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1.
Int J Oral Sci ; 12(1): 23, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32826859

RESUMO

The integrity of the basal stem cell layer is critical for epithelial homoeostasis. In this paper, we review the expression of oral mucosal stem cell markers (OM-SCMs) in oral submucous fibrosis (OSF), oral potentially malignant disorders (OPMDs) and oral squamous cell carcinoma (OSCC) to understand the role of basal cells in potentiating cancer stem cell behaviour in OSF. While the loss of basal cell clonogenicity triggers epithelial atrophy in OSF, the transition of the epithelium from atrophic to hyperplastic and eventually neoplastic involves the reactivation of basal stemness. The vacillating expression patterns of OM-SCMs confirm the role of keratins 5, 14, 19, CD44, ß1-integrin, p63, sex-determining region Y box (SOX2), octamer-binding transcription factor 4 (Oct-4), c-MYC, B-cell-specific Moloney murine leukaemia virus integration site 1 (Bmi-1) and aldehyde dehydrogenase 1 (ALDH1) in OSF, OPMDs and OSCC. The downregulation of OM-SCMs in the atrophic epithelium of OSF and their upregulation during malignant transformation are illustrated with relevant literature in this review.


Assuntos
Carcinoma de Células Escamosas/patologia , Transformação Celular Neoplásica/patologia , Neoplasias Bucais/patologia , Fibrose Oral Submucosa/patologia , Animais , Camundongos , Mucosa Bucal , Células-Tronco
2.
J Nippon Med Sch ; 87(3): 157-161, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32655092

RESUMO

Screening esophagogastroduodenoscopy of a 65-year-old man revealed a 4.7-cm polypoid in the gastric high body. Clinical and laboratory findings, including serum gastrin level (460 pg/mL) and biopsy findings, were consistent with a diagnosis of type I neuroendocrine tumor (NET). Histologically, the mass consisted of dilated tortuous glands at the surface and grade 1 NET in deeper tissue. Some hyperplastic glands exhibited a transition to adenocarcinoma, which invaded the NET, simulating a "tumor in tumor" appearance. Next-generation sequencing revealed that the adenocarcinoma component harbored a TP53 mutation, whereas the NET component showed no pathogenic mutation. To our knowledge, this unusual collision of adenocarcinoma and NET within a single gastric hyperplastic polyp has not been previously described. This case suggests that large gastric hyperplastic polyps should be carefully examined because of the possibility of underlying NET and malignant transformation of surface epithelium.


Assuntos
Adenocarcinoma/patologia , Pólipos Intestinais/patologia , Neoplasias Primárias Múltiplas/patologia , Tumores Neuroendócrinos/patologia , Neoplasias Gástricas/patologia , Idoso , Transformação Celular Neoplásica/patologia , Humanos , Masculino
4.
Toxicol Lett ; 332: 155-163, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32645460

RESUMO

Chronic exposure to arsenic increases the risk of developing a variety of human cancers including lung carcinomas. However, the exact molecular mechanism underlying arsenic carcinogenicity remains largely unknown. Autophagy is a conserved catabolic process for maintaining cellular protein homeostasis whose defects might result in accumulation of dysfunctional organelles and damaged proteins thus promoting tumorigenesis. In the present study, we found that chronic exposure of human bronchial epithelial BEAS-2B cells to sub-lethal dose of sodium arsenite led to autophagy activation and induced an epithelial-to-mesenchymal transition (EMT) to enhance cell migratory and invasive capability. The malignant transformation was mediated via activation of MEK/ERK1/2 signaling. Importantly, inhibition of autophagy in these arsenic-exposed cells by pharmacological intervention or genetic deletion further promoted the EMT and increased the generation of inflammasomes. Both autophagy inhibitor and genetic deletion of autophagy core gene Beclin-1 produced similar effects. These results may suggest the important role of autophagy in sodium arsenite-induced lung tumorigenesis which may serve as a potential target in prevention and treatment of arsenic-imposed lung cancer.


