Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.580
Filtrar
1.
Medicine (Baltimore) ; 99(16): e19828, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32312003

RESUMO

BACKGROUND: The methylation status of the adenomatous polyposis coli (APC) promoter has been shown to be associated with the occurrence of gastric cancer, but this finding remains controversial. The aim of this study was to investigate the relationship between methylation of the APC gene promoter and gastric cancer. METHODS: We searched the Web of Science, EMBASE, Medline, and Cochrane Central Register of Controlled Trials (CENTRAL) databases from the date of creation until August 1, 2019. According to the inclusion criteria, the relationship between the methylation status of the APC gene promoter and gastric cancer was investigated. The incidence of APC promoter methylation in the tissues or blood of patients with and without gastric cancer was compared. The results are expressed as the odds ratio (OR) and 95% confidence interval (CI). The pooled OR of each study was estimated using a fixed effects model or a random effects model to generate forest plots. We further validated the results using the MethHC database. RESULTS: Eight studies (985 samples) were included. Our meta-analysis showed that the incidence of APC promoter methylation in patients with gastric cancer was higher than that of patients without gastric cancer (OR = 3.86, 95% CI 1.71-8.74, P = .001). Methylation of the APC promoter is associated with the incidence of gastric cancer, and it increases the risk of gastric cancer. CONCLUSION: This study provides a new strategic direction for research on gastric cancer. Methylation of the APC promoter may be a potential biomarker for the diagnosis of gastric cancer, but the results of this work require further confirmation.


Assuntos
Biologia Computacional/métodos , Metilação de DNA/genética , Genes APC/fisiologia , Regiões Promotoras Genéticas/genética , Neoplasias Gástricas/genética , Polipose Adenomatosa do Colo/genética , Biomarcadores Tumorais/genética , Predisposição Genética para Doença , Humanos , Incidência , Fatores de Risco , Neoplasias Gástricas/sangue , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/mortalidade
2.
Toxicol Lett ; 324: 12-19, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32035981

RESUMO

APC mutation is the first event triggering colon carcinogenesis (CRC). The contribution of APC to colon mucosa DNA damage is not well characterized yet. Similarly, the role of genotoxin-producer gut microorganisms is unclear. DNA strand breaks and oxidative damage were measured in Pirc rats, mutated in Apc, with the COMET assay at age 1 (T1) and 11 months (T11), i.e. in absence and presence of colon adenomas. In Pirc colon mucosa a 2-fold increase in the mean level of DNA oxidative damage was found at T11 compared to T1. Moreover, the analysis of DNA damage distribution showed that the proportion of Pirc mucosa cells in the highest DNA damage class was increased compared to wt rats at T1 and T11 months (p < 0.05 and <0.001, respectively). The analysis of colon mucosa-associated microbiota composition showed that this result was not attributable to the presence of genotoxin-producer bacteria B. fragilis nor E. coli. However, Pirc colon mucosa was enriched in Clostridium cluster XI, harmful bacteria in the large intestine, while the wt colon mucosa was enriched in Clostridium cluster IV. This work provides an original way to investigate the interplay between Apc and gut microbiota in affecting DNA stability during CRC.


Assuntos
Colo/metabolismo , Neoplasias do Colo/etiologia , Dano ao DNA , Genes APC , Mucosa Intestinal/metabolismo , Mutação , Animais , Neoplasias do Colo/genética , Modelos Animais de Doenças , Microbioma Gastrointestinal , Ratos , Ratos Endogâmicos F344
3.
Bull Cancer ; 107(3): 346-351, 2020 Mar.
Artigo em Francês | MEDLINE | ID: mdl-31955867

RESUMO

Desmoid tumors (TDs) are derived from mesenchymal stem cells and their pathogenesis is strongly linked to the Wingless/Wnt cascade where the deregulation of ß-catenin plays a major role. A mutation of the CTNNB1 encoding ß-catenin is found in the majority of sporadic TD cases and constitutional mutations of APC have been described in heritable forms in patients with familial adenomatous polyposis (FAP). Estrogens could also play a role in pathogenesis and this is the basis for the use of hormone therapy. Other signaling pathways have been involved in the development of TDs such as Notch, Hedgehog, JAK/STAT, PI3 Kinase/AKT and mTOR. Metalloproteases are expressed in TDs and play a role in invasiveness. TGF-ß, as a growth factor, stimulates the transcriptional activity of ß-catenin. Future studies will need to focus on better describing and understanding the immune environment of TDs. One of the major difficulties for the experimental study of TDs is the virtual absence of a preclinical model, either in vitro or in vivo. This is partly why the interactions between the different signaling pathways presented here and their consequences for the development of TDs are still poorly understood.


