAs were downregulated in cancer patients. Five miRNAs were differentially expressed. Moreover, 75 miRNAs were found to be related to radioresistance, while 5 were observed to be related to radiosensitivity. The pooled HR and 95 % confidence interval for the combined studies was 1.135 (0.819-1.574; P-value = 0.4). The HR values of the subgroup analysis for miR-21 (HR = 2.344; 95 % CI: 1.927-2.850; P-value = 0.000), nasopharyngeal carcinoma (HR = 0.448; 95 % CI: 0.265-0.760; P = 0.003) and breast cancer (HR = 1.131; 95 % CI: 0.311-4.109; P = .85) were obtained. Our results highlighted that across the published literature, miRNAs can modulate tumor radioresistance or sensitivity by affecting radiation-related signaling pathways. It seems that miRNAs could be considered as a theragnostic biomarker to predict and monitor clinical response to radiotherapy. Thus, the prediction of radioresistance in malignant patients will improve radiotherapy outcomes and radiotherapeutic resistance.


Assuntos
MicroRNAs , Neoplasias Nasofaríngeas , Biomarcadores Tumorais/genética , Humanos , MicroRNAs/genética , Prognóstico , Tolerância a Radiação/genética
3.
Oncogene ; 39(37): 5933-5949, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32753649

RESUMO

Gastric cancer (GC) is the third leading cause of cancer-related mortality worldwide and prognosis after potentially curative gastrectomy remains poor. Administration of GC-targeting molecules in combination with adjuvant chemo- or radiotherapy following surgical resection has been proposed as a potentially effective treatment option. Here, we have identified DOCK6, a guanine nucleotide exchange factor (GEF) for Rac1 and CDC42, as an independent biomarker for GC prognosis. Clinical findings indicate the positive correlation of higher DOCK6 expression with tumor size, depth of invasion, lymph node metastasis, vascular invasion, and pathological stage. Furthermore, elevated DOCK6 expression was significantly associated with shorter cumulative survival in both univariate and multivariate analyses. Gene ontology analysis of three independent clinical GC cohorts revealed significant involvement of DOCK6-correlated genes in the WNT/ß-catenin signaling pathway. Ectopic expression of DOCK6 promoted GC cancer stem cell (CSC) characteristics and chemo- or radioresistance concomitantly through Rac1 activation. Conversely, depletion of DOCK6 suppressed CSC phenotypes and progression of GC, further demonstrating the pivotal role of DOCK6 in GC progression. Our results demonstrate a novel mechanistic link between DOCK6, Rac1, and ß-catenin in GCCSC for the first time, supporting the utility of DOCK6 as an independent marker of GC.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Células-Tronco Neoplásicas/metabolismo , Tolerância a Radiação/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Via de Sinalização Wnt , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Modelos Animais de Doenças , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Xenoenxertos , Humanos , Imuno-Histoquímica , Imunofenotipagem , Camundongos , Fenótipo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia
5.
Environ Sci Pollut Res Int ; 27(34): 42778-42790, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32748357

RESUMO

Hepatocellular carcinoma (HCC), a common type of human malignancies, leads to increasing incidence and fairly high mortality. An increasing number of studies have verified that long noncoding RNAs (lncRNAs) played key roles in the development of multiple human cancers. As a biomarker, SLC16A1-AS1 has been reported in non-small cell lung cancer (NSCLC) and oral squamous cell carcinoma (OSCC). Thus, we decided to investigate whether SLC16A1-AS1 exerts its biological function in HCC. In this study, we discovered that SLC16A1-AS1 was obviously downregulated in HCC tissues and cells. Overexpression of SLC16A1-AS1 inhibited HCC cell proliferation, invasion, and epithelial-mesenchymal transition (EMT) process as well as promoted cell apoptosis. Moreover, SLC16A1-AS1 was confirmed to enhance the radiosensitivity of HCC cells. Molecular mechanism exploration suggested that SLC16A1-AS1 served as a sponge for miR-301b-3p and CHD5 was the downstream target gene of miR-301b-3p in HCC cells. Rescue assays implied that CHD5 knockdown could recover the effects of SLC16A1-AS1 overexpression on HCC cellular processes. In brief, our study clarified that SLC16A1-AS1 acted as a tumor suppressor in HCC by targeting the miR-301b-3p/CHD5 axis, which may be a promising diagnostic biomarker and provide promising treatment for HCC patients.


