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1.
BMC Vet Res ; 20(1): 233, 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38807154

RESUMO

Canine mammary gland tumors (MGT) have a poor prognosis in intact female canines, posing a clinical challenge. This study aimed to establish novel canine mammary cancer cell lines from primary tumors and characterize their cellular and molecular features to find potential therapeutic drugs. The MGT cell lines demonstrated rapid cell proliferation and colony formation in an anchorage-independent manner. Vimentin and α-SMA levels were significantly elevated in MGT cell lines compared to normal canine kidney (MDCK) cells, while CDH1 expression was either significantly lower or not detected at all, based on quantitative real-time PCR (qRT-PCR) analysis. Functional annotation and enrichment analysis revealed that epithelial-mesenchymal transition (EMT) phenotypes and tumor-associated pathways, particularly the PI3K/Akt signaling pathway, were upregulated in MGT cells. BYL719 (Alpelisib), a PI3K inhibitor, was also examined for cytotoxicity on the MGT cell lines. The results show that BYL719 can significantly inhibit the proliferation of MGT cell lines in vitro. Overall, our findings suggest that the MGT cell lines may be valuable for future studies on the development, progression, metastasis, and management of tumors.


Assuntos
Doenças do Cão , Neoplasias Mamárias Animais , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Animais , Cães , Feminino , Linhagem Celular Tumoral , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Doenças do Cão/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/genética , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transdução de Sinais , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia
2.
J Med Internet Res ; 26: e57762, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39008834

RESUMO

BACKGROUND: Early detection of cancer and provision of appropriate treatment can increase the cancer cure rate and reduce cancer-related deaths. Early detection requires improving the cancer screening quality of each medical institution and enhancing the capabilities of health professionals through tailored education in each field. However, during the COVID-19 pandemic, regional disparities in educational infrastructure emerged, and educational accessibility was restricted. The demand for remote cancer education services to address these issues has increased, and in this study, we considered medical metaverses as a potential means of meeting these needs. In 2022, we used Metaverse Educational Center, developed for the virtual training of health professionals, to train radiologic technologists remotely in mammography positioning. OBJECTIVE: This study aims to investigate the user experience of the Metaverse Educational Center subplatform and the factors associated with the intention for continuous use by focusing on cases of using the subplatform in a remote mammography positioning training project. METHODS: We conducted a multicenter, cross-sectional survey between July and December 2022. We performed a descriptive analysis to examine the Metaverse Educational Center user experience and a logistic regression analysis to clarify factors closely related to the intention to use the subplatform continuously. In addition, a supplementary open-ended question was used to obtain feedback from users to improve Metaverse Educational Center. RESULTS: Responses from 192 Korean participants (male participants: n=16, 8.3%; female participants: n=176, 91.7%) were analyzed. Most participants were satisfied with Metaverse Educational Center (178/192, 92.7%) and wanted to continue using the subplatform in the future (157/192, 81.8%). Less than half of the participants (85/192, 44.3%) had no difficulty in wearing the device. Logistic regression analysis results showed that intention for continuous use was associated with satisfaction (adjusted odds ratio 3.542, 95% CI 1.037-12.097; P=.04), immersion (adjusted odds ratio 2.803, 95% CI 1.201-6.539; P=.02), and no difficulty in wearing the device (adjusted odds ratio 2.020, 95% CI 1.004-4.062; P=.049). However, intention for continuous use was not associated with interest (adjusted odds ratio 0.736, 95% CI 0.303-1.789; P=.50) or perceived ease of use (adjusted odds ratio 1.284, 95% CI 0.614-2.685; P=.51). According to the qualitative feedback, Metaverse Educational Center was useful in cancer education, but the experience of wearing the device and the types and qualities of the content still need to be improved. CONCLUSIONS: Our results demonstrate the positive user experience of Metaverse Educational Center by focusing on cases of using the subplatform in a remote mammography positioning training project. Our results also suggest that improving users' satisfaction and immersion and ensuring the lack of difficulty in wearing the device may enhance their intention for continuous use of the subplatform.