Assuntos
Fibromatose Agressiva/etiologia , Transdução de Sinais/fisiologia , Polipose Adenomatosa do Colo/genética , Carcinogênese , Elafina/metabolismo , Estrogênios/metabolismo , Fibromatose Agressiva/genética , Fibromatose Agressiva/metabolismo , Fibromatose Agressiva/patologia , Genes APC , Proteínas Hedgehog/metabolismo , Humanos , Janus Quinases/metabolismo , Linfotoxina-alfa/metabolismo , Metaloproteases/metabolismo , Mutação , Invasividade Neoplásica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Notch/metabolismo , Fatores de Transcrição STAT/metabolismo , Serina-Treonina Quinases TOR/metabolismo , beta Catenina/genética
4.
Bull Cancer ; 107(3): 364-370, 2020 Mar.
Artigo em Francês | MEDLINE | ID: mdl-31812283

RESUMO

After an adapted imaging, the diagnosis of a desmoid tumor (DT) is provided by a percutaneous microbiopsy, with a molecular analysis for beta-catenin or APC gene mutation. The therapeutic strategy must be decided in a specialized multidisciplinary tumor board (MTB). Surgery is no longer the first-line treatment for a DT. Except within a surgical complication, active surveillance is offered to the majority of patients, since more than half stabilize or regress after an initial progression, whether the location is peripheral or intra-abdominal. If the localization and/or volume are likely to be functional or life-threatening, medical induction therapy is discussed in MTB, before a local treatment whose potential sequelae would be definitive. Incomplete unplanned resection, recurrence, pregnancy or desmoids occurring in a polyposis context are no longer routine surgical indications. In an emergency setting (occlusion, peritonitis), it is discussed to treat only the mechanical complication and leave the DT in place, if its resection would lead to too much digestive resection, especially in patients who have already undergone colectomy for polyposis. The best indications for surgery are patients who have parietal locations with significant and documented progression, because surgery can be easily completed at the cost of an acceptable morbidity. In localizations where surgery would cause sequelae, medical treatment or other regional loco treatments are discussed in MTB.


Assuntos
Fibromatose Agressiva/cirurgia , Polipose Adenomatosa do Colo/cirurgia , Biópsia/métodos , Progressão da Doença , Feminino , Fibromatose Agressiva/complicações , Fibromatose Agressiva/patologia , Genes APC , Humanos , Obstrução Intestinal/terapia , Recidiva Local de Neoplasia , Regressão Neoplásica Espontânea , Peritonite/terapia , Complicações Pós-Operatórias/cirurgia , Gravidez , Complicações Neoplásicas na Gravidez/cirurgia , Indução de Remissão , Carga Tumoral , Conduta Expectante
5.
Bull Cancer ; 107(3): 352-358, 2020 Mar.
Artigo em Francês | MEDLINE | ID: mdl-31882269

RESUMO

About 15 % of patients with familial adenomatous polyposis "PAF" develop one or more desmoid tumors in their lifetime. These are benign mesenchymal tumors with local aggressivity but with no potential for metastases. Most of the desmoids tumors result from a sporadic genetic anomaly in the ß catenin gene. When related to familial adenomatous polyposis or "PAF", this mutation is not present, and the patients must be sent in genetic counselling. The PAF is a dominant autosomic illness related to a germinal mutation in the APC gene. Sometimes, these tumors can be the first manifestation of the illness. The diagnosis in a context of PAF can be easily done by imaging, but a pathological confirmation is needed. These tumors raise a therapeutic problem because of their heterogeneity and the absence of predictive biomarkers along illness evolution. The identification of prognostic biological and clinical factors would make easier the selection of patients requiring first-line treatment, as spontaneous remissions have also been observed in patients with FAP whom which an active surveillance could also be a valid therapeutic option. The particularity of desmoids tumors associated to PAF lies in their predominantly intra-abdominal location and the risk of complication. In the last ten years, surgery has largely given way to conservative treatments such as chemotherapy and more recently to tyrosine kinase inhibitors that have shown their efficacy with a significant improvement in progression-free survival of patients.