Assuntos
Carcinoma Hepatocelular , Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Hepáticas , Neoplasias Pulmonares , MicroRNAs , Transportadores de Ácidos Monocarboxílicos , Neoplasias Bucais , Simportadores , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Proliferação de Células , DNA Helicases , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , MicroRNAs/genética , Transportadores de Ácidos Monocarboxílicos/fisiologia , Proteínas do Tecido Nervoso , Tolerância a Radiação/genética , Simportadores/fisiologia
6.
Nat Commun ; 11(1): 3811, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732914

RESUMO

Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming therapy resistance. Treatments that are effective independent of genotype are urgently needed. By correlating intracellular metabolite levels with radiation resistance across dozens of genomically-distinct models of GBM, we find that purine metabolites, especially guanylates, strongly correlate with radiation resistance. Inhibiting GTP synthesis radiosensitizes GBM cells and patient-derived neurospheres by impairing DNA repair. Likewise, administration of exogenous purine nucleosides protects sensitive GBM models from radiation by promoting DNA repair. Neither modulating pyrimidine metabolism nor purine salvage has similar effects. An FDA-approved inhibitor of GTP synthesis potentiates the effects of radiation in flank and orthotopic patient-derived xenograft models of GBM. High expression of the rate-limiting enzyme of de novo GTP synthesis is associated with shorter survival in GBM patients. These findings indicate that inhibiting purine synthesis may be a promising strategy to overcome therapy resistance in this genomically heterogeneous disease.


Assuntos
Neoplasias Encefálicas/radioterapia , Reparo do DNA/genética , Glioblastoma/radioterapia , Guanosina Monofosfato/metabolismo , Tolerância a Radiação/genética , Animais , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Feminino , Glioblastoma/genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos SCID , Nucleosídeos de Purina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Cancer Sci ; 111(9): 3122-3131, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32506767

RESUMO

MircoRNA (miRNA) are a group of small, non-coding, regulatory RNA with an average length of approximately 22 nucleotides, which mostly modulate gene expression post-transcriptionally through complementary binding to the 3'-untranslated region (3'-UTR) of multiple target genes. Emerging evidence has shown that miRNA are frequently dysregulated in a variety of human malignancies. Among them, microRNA-145 (miR-145) has been increasingly identified as a critical suppressor of carcinogenesis and therapeutic resistance. Resistance to tumor therapy is a challenge in cancer treatment due to the daunting range of resistance mechanisms. We reviewed the status quo of recent advancements in the knowledge of the functional role of miR-145 in therapeutic resistance and the tumor microenvironment. It may serve as an innovative biomarker for therapeutic response and cancer prognosis.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs , Neoplasias/genética , Regiões 3' não Traduzidas , Biomarcadores Tumorais , Biologia Computacional/métodos , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Interferência de RNA , RNA Mensageiro , Tolerância a Radiação/genética
8.
Anticancer Res ; 40(5): 2627-2635, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366407

RESUMO

BACKGROUND/AIM: Head and neck squamous cell carcinoma (HNSCC) is an aggressive head and neck malignancy. The aim of this study was to elucidate the role of periostin (POSTN) in the epithelial-to-mesenchymal transition (EMT) process mediating the acquisition of radioresistance in HNSCC. MATERIALS AND METHODS: The expression levels of EMT hallmark genes including POSTN and Erk/Akt signaling pathways were compared between radiosensitive and radioresistant HNSCC cells. RESULTS: POSTN mRNA expression was higher in radioresistant HNSCC cells, and silencing POSTN significantly impaired their invasiveness under the effect of EMT process represented by up-regulation of mesenchymal markers and down-regulation of an epithelial marker. Expression levels of Erk and Akt were higher in radioresistant cells. CONCLUSION: POSTN in association with the Erk and Akt signaling pathways was up-regulated during the EMT process, leading to the conversion of radiosensitive to radioresistant HNSCC cells. POSTN may be a key marker for predicting the radioresistance and therapeutic target of HNSCC.