Assuntos
Arsênico/toxicidade , Autofagia/fisiologia , Brônquios/patologia , Neoplasias Brônquicas/induzido quimicamente , Neoplasias Brônquicas/patologia , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteína Beclina-1/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Inflamassomos/efeitos dos fármacos , Cicatrização/efeitos dos fármacos
5.
Adv Cancer Res ; 148: 1-26, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32723561

RESUMO

As a unique subpopulation of cancer cells, cancer stem cells (CSCs) acquire the resistance to conventional therapies and appear to be the prime cause of cancer recurrence. Like their normal counterparts, CSCs can renew themselves and generate differentiated progenies. Cancer stem cells are distinguished among heterogenous cancer cells by molecular markers and their capacity of efficiently forming new tumors composed of diverse and heterogenous cancer cells. Tumor heterogeneity can be inter- or intra-tumor, molecularly resulting from the accumulation of genetic and non-genetic alterations. Non-genetic alterations are mainly changes on epigenetic modifications of DNA and histone, and chromatin remodeling. As tumor-initiating cells and contributing to the tumor heterogeneity in the brain, glioblastoma stem cells (GSCs) attract extensive research interests. Epigenetic modifications confer on tumor cells including CSCs reversible and inheritable genomic changes and affect gene expression without alteration in DNA sequence. Here, we will review recent advances in histone demethylation, DNA methylation, RNA methylation and ubiquitination in glioblastomas and their impacts on tumorigenesis with a focus on CSCs.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Transformação Celular Neoplásica/patologia , Glioblastoma/genética , Glioblastoma/patologia , Células-Tronco Neoplásicas/patologia , Animais , Neoplasias Encefálicas/metabolismo , Transformação Celular Neoplásica/genética , Metilação de DNA , Epigênese Genética , Glioblastoma/metabolismo , Humanos , Células-Tronco Neoplásicas/metabolismo
6.
Adv Cancer Res ; 148: 171-199, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32723563

RESUMO

Cancer is a complex disease with high incidence and mortality rates. The important role played by the tumor microenvironment in regulating oncogenesis, tumor growth, and metastasis is by now well accepted in the scientific community. SPARC is known to participate in tumor-stromal interactions and impact cancer growth in ambiguous ways, which either enhance or suppress cancer aggressiveness, in a context-dependent manner. p53 transcription factor, a well-established tumor suppressor, has been reported to promote tumor growth in certain situations, such as hypoxia, thus displaying a duality in its action. Although both proteins are being tested in clinical trials, the synergistic relation between them is yet to be explored in clinical practice. In this review, we address the controversial roles of SPARC and p53 as double agents in cancer, briefly summarizing the interaction found between these two molecules and its importance in cancer.


Assuntos
Neoplasias/metabolismo , Neoplasias/patologia , Osteonectina/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Humanos , Neoplasias/genética , Osteonectina/genética , Proteína Supressora de Tumor p53/genética
7.
Braz Oral Res ; 34: e052, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32578762

RESUMO

The purpose of this study was to analyze the differential expression of DEC1 in oral normal mucosa (NM), oral leukoplakia (OLK) and oral squamous cell carcinoma (OSCC). Surgically excised specimens from patients with OLK (n = 47), OSCC (n = 30) and oral normal mucosa (n=11) were immunostained for DEC1. The expression of DEC1 protein was evaluated, and its association with the clinicopathological features was analyzed. The expression of DEC1 in NM, OLK and OSCC tissues increased in turn, and significant differences were observed among the groups (P < 0.0001). In terms of the association between DEC1 expression and epithelial dysplasia, DEC1 expression was lower in hyperkeratosis without dysplasia (H-OLK) than in OLK with moderate to severe dysplasia (S-OLK), and these differences were significant (p < 0.05). The expression of DEC1 in OSCC with OLK was significantly higher than that in OSCC without OLK (p < 0.01). Therefore, DEC1 could be a potential biomarker of malignant transformation in the carcinogenesis of OSCC, which may provide a new research direction for the transformation of oral potentially malignant disorders (OPMDs) into OSCC.


Assuntos
Carcinoma de Células Escamosas/patologia , Leucoplasia Oral/patologia , Neoplasias Bucais/patologia , Proteínas Supressoras de Tumor/análise , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Biomarcadores Tumorais/análise , Transformação Celular Neoplásica/patologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Valores de Referência , Reprodutibilidade dos Testes , Fatores de Risco , Estatísticas não Paramétricas
8.
Gene ; 754: 144839, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32504654