Assuntos
Fibromatose Agressiva/genética , Síndrome de Gardner/genética , Neoplasias Abdominais/diagnóstico , Neoplasias Abdominais/genética , Neoplasias Abdominais/terapia , Parede Abdominal , Polipose Adenomatosa do Colo/genética , Feminino , Fibromatose Agressiva/diagnóstico , Fibromatose Agressiva/terapia , Síndrome de Gardner/diagnóstico , Síndrome de Gardner/terapia , Genes APC , Humanos , Masculino , Seleção de Pacientes , Gravidez , Complicações Neoplásicas na Gravidez/etiologia , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Conduta Expectante
6.
Gastroenterology ; 158(4): 1029-1043.e10, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31857074

RESUMO

BACKGROUND & AIMS: The ß-catenin signaling pathway is one of the most commonly deregulated pathways in cancer cells. Amino acid substitutions within armadillo repeats 5 and 6 (K335, W383, and N387) of ß-catenin are found in several tumor types, including liver tumors. We investigated the mechanisms by which these substitutions increase signaling and the effects on liver carcinogenesis in mice. METHODS: Plasmids encoding tagged full-length ß-catenin (CTNNB1) or ß-catenin with the K335I or N387K substitutions, along with MET, were injected into tails of FVB/N mice. Tumor growth was monitored, and livers were collected and analyzed by histology, immunohistochemistry, and quantitative reverse-transcription polymerase chain reaction. Tagged full-length and mutant forms of ß-catenin were expressed in HEK293, HCT116, and SNU449 cells, which were analyzed by immunoblots and immunoprecipitation. A panel of ß-catenin variants and cell lines with knock-in mutations were analyzed for differences in N-terminal phosphorylation, half-life, and association with other proteins in the signaling pathway. RESULTS: Mice injected with plasmids encoding K335I or N387K ß-catenin and MET developed larger, more advanced tumors than mice injected with plasmids encoding WT ß-catenin and MET. K335I and N387K ß-catenin bound APC with lower affinity than WT ß-catenin but still interacted with scaffold protein AXIN1 and in the nucleus with TCF7L2. This interaction resulted in increased transcription of genes regulated by ß-catenin. Studies of protein structures supported the observed changes in relative binding affinities. CONCLUSION: Expression of ß-catenin with mutations in armadillo repeats 5 and 6, along with MET, promotes formation of liver tumors in mice. In contrast to N-terminal mutations in ß-catenin that directly impair its phosphorylation by GSK3 or binding to BTRC, the K335I or N387K substitutions increase signaling via reduced binding to APC. However, these mutant forms of ß-catenin still interact with the TCF family of transcription factors in the nucleus. These findings show how these amino acid substitutions increase ß-catenin signaling in cancer cells.


Assuntos
Carcinogênese/genética , Genes APC/fisiologia , Neoplasias Hepáticas/genética , Via de Sinalização Wnt/genética , beta Catenina/genética , Animais , Células HCT116 , Células HEK293 , Humanos , Fígado/metabolismo , Camundongos , Mutação , Plasmídeos/farmacologia , Proteínas Proto-Oncogênicas c-met , Transcrição Genética
7.
Neoplasia ; 21(12): 1143-1150, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31759252

RESUMO

Chemoresistance is one of the leading causes of cancer-related deaths in the United States. Triple negative breast cancer (TNBC), a subtype lacking the known breast cancer receptors used for targeted therapy, is reliant on chemotherapy as the standard of care. The Adenomatous Polyposis Coli (APC) tumor suppressor is mutated or hypermethylated in 70% of sporadic breast cancers with APC-deficient tumors resembling the TNBC subtype. Using mammary tumor cells from the ApcMin/+ mouse model crossed to the Polyoma middle T antigen (PyMT) transgenic model, we previously showed that APC loss decreased sensitivity to doxorubicin (DOX). Understanding the molecular basis for chemoresistance is essential for the advancement of novel therapeutic approaches to ultimately improve patient outcomes. Resistance can be caused via different methods, but here we focus on the DNA repair response with DOX treatment. We show that MMTV-PyMT;ApcMin/+ cells have decreased DNA damage following 24 hour DOX treatment compared to MMTV-PyMT;Apc+/+ cells. This decreased damage is first observed 24 hours post-treatment and continues throughout 24 hours of drug recovery. Activation of DNA damage response pathways (ATM, Chk1, and Chk2) are decreased at 24 hours DOX-treatment in MMTV-PyMT;ApcMin/+ cells compared to control cells, but show activation at earlier time points. Using inhibitors that target DNA damage repair kinases (ATM, ATR, and DNA-PK), we showed that ATM and DNA-PK inhibition increased DOX-induced apoptosis in the MMTV-PyMT;ApcMin/+ cells. In the current work, we demonstrated that APC loss imparts resistance through decreased DNA damage response, which can be attenuated through DNA repair inhibition, suggesting the potential clinical use of DNA repair inhibitions as combination therapy.