Assuntos
COVID-19 , Humanos , Feminino , COVID-19/prevenção & controle , Estudos Transversais , Detecção Precoce de Câncer/métodos , Detecção Precoce de Câncer/estatística & dados numéricos , Mamografia/estatística & dados numéricos , Mamografia/métodos , Masculino , Neoplasias da Mama/diagnóstico por imagem , Adulto , Educação a Distância/métodos , Pessoa de Meia-Idade , SARS-CoV-2
3.
Biochem Biophys Res Commun ; 612: 188-195, 2022 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-35567901

RESUMO

Glioblastoma (GBM) stem cells (GSCs) are responsible for GBM initiation, progression, infiltration, standard therapy resistance, and recurrence. However, the mechanisms underlying GSC invasion remain incompletely understood. Using public single-cell RNA-Seq data, we identified MAP3K1 as a master regulator of infiltrative GSCs through c-JUN signaling regulation. MAP3K1 knockdown significantly decreased GSC invasion capacity, proliferation, and stemness in vitro. Moreover, in an orthotopic xenograft model, knockdown of MAP3K1 prominently suppressed GSC infiltration along the corpus callosum and tumor progression and prolonged mouse survival. Mechanistically, MAP3K1 regulates GSC invasion through phosphorylation of downstream c-JUN at serine 63 and 73, as confirmed using the CPTAC phosphoproteome dataset. Furthermore, the c-JUN inhibitor JNK-IN-8 significantly decreased GSC invasion, proliferation, and stemness. Taken together, our study demonstrates that MAP3K1 regulates GSC invasion and tumor progression via activation of c-JUN signaling and indicates that the MAP3K1/c-JUN signaling axis is a therapeutic target for infiltrative GBM.


Assuntos
Neoplasias Encefálicas , Glioblastoma , MAP Quinase Quinase Quinase 1 , Animais , Benzamidas , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Glioblastoma/patologia , Humanos , Camundongos , Células-Tronco Neoplásicas/patologia , Piridinas , Pirimidinas
4.
J Health Commun ; 27(3): 152-163, 2022 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-35506487

RESUMO

One possible way of enhancing the effectiveness of health narratives is by using tailoring. However, evidence of the effectiveness of narrative tailoring is mixed. Some studies have found tailoring to be effective, while others have found no difference between tailored and non-tailored stories. One explanation for these mixed results is that much of the previous research in this area has focused on purely demographic factors. This study aimed to determine whether or not adding theoretically derived tailoring dimensions provides benefits above and beyond demographic tailoring. Participants (N = 812, aged 18-26) were assigned to either a facts only control condition, a non-tailored narrative, a demographically tailored narrative, or a demographically and theoretically tailored narrative. Across all conditions, the stimuli focused on the benefits of the HPV vaccine. Results found that the narrative conditions outperformed the control, but there was no significant difference between tailoring conditions on vaccination expectations, narrative transportation, identification, or perceived personalization. Further analysis showed that perceived personalization and narrative transportation predicted vaccination expectations across all narrative conditions.


Assuntos
Comunicação em Saúde , Vacinas contra Papillomavirus , Humanos , Narração , Vacinas contra Papillomavirus/uso terapêutico , Vacinação
5.
J Med Internet Res ; 24(11): e39501, 2022 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-36449344

RESUMO

BACKGROUND: Mindfulness has emerged as a promising approach toward improving mental health. Interest in mindfulness mobile app services has also increased in recent years. Understanding the determinants of mindfulness behavior is essential to predict people's utilization of mindfulness mobile apps and beneficial for developing and implementing relevant intervention strategies. Nevertheless, little has been done to determine the predictors of mindfulness behavior. OBJECTIVE: This study investigates the association between the Big Five personality traits and the Theory of Planned Behavior (TPB) variables in the context of using mindfulness mobile apps to explore the potential indirect effects of conscientiousness and neuroticism on people's behavioral intention for mindfulness, mediated by their attitude toward mindfulness, subjective norm about mindfulness, and perceived behavior control over mindfulness. METHODS: The authors conducted an online, cross-sectional survey in December 2021. Structural equation modeling was conducted to evaluate the overall model fit and test possible linkages among conscientiousness, neuroticism, attitude toward mindfulness, subjective norm about mindfulness, perceived behavior control over mindfulness, and behavioral intention for mindfulness. Bootstrapping mediation analyses were also conducted to test the potential mediating effect in the model. RESULTS: A total of 297 Korean participants' responses (153 males and 144 females) were analyzed. The proposed model had a good fit. Conscientiousness was correlated with attitude toward mindfulness (ß=.384, P<.001), subjective norm about mindfulness (ß=.249, P<.001), and perceived behavior control over mindfulness (ß=.443, P<.001). Neuroticism was not correlated with attitude toward mindfulness (ß=-.072, P=.28), but was correlated with subjective norm about mindfulness (ß=.217, P=.003) and perceived behavior control over mindfulness (ß=-.235, P<.001). Attitude toward mindfulness (ß=.508, P<.001), subjective norm about mindfulness (ß=.132, P=.01), and perceived behavior control over mindfulness (ß=.540, P<.001) were separately correlated with behavioral intention for mindfulness. Conscientiousness was not directly correlated with behavioral intention for mindfulness (ß=-.082, P=.27), whereas neuroticism was directly correlated with behavioral intention for mindfulness (ß=.194, P=.001). Conscientiousness was indirectly linked with behavioral intention for mindfulness through attitude toward mindfulness (B=0.171, 95% CI 0.103-0.251) and perceived behavior control over mindfulness (B=0.198, 95% CI 0.132-0.273) but not through subjective norm about mindfulness (B=0.023, 95% CI -0.002 to 0.060). Neuroticism was indirectly linked with behavioral intention for mindfulness via perceived behavior control over mindfulness (B=-0.138, 95% CI -0.197 to -0.088) but not via subjective norm about mindfulness (B=0.021, 95% CI -0.002 to 0.059). CONCLUSIONS: The results show that the integration of the Big Five personality traits and TPB constructs is useful in predicting the use of mindfulness mobile apps. Focusing on conscientiousness and neuroticism in developing information dissemination and implementation strategies for enhancing mindfulness behavior using mobile apps may lead to the successful promotion of mindfulness mobile apps and adherence to mindfulness techniques.