RESUMO

Wilms tumor is the most frequently occurring pediatric renal malignancy. Wilms tumor suppressor-1-associated protein (WTAP) is a vital component of N6-methyltransferase complex involved in tumorigenesis. However, the roles of WTAP gene single nucleotide polymorphisms (SNPs) in Wilms tumor risk have not been clarified to date. We successfully genotyped three WTAP gene SNPs using TaqMan assay in 405 Wilms tumor patients and 1197 cancer-free controls of Chinese children. Odds ratios (ORs) and 95% confidence intervals (CIs) were applied to determine the effects of WTAP gene SNPs on Wilms tumor risk. Carriers of the rs1853259 G variant are less susceptible to developing Wilms tumor, with an adjusted OR of 0.78 (AG vs. AA: 95% CI = 0.61-0.995, P = 0.046). Single locus analysis of rs9457712 G > A and rs7766006 G > T, as well as the combined analysis of risk genotypes, failed to unveil an association with Wilms tumor risk, respectively. Stratified analysis of the three SNPs and their combined risk effects showed more significant relationships with Wilms tumor risk under certain subgroups. In all, we found weak evidence of the association between WTAP gene SNPs and the risk of Wilms tumor. Further replication studies with greater sample size and different ethnicities are necessary to verify our findings.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Proteínas de Ciclo Celular/genética , Transformação Celular Neoplásica/genética , Neoplasias Renais/genética , Polimorfismo de Nucleotídeo Único , Fatores de Processamento de RNA/genética , Tumor de Wilms/genética , Estudos de Casos e Controles , Transformação Celular Neoplásica/patologia , China/epidemiologia , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Humanos , Lactente , Neoplasias Renais/epidemiologia , Neoplasias Renais/patologia , Masculino , Prognóstico , Tumor de Wilms/epidemiologia , Tumor de Wilms/patologia
9.
Nat Commun ; 11(1): 3231, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32591511

RESUMO

Genomic instability (GI) predisposes cells to malignant transformation, however the molecular mechanisms that allow for the propagation of cells with a high degree of genomic instability remain unclear. Here we report that miR-181a is able to transform fallopian tube secretory epithelial cells through the inhibition of RB1 and stimulator-of-interferon-genes (STING) to propagate cells with a high degree of GI. MiR-181a targeting of RB1 leads to profound nuclear defects and GI generating aberrant cytoplasmic DNA, however simultaneous miR-181a mediated inhibition of STING allows cells to bypass interferon mediated cell death. We also found that high miR-181a is associated with decreased IFNγ response and lymphocyte infiltration in patient tumors. DNA oncoviruses are the only known inhibitors of STING that allow for cellular transformation, thus, our findings are the first to identify a miRNA that can downregulate STING expression to suppress activation of intrinsic interferon signaling. This study introduces miR-181a as a putative biomarker and identifies the miR-181a-STING axis as a promising target for therapeutic exploitation.


Assuntos
Carcinogênese/genética , Transformação Celular Neoplásica/genética , Imunidade Inata/genética , MicroRNAs/metabolismo , Transdução de Sinais , Animais , Linhagem Celular Tumoral , Núcleo Celular/patologia , Transformação Celular Neoplásica/patologia , Citocinese , Dano ao DNA , Células Epiteliais/patologia , Tubas Uterinas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Instabilidade Genômica , Células HEK293 , Humanos , Interferons/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , MicroRNAs/genética , Mitose , Gradação de Tumores , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo
10.
Surg Clin North Am ; 100(3): 581-588, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32402302

RESUMO

This article outlines the principles behind the management of pancreatic cystic lesions. We outline what the general surgeon needs to know in managing and triaging these patients. It is our feeling that the general surgeon is often the first line of evaluation of these complex patients and a working knowledge of the different types of cysts is critical to safe care of the patient.


Assuntos
Cisto Pancreático/cirurgia , Neoplasias Pancreáticas/cirurgia , Adulto , Idoso , Transformação Celular Neoplásica/patologia , Diagnóstico Diferencial , Diagnóstico Precoce , Endossonografia , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Pâncreas/patologia , Pancreatectomia , Cisto Pancreático/diagnóstico , Cisto Pancreático/patologia , Ductos Pancreáticos/patologia , Neoplasias Intraductais Pancreáticas/diagnóstico , Neoplasias Intraductais Pancreáticas/patologia , Neoplasias Intraductais Pancreáticas/cirurgia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/patologia , Tomografia Computadorizada por Raios X
11.
J Vis Exp ; (159)2020 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-32449713

RESUMO

Cancer stem cells (CSCs) are implicated in tumor initiation, development and recurrence after treatment, and have become the center of attention of many studies in the last decades. Therefore, it is important to develop methods to investigate the role of key genes involved in cancer cell stemness. Gastric cancer (GC) is one of the most common and mortal types of cancers. Gastric cancer stem cells (GCSCs) are thought to be the root of gastric cancer relapse, metastasis and drug resistance. Understanding GCSCs biology is needed to advance the development of targeted therapies and eventually to reduce mortality among patients. In this protocol, we present an experimental design using a conditional knockdown system and an adapted sphere formation assay to study the effect of clusterin on the stemness of patient-derived GCSCs. The protocol can be easily adapted to study both in vitro and in vivo function of stemness-associated genes in different types of CSCs.