Assuntos
Dano ao DNA , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Deleção de Genes , Genes APC , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama , Linhagem Celular Tumoral , Proliferação de Células , Reparo do DNA/efeitos dos fármacos , Feminino , Humanos , Camundongos , Transdução de Sinais
8.
Mucosal Immunol ; 12(6): 1304-1315, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31534167

RESUMO

Enhanced gut permeability due to dysregulated epithelial tight junction is often associated with inflammatory bowel diseases (IBD), which have a greater risk for developing colorectal cancer. STAT6 activation was detected in inflamed colonic epithelium of active IBD patients, suggesting a role of epithelial STAT6 in colitis development. Here, we demonstrated that non-hematopoietic STAT6, but not hematopoietic STAT6, triggered DSS-induced colitis and subsequent tumorigenesis. This could be due to the enhancing-effect of STAT6 on gut permeability and microbiota translocation via interruption of epithelial tight junction integrity. Mechanistically, long-myosin light-chain kinase (MLCK1) was identified as a target of STAT6, leading to epithelial tight junction dysfunction and microbiota-driven colitis. Furthermore, neutralization of IL-13, which was primarily derived from type 2 innate lymphoid cells (ILC2) in a microbiota-dependent way, inhibited epithelial STAT6 activation and improved gut permeability and DSS-induced colitis. Importantly, pharmacological inhibition of STAT6 reduces murine intestinal tumor formation, and tumoral p-STAT6 levels positively correlated to the clinical stage and poor prognosis of human colorectal cancer. Thus, our study reveals a direct role of STAT6 in the disruption of epithelial tight junction integrity and colitis development, and suggests STAT6 as a potential therapeutic and prophylactic target for IBD and colitis-associated cancer.


Assuntos
Colite/metabolismo , Colo/metabolismo , Neoplasias do Colo/metabolismo , Mucosa Intestinal/metabolismo , Fator de Transcrição STAT6/metabolismo , Junções Íntimas/metabolismo , Animais , Translocação Bacteriana , Células CACO-2 , Colite/genética , Colite/microbiologia , Colite/patologia , Colo/efeitos dos fármacos , Colo/microbiologia , Colo/patologia , Neoplasias do Colo/microbiologia , Neoplasias do Colo/patologia , Neoplasias do Colo/prevenção & controle , Modelos Animais de Doenças , Impedância Elétrica , Microbioma Gastrointestinal , Genes APC , Humanos , Interleucina-13/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Linfócitos/metabolismo , Linfócitos/patologia , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Quinase de Cadeia Leve de Miosina/genética , Quinase de Cadeia Leve de Miosina/metabolismo , Permeabilidade , Fosforilação , Pirimidinas/farmacologia , Fator de Transcrição STAT6/antagonistas & inibidores , Fator de Transcrição STAT6/deficiência , Fator de Transcrição STAT6/genética , Transdução de Sinais , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/microbiologia , Junções Íntimas/patologia , Técnicas de Cultura de Tecidos
9.
Anticancer Res ; 39(9): 4673-4679, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519566

RESUMO

BACKGROUND/AIM: Rats of the adenomatous polyposis coli (Apc)-mutated female polyposis in rat (PIRC) (F344/NTac-Apcam1137) model exhibit a low level of intestinal tumorigenesis and are thus potentially exploitable as a model for identifying substances increasing colorectal cancer (CRC). MATERIALS AND METHODS: To test this possibility, we treated such rats with the bile acid (BA) cholic acid (CA) (0.3% w/w in the diet), known to promote CRC, and assessed tumorigenesis. RESULTS: Precancerous colonic lesions (mucin-depleted foci) and intestinal tumors were dramatically increased in CA-treated rats compared to controls (p<0.01). Colon mucosa proliferation was higher and apoptosis lower than those in controls. Expression of nuclear receptor 1h4 (Nr1h4) gene [encoding for BA receptor farnesoid X receptor (FXR)], organic solute transporter beta (Ostb) and fatty acid-binding protein 6 (Fabp6), FXR-dependent BA transporters, were dramatically down-regulated in CA-treated rats. CONCLUSION: CA-increased tumorigenesis in female PIRC rats, with mechanisms involving increased proliferation, reduced apoptosis and marked down-regulation of genes controlling BA homeostasis. Since BAs have been implicated in CRC, we suggest that female PIRC rats can be used to identify CRC-promoting agents.