Assuntos
Atenção Plena , Aplicativos Móveis , Feminino , Masculino , Humanos , Estudos Transversais , Intenção , Personalidade
6.
Int J Mol Sci ; 23(23)2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36499416

RESUMO

SMILE (small heterodimer partner-interacting leucine zipper protein) is a transcriptional corepressor that potently regulates various cellular processes such as metabolism and growth in numerous tissues. However, its regulatory role in skin tissue remains uncharacterized. Here, we demonstrated that SMILE expression markedly decreased in human melanoma biopsy specimens and was inversely correlated with that of microphthalmia-associated transcription factor (MITF). During melanogenesis, α-melanocyte-stimulating hormone (α-MSH) induction of MITF was mediated by a decrease in SMILE expression in B16F10 mouse melanoma cells. Mechanistically, SMILE was regulated by α-MSH/cAMP/protein kinase A signaling and suppressed MITF promoter activity via corepressing transcriptional activity of the cAMP response element-binding protein. Moreover, SMILE overexpression significantly reduced α-MSH-induced MITF and melanogenic genes, thereby inhibiting melanin production in melanocytes. Conversely, SMILE inhibition increased the transcription of melanogenic genes and melanin contents. These results indicate that SMILE is a downstream effector of cAMP-mediated signaling and is a critical factor in the regulation of melanogenic transcription; in addition, they suggest a potential role of SMILE as a corepressor in skin pigmentation.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica , Melanoma , Fator de Transcrição Associado à Microftalmia , Animais , Humanos , Camundongos , alfa-MSH/farmacologia , alfa-MSH/metabolismo , Linhagem Celular Tumoral , AMP Cíclico/metabolismo , Melaninas/metabolismo , Melanócitos/metabolismo , Melanoma/metabolismo , Fator de Transcrição Associado à Microftalmia/genética , Fator de Transcrição Associado à Microftalmia/metabolismo , Monofenol Mono-Oxigenase/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/genética
7.
Int J Med Sci ; 18(3): 706-714, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33437205

RESUMO

Objective: Fhit gene is known as a genome "caretaker" and frequently inactivated by deletion or hypermethylation on the promoter in several cancers. In spite of several lines of evidence, the exact mechanism underlying Fhit-induced biology is relatively less studied. This study will focus the role of Fhit in regulating Lin28 and microRNAs (miRNAs) loop. Material and Methods: To this end, we employed Fhit overexpressing isogenic cell lines to conduct miRNA nanostring array, and differentially expressed miRNAs were identified. Using real-time PCR and Western blot analysis, expression levels of Lin28b or miRNAs were investigated in response to the overexpression of Fhit gene in H1299 lung cancer cells. Results: A series of in vitro including gene nanostring analyses revealed that Lin28B protein was induced by Fhit gene overexpression, which consequently suppressed Let-7 miRNAs. Also, we found that miRNAs in miR-17/92 clusters are redundantly increased and there is an inverse correlation between Let-7 and miR-17/92 clusters in Fhit-expressing cells. Also, a series of in vitro experiments suggests that ELF-1- and/or STAT1-dependent Lin28b regulation is responsible for Let-7 induction in Fhit-expressing cancer cells. Conclusions: Based on the same experimental system proving that Fhit gene has a robust role in suppressing tumor progression and epithelial-mesenchymal transition, our data show that Fhit mediates the negative feedback between Lin28/Let-7 axis and miR-17/-92 miRNA although the physiological relevance of current interesting observation should be further investigated.