Assuntos
Moléculas de Adesão Celular/metabolismo , Transição Epitelial-Mesenquimal , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Tolerância a Radiação , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Epitélio/metabolismo , Epitélio/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Humanos , Mesoderma/patologia , Invasividade Neoplásica , Tolerância a Radiação/genética , Transdução de Sinais/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
9.
Exp Mol Pathol ; 115: 104448, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32380053

RESUMO

Colorectal cancer (CRC) is one of deadly malignancies that affects humans globally. Herein, the effects of MALAT1 on CRC cellular functions were investigated. RT-qPCR measured expression of MALAT1 in human cell lines for colorectal Cancer. Radiation-resistance CRC cells (CRC-IR) were generated by increasing treatments of irradiation. Cell transfection upregulated or silenced genes in CRC-IR cells so as to study the correlation between MALAT1/miR-101-3p expression and cellular resistance to irradiation through evaluation of CCK-8, FCM apoptosis, Transwell migration and invasion and western blot assays for cell viability,apoptosis, migration and invasion and EMT. MALAT1 was upregulated in radio-resistance cell lines compared to normal CRC cells and upregulation promoted cell viability. In addition, decreased MALAT1 inhibited cell proliferation and metastasis and promoted apoptosis of CRC-IR cells. The luciferase assays confirmed that MALAT1 targeted and regulated miR-101-3p expression in radio-resistance cells. MiR-101-3p counteracted the effect exerted by MALAT1 in CRC-IR cells, indicating that MALAT1 added to the radio-resistance in vitro while miR-101-3p mimics could decrease the resistance to irradiation in CRC. In this study we have demonstrated that MALAT1 could regulate the radio-resistance in colorectal cancer via sponging miR-101-3p. Eventually, these outcomes unearthed a novel axis lncRNA MALAT1/miR-101-3p,which might be a prospective treatment to regulate radio-therapy in the near future.


Assuntos
Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , RNA Longo não Codificante/genética , Tolerância a Radiação/genética , Apoptose/genética , Sequência de Bases , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Neoplasias Colorretais/patologia , Regulação para Baixo/genética , Humanos , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Regulação para Cima/genética
10.
Toxicol Appl Pharmacol ; 399: 115054, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32422326

RESUMO

Radiation-induced rectal injury is a major side-effect observed in patients with pelvic malignancies who receive radiotherapy. MicroRNA (miRNA), involved in many cellular biological processes, can be disturbed by ionizing radiation (IR). In this study, we have investigated the function of microRNA-122-5p (miR-122-5p) in radiation-induced rectal injury. MiR-122-5p levels in the serum of rectal cancer patients or in the rectal tissues of C57BL/6 mice before and after IR were detected by quantitative real-time PCR (qRT-PCR). We found that the miR-122-5p levels were significantly up-regulated in patients' serum or in mice rectal tissues after IR. Elevation of miR-122-5p levels sensitized human intestinal epithelial crypt (HIEC) cells to IR both in vitro and in vivo. MiR-122-5p mimic was transfected to HIEC cells and the downstream targets were predicted by bioinformatic analysis. Two putative target sites of miR-122-5p in the 3'UTR of the cell cycle and apoptosis regulator 1 (CCAR1) mRNA were found and verified by luciferase reporter assay. Overexpression of miR-122-5p or silencing CCAR1 combined with IR significantly inhibited cell survival, enhanced radiosensitivity, and increased cell apoptosis compared to that in the negative control group in vitro. In vivo injection of miR-122-5p antagomir after IR significantly alleviated radiation-induced rectal injury in mice. These results suggest that miR-122-5p aggravates radiation-induced rectal injury through targeting CCAR1.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Proteínas de Ciclo Celular/genética , MicroRNAs/genética , Lesões por Radiação/genética , Tolerância a Radiação/genética , Reto/efeitos da radiação , Regiões 3' não Traduzidas/genética , Animais , Apoptose/genética , Ciclo Celular/genética , Linhagem Celular , Proliferação de Células/genética , Sobrevivência Celular/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , RNA Mensageiro/genética , Regulação para Cima/genética
11.
Technol Cancer Res Treat ; 19: 1533033820909112, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32329416