Assuntos
Transformação Celular Neoplásica/induzido quimicamente , Ácido Cólico/efeitos adversos , Neoplasias Colorretais/etiologia , Polipose Adenomatosa do Colo/complicações , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Animais , Apoptose/genética , Proliferação de Células , Modelos Animais de Doenças , Feminino , Expressão Gênica , Genes APC , Mutação , Lesões Pré-Cancerosas , Ratos
10.
Medicina (Kaunas) ; 55(10)2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31547110

RESUMO

Background and objectives: Familial adenomatous polyposis is one of the APC-associated polyposis conditions described as genetically predetermined colorectal polyposis syndrome with a variety of symptoms. The purpose of this study was to determine sequence variants of the APC gene in patients with familial adenomatous polyposis (FAP) phenotype and positive or negative family history. Materials and Methods: Eight families with defined criteria of adenomatous polyposis underwent molecular genetic testing. Coding regions and flanking intron regions of the APC gene were analyzed by Sanger sequencing. Results: Eight allelic variants of the APC gene coding sequence were detected. All allelic variants of the APC gene were predicted to be pathogenic based on criteria according to the "Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology" (2015), four of them c.1586_1587insAT, c.2336delT, c.3066_3067insGA, and c.4303_4304insC, were considered novel. Conclusions: The timely molecular genetic analysis of APC germline variants and standardized interpretation of the pathogenicity of novel allelic variants has a high impact on choice for treatment, cancer prevention, and family genetic counseling.


Assuntos
Polipose Adenomatosa do Colo/genética , Genes APC , Variação Genética , Adulto , Feminino , Mutação em Linhagem Germinativa , Humanos , Letônia , Masculino , Pessoa de Meia-Idade , Linhagem , Análise de Sequência de DNA
12.
Thromb Res ; 181: 52-58, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31351266

RESUMO

INTRODUCTION: Patients with systemic lupus erythematosus (SLE) possessing anti-phospholipid antibodies (aPLs) are often complicated by thrombotic vascular events. aPLs commonly associated with the complications are anti-cardiolipin/ß2-glycoprotein I antibodies (aCL/ß2GPI) and anti-phosphatidylserine/prothrombin antibodies (aPS/PT). However, the pathological mechanisms leading to thrombosis remain unclear. We explored clinical features of SLE patients with aCL/ß2GPI and aPS/PT and investigated thrombogenic effects of their IgG fractions. MATERIALS AND METHODS: We enrolled 97 SLE patients and 38 healthy control volunteers and performed activated protein C (APC) resistance screening test using their plasma samples. To detect the direct effect of aPLs IgG on APC, we developed an APC sensitivity ratio assay. Effects of aPLs IgG on monocytes were studied by measuring the surface expression of tissue factor (TF) and excretion of TNF-α from peripheral blood mononuclear cell culture. RESULTS AND CONCLUSION: Thrombotic complications among SLE patients were closely associated with aCL/ß2GPI or aPS/PT, with higher prevalence in patients with both antibodies. Addition of aPLs(+)-IgG to the APC sensitivity ratio assay led to significant suppression of the anticoagulant activity of APC. The suppression was more pronounced in double-positive cases. TF expression on monocytes and concentration of TNF-α in culture medium were increased by aPLs, again more pronounced in double-positive cases. These results indicate that the effects of aCL/ß2GPI and aPS/PT are synergic both for APC anticoagulant activity and for production of TF and TNF-α from mononuclear cells. These modes of thrombogenic action of aPLs could be an important target for developing specific measures to prevent complications of SLE.


Assuntos
Anticorpos Antifosfolipídeos/imunologia , Anticoagulantes/uso terapêutico , Genes APC/fisiologia , Leucócitos Mononucleares/metabolismo , Tromboplastina/metabolismo , Trombose/sangue , Fator de Necrose Tumoral alfa/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/farmacologia , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
13.
Int J Radiat Oncol Biol Phys ; 105(3): 525-536, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31271826