Assuntos
Hidrolases Anidrido Ácido/genética , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Proteínas de Neoplasias/genética , Neoplasias/genética , Hidrolases Anidrido Ácido/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Retroalimentação Fisiológica , Humanos , Perda de Heterozigosidade , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/patologia , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
8.
Int J Neurosci ; 131(1): 7-14, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32075484

RESUMO

Aim: Glioma stem cells (GSCs) have been shown to contribute to tumor development and recurrence, therapeutic resistance, and cellular heterogeneity of glioblastoma multiforme (GBM). Recently, it has been reported that GSCs lose their self-renewal ability and tumorigenic potential upon differentiation. In this study, we identified Regulatory Factor X4 (RFX4) gene to regulate GSCs' survival and self-renewal activity in the GBM patients samples.Materials and methods: We utilized public datasets from the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Ivy Glioblastoma Atlas Project, and The Human Protein Atlas to screen candidate genes which are associated with the development of GBM and poor patients survival. Small hairpin RNA (shRNA) lentivirus was applied to knockdown RFX4 gene in GSCs.Results: We found that RFX4 mRNA expression among the RFX family was particularly reduced during GSC differentiation. RT-qPCR analysis revealed significant downregulation of RFX4 and stem cell markers (CD15 and CD133) mRNA expressions in primary human GBM-derived GSCs cultured under serum condition. Consistently, GSCs showed significantly elevated RFX4 mRNA expression levels compared to normal astrocytes, NHA, whereas glioma cells did not. Furthermore, analysis of the TCGA data set revealed that RFX4 is highly expressed in GBM, and contributes to the lowering of patient survival. Depletion of RFX4 using shRNA lentivirus in patient GBM-derived GSCs decreased neurosphere formation and cell viability.Conclusion: These results suggest that RFX4 is a potential risk factor for maintaining the stemness of GSCs and making glioma more malignant, and thus, could be a promising target of GBM treatment.


Assuntos
Biomarcadores Tumorais/biossíntese , Neoplasias Encefálicas/metabolismo , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Glioblastoma/metabolismo , Fatores de Transcrição de Fator Regulador X/biossíntese , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Prognóstico , Fatores de Transcrição de Fator Regulador X/genética
9.
Molecules ; 26(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203232

RESUMO

Colorectal cancer is one of the life-threatening ailments causing high mortality and morbidity worldwide. Despite the innovation in medical genetics, the prognosis for metastatic colorectal cancer in patients remains unsatisfactory. Recently, lichens have attracted the attention of researchers in the search for targets to fight against cancer. Lichens are considered mines of thousands of metabolites. Researchers have reported that lichen-derived metabolites demonstrated biological effects, such as anticancer, antiviral, anti-inflammatory, antibacterial, analgesic, antipyretic, antiproliferative, and cytotoxic, on various cell lines. However, the exploration of the biological activities of lichens' metabolites is limited. Thus, the main objective of our study was to evaluate the anticancer effect of secondary metabolites isolated from lichen (Usnea barbata 2017-KL-10) on the human colorectal cancer cell line HCT116. In this study, 2OCAA exhibited concentration-dependent anticancer activities by suppressing antiapoptotic genes, such as MCL-1, and inducing apoptotic genes, such as BAX, TP53, and CDKN1A(p21). Moreover, 2OCAA inhibited the migration and invasion of colorectal cancer cells in a concentration-dependent manner. Taken together, these data suggest that 2OCAA is a better therapeutic candidate for colorectal cancer.


Assuntos
Antineoplásicos , Apoptose/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Triterpenos , Usnea/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias Colorretais/metabolismo , Células HCT116 , Humanos , Triterpenos/química , Triterpenos/farmacologia
10.
Health Commun ; 35(14): 1800-1810, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-31496288

RESUMO

According to the influence of presumed influence (IPI) hypothesis, people's presumption of media effects tend to impact their willingness to engage in unhealthy behaviors (e.g., smoking) by shaping the normative perception of such behaviors. By applying the IPI hypothesis to media content for health promotion, this study explores how presumed media influence promotes health prevention behaviors in college students. Moreover, this study adopts three health behaviors to test the IPI processing mechanisms across different types of prevention behaviors (i.e., ambiguity and privacy). The results show that one's perceived influence of health promotion media content on others promotes one's own intentions to engage in healthy behaviors of safe sex, diet and nutrition, and skin cancer prevention. The findings also indicate that descriptive norms play various roles depending on the types of behavior. We discuss the IPI hypothesis as a persuasive strategy for health campaigns using mass media.