RESUMO

Radiotherapy is one of the most important cancer treatments, but its response varies greatly among individual patients. Therefore, the prediction of radiosensitivity, identification of potential signature genes, and inference of their regulatory networks are important for clinical and oncological reasons. Here, we proposed a novel multiple genomic fused partial least squares deep regression method to simultaneously analyze multi-genomic data. Using 60 National Cancer Institute cell lines as examples, we aimed to identify signature genes by optimizing the radiosensitivity prediction model and uncovering regulatory relationships. A total of 113 signature genes were selected from more than 20,000 genes. The root mean square error of the model was only 0.0025, which was much lower than previously published results, suggesting that our method can predict radiosensitivity with the highest accuracy. Additionally, our regulatory network analysis identified 24 highly important 'hub' genes. The data analysis workflow we propose provides a unified and computational framework to harness the full potential of large-scale integrated cancer genomic data for integrative signature discovery. Furthermore, the regression model, signature genes, and their regulatory network should provide a reliable quantitative reference for optimizing personalized treatment options, and may aid our understanding of cancer progress mechanisms.


Assuntos
Biologia Computacional/métodos , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Neoplasias/genética , Neoplasias/radioterapia , Medicina de Precisão , Tolerância a Radiação/genética , Linhagem Celular Tumoral , Perfilação da Expressão Gênica/métodos , Humanos , Modelos Genéticos , Modelos Estatísticos , Neoplasias/metabolismo
12.
Cancer Res ; 80(12): 2651-2662, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32291318

RESUMO

Ceramide-induced endothelial cell apoptosis boosts intestinal stem cell radiosensitivity. However, the molecular connection between these two cellular compartments has not been clearly elucidated. Here we report that ceramide and its related enzyme acid sphingomyelinase (ASM) are secreted by irradiated endothelial cells and act as bystander factors to enhance the radiotoxicity of intestinal epithelium. Ceramide and the two isoforms of ASM were acutely secreted in the blood serum of wild-type mice after 15 Gy radiation dose, inducing a gastrointestinal syndrome. Interestingly, serum ceramide was not enhanced in irradiated ASMKO mice, which are unable to develop intestinal failure injury. Because ASM/ceramide were secreted by primary endothelial cells, their contribution was studied in intestinal epithelium dysfunction using coculture of primary endothelial cells and intestinal T84 cells. Adding exogenous ASM or ceramide enhanced epithelial cell growth arrest and death. Conversely, blocking their secretion by endothelial cells using genetic, pharmacologic, or immunologic approaches abolished intestinal T84 cell radiosensitivity. Use of enteroid models revealed ASM and ceramide-mediated deleterious mode-of-action: when ceramide reduced the number of intestinal crypt-forming enteroids without affecting their structure, ASM induced a significant decrease of enteroid growth without affecting their number. Identification of specific and different roles for ceramide and ASM secreted by irradiated endothelial cells opens new perspectives in the understanding of intestinal epithelial dysfunction after radiation and defines a new class of potential therapeutic radiomitigators. SIGNIFICANCE: This study identifies secreted ASM and ceramide as paracrine factors enhancing intestinal epithelial dysfunction, revealing a previously unknown class of mediators of radiosensitivity.


Assuntos
Ceramidas/metabolismo , Células Endoteliais/metabolismo , Mucosa Intestinal/patologia , Lesões por Radiação/patologia , Esfingomielina Fosfodiesterase/metabolismo , Animais , Efeito Espectador/efeitos da radiação , Células Cultivadas , Ceramidas/sangue , Técnicas de Cocultura , Desipramina/farmacologia , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/efeitos da radiação , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Células Epiteliais/efeitos da radiação , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos da radiação , Masculino , Camundongos , Camundongos Knockout , Comunicação Parácrina/genética , Comunicação Parácrina/efeitos da radiação , Cultura Primária de Células , RNA Interferente Pequeno/metabolismo , Lesões por Radiação/sangue , Lesões por Radiação/etiologia , Lesões por Radiação/prevenção & controle , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/genética , Esfingomielina Fosfodiesterase/antagonistas & inibidores , Esfingomielina Fosfodiesterase/sangue , Esfingomielina Fosfodiesterase/genética
13.
Biochem Biophys Res Commun ; 526(4): 857-864, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32278547