RESUMO

PURPOSE: Proton radiation is a major component of the radiation field in outer space and is used clinically in radiation therapy of resistant cancers. Although epidemiologic studies in atom bomb survivors and radiologic workers have established radiation as a risk factor for colorectal cancer (CRC), we have yet to determine the risk of CRC posed by proton radiation owing to a lack of sufficient human or animal data. The purpose of the current study was to quantitatively and qualitatively characterize differential effects of acute and fractionated high-energy protons on colorectal carcinogenesis. METHODS AND MATERIALS: We used ApcMin/+ mice, a well-studied CRC model, to examine acute versus fractionated proton radiation-induced differences in intestinal tumorigenesis and associated signaling pathways. Mice were exposed to 1.88 Gy of proton radiation delivered in a single fraction or in 4 equal daily fractions (0.47 Gy × 4). Intestinal tumor number and grade were scored 100 to 110 days after irradiation, and tumor and tumor-adjacent normal tissues were harvested to assess proliferative ß-catenin/Akt pathways and DNA damage response and repair pathways relevant to colorectal carcinogenesis. RESULTS: Significantly higher intestinal tumor number and grade, along with decreased differentiation, were observed after acute radiation relative to fractionated radiation. Acute protons induced upregulation of ß-catenin and Akt pathways with increased proliferative marker phospho-histone H3. Increased DNA damage along with decreased DNA repair factors involved in mismatch repair and nonhomologous end joining were also observed after exposure to acute protons. CONCLUSIONS: We show increased γH2AX, 53BP1, and 8-oxo-dG, suggesting that increased ongoing DNA damage along with decreased DNA repair factors and increased proliferative responses could be triggering a higher number of intestinal tumors after acute relative to fractionated proton exposures in ApcMin/+ mice. Taken together, our data suggest greater carcinogenic potential of acute relative to fractionated proton radiation.


Assuntos
Quebras de DNA de Cadeia Dupla , Reparo de Erro de Pareamento de DNA , Neoplasias Intestinais/genética , Neoplasias Induzidas por Radiação/genética , Prótons/efeitos adversos , 8-Hidroxi-2'-Desoxiguanosina/metabolismo , Animais , Carcinogênese/genética , Diferenciação Celular , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Ciclina D1/metabolismo , Reparo do DNA por Junção de Extremidades , Modelos Animais de Doenças , Fracionamento da Dose de Radiação , Feminino , Expressão Gênica , Genes APC , Histonas/metabolismo , Immunoblotting/métodos , Neoplasias Intestinais/patologia , Intestino Delgado/metabolismo , Intestino Delgado/efeitos da radiação , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Induzidas por Radiação/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Doses de Radiação , Exposição à Radiação/efeitos adversos , Voo Espacial , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima/efeitos da radiação , beta Catenina/metabolismo
14.
Gastroenterology ; 157(3): 807-822, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31194980

RESUMO

BACKGROUND & AIMS: In one-third of hepatocellular carcinomas (HCCs), cancer cells have mutations that activate ß-catenin pathway. These cells have alterations in glutamine, bile, and lipid metabolism. We investigated whether positron emission tomography (PET) imaging allows identification of altered metabolic pathways that might be targeted therapeutically. METHODS: We studied mice with activation of ß-catenin in liver (Apcko-liv mice) and male C57Bl/6 mice given injections of diethylnitrosamine, which each develop HCCs. Mice were fed a conventional or a methionine- and choline-deficient diet or a choline-deficient (CD) diet. Choline uptake and metabolism in HCCs were analyzed by micro-PET imaging of mice; livers were collected and analyzed by histologic, metabolomic, messenger RNA quantification, and RNA-sequencing analyses. Fifty-two patients with HCC underwent PET imaging with 18F-fluorodeoxyglucose, followed by 18F-fluorocholine tracer metabolites. Human HCC specimens were analyzed by immunohistochemistry, quantitative polymerase chain reaction, and DNA sequencing. We used hepatocytes and mouse tumor explants for studies of incorporation of radiolabeled choline into phospholipids and its contribution to DNA methylation. We analyzed HCC progression in mice fed a CD diet. RESULTS: Livers and tumors from Apcko-liv mice had increased uptake of dietary choline, which contributes to phospholipid formation and DNA methylation in hepatocytes. In patients and in mice, HCCs with activated ß-catenin were positive in 18F-fluorocholine PET, but not 18F-fluorodeoxyglucose PET, and they overexpressed the choline transporter organic cation transporter 3. The HCC cells from Apcko-liv mice incorporated radiolabeled methyl groups of choline into phospholipids and DNA. In Apcko-liv mice, the methionine- and choline-deficient diet reduced proliferation and DNA hypermethylation of hepatocytes and HCC cells, and the CD diet reduced long-term progression of tumors. CONCLUSIONS: In mice and humans, HCCs with mutations that activate ß-catenin are characterized by increased uptake of a fluorocholine tracer, but not 18F-fluorodeoxyglucose, revealed by PET. The increased uptake of choline by HCCs promotes phospholipid formation, DNA hypermethylation, and hepatocyte proliferation. In mice, the CD diet reverses these effects and promotes regression of HCCs that overexpress ß-catenin.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/genética , Mutação , Tomografia por Emissão de Pósitrons , beta Catenina/genética , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/patologia , Proliferação de Células , Colina/administração & dosagem , Colina/análogos & derivados , Deficiência de Colina/complicações , Metilação de DNA , Dietilnitrosamina , Modelos Animais de Doenças , Genes APC , Predisposição Genética para Doença , Humanos , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/patologia , Masculino , Metionina/deficiência , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Fosfolipídeos/metabolismo , Valor Preditivo dos Testes , Compostos Radiofarmacêuticos/administração & dosagem , beta Catenina/metabolismo
15.
Med Sci Monit ; 25: 3796-3803, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31113927