Assuntos
Comportamentos Relacionados com a Saúde , Promoção da Saúde , Humanos , Intenção , Meios de Comunicação de Massa , Estudantes
11.
BMC Biotechnol ; 19(1): 1, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30606176

RESUMO

BACKGROUND: Genetic engineering technology such as clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system provides a powerful tool for developing disease models and determining gene functions. Recent interests in canine cancer models have highlighted the necessity of developing genetic engineering tools for dogs. In this study, we attempted to generate optimized CRISPR/Cas9 system to target canine tumor protein 53 (TP53), one of the most crucial tumor suppressor genes, to establish TP53 knockout canine cells for canine cancer research. RESULTS: We constructed CRISPR/Cas9 vectors using each of three TP53 gene-targeting guide RNAs (gRNAs) with minimal off-target potential. After transfection, we obtained several clones of TP53 knockout cells containing "indel" mutations in the targeted locus which had infinite cellular life span, resistance to genotoxicity, and unstable genomic status in contrast to normal cells. Of the established TP53 knockout cells, TP53KO#30 cells targeted by TP53 gRNA #30 showed non-cancerous phenotypes without oncogenic activation both in vitro and in vivo. More importantly, no off-target alteration was detected in TP53KO#30 cells. We also tested the developmental capacity of TP53 knockout cells after application of the somatic cell nuclear transfer technique. CONCLUSIONS: Our results indicated that TP53 in canine cells was effectively and specifically targeted by our CRISPR/Cas9 system. Thus, we suggest our CRISPR/Cas9-derived canine TP53 knockout cells as a useful platform to reveal novel oncogenic functions and effects of developing anti-cancer therapeutics.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes/métodos , Técnicas de Inativação de Genes/métodos , Genes p53 , Neoplasias/genética , Neoplasias/veterinária , Animais , Animais Geneticamente Modificados , Cães , Fibroblastos/fisiologia , Masculino , Neoplasias/prevenção & controle
12.
J Pineal Res ; 66(3): e12556, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30648757

RESUMO

Glioblastoma (GBM) is the most aggressive malignant glioma and most lethal form of human brain cancer (Clin J Oncol Nurs. 2016;20:S2). GBM is also one of the most expensive and difficult cancers to treat by the surgical resection, local radiotherapy, and temozolomide (TMZ) and still remains an incurable disease. Oncomine platform analysis and Gene Expression Profiling Interactive Analysis (GEPIA) show that the expression of transcription factor EB (TFEB) was significantly increased in GBMs and in GBM patients above stage IV. TFEB requires the oligomerization and localization to regulate transcription in the nucleus. Also, the expression and oligomerization of TFEB proteins contribute to the resistance of GBM cells to conventional chemotherapeutic agents such as TMZ. Thus, we investigated whether the combination of vorinostat and melatonin could overcome the effects of TFEB and induce apoptosis in GBM cells and glioma cancer stem cells (GSCs). The downregulation of TFEB and oligomerization by vorinostat and melatonin increased the expression of apoptosis-related genes and activated the apoptotic cell death process. Significantly, the inhibition of TFEB expression dramatically decreased GSC tumor-sphere formation and size. The inhibitory effect of co-treatment resulted in decreased proliferation of GSCs and induced the expression of cleaved PARP and p-γH2AX. Taken together, our results definitely demonstrate that TFEB expression contributes to enhanced resistance of GBMs to chemotherapy and that vorinostat- and melatonin-activated apoptosis signaling in GBM cells by inhibiting TFEB expression and oligomerization, suggesting that co-treatment of vorinostat and melatonin may be an effective therapeutic strategy for human brain cancers.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Melatonina/farmacologia , Camundongos , Camundongos Nus , Polimerização/efeitos dos fármacos , Vorinostat/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Biochem Biophys Res Commun ; 496(4): 1013-1018, 2018 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-28216164

RESUMO

Glioma stem-like cells (GSCs) contribute to tumor initiation, progression, and therapeutic resistance, but their cellular origin remains largely unknown. Here, using a stem/progenitor cell-fate tracking reporter system in which eGFP is expressed by promoter of OCT4 that is activated in stem/progenitor cells, we demonstrate that eGFP-negative glioma cells (GCs) became eGFP-positive-GCs in both in vitro cultures and in vivo xenografts. These eGFP-positive-GCs exhibited GSC features and primarily localized to the perivascular region in tumor xenografts, similar to the existence of OCT4-expressing GCs in the perivascular region of human glioblastoma specimens. Angiocrine factors, including nitric oxide (NO), converted eGFP-negative-GCs into eGFP-positive-GCs. Mechanistically, NO signaling conferred GSC features to GCs by increasing OCT4 and NOTCH signaling via ID4. NO signaling blockade and a suicide gene induction prevented tumorigenicity with a decrease in eGFP-positive-GCs in the perivascular region. Taken together, our results reveal the molecular mechanism underlying GSCs generation by cancer cell dedifferentiation.