RESUMO

Ovarian cancer is diagnosed as the most deadly gynecological tumor. Ovarian cancer metastasis affects chemoresistance and confers poor patient prognosis. In present work, we intended to elucidate whether long non-coding RNAs (lncRNAs) TLR8-AS1 regulated cell metastasis and chemoresistance of ovarian cancer, and uncover the molecular mechanism of TLR8-AS1 in the modulation of ovarian cancer progression. Firstly, bioinformatics analyses identified TLR8-AS1 as a cancer-associated fibroblasts regulated lncRNA in ovarian cancer. Further experiments revealed that TLR8-AS1 augmented cell metastasis and chemoresistance of ovarian cancer in vitro and in vivo. Moreover, TLR8-AS1 upregulates TLR8 by stabilizing TLR8 mRNA, thus activating NF-κB signaling and promoting ovarian cancer metastasis and chemoresistance. Besides, TCGA data analysis suggested that TLR8-AS1 is elevated in ovarian cancer in comparison to adjacent non-cancerous tissues. High TLR8-AS1 expression levels were measured in metastatic ovarian cancer and correlated with poor patient prognosis. The clinical data supported the mechanism and biological significance of TLR8-AS1 dysregulation in ovarian cancer development. Our work demonstrates that TLR8-AS1 can be applied as a diagnostic and prognostic indicator for ovarian cancer, and maybe an alternative target for the treatment of ovarian cancer.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Estabilidade de RNA/genética , RNA Longo não Codificante/metabolismo , Receptor 8 Toll-Like/genética , Animais , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/metabolismo , Metástase Neoplásica , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Prognóstico , RNA Longo não Codificante/genética , Tolerância a Radiação/genética , Transdução de Sinais , Análise de Sobrevida , Receptor 8 Toll-Like/metabolismo , Regulação para Cima/genética
14.
Mol Carcinog ; 59(6): 651-660, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32253787

RESUMO

Postoperative radiotherapy combined with chemotherapy is a commonly used treatment for glioblastoma (GBM) but radiotherapy often fails to achieve the expected results mainly due to tumor radioresistance. In this study, we established a radioresistant subline from human glioma cell line U251 and found that Cathepsin D (CTSD), a gene closely related to the clinical malignancy and prognosis in glioma, had higher expression level in radioresistant clones than that in parental cells, and knocking down CTSD by small interfering RNA (siRNA) or its inhibitor Pepstatin-A increased the radiosensitivity. The level of autophagy was enhanced in the radioresistant GBM cells compared with its parent cells, and silencing autophagy by light chain 3 (LC3) siRNA significantly sensitized GBM cells to ionizing radiation (IR). Moreover, the protein expression level of CTSD was positively correlated with the autophagy marker LC3 II/I and negatively correlated with P62 after IR in radioresistant cells. As expected, through the combination of Western blot and immunofluorescence assays, inhibition of CTSD increased the formation of autophagosomes, while decreased the formation of autolysosomes, which indicating an attenuated autophagy level, leading to radiosensitization ultimately. Our results revealed for the first time that CTSD regulated the radiosensitivity of glioblastoma by affecting the fusion of autophagosomes and lysosomes. In significance, CTSD might be a potential molecular biomarker and a new therapeutic target in glioblastoma.


Assuntos
Autofagia , Neoplasias Encefálicas/radioterapia , Catepsina D/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Glioblastoma/radioterapia , RNA Interferente Pequeno/genética , Tolerância a Radiação/genética , Apoptose , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Catepsina D/genética , Proliferação de Células , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Prognóstico , Radiação Ionizante , Taxa de Sobrevida , Células Tumorais Cultivadas
15.
Oncogene ; 39(18): 3710-3725, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32157210

RESUMO

Radioresistance becomes the major obstacle to reduce tumor recurrence and improve prognosis in the treatment of esophageal squamous cell carcinoma (ESCC). Thus new strategies for radioresistant ESCC are urgently needed. Herein, we reported that tribbles pseudokinase 3 (TRIB3) serves as a key regulator of radioresistance in ESCC. TRIB3 is overexpressed in ESCC tissues and cell lines. High expression of TRIB3 significantly correlates with poor radiotherapy response and prognosis in ESCC patients. Upregulation of TRIB3 in ESCC cells conferred radioresistance in vitro and in vivo by interacting with TAZ thus impeding ß-TrCP-mediated TAZ ubiquitination and degradation. Conversely, silencing TRIB3 sensitized ESCC cells to ionizing radiation. More importantly, TRIB3 was significantly correlated with TAZ activation in ESCC biopsies, and patients with high expression of both TRIB3 and TAZ suffered the worst radiotherapy response and survival. Our study uncovers the critical mechanism of ESCC resistance to radiotherapy, and provides a new pharmacological opportunity for developing a mechanism-based strategy to eliminate radioresistant ESCC in clinical practice.


Assuntos
Proteínas de Ciclo Celular/genética , Carcinoma de Células Escamosas do Esôfago/radioterapia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Tolerância a Radiação/genética , Proteínas Repressoras/genética , Transativadores/genética , Animais , Intervalo Livre de Doença , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Células HEK293 , Xenoenxertos , Humanos , Masculino , Camundongos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/radioterapia , Prognóstico , Ligação Proteica/genética , Proteínas Serina-Treonina Quinases/genética , Proteólise/efeitos da radiação , Radiossensibilizantes/farmacologia , Transdução de Sinais/genética , Ubiquitinação/efeitos da radiação
16.
Oncogene ; 39(18): 3638-3649, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32157215

RESUMO

Radiation is a significant treatment for patients with head and neck cancer. Despite advances to improve treatment, many tumors acquire radiation resistance resulting in poor survival. Radiation kills cancer cells by inducing DNA double-strand breaks. Therefore, radiation resistance is enhanced by efficient repair of damaged DNA. Head and neck cancers overexpress EGFR and have a high frequency of p53 mutations, both of which enhance DNA repair. This review discusses the clinical criteria for radiation resistance in patients with head and neck cancer and summarizes how cancer cells evade radiation-mediated apoptosis by p53- and epidermal growth factor receptor (EGFR)-mediated DNA repair. In addition, we explore the role of cancer stem cells in promoting radiation resistance, and how the abscopal effect provides rationale for combination strategies with immunotherapy.


Assuntos
Tolerância a Radiação/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Proteína Supressora de Tumor p53/genética , Apoptose/efeitos da radiação , Proliferação de Células/efeitos da radiação , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Dano ao DNA/efeitos da radiação , Reparo do DNA/efeitos da radiação , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
17.
Gene ; 742: 144554, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32173539

RESUMO

The relationship between patterns of codon usage bias (CUB), the preferential usage of synonimous nucleotide triplets encoding the same amino acid, and radioresistance was investigated int he genomes of 16 taxonomically distinct radioresistant prokaryotic organisms and in a control set of 11 non-radioresistant bacteria. The radioresistant species were found to be strongly biased towards G and C in the third synonimous codon position. ENC and neutrality plots also sugest that CUB in radioresistant bacteria is mainly affected by mutational bias. Furthermore, the availability of tRNA gene copy number was analyzed and it was found that nine radioresistant species have the sam number of tRNA gene copies for each codon. This suggests that tRNA gene copies and codon bias co-evolved in a specific way in radioresistant species.


Assuntos
Bactérias/genética , Uso do Códon/efeitos da radiação , Genoma Bacteriano/efeitos da radiação , Tolerância a Radiação/genética , Seleção Genética/efeitos da radiação , Bactérias/efeitos da radiação , Mutação/efeitos da radiação , RNA de Transferência/genética
18.
Sci Rep ; 10(1): 2716, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066820

RESUMO

A growing proportion of head and neck cancers (HNC) result from HPV infection. Between HNC aetiological groups (HPV positive and HPV negative) clinical evidence demonstrates significantly better treatment response among HPV positive cancers. Cancer stem cells (CSCs) are identified in HNC tumour populations as agents of treatment resistance and a target for tumour control. This study examines dynamic responses in populations of a CSC phenotype in HNC cell lines following X-irradiation at therapeutic levels, and comparing between HPV statuses. Variations in CSC density between HPV groups showed no correlation with better clinical outcomes seen in the HPV positive status. CSC populations in HPV positive cell lines ranged from 1.9 to 4.8%, and 2.6 to 9.9% for HPV negative. Following 4 Gy X- irradiation however, HPV negative cell lines demonstrated more frequent and significantly greater escalation in CSC proportions, being 3-fold that of the HPV positive group at 72 hours post irradiation. CSC proportions of tumour populations are not fixed but subject to change in response to radiation at therapeutic dose levels. These findings imply a potential effect of aetiology on radio-responsiveness in CSCs, illustrating that clonogen treatment response may be more informative of therapy outcomes than inherent population density alone.


Assuntos
Aldeído Desidrogenase/genética , Receptores de Hialuronatos/genética , Células-Tronco Neoplásicas/efeitos da radiação , Papillomaviridae/patogenicidade , Tolerância a Radiação/genética , Idoso , Aldeído Desidrogenase/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , Contagem de Células , Linhagem Celular Tumoral , Feminino , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Receptores de Hialuronatos/imunologia , Masculino , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/patologia , Papillomaviridae/crescimento & desenvolvimento , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/radioterapia , Tolerância a Radiação/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Raios X
19.
Biochem Biophys Res Commun ; 524(4): 869-875, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32051089

RESUMO

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neuroprotective factor produced in response to endoplasmic reticulum (ER) stress induced by various stressors, but its involvement in the radioresistance of tumor cells is unknown. Here, we found that MANF is released after γ-irradiation (2 Gy and 4 Gy) of B16 melanoma cells, and its release was suppressed by 4-phenylbutyric acid, an ER stress inhibitor. MANF was not released after low-dose (1 Gy) γ-irradiation, but pretreatment of 1 Gy-irradiated cells with recombinant MANF enhanced the cellular DNA damage response and attenuated reproductive cell death. In MANF-knockdown cells, the DNA damage response and p53 activation by γ-irradiation (2 Gy) were suppressed, and reproductive cell death was increased. MANF also activated the ERK signaling pathway. Our findings raise the possibility that MANF could be a new target for overcoming radioresistance.


Assuntos
Estresse do Retículo Endoplasmático/efeitos da radiação , Retículo Endoplasmático/efeitos da radiação , Regulação Neoplásica da Expressão Gênica , Fatores de Crescimento Neural/genética , Tolerância a Radiação/genética , Animais , Linhagem Celular Tumoral , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Raios gama , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Melanoma Experimental/radioterapia , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fatores de Crescimento Neural/antagonistas & inibidores , Fatores de Crescimento Neural/metabolismo , Fenilbutiratos/farmacologia , Fosforilação , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
20.
Sci Rep ; 10(1): 2687, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-32060308

RESUMO

Radiotherapy combined with chemotherapy is the major treatment modality for human glioblastoma multiforme (GBM). GBMs eventually relapse after treatment and the average survival of GBM patients is less than two years. There is some evidence that cannabidiol (CBD) can induce cell death and increases the radiosensitivity of GBM by enhancing apoptosis. Beside initiation of death, CBD has been demonstrated as an inducer of autophagy. In the present study, we address the question whether CBD simultaneously induces a protective effect in GBM by upregulating autophagy. Addition of chloroquine that suppressed autophagic flux to 2D GBM cultures increased CBD-induced cell death, presenting proof for the protective autophagy. Blockage of autophagy upregulated radiation-induced cytotoxicity but only modestly affected the levels of cell death in CBD- or CBD/γ-irradiated 3D GBM cultures. Furthermore, CBD enhanced the pro-apoptotic activities of JNK1/2 and MAPK p38 signaling cascades while partially downregulated the pro-survival PI3K-AKT cascade, thereby changing a balance between cell death and survival. Suppression of JNK activation partially reduced CBD-induced cell death in 3D GBM cultures. In contrast, co-treatment of CBD-targeted cells with inhibitors of PI3K-AKT-NF-κB, IKK-NF-κB or JAK2-STAT3 pathways killed surviving GBM cells in both 2D and 3D cultures, potentially improving the therapeutic ratio of GBM.


Assuntos
Autofagia/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Canabidiol/farmacologia , Glioblastoma/tratamento farmacológico , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/radioterapia , Humanos , Janus Quinase 2/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Fosfatidilinositol 3-Quinases/genética , Tolerância a Radiação/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais/efeitos dos fármacos
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