RESUMO

BACKGROUND Familial adenomatous polyposis (FAP), which has a very high tendency of progression to colorectal cancer, is mainly caused by mutations of the adenomatous polyposis coli (APC) gene. This study systematically screened the APC mutations and observed the correlation of APC mutations with clinical manifestations of FAP. MATERIAL AND METHODS Eighty subjects (probands and their family members of 22 FAP pedigrees) were enrolled, underwent abdominal ultrasound, computed tomography, and colonoscopic examinations, and were assessed for APC mutations between January 2010 and June 2015 at Tianjin Union Medical Center. Peripheral blood was collected from subjects, and DNA was extracted and screened for APC mutations using multiplex ligation-dependent probe amplification for large-fragment deletions or PCR-denaturing high-performance liquid chromatography with DNA sequencing for micromutations. RESULTS Nineteen of 22 FAP pedigrees were found to have mutations of APC, and 17 types APC mutations were identified. All the mutations were heterozygosity with autosomal dominant inheritance. APC mutations included 8 caused by frameshift, 3 by aberrant splicing, 2 by missense mutation, 2 by nonsense mutation, and 2 by large-fragment deletion. Frameshift mutation was the most common type of APC mutation, and Coding DNA Sequence 15 was the most common mutation site. Five novel APC mutations, including 1 with large-fragment deletion, were identified. CONCLUSIONS We systematically screened 17 mutations of APC from 22 Chinese pedigrees with FAP. This study will broaden the spectrum of known APC germline mutations and help understand the types and distribution of APC mutations among Chinese patients with FAP.


Assuntos
Polipose Adenomatosa do Colo/genética , Adolescente , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases/genética , China , Colonoscopia , Neoplasias Colorretais/genética , Éxons/genética , Feminino , Genes APC/fisiologia , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa/genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Análise de Sequência de DNA , Deleção de Sequência/genética
17.
Biosci Biotechnol Biochem ; 83(6): 1062-1071, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30950326

RESUMO

BACKGROUND/AIM: MiR-125b plays an important role in breast cancer. The current study was to explore the expression and function of miR-125b in triple negative breast cancer cells. MATERIALS AND METHODS: The expression of miR-125b in human TNBC samples and cell lines were examined by qRT-PCR. MTT, scratch assays and transwell assays were utilized to observe the proliferation, migration and invasion ability. MiR-125b's target gene and downstream signaling pathways were investigated by Luciferase Reporter Assays, qRT-PCR, immunofluorescence assays and western bolt. RESULTS: MiR-125b was highly expressed in human TNBC tissues and cell lines. Inhibiting miR-125b expression suppressed the proliferation, cell migration and invasion. The three-prime untranslated region (3´-UTR) of adenomatous polyposis coli (APC) mRNA contains miR-125b binding sites, and inhibiting miR-125b expression suppressed the activity of the intracellular Wnt/ß-catenin pathways and EMT. CONCLUSION: Inhibiting miR-125b regulates the Wnt/ß-catenin pathway and EMT to suppress the proliferation and migration of MDA-MB-468 TNBC cells.


Assuntos
Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , MicroRNAs/fisiologia , Metástase Neoplásica/genética , Neoplasias de Mama Triplo Negativas/patologia , Via de Sinalização Wnt/genética , beta Catenina/metabolismo , Regiões 3' não Traduzidas , Linhagem Celular Tumoral , Feminino , Genes APC , Humanos , Reação em Cadeia da Polimerase em Tempo Real , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Regulação para Cima
18.
Fam Cancer ; 18(3): 327-330, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30919136