Assuntos
Transformação Celular Neoplásica/patologia , Regulação Neoplásica da Expressão Gênica/genética , Células-Tronco Neoplásicas/metabolismo , Neoplasias Gástricas/genética , Linhagem Celular Tumoral , Proliferação de Células , Humanos
12.
Nat Cell Biol ; 22(7): 779-790, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32451440

RESUMO

Tissue stem cells are the cell of origin for many malignancies. Metabolites regulate the balance between self-renewal and differentiation, but whether endogenous metabolic pathways or nutrient availability predispose stem cells towards transformation remains unknown. Here, we address this question in epidermal stem cells (EpdSCs), which are a cell of origin for squamous cell carcinoma. We find that oncogenic EpdSCs are serine auxotrophs whose growth and self-renewal require abundant exogenous serine. When extracellular serine is limited, EpdSCs activate de novo serine synthesis, which in turn stimulates α-ketoglutarate-dependent dioxygenases that remove the repressive histone modification H3K27me3 and activate differentiation programmes. Accordingly, serine starvation or enforced α-ketoglutarate production antagonizes squamous cell carcinoma growth. Conversely, blocking serine synthesis or repressing α-ketoglutarate-driven demethylation facilitates malignant progression. Together, these findings reveal that extracellular serine is a critical determinant of EpdSC fate and provide insight into how nutrient availability is integrated with stem cell fate decisions during tumour initiation.


Assuntos
Carcinoma de Células Escamosas/patologia , Transformação Celular Neoplásica/patologia , Células Epidérmicas/patologia , Ácidos Cetoglutáricos/metabolismo , Serina/metabolismo , Células-Tronco/patologia , Animais , Carcinoma de Células Escamosas/metabolismo , Diferenciação Celular , Transformação Celular Neoplásica/metabolismo , Células Cultivadas , Células Epidérmicas/metabolismo , Feminino , Humanos , Masculino , Camundongos , Células-Tronco/metabolismo
14.
Nat Commun ; 11(1): 2649, 2020 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-32461571

RESUMO

Pregnancy causes a series of cellular and molecular changes in mammary epithelial cells (MECs) of female adults. In addition, pregnancy can also modify the predisposition of rodent and human MECs to initiate oncogenesis. Here, we investigate how pregnancy reprograms enhancer chromatin in the mammary epithelium of mice and influences the transcriptional output of the oncogenic transcription factor cMYC. We find that pregnancy induces an expansion of the active cis-regulatory landscape of MECs, which influences the activation of pregnancy-related programs during re-exposure to pregnancy hormones in vivo and in vitro. Using inducible cMYC overexpression, we demonstrate that post-pregnancy MECs are resistant to the downstream molecular programs induced by cMYC, a response that blunts carcinoma initiation, but does not perturb the normal pregnancy-induced epigenomic landscape. cMYC overexpression drives post-pregnancy MECs into a senescence-like state, and perturbations of this state increase malignant phenotypic changes. Taken together, our findings provide further insight into the cell-autonomous signals in post-pregnancy MECs that underpin the regulation of gene expression, cellular activation, and resistance to malignant development.


Assuntos
Glândulas Mamárias Animais/metabolismo , Animais , Carcinogênese/genética , Transformação Celular Neoplásica/patologia , Epigênese Genética , Epigenoma , Células Epiteliais/metabolismo , Feminino , Regulação da Expressão Gênica , Glândulas Mamárias Animais/citologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Oncogenes/genética , Gravidez , Complicações na Gravidez/etiologia , Complicações na Gravidez/genética , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
15.
PLoS One ; 15(5): e0233449, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32442224

RESUMO

Follicular lymphoma (FL) is an indolent neoplasia comprising approximately 20% of lymphomas. FL is generally considered incurable, with a median survival exceeding 10 years. A subset of FL patients experiences histological transformation (HT) to a more aggressive lymphoma, resulting in markedly poorer clinical outcome, with a reduced median survival after transformation of 1-2 years. Early, reliable prediction of HT would be valuable in the clinical setting, allowing pre-emptive therapeutic intervention. We previously used proteomics to identify the glycolytic enzymes fructose-bisphosphate aldolase A (aldolase A) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as candidate predictors of FL transformation. Now, we use immunohistochemistry to evaluate expression of these enzymes in paired primary FLs from patients with (n = 41) or without subsequent HT (n = 49), to test their value as predictive biomarkers. At initial FL diagnosis, patients with subsequent HT had significantly higher expression of aldolase A and GAPDH (p<0.001 and p<0.01) compared with patients without HT. Furthermore, high expression of aldolase A and GAPDH was associated with significantly shorter transformation free survival (p = 0.018, p = 0.001). These data suggest that high expression of aldolase A and GAPDH, may indicate increased metabolic turnover, and that these enzymes may be useful biomarkers in primary FL for predicting the risk of subsequent lymphoma transformation.


Assuntos
Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Frutose-Bifosfato Aldolase/metabolismo , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/metabolismo , Glicólise , Linfoma Folicular/metabolismo , Linfoma Folicular/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Estudos de Coortes , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Prognóstico
16.
Nat Commun ; 11(1): 2682, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32472071

RESUMO

Pancreatic cancer stem cells (PaCSCs) drive pancreatic cancer tumorigenesis, chemoresistance and metastasis. While eliminating this subpopulation of cells would theoretically result in tumor eradication, PaCSCs are extremely plastic and can successfully adapt to targeted therapies. In this study, we demonstrate that PaCSCs increase expression of interferon-stimulated gene 15 (ISG15) and protein ISGylation, which are essential for maintaining their metabolic plasticity. CRISPR-mediated ISG15 genomic editing reduces overall ISGylation, impairing PaCSCs self-renewal and their in vivo tumorigenic capacity. At the molecular level, ISG15 loss results in decreased mitochondrial ISGylation concomitant with increased accumulation of dysfunctional mitochondria, reduced oxidative phosphorylation (OXPHOS) and impaired mitophagy. Importantly, disruption in mitochondrial metabolism affects PaCSC metabolic plasticity, making them susceptible to prolonged inhibition with metformin in vivo. Thus, ISGylation is critical for optimal and efficient OXPHOS by ensuring the recycling of dysfunctional mitochondria, and when absent, a dysregulation in mitophagy occurs that negatively impacts PaCSC stemness.


Assuntos
Carcinoma Ductal Pancreático/patologia , Transformação Celular Neoplásica/genética , Citocinas/metabolismo , Mitofagia/genética , Células-Tronco Neoplásicas/patologia , Neoplasias Pancreáticas/patologia , Ubiquitinas/metabolismo , Linhagem Celular , Plasticidade Celular/fisiologia , Transformação Celular Neoplásica/patologia , Citocinas/genética , Humanos , Metformina/farmacologia , Mitocôndrias/genética , Mitocôndrias/metabolismo , Fosforilação Oxidativa , Neoplasias Pancreáticas/mortalidade , Edição de RNA/genética , Ubiquitinas/genética
17.
Int J Exp Pathol ; 101(1-2): 45-54, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32436348

RESUMO

Oral cancer causes significant global mortality and has a five-year survival rate of around 64%. Poor prognosis results from late-stage diagnosis, highlighting an important need to develop better approaches to detect oral premalignant lesions (OPLs) and identify which OPLs are at highest risk of progression to oral squamous cell carcinoma (OSCC). An appropriate animal model that reflects the genetic, histologic, immunologic, molecular and gross visual features of human OSCC would aid in the development and evaluation of early detection and risk assessment strategies. Here, we present an experimental PIK3CA + 4NQO transgenic mouse model of oral carcinogenesis that combines the PIK3CA oncogene mutation with oral exposure to the chemical carcinogen 4NQO, an alternate experimental transgenic mouse model with PIK3CA as well as E6 and E7 mutations, and an existing wild-type mouse model based on oral exposure to 4NQO alone. We compare changes in dorsal and ventral tongue gross visual appearance, histologic features and molecular biomarker expression over a time course of carcinogenesis. Both transgenic models exhibit cytological and architectural features of dysplasia that mimic human disease and exhibit slightly increased staining for Ki-67, a cell proliferation marker. The PIK3CA + 4NQO model additionally exhibits consistent lymphocytic infiltration, presents with prominent dorsal and ventral tongue tumours, and develops cancer quickly relative to the other models. Thus, the PIK3CA + 4NQO model recapitulates the multistep genetic model of human oral carcinogenesis and host immune response in carcinogen-induced tongue cancer, making it a useful resource for future OSCC studies.


Assuntos
Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Mutação , Quinolonas , Carcinoma de Células Escamosas de Cabeça e Pescoço/induzido quimicamente , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Neoplasias da Língua/induzido quimicamente , Neoplasias da Língua/genética , 4-Nitroquinolina-1-Óxido , Animais , Proliferação de Células , Transformação Celular Neoplásica/patologia , Modelos Animais de Doenças , Progressão da Doença , Linfócitos/patologia , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Proteínas Oncogênicas Virais/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Fatores de Tempo , Neoplasias da Língua/patologia
18.
Nat Commun ; 11(1): 2019, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332747

RESUMO

Retinoblastoma protein (Rb) is a tumor suppressor that binds and represses E2F transcription factors. In cervical cancer cells, human papilloma virus (HPV) protein E7 binds to Rb, releasing it from E2F to promote cell cycle progression, and inducing ubiquitination of Rb. E7-mediated proteasomal degradation of Rb requires action by another protease, calpain, which cleaves Rb after Lys 810. However, it is not clear why cleavage is required for Rb degradation. Here, we report that the proteasome cannot initiate degradation efficiently on full-length Rb. Calpain cleavage exposes a region that is recognized by the proteasome, leading to rapid proteolysis of Rb. These findings identify a mechanism for regulating protein stability by controlling initiation and provide a better understanding of the molecular mechanism underlying transformation by HPV.


Assuntos
Calpaína/metabolismo , Fatores de Transcrição E2F/genética , Regulação Neoplásica da Expressão Gênica , Proteínas E7 de Papillomavirus/metabolismo , Proteínas de Ligação a Retinoblastoma/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Neoplasias do Colo do Útero/genética , Acrilatos/farmacologia , Calpaína/antagonistas & inibidores , Ciclo Celular/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Ciclopentanos/farmacologia , Fatores de Transcrição E2F/metabolismo , Feminino , Células HEK293 , Papillomavirus Humano 16/metabolismo , Papillomavirus Humano 16/patogenicidade , Humanos , Proteína NEDD8/antagonistas & inibidores , Proteína NEDD8/metabolismo , Oligopeptídeos/farmacologia , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Estabilidade Proteica/efeitos dos fármacos , Pirimidinas/farmacologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas de Ligação a Retinoblastoma/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/efeitos dos fármacos , Ubiquitinação/genética , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia
19.
Mol Carcinog ; 59(8): 886-896, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32291806

RESUMO

Inhibiting the disease progression in KRAS-driven cancers after diagnosis has been a difficult task for clinicians to manage due to the lack of effective intervention/preventive therapies. KRAS-driven cancers depend on sustained KRAS signaling. Although developing inhibitors of KRAS signaling has proven difficult in the past, the quest for identifying newer agents has not stopped. Based on studies showing terpenoids as modulators of KRAS-regulated downstream molecular pathways, we asked if this chemical family has an affinity of inhibiting KRAS protein activity. Using crystal structure as a bait in silico, we identified 20 terpenoids for their KRAS protein-binding affinity. We next carried out biological validation of in silico data by employing in situ, in vitro, patient-derived explant ex vivo, and KPC transgenic mouse models. In this report, we provide a comprehensive analysis of a lup-20(29)-en-3b-ol (lupeol) as a KRAS inhibitor. Using nucleotide exchange, isothermal titration calorimetry, differential scanning fluorimetry, and immunoprecipitation assays, we show that lupeol has the potential to reduce the guanosine diphosphate/guanosine triphosphate exchange of KRAS protein including mutant KRASG12V . Lupeol treatment inhibited the KRAS activation in KRAS-activated cell models (NIH-panel, colorectal, lung, and pancreatic intraepithelial neoplasia) and patient tumor explants ex vivo. Lupeol reduced the three-dimensional growth of KRAS-activated cells. The pharmacokinetic analysis showed the bioavailability of lupeol after consumption via oral and intraperitoneal routes in animals. Tested under prevention settings, the lupeol consumption inhibited the development of pancreatic intraepithelial neoplasia in LSL-KRASG12D/Pdx-cre mice (pancreatic ductal adenocarcinoma progression model). These data suggest that the selected members of the triterpene family (such as lupeol) could be exploited as clinical agents for preventing the disease progression in KRAS-driven cancers which however warrants further investigation.


Assuntos
Anti-Inflamatórios/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Modelos Animais de Doenças , Neoplasias Pancreáticas/tratamento farmacológico , Triterpenos Pentacíclicos/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Animais , Apoptose , Proliferação de Células , Transformação Celular Neoplásica/patologia , Progressão da Doença , Feminino , Humanos , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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