Assuntos
Proteínas Angiogênicas/metabolismo , Desdiferenciação Celular , Glioma/metabolismo , Glioma/patologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Humanos , Camundongos , Camundongos Nus , Neovascularização Patológica
14.
Stem Cells ; 34(8): 2026-39, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27145382

RESUMO

Shifting the balance away from tumor-mediated immune suppression toward tumor immune rejection is the conceptual foundation for a variety of immunotherapy efforts currently being tested. These efforts largely focus on activating antitumor immune responses but are confounded by multiple immune cell populations, including myeloid-derived suppressor cells (MDSCs), which serve to suppress immune system function. We have identified immune-suppressive MDSCs in the brains of GBM patients and found that they were in close proximity to self-renewing cancer stem cells (CSCs). MDSCs were selectively depleted using 5-flurouracil (5-FU) in a low-dose administration paradigm, which resulted in prolonged survival in a syngeneic mouse model of glioma. In coculture studies, patient-derived CSCs but not nonstem tumor cells selectively drove MDSC-mediated immune suppression. A cytokine screen revealed that CSCs secreted multiple factors that promoted this activity, including macrophage migration inhibitory factor (MIF), which was produced at high levels by CSCs. Addition of MIF increased production of the immune-suppressive enzyme arginase-1 in MDSCs in a CXCR2-dependent manner, whereas blocking MIF reduced arginase-1 production. Similarly to 5-FU, targeting tumor-derived MIF conferred a survival advantage to tumor-bearing animals and increased the cytotoxic T cell response within the tumor. Importantly, tumor cell proliferation, survival, and self-renewal were not impacted by MIF reduction, demonstrating that MIF is primarily an indirect promoter of GBM progression, working to suppress immune rejection by activating and protecting immune suppressive MDSCs within the GBM tumor microenvironment. Stem Cells 2016;34:2026-2039.


Assuntos
Neoplasias Encefálicas/imunologia , Glioblastoma/imunologia , Evasão da Resposta Imune , Fatores Inibidores da Migração de Macrófagos/metabolismo , Células Supressoras Mieloides/metabolismo , Células-Tronco Neoplásicas/metabolismo , Animais , Arginase/metabolismo , Neoplasias Encefálicas/patologia , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Feminino , Glioblastoma/patologia , Humanos , Evasão da Resposta Imune/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Nus , Células Supressoras Mieloides/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Microambiente Tumoral/efeitos dos fármacos
15.
Proc Natl Acad Sci U S A ; 111(11): 4173-8, 2014 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-24594601

RESUMO

The mechanism by which the 8q24 MYC enhancer region, including cancer-associated variant rs6983267, increases cancer risk is unknown due to the lack of protein-coding genes at 8q24.21. Here we report the identification of long noncoding RNAs named cancer-associated region long noncoding RNAs (CARLos) in the 8q24 region. The expression of one of the long noncoding RNAs, CARLo-5, is significantly correlated with the rs6983267 allele associated with increased cancer susceptibility. We also found the MYC enhancer region physically interacts with the active regulatory region of the CARLo-5 promoter, suggesting long-range interaction of MYC enhancer with the CARLo-5 promoter regulates CARLo-5 expression. Finally, we demonstrate that CARLo-5 has a function in cell-cycle regulation and tumor development. Overall, our data provide a key of the mystery of the 8q24 gene desert.


Assuntos
Cromossomos Humanos Par 8/genética , Regulação Neoplásica da Expressão Gênica/genética , Predisposição Genética para Doença/genética , Neoplasias/genética , RNA Longo não Codificante/genética , Sequência de Bases , Linhagem Celular Tumoral , Elementos Facilitadores Genéticos/genética , Citometria de Fluxo , Humanos , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA
16.
Nano Lett ; 16(9): 5326-32, 2016 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-27420544

RESUMO

Enhanced glioma-stem-cell (GSC) motility and therapy resistance are considered to play key roles in tumor cell dissemination and recurrence. As such, a better understanding of the mechanisms by which these cells disseminate and withstand therapy could lead to more efficacious treatments. Here, we introduce a novel micro-/nanotechnology-enabled chip platform for performing live-cell interrogation of patient-derived GSCs with single-clone resolution. On-chip analysis revealed marked intertumoral differences (>10-fold) in single-clone motility profiles between two populations of GSCs, which correlated well with results from tumor-xenograft experiments and gene-expression analyses. Further chip-based examination of the more-aggressive GSC population revealed pronounced interclonal variations in motility capabilities (up to ∼4-fold) as well as gene-expression profiles at the single-cell level. Chip-supported therapy resistance studies with a chemotherapeutic agent (i.e., temozolomide) and an oligo RNA (anti-miR363) revealed a subpopulation of CD44-high GSCs with strong antiapoptotic behavior as well as enhanced motility capabilities. The living-cell-interrogation chip platform described herein enables thorough and large-scale live monitoring of heterogeneous cancer-cell populations with single-cell resolution, which is not achievable by any other existing technology and thus has the potential to provide new insights into the cellular and molecular mechanisms modulating glioma-stem-cell dissemination and therapy resistance.


Assuntos
Neoplasias Encefálicas/patologia , Movimento Celular , Glioblastoma/patologia , Células-Tronco Neoplásicas/citologia , Animais , Apoptose , Humanos , Camundongos , Células Tumorais Cultivadas
17.
Hepatology ; 61(6): 1978-97, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25627085

RESUMO

UNLABELLED: Tumor metastasis involves circulating and tumor-initiating capacities of metastatic cancer cells. Epithelial-mesenchymal transition (EMT) is related to self-renewal capacity and circulating tumor cell (CTC) characteristics for tumor metastasis. Although tumor metastasis is a life-threatening, complicated process that occurs through circulation of tumor cells, mechanistic aspects of self-renewal and circulating capacities have been largely unknown. Hepatic transmembrane 4 L six family member 5 (TM4SF5) promotes EMT for malignant growth and migration, so it was rationalized that TM4SF5, as a hepatocellular carcinoma (HCC) biomarker, might be important for metastatic potential. Here, self-renewal capacity by TM4SF5 was mechanistically explored using hepatocarcinoma cells with or without TM4SF5 expression, and we explored whether they became CTCs using mouse liver-orthotopic model systems. We found that TM4SF5-dependent sphere growth correlated with CD24(-) , aldehyde dehydrogenase (ALDH) activity, as well as a physical association between CD44 and TM4SF5. Interaction between TM4SF5 and CD44 was through their extracellular domains with N-glycosylation modifications. TM4SF5/CD44 interaction activated proto-oncogene tyrosine-protein kinase Src (c-Src)/signal transducer and activator of transcription 3 (STAT3)/Twist-related protein 1 (Twist1)/B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi1) signaling for spheroid formation, whereas disturbing the interaction, expression, or activity of any component in this signaling pathway inhibited spheroid formation. In serial xenografts using 200∼5,000 cells per injection, TM4SF5-positive tumors exhibited subpopulations with locally increased CD44 expressions, supporting for tumor cell differentiation. TM4SF5-positive, but not TM4SF5- or CD44-knocked-down, cells were identified circulating in blood 4-6 weeks after orthotopic liver injection using in vivo laser scanning endomicroscopy. Anti-TM4SF5 reagent blocked their metastasis to distal intestinal organs. CONCLUSION: TM4SF5 promotes self-renewal and CTC properties supported by TM4SF5(+) /CD44(+(TM4SF5-bound)) /ALDH(+) /CD24(-) markers during HCC metastasis.


Assuntos
Carcinoma Hepatocelular/metabolismo , Receptores de Hialuronatos/metabolismo , Neoplasias Hepáticas Experimentais/metabolismo , Proteínas de Membrana/metabolismo , Células Neoplásicas Circulantes/metabolismo , Animais , Proteína Tirosina Quinase CSK , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Complexo Repressor Polycomb 1/metabolismo , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Esferoides Celulares , Proteína 1 Relacionada a Twist/metabolismo , Quinases da Família src/metabolismo
18.
Tumour Biol ; 37(2): 2473-80, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26383528

RESUMO

High-grade gliomas are considered the most malignant of brain tumors and have a poor prognosis. In a previous study, we showed that LIM domain only 2 (LMO2) regulates glioma stem cell properties and tumor angiogenesis and gave rise to highly invasive glioma xenografts. Glioma invasion in the surrounding parenchymal tissues is a major hurdle with respect to eliminating glioma by surgery. Invasive glioma cells are considered one of the main culprits for the recurrence of tumors after therapies. In the current study, we focused on determining the molecular mechanism(s) by which LMO2 regulates glioma cell migration and invasion. Forced expression of LMO2 in human U87MG glioma cells led to glioma invasion, as determined by in vivo xenograft assays and enhanced in vitro migration and invasion. LMO2 was associated with increased levels of cytosolic p27(Kip1) protein. LMO2 possibly induced the stabilization and augmented interactions between p27(Kip1) and RhoA. We knocked down the expression of p27(Kip1), which led to a decrease in LMO2-driven glioma cell migration and invasion. Taken together, our findings indicate that LMO2 promotes glioma cell migration and invasion by increasing the levels of cytosolic p27(Kip1).


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Movimento Celular/fisiologia , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Citosol/metabolismo , Glioma/metabolismo , Glioma/patologia , Proteínas com Domínio LIM/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular , Linhagem Celular Tumoral , Citosol/patologia , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Proteína rhoA de Ligação ao GTP/metabolismo
19.
Proc Natl Acad Sci U S A ; 110(21): 8644-9, 2013 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-23650391

RESUMO

Tumor heterogeneity of high-grade glioma (HGG) is recognized by four clinically relevant subtypes based on core gene signatures. However, molecular signaling in glioma stem cells (GSCs) in individual HGG subtypes is poorly characterized. Here we identified and characterized two mutually exclusive GSC subtypes with distinct dysregulated signaling pathways. Analysis of mRNA profiles distinguished proneural (PN) from mesenchymal (Mes) GSCs and revealed a pronounced correlation with the corresponding PN or Mes HGGs. Mes GSCs displayed more aggressive phenotypes in vitro and as intracranial xenografts in mice. Further, Mes GSCs were markedly resistant to radiation compared with PN GSCs. The glycolytic pathway, comprising aldehyde dehydrogenase (ALDH) family genes and in particular ALDH1A3, were enriched in Mes GSCs. Glycolytic activity and ALDH activity were significantly elevated in Mes GSCs but not in PN GSCs. Expression of ALDH1A3 was also increased in clinical HGG compared with low-grade glioma or normal brain tissue. Moreover, inhibition of ALDH1A3 attenuated the growth of Mes but not PN GSCs. Last, radiation treatment of PN GSCs up-regulated Mes-associated markers and down-regulated PN-associated markers, whereas inhibition of ALDH1A3 attenuated an irradiation-induced gain of Mes identity in PN GSCs. Taken together, our data suggest that two subtypes of GSCs, harboring distinct metabolic signaling pathways, represent intertumoral glioma heterogeneity and highlight previously unidentified roles of ALDH1A3-associated signaling that promotes aberrant proliferation of Mes HGGs and GSCs. Inhibition of ALDH1A3-mediated pathways therefore might provide a promising therapeutic approach for a subset of HGGs with the Mes signature.


Assuntos
Aldeído Desidrogenase/biossíntese , Glioma/enzimologia , Glicólise , Células-Tronco Mesenquimais/enzimologia , Proteínas de Neoplasias/biossíntese , Células-Tronco Neoplásicas/enzimologia , Transdução de Sinais , Aldeído Desidrogenase/genética , Aldeído Oxirredutases , Animais , Proliferação de Células , Feminino , Regulação Enzimológica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Glioma/patologia , Humanos , Masculino , Células-Tronco Mesenquimais/patologia , Camundongos , Proteínas de Neoplasias/genética , Transplante de Neoplasias , Células-Tronco Neoplásicas/patologia , Transplante Heterólogo , Células Tumorais Cultivadas
20.
Tumour Biol ; 36(7): 5561-9, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25680411

RESUMO

Interferon regulatory factor 7 (IRF7) is the master transcription factor that plays a pivotal role in the transcriptional activation of type I interferon genes in the inflammatory response. Our previous study revealed that IRF7 is an important regulator of tumor progression via the expression of inflammatory cytokines in glioma. Here, we report that IRF7 promotes glioma invasion and confers resistance to both chemotherapy and radiotherapy by inhibiting expression of argonaute 2 (AGO2), a regulator of microRNA biogenesis. We found that IRF7 and AGO2 expression levels were negatively correlated in patients with glioblastoma multiforme. Ectopic IRF7 expression led to a reduction in AGO2 expression, while depletion of IRF7 resulted in increased AGO2 expression in the LN-229 glioma cell line. In an in vitro invasion assay, IRF7 overexpression enhanced glioma cell invasion. Furthermore, reconstitution of AGO2 expression in IRF7-overexpressing cells led to decreased cell invasion, whereas the reduced invasion due to IRF7 depletion was rescued by AGO2 depletion. In addition, IRF7 induced chemoresistance and radioresistance of glioma cells by diminishing AGO2 expression. Finally, AGO2 depletion alone was sufficient to accelerate glioma cell invasion in vitro and in vivo, indicating that AGO2 regulates cancer cell invasion. Taken together, our results indicate that IRF7 promotes glioma cell invasion and both chemoresistance and radioresistance through AGO2 inhibition.


Assuntos
Proteínas Argonautas/biossíntese , Neoplasias Encefálicas/genética , Glioma/genética , Fator Regulador 7 de Interferon/biossíntese , Proteínas Argonautas/antagonistas & inibidores , Proteínas Argonautas/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/efeitos da radiação , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Glioma/tratamento farmacológico , Glioma/patologia , Glioma/radioterapia , Humanos , Fator Regulador 7 de Interferon/genética , MicroRNAs/genética , Invasividade Neoplásica/genética , Tolerância a Radiação/genética
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