RESUMO

Familial adenomatous polyposis (FAP) is a cancer predisposition syndrome driven by germline loss-of-function of the APC gene and phenotypically manifests with intestinal polyposis and a variety of extra-intestinal bone and soft tissue tumors. Craniopharyngioma is not a well-described FAP-associated tumor, however, six cases have been reported in adults, all demonstrating ectopic location and adamantinomatous histology. We report the first case of craniopharyngioma associated with FAP in a pediatric patient. A seven-year-old girl who presented with headache and vomiting was found on magnetic resonance imaging to have a suprasellar mass with cystic extension to the pre-pontine space. The tumor represented an adamantinomatous craniopharyngioma (aCP) with nuclear ß-catenin expression. Whole exome sequencing confirmed a CTNNB1 activating point mutation and a germline APC frameshift variant. This case represents the first FAP-associated craniopharyngioma in childhood…. expanding our understanding of the molecular underpinnings driving tumorigenesis in this unique patient.


Assuntos
Polipose Adenomatosa do Colo/complicações , Craniofaringioma/complicações , Neoplasias Hipofisárias/complicações , beta Catenina/genética , Polipose Adenomatosa do Colo/genética , Criança , Craniofaringioma/diagnóstico por imagem , Craniofaringioma/genética , Feminino , Genes APC , Mutação em Linhagem Germinativa , Humanos , Fenótipo , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/genética , Mutação Puntual , beta Catenina/metabolismo
19.
Neoplasma ; 66(3): 470-480, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-30868894

RESUMO

The clinical role of APC promoter methylation in patients with bladder cancer remains to be determined. The relevant databases (PubMed, EMBASE, EBSCO, Wangfang, CNKI and Cochrane Library) were searched to get eligible studies. The overall odds ratios (ORs) and the corresponding 95% confidence intervals (95% CIs) were calculated to assess the effects of APC promoter methylation on bladder cancer risk and clinicopathological features. 2214 patients with bladder cancer and 665 controls were identified. APC promoter methylation was significantly higher in bladder cancer than in nonmalignant tissue and urine samples (tissue: OR = 11.14, 95% CI = 4.29-28.91, P < 0.001; urine: OR = 24.31, 95% CI = 6.26-94.38, P < 0.001), but not in blood samples (P = 0.242). The relationship was observed between APC promoter methylation and gender (male vs. female: OR = 1.46, 95% CI = 0.96-2.22, P = 0.074), tumor stage (stage T2-T4 vs. Ta-T1: OR = 3.00, 95% CI = 1.66-5.42, P < 0.001), and tumor grade (grade 3-4 vs. grade 1-2: OR = 1.99, 95% CI = 1.15-3.42, P = 0.013). But no correlation was found between APC promoter methylation and age, lymph node status, and tumor number (P > 0.1). APC gene was not associated with overall survival of bladder cancer. Our findings indicate that APC promoter methylation may be associated with the development and progression of bladder cancer and may serve as a promising noninvasive biomarker using urine samples for the detection of bladder cancer.


Assuntos
Metilação de DNA , Genes APC/fisiologia , Regiões Promotoras Genéticas , Neoplasias da Bexiga Urinária , Progressão da Doença , Feminino , Humanos , Masculino , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/urina
20.
Dig Dis ; 37(5): 400-405, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30836352

RESUMO

Hereditary polyposis syndromes in which APC gene germline mutations can lead to colorectal carcinogenesis are familial adenomatous polyposis (FAP), attenuated FAP (AFAP) and MUTYH-associated polyposis. All 3 syndromes increase the potential for the development of colorectal cancer. AFAP is diagnosed if less than 100 adenomas are detected in the colon at presentation. AFAP is inherited in an autosomal dominant manner. We present a case of a 22-year-old female with AFAP who was treated with endoscopic polypectomy and surveilled by annual colonoscopy. Guidelines for AFAP surveillance suggest annual colonoscopy with endoscopic polypectomy in asymptomatic individuals. Indications for immediate surgery include documented or suspected cancer or significant symptoms. Preferred surgical option in AFAP is colectomy and ileo-rectal anastomosis. Surveillance of the AFAP patients should include upper GI endoscopy and duodenoscopy with random biopsies of fundic gland polyps and endoscopic resection of detected adenomas. Annual thyroid ultrasound is indicated due to increased risk for thyroid cancer. In pediatric patients tested positive for germline mutation of APC gene screening for hepatoblastoma using alpha-fetoprotein and liver ultrasound should be performed.


Assuntos
Polipose Adenomatosa do Colo/terapia , Polipose Adenomatosa do Colo/diagnóstico , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/cirurgia , Colonoscopia , Feminino , Genes APC , Predisposição Genética para Doença , Testes Genéticos , Humanos , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA