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1.
Oncology ; 97(5): 311-318, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31550723

RESUMO

INTRODUCTION: Human epidermal growth factor 2 (HER2) gene overexpression in breast carcinoma cell lines has been shown to drive mammary carcinogenesis and tumor growth and invasion through its effects on mammary stem cells. OBJECTIVE: Therefore, we investigated the mechanism by which HER2 regulates cancer stem cell (CSC) activity in gastric cancer cells. METHODS: HER2 was transfected into MKN28 gastric cancer cells, and its role in regulating CSC activity was determined by characterizing the HER2-overexpressing cells. RESULTS: The sphere formation assay revealed that the sphere sizes and frequency of sphere formation were significantly greater for the HER2-overexpressing cells than for the MKN28 control cells. The CSC markers Oct-4 and BMI1 were more highly expressed in the HER2-overexpressing cells, as were the EMT markers. This was accompanied by a significant enhancement in cellular invasion of the Matrigel and migration. The E-cadherin level was significantly downregulated, and the mesenchymal marker Snail upregulated, in the HER2-transfected cells. HER2 overexpression activated the well-characterized CSC-associated Wnt/ß-catenin signaling pathway, as shown by the luciferase assay. After treatment of these cells with the Wnt signal inhibitor PRI-724, the BMI1 and Oct-4 levels were decreased for 24 h and Snail was also downregulated. Immunofluorescence staining revealed the significant restoration of E-cadherin levels in the HER2-transfected cells after PRI-724 treatment. CONCLUSIONS: These results established a role for HER2 in regulating gastric CSC activity, with Wnt/ß-catenin signaling being mediated via a HER2-dependent pathway. In summary, HER2-overexpressing gastric cancer cells exhibited increased stemness and invasiveness and were regulated by Wnt/ß-catenin signaling.


Assuntos
Células-Tronco Neoplásicas/fisiologia , Receptor ErbB-2/fisiologia , Neoplasias Gástricas/patologia , Via de Sinalização Wnt/fisiologia , Antígenos CD/análise , Caderinas/análise , Linhagem Celular Tumoral , Humanos , Invasividade Neoplásica , Fator 3 de Transcrição de Octâmero/análise , Complexo Repressor Polycomb 1/análise , Receptor ErbB-2/análise , Neoplasias Gástricas/química , beta Catenina/análise
2.
Medicine (Baltimore) ; 98(29): e16455, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31335701

RESUMO

RATIONALE: About 8384 cases of solid pseudopapillary neoplasms (SPN) of pancreas have been published in English literature, from 1933 to 2018. This is a low-grade tumor that usually occurs in children but is rare in adults and, in exceptional cases, can show extrapancreatic localization. In this paper we present 2 unusual cases of SPNs, 1 with retroperitoneal location (case 1) and 1 that was firstly diagnosed as a G1 neuroendocrine tumor (NET) and showed hepatic metastases after 13 years (case 2). PATIENT CONCERNS: No symptoms in first case. The tumor was incidentally diagnosed, during ultrasound examination. In the second case, the metastasis was observed during regular follow-up. DIAGNOSES: The diagnosis was established based on the histological features and immunohistochemical profile that showed positivity for vimentin, nuclear ß-catenin, cyclin D1, CD10, and SRY-related high-mobility group box 11 and negativity for maspin. INTERVENTIONS: Surgical excision, in both cases. OUTCOMES: No recurrences in first case, at 5 months after diagnosis. Hepatic metastases in the second case, at 13 years after diagnosis, with portal invasion after another 15 months. LESSONS: Without a complex immunoprofile, SPN can be misdiagnosed as NET. SPN can be a low-grade tumor but long-time follow-up is mandatory to detect delayed metastases. A correct diagnosis is necessary for a proper therapeutic management.


Assuntos
Adenocarcinoma Papilar , Biomarcadores Tumorais/análise , Neoplasias Císticas, Mucinosas e Serosas , Tumores Neuroendócrinos/diagnóstico , Pâncreas/patologia , Neoplasias Pancreáticas , Adenocarcinoma Papilar/imunologia , Adenocarcinoma Papilar/patologia , Adenocarcinoma Papilar/fisiopatologia , Adenocarcinoma Papilar/terapia , Adulto , Ciclina D1/análise , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Neoplasias Císticas, Mucinosas e Serosas/imunologia , Neoplasias Císticas, Mucinosas e Serosas/patologia , Neoplasias Císticas, Mucinosas e Serosas/fisiopatologia , Neoplasias Císticas, Mucinosas e Serosas/terapia , Neprilisina/análise , Pancreatectomia/efeitos adversos , Pancreatectomia/métodos , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/fisiopatologia , Neoplasias Pancreáticas/terapia , Prognóstico , Resultado do Tratamento , Vimentina/análise , beta Catenina/análise
3.
Acta Cir Bras ; 34(5): e201900502, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31166463

RESUMO

PURPOSE: To investigate inhibitory effect of Astragalus polysaccharide (APS) on osteoporosis in ovariectomized rats by regulating FoxO3a/Wnt2 signaling pathway. METHODS: Postmenopausal osteoporosis (PMOP) animal model was developed by excising the bilateral ovaries of rats. The model rats were administered with APS (200 mg/kg, 400 mg/kg, 800 mg/kg) by intragastric administration once daily for 12 weeks. Bone density, bone metabolism index and oxidative stress index were measured in all groups. Furthermore, the regulation of APS of FoxO3a / Wnt2 signaling pathway was observed. RESULTS: APS has an estrogen-like effect, which can increase bone mass, lower serum ALP and BGP values, increase blood calcium content, and increase bone density of the femur and vertebrae in rats. At the same time, APS can increase the bone mineral content of the femur, increase the maximum stress, maximum load and elastic modulus of the ovariectomized rats, improve oxidative stress in rats by increasing the gene expression of ß-catenin and Wnt2 mRNA and inhibiting the gene expression of FoxO3a mRNA. CONCLUSION: Astragalus polysaccharide can effectively alleviate oxidative stress-mediated osteoporosis in ovariectomized rats, which may be related to its regulation of FoxO3a/Wnt2/ß-catenin pathway.


Assuntos
Astrágalo (Planta)/química , Proteína Forkhead Box O3/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Polissacarídeos/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Densidade Óssea/efeitos dos fármacos , Feminino , Fêmur/efeitos dos fármacos , Fêmur/metabolismo , Proteína Forkhead Box O3/análise , Expressão Gênica/efeitos dos fármacos , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/análise , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/efeitos dos fármacos , Osteoporose/metabolismo , Ovariectomia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Distribuição Aleatória , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Valores de Referência , Reprodutibilidade dos Testes , Resultado do Tratamento , Via de Sinalização Wnt/fisiologia , Proteína Wnt2/análise , Proteína Wnt2/efeitos dos fármacos , beta Catenina/análise , beta Catenina/efeitos dos fármacos
4.
Microb Pathog ; 129: 257-265, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30807813

RESUMO

Gastric cancer is a major global health threat and is often related with Helicobacter pylori (H. pylori) infection. FRA-1 is a subunit of the activator protein-1 transcription factor complex, which played a central role in cell proliferation and migration. It has also been implicated in stomach inflammation and malignancy. The present study aimed to clarify the relationship between H. pylori infection and production of FRA-1 in controlling cell proliferation and migration and its molecular mechanisms. Cell proliferation was measured by colony formation assay. Cell migration was monitored by transwell migration assay. Gastric mucosal epithelial cells were treated with FRA-1-specific siRNA with or without H. pylori infection in vitro, and RNA and proteins were extracted. The expression of FRA-1 and indicators in cells was determined by RT-PCR and western blot analysis. ß-Catenin and TGF-ß activities were then assessed by western blotting and immunofluorescence. The expression of FRA-1 increased after H. pylori infection. Additional analysis identified that knockdown of FRA-1 attenuated the H. pylori-induced proliferative activity and migration of gastric cancer cells. Furthermore, upregulation of FRA-1 by H. pylori led to increase in Wnt/ß-Catenin levels and TGF-ß dependent signaling events. These results demonstrate that the upregulation of FRA-1 in H. pylori-infected gastric epithelial cells plays a key role in the carcinogenic process.


Assuntos
Células Epiteliais/microbiologia , Células Epiteliais/fisiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/crescimento & desenvolvimento , Proteínas Proto-Oncogênicas c-fos/biossíntese , Western Blotting , Linhagem Celular , Movimento Celular , Proliferação de Células , Técnicas Citológicas , Imunofluorescência , Perfilação da Expressão Gênica , Humanos , Modelos Biológicos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Crescimento Transformador beta/análise , beta Catenina/análise
5.
Am J Clin Pathol ; 151(5): 529-538, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30715091

RESUMO

OBJECTIVES: CTNNB1 exon 3 mutations have shown independent prognostic value in endometrial cancer. We aimed to assess whether nuclear ß-catenin expression is an accurate surrogate, as immunohistochemistry is cheaper, faster, and more widely applicable than sequencing. METHODS: A systematic review was performed by searching electronic databases for all studies assessing the association between ß-catenin immunohistochemical expression and CTNNB1 mutations. Meta-analysis of diagnostic accuracy was performed by calculating sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR-), diagnostic odds ratio (DOR), and area under the curve (AUC) on summary receiver operating characteristic curves. RESULTS: Fifteen observational studies with 1,158 endometrial carcinomas were included. Pooled estimates showed sensitivity = 0.88, specificity = 0.85, LR+ = 4.57, LR- = 0.20, DOR = 27.16, and high diagnostic accuracy (AUC = 0.91). CONCLUSIONS: Nuclear expression of ß-catenin is an accurate immunohistochemical surrogate of CTNNB1 exon 3 mutations and thus might be considered in the risk stratification of endometrial cancer.


Assuntos
Núcleo Celular/química , Neoplasias do Endométrio/química , Mutação , beta Catenina/análise , beta Catenina/genética , Neoplasias do Endométrio/genética , Feminino , Humanos , Imuno-Histoquímica
6.
Clin Transl Oncol ; 21(2): 220-231, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29956073

RESUMO

PURPOSE: The aim of this study is to explore the roles of ß-catenin, decorin, septin-7, and S100A10 expression in colorectal cancer development. METHODS: Twenty-five BALB/c mice were divided into five groups; four groups were administrated N,N-dimethylhydrazine for 0, 10, 15, and 20 weeks, and one group was administrated normal saline for 20 weeks. The colons were collected for histopathological analysis. Protein samples prepared from the frozen colon tissues of mice treated with N,N-dimethylhydrazine for the different time points were evaluated using the isobaric tags for relative and absolute quantification (iTRAQ) labeling technique coupled with the 2D liquid chromatography-tandem mass spectrometry analysis. Based on the proteomic analysis results, immunohistochemical staining of ß-catenin, decorin, septin-7, and S100A10 was performed in paraffin-embedded mice colorectal tissue, and 53 cases of human hereditary polyposis colorectal cancer samples. RESULTS: Colorectal cancer was observed in mice treated with N,N-dimethylhydrazine for 20 weeks, and adenomas were observed in mice subjected to the 10-, and 15-week treatments. Seventy-two differentially expressed proteins were involved in the development of cancer as per the iTRAQ and spectrometry analysis. In normal epithelium, adenoma, and cancer from human hereditary polyposis colorectal cancer, S100A10 expression (c2 = 100.989, P = 0.000) was highest in cancer, whereas decorin (c2 = 12.852, P = 0.002) and septin-7 (c2 = 66.519, P = 0.002) expressions were highest in the normal epithelium, which was confirmed via immunohistochemical staining. CONCLUSIONS: The subcellular localization of ß-catenin and decorin, septin-7, and S100A10 expressions are associated with the development of colorectal cancer in mice after N,N-dimethylhydrazine treatment and in human hereditary polyposis colorectal cancers.


Assuntos
Polipose Adenomatosa do Colo/patologia , Biomarcadores Tumorais/análise , Neoplasias Colorretais/patologia , Adulto , Animais , Anexina A2/análise , Anexina A2/biossíntese , Carcinógenos/toxicidade , Neoplasias Colorretais/induzido quimicamente , Decorina/análise , Decorina/biossíntese , Dimetilidrazinas/toxicidade , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Proteômica/métodos , Proteínas S100/análise , Proteínas S100/biossíntese , Septinas/análise , Septinas/biossíntese , beta Catenina/análise , beta Catenina/biossíntese
8.
Hum Pathol ; 84: 155-163, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30292627

RESUMO

Immunohistochemical staining with anti-ß-catenin antibody has been applied as a diagnostic tool for desmoid-type fibromatoses (DFs). In recent years, specific gene mutation (CTNNB1) analysis has also been reported to be useful for diagnosis of DF; however, the association between CTNNB1 mutation status and immunohistochemical staining pattern of ß-catenin is rarely reported. The purposes of this study are to clarify the relationship of the staining pattern of ß-catenin with the CTNNB1 mutation status and various clinical variables, and to investigate the significance of immunohistochemical staining of ß-catenin in cases diagnosed as DF. Between 1997 and 2017, 104 cases diagnosed as DF from 6 institutions in Japan were enrolled in this study: Nagoya University, National Cancer Center Hospital, Niigata University, Okayama University, Kyushu University, and Cancer Institute Hospital. For all cases, immunohistochemical staining of ß-catenin and gene mutation analysis of CTNNB1 were performed. Of 104 cases, 87 (84%) showed nuclear staining of ß-catenin, and 95 (91%) showed positive staining in the cytoplasm. The proportion of cases showing strong nuclear staining of ß-catenin was significantly higher in the cases with S45F than in those with T41A or wild type. The proportion of cases stained strongly in the cytoplasm rather than in the nucleus was significantly higher in the group of T41A than that of S45F or wild type. Among 17 cases in which nuclear immunostaining was absent, CTNNB1 mutation was observed in 5 cases (29.4%). There were unignorable cases of DF with negative ß-catenin immunostaining despite a definitive clinical and pathological diagnosis of DF and/or positive CTNNB1 mutation.


Assuntos
Biomarcadores Tumorais/análise , Fibromatose Agressiva/diagnóstico , beta Catenina/análise , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Fibromatose Agressiva/genética , Humanos , Imuno-Histoquímica/métodos , Masculino , Pessoa de Meia-Idade , Mutação , Adulto Jovem , beta Catenina/genética
9.
J Histochem Cytochem ; 67(4): 245-256, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30452872

RESUMO

Recurrent or chronic oral pain is a great burden for patients. Recently, the links between epithelial barrier loss and disease were extended to include initiation and propagation. To explore the effects of pathohistological changes in oral epithelia on pain, we utilized labial mucosa samples in diagnostic labial gland biopsies from patients with suspected Sjögren's syndrome (SS), because they frequently experience pain and discomfort. In most labial mucosa samples from patients diagnosed with SS, disseminated epithelial cellular edema was prevalent as ballooning degeneration. The disrupted epithelia contained larger numbers of infiltrating macrophages in patients with oral pain than in patients without pain. Immunohistochemistry revealed that edematous areas were distinct from normal areas, with disarranged cell-cell adhesion molecules (filamentous actin, E-cadherin, ß-catenin). Furthermore, edematous areas were devoid of immunostaining for transient receptor potential channel vanilloid 4 (TRPV4), a key molecule in adherens junctions. In an investigation on whether impaired TRPV4 affect cell-cell adhesion, calcium stimulation induced intimate cell-cell contacts among oral epithelial cells from wild-type mice, while intercellular spaces were apparent in cells from TRPV4-knockout mice. The present findings highlight the relationship between macrophages and epithelia in oral pain processing, and identify TRPV4-mediated cell-cell contacts as a possible target for pain treatment.


Assuntos
Células Epiteliais/patologia , Macrófagos/patologia , Boca/patologia , Dor/patologia , Actinas/análise , Adulto , Idoso , Animais , Caderinas/análise , Adesão Celular , Feminino , Humanos , Imuno-Histoquímica/métodos , Masculino , Camundongos , Pessoa de Meia-Idade , Canais de Cátion TRPV/análise , Adulto Jovem , beta Catenina/análise
10.
Dig Dis Sci ; 64(1): 76-83, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30382540

RESUMO

BACKGROUND: Wnt-ß-catenin signaling is essential for homeostasis of intestinal stem cells in mice and is thought to promote intestinal crypt fission. AIMS: The aim of this study was to investigate Wnt-ß-catenin signaling in intestinal crypts of human infants. METHODS: Duodenal biopsies from nine infants (mean, range 0.9 years, 0.3-2 years) and 11 adults (mean, range 43 years, 34-71 years) were collected endoscopically. Active ß-catenin signaling was assessed by cytoplasmic and nuclear ß-catenin, nuclear c-Myc, and cytoplasmic Axin-2 expression in the base of crypts. Tissues were stained by an immunoperoxidase staining technique and quantified as pixel energy using cumulative signal analysis. Data were expressed as mean ± SD and significance assessed by Student's t test. RESULTS: Crypt fission was significantly higher in infants compared to adults (16 ± 8.6% versus 0.7 ± 0.6%, respectively, p < 0.0001). Expression of cytoplasmic and nuclear ß-catenin was 1.8-fold (p < 0.0001) and 2.9-fold (p < 0.0001) higher in infants, respectively, while cytoplasmic Axin-2 was 3.1-fold (p < 0.0001) increased in infants. c-Myc expression was not significantly different between infants and adults. Expression was absent in Paneth cells but present in the transit amplifying zone of crypts. Crypt base columnar cells, which were intercalated between Paneth cells, expressed c-Myc. CONCLUSIONS: Wnt-ß-catenin signaling was active in crypt base columnar cells (i.e., intestinal stem cells) in human infants. This signaling could promote crypt fission during infancy. Wnt-ß-catenin signaling likely acts in concert with other pathways to promote postnatal growth.


Assuntos
Duodeno/química , Mucosa Intestinal/química , Via de Sinalização Wnt , beta Catenina/análise , Adulto , Fatores Etários , Idoso , Proteína Axina/análise , Duodeno/crescimento & desenvolvimento , Feminino , Humanos , Lactente , Mucosa Intestinal/crescimento & desenvolvimento , Masculino , Pessoa de Meia-Idade , Celulas de Paneth/química , Proteínas Proto-Oncogênicas c-myc/análise , Células-Tronco/química
11.
J Vasc Res ; 55(6): 350-364, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30544118

RESUMO

Endothelial cells of the vascular system are dynamic cells whose molecular adaptability is decisive for the adjustment of homeostasis and organ perfusion. Advanced microscopic techniques, automation processing, and image analysis software was shown to improve the understanding of vascular biology. In this work, we describe advanced methods that allow investigating the dynamics of endothelial cell contacts. The development of viral vectors has contributed significantly to the genetic manipulation of endothelial cells. We used the Gibson assembly as a quick and cheap cloning system for introducing sequences into the lentiviral-based pFUGW vector. Furthermore, classical fluorescence tags such as mCherry and EGFP were compared with self-labeling tags such as Halo and SNAP for their suitability to study junction dynamics in cultured endothelium, and found the self-labeling tags as useful tools. Using such combinations, we found maintained cell junction integrity during shear stress-induced junction remodeling using VE-cadherin-EGFP. Remodeling was accompanied by VE-cadherin plaque formation, indicating that this process is mediated by the for-mation of the actin-driven junction-associated intermittent lamellipodia, JAIL. The combined methods including the Gibson assembly, lentiviral mediated gene transfer, spinning disk-based live cell imaging, and software for quantification allow analyses of the endothelial cell junction dynamics under static and under shear stress conditions.


Assuntos
Clonagem Molecular/métodos , Células Endoteliais/fisiologia , Células Endoteliais/ultraestrutura , Corantes Fluorescentes , Junções Intercelulares/fisiologia , Animais , Anticorpos , Anticorpos Monoclonais , Caderinas/análise , Caderinas/genética , Expressão Gênica , Vetores Genéticos , Cabras/imunologia , Proteínas de Fluorescência Verde/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Immunoblotting , Junções Intercelulares/química , Camundongos , Coelhos/imunologia , beta Catenina/análise , gama Catenina/análise
12.
Nutr Cancer ; 70(6): 928-937, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30273050

RESUMO

Chronic intestinal inflammation is critical risk factor of colorectal cancer. Triticum aestivum sprouts have been reported to provide a number of health benefits and used as a dietary supplement. In this study, the authors investigated the regulatory effects of T. aestivum sprouts ethanol extract (TAEE) on experimental colorectal carcinogenesis in an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced mouse model. Oral administration of TAEE significantly attenuated crypt destruction and tumor formation in AOM/DSS-treated mice. Levels of inflammatory mediators involved in colorectal carcinogenesis, that is, tumor necrosis factor-α, interkeukin (IL)-1ß, IL-6, cyclooxygenase-2, and inducible nitric oxide synthase, were lower in the colons of 200 mg/kg TAEE-treated mice than in AOM/DSS controls (p < 0.05). Immunohistochemical staining showed that levels of nuclear factor-kappa B p65 and ß-catenin were attenuated by TAEE in the colon tissues of AOM/DSS-treated mice. Furthermore, levels of ß-catenin-related genes (cyclin D1 and c-Myc), which are known to contribute to cell cycle regulation, were decreased in the colon tissues of TAEE-treated mice versus AOM/DSS controls (p < 0.01). These results showed TAEE inhibited colon inflammation and neoplasm formation caused by AOM/DSS treatment, suggesting that TAEE could be useful for the prevention and treatment of colitis-associated colon cancer.


Assuntos
Neoplasias do Colo/prevenção & controle , Extratos Vegetais/uso terapêutico , Triticum , Animais , Azoximetano , Neoplasias do Colo/induzido quimicamente , Sulfato de Dextrana , Mediadores da Inflamação/análise , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fator de Transcrição RelA/análise , Triticum/química , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/análise , beta Catenina/fisiologia
14.
Nutr Cancer ; 70(6): 946-955, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30183370

RESUMO

Epidemiological and experimental observations have shown that nonsteroidal anti-inflammatory drugs especially selective cyclooxygenase-2 (COX-2) inhibitors and probiotics reduce the incidence risk of colon cancer. Therefore, the present study was designed to assess the prophylactic potentials of probiotics (Lactobacillus acidophilus and Lactobacillus rhamnosus GG) in conjunction with celecoxib, a selective cox-2 inhibitor in 1,2 dimethylhydrazine dihydrochloride (DMH)-induced experimental colon carcinogenesis, a well-established, well appreciated and widely used model for colorectal cancer that shares many similarities to human sporadic colorectal cancer with respect to response to some promotional and preventive agents. More specifically, it was observed that L. rhamnosus GG + celecoxib + DMH-treated animals had significantly reduced aberrant crypt foci (ACF) count and the expression of procarcinogenic molecular markers (ß-catenin, NF-κB, and COX-2) in early experimental colon carcinogenesis compared with probiotic-DMH, celecoxib-DMH or DMH-treated animals. This is the first ever such study to demonstrate that probiotic in conjunction with celecoxib can be opted as an alternate prophylactic strategy in highly susceptible individuals to reduce both the incidence and severity of the life style diseases as prevention is better than cure.


Assuntos
Celecoxib/administração & dosagem , Neoplasias do Colo/prevenção & controle , Lactobacillus acidophilus , Lactobacillus rhamnosus , Probióticos/administração & dosagem , 1,2-Dimetilidrazina , Focos de Criptas Aberrantes/prevenção & controle , Animais , Colo/patologia , Neoplasias do Colo/induzido quimicamente , Ciclo-Oxigenase 2/análise , NF-kappa B/análise , Ratos , Ratos Sprague-Dawley , beta Catenina/análise
15.
Int J Mol Sci ; 19(8)2018 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-30126180

RESUMO

Relaxin is known to play an important role in animal pregnancies, including those of humans. It is suggested that relaxin induces aggressive cell growth and invasiveness in several types of cancer, including endometrial cancer. However, the mechanisms of relaxin remain largely unclear. In this study, we examined the effects of relaxin 2 (RLN2), the major circulating relaxin in humans, on human endometrial carcinoma cell lines. RLN2 treatment induced invasion in HEC-1B and Ishikawa cells. RLN2-induced cell invasion was significantly decreased by transfection of relaxin receptor 1 (RXFP1) siRNAs. The ß-catenin inhibitor, XAV939, also significantly inhibited the RLN2-induced cell invasions. Both a decrease of cadherin expression and an increase of ß-catenin phosphorylation were observed in response to the RLN2 treatment in HEC-1B and Ishikawa cells. We then examined RLN2 and RXFP1 expression in 80 human endometrioid endometrial carcinoma tissues. RLN2 immunoreactivity was detected in the human endometrial carcinoma cells and had a correlative tendency with histological grade and RXFP1. These results suggest that adherens junctions in cancer cells are weakened by the breakdown of the cadherin/catenin complex, which is induced by ß-catenin phosphorylation via RLN2/RXFP1 signaling.


Assuntos
Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/patologia , Invasividade Neoplásica/patologia , Receptores Acoplados a Proteínas-G/metabolismo , Receptores de Peptídeos/metabolismo , Relaxina/metabolismo , Transdução de Sinais , beta Catenina/metabolismo , Carcinoma Endometrioide/metabolismo , Neoplasias do Endométrio/metabolismo , Feminino , Humanos , Receptores Acoplados a Proteínas-G/análise , Receptores de Peptídeos/análise , Relaxina/análise , beta Catenina/análise
16.
Zhonghua Bing Li Xue Za Zhi ; 47(8): 580-584, 2018 Aug 08.
Artigo em Chinês | MEDLINE | ID: mdl-30107661

RESUMO

Objective: To investigate the clinicopathologic and differential diagnostic features of glomus tumor of the kidney. Methods: Four cases of glomus tumor of the kidney were collected from the archives of Peking University Third Hospital, the Second Hospital of Tianjin Medical University, Ningbo Yinzhou Second Hospital and Zhejiang Provincial People's Hospital between January 2012 to June 2017; the clinical and radiologic features, histomorphology, immunohistochemistry, ultrastucture and prognosis were analyzed and the relevant literature was reviewed. Results: Patients consisted of 2 men and 2 women with ages ranging from 37 years to 66 years (mean 55 years). Three patients had history of hypertensive disease (grade Ⅱ, 3 to 10 years). The tumors measured in maximum diameter from 3.0 cm to 4.0 cm (mean 3.6 cm) and showed gray-white to yellow and tan on cut surface. Macroscopical examinations showed all tumors were circumscribed but non-encapsulated. Histologically, 1 tumor presented as glomus tumor with extensive myxoid change, 1 as cellular and solid pattern glomus tumor, 1 as glomangioma with focal myopericytoma-like pattern and 1 as symplastic glomus tumor with areas resembling myopericytoma. The tumor cells in two cases showed scant cytoplasm and uniform, bland-appearing nuclei without mitoses. In one case, the tumor cells were epithelioid with abundant eosinophilic cytoplasm and relatively well-defined cell borders. There was an increased mitosis of 4/50 HPF; however, no evidence of atypical mitosis or nuclear atypia was noted. In the symplastic glomus tumor the tumor cells showed frequently nuclear pleomorphism without mitoses. By immunohistochemistry, all tumors showed strong and diffuse reactivities to at least 3 of the 4 muscle-associated markers (SMA, h-Caldesmon, MSA and Calponin), 3 tumors strongly and diffusely expressed collagen Ⅳ, 2 expressed CD34 and 1 focally expressed desmin; whereas markers including epithelial, neuroendocrine, nephrogenic, melanoma-associated, STAT6, S-100 protein, CD117 and ß-catenin all were negative in all the 4 tumors. Ultrastuctural analysis was done in 2 cases and showed prominent cytoplasmic actin bundles and pericellular basement membrane, and lacking of rhomboid renin crystals in both tumors. The hypertension persisted after surgical resection for all the 3 patients with this medical history. Follow-up information (range: 6-64 months, mean: 44 months)showed that no evidence of local recurrence or distant metastasis was identified in all 4 patients. Conclusions: Glomus tumor rarely occurs in the kidney and usually has a good prognosis. Careful attention to its morphology with the judicious use of immunohistochemistry and ultrastuctural analysis can be helpful for its diagnosis and differential diagnosis.


Assuntos
Tumor Glômico/patologia , Neoplasias Renais/patologia , Adulto , Idoso , Biomarcadores Tumorais/análise , Proteínas de Ligação ao Cálcio/análise , Núcleo Celular , Citoplasma , Desmina/análise , Diagnóstico Diferencial , Feminino , Tumor Glômico/química , Tumor Glômico/diagnóstico por imagem , Humanos , Imuno-Histoquímica , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/metabolismo , Masculino , Proteínas dos Microfilamentos/análise , Pessoa de Meia-Idade , Mitose , Recidiva Local de Neoplasia , Prognóstico , Proteínas Proto-Oncogênicas c-kit/análise , Proteínas S100/análise , Fator de Transcrição STAT6/análise , Carga Tumoral , beta Catenina/análise
17.
Zhonghua Bing Li Xue Za Zhi ; 47(7): 505-510, 2018 Jul 08.
Artigo em Chinês | MEDLINE | ID: mdl-29996314

RESUMO

Objective: To investigate the histomorpholgic spectrum, immunophenotypic, and molecular genetic features of Sertoli cell tumor, not otherwise specified (SCT, NOS) of the testis. Methods: Seven cases of SCT, NOS of the testis were analyzed(4 from Peking University Third Hospital and 3 from Zhejiang Provincial People's Hospital) between 2008 and 2017. The histopathologic features were examined based on HE staining, and EnVision method was used for immunohistochemistry staining of calretinin, inhibin, ß-catenin, cyclinD1, CD10, CKpan, neuroendocrine markers, WT1, Melan A, vimentin, SALL4, GATA3, PAX8, and S-100 protein. Mutational analysis of exon 3 of the CTNNB1 gene by polymerase chain reaction (PCR)-amplified sequences and direct sequencing was performed. Results: Patients ages ranged from 22 to 65 years (mean 43 years). The clinical manifestation in all was a slowly enlarging, painless testicular mass.The maximum diameter of the tumor ranged from 1.5 cm to 3.0 cm (mean 2.1 cm). Sectioning usually disclosed a tan-gray to white mass with vague lobular cut-surface. Microscopically, the tumors were well circumscribed and non-encapsulated; the tumor cells were rearranged in multiple growth patterns from diffuse solid sheets to trabeculae and cords, ribbon and solid or hollow tubules setting in variable amount of acellular fibrous stroma. Two cases showed acellular collagenous stroma constituted >50% of the tumor confirming to the diagnosis of sclerosing SCT. One case demonstrated a prominent myxoid stromal change. The tumor cells typically had moderate amounts of pale to lightly eosinophilic cytoplasm, 2 tumors had variable cells with abundant lipid-rich cytoplasm, and 1 other tumor showed scattered aggregates of multinucleated tumor cells. The tumor cells were bland-appearing without any evidence of atypia, mitoses were noted in 2 tumors (both were 1/50 HPF), but necrosis was absent. Immunohistochemical staining results as follows: vimentin (diffuse, 7/7), CD10 (diffuse membrane, 7/7); diffuse ß-catenin nuclear and cytoplasm staining in 5 of 7 cases, and all the 5 cases showed diffuse cyclin D1 nuclear staining, ß-catenin membrane staining in 2 of 7 cases, CKpan (5/7, focal or diffuse), calretinin (focal, 5/6), inhibin (focal, 3/7), synaptophysin (focal, 2/6), CD56 (focal or diffuse, 4/5), WT1 (diffuse nuclear, 4/5), and S-100 protein (diffuse, 3/7), and chromogranin A, Melan A, PAX8, GATA3 and SALL4 all were negative. Molecular genetic studies of PCR and direct sequencing showed CTNNB1 mutations in 4 of 7 (4/7) cases, 4 of the four mutation-carrying cases showed diffuse ß-catenin nuclear and cytoplasm immunoreactivity and diffuse cyclin D1 nuclear immunoreactivity in the tumor cells. Conclusions: SCT, NOS of the testis typically shows significant heterogeneities in both morphology and immunohistochemistry, thus causing differential diagnostic confusions. Molecular analyses showed mutations of exon 3 of CTNNB1 in more than half of these tumors, and nuclear accumulation of ß-catenin and over expression of cyclin D1 can be useful for the differential diagnosis of SCT, NOS.


Assuntos
Biomarcadores Tumorais/análise , Tumor de Células de Sertoli/genética , Tumor de Células de Sertoli/patologia , Neoplasias Testiculares/genética , Neoplasias Testiculares/patologia , Adulto , Idoso , Biópsia , Calbindina 2/análise , Núcleo Celular , Ciclina D1/análise , Citoplasma/química , Análise Mutacional de DNA , Diagnóstico Diferencial , Éxons , Feminino , Humanos , Imuno-Histoquímica , Inibinas/análise , Masculino , Pessoa de Meia-Idade , Mitose , Mutação , Tumor de Células de Sertoli/metabolismo , Neoplasias Testiculares/metabolismo , Adulto Jovem , beta Catenina/análise
18.
Diagn Pathol ; 13(1): 48, 2018 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-30053869

RESUMO

BACKGROUND: Basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC) are benign and malignant, basaloid salivary gland neoplasms, respectively. These tumors show a dual-cell proliferation of inner luminal/ductal cells and outer abluminal/myoepithelial or basal cells. The only difference between them is defined as a malignant morphology such as invasion. Recently, the nuclear expression of ß-catenin and a catenin beta-1 (CTNNB1) mutation were found in BCA. Transducin-like enhancer of split 1 (TLE1) belongs to the Groucho/TLE family, and it functions in the "off" state in the Wnt/ß-catenin signaling pathway. We hypothesized that if the dysregulation of the Wnt/ß-catenin signaling pathway could be attributed to the tumorigenesis of BCA/BCAC, there might be differences in TLE1 expression between BCA and BCAC. METHOD: The study included 35 BCA and 4 BCAC cases. We performed immunohistochemistry to detect TLE1 and ß-catenin and investigated the catenin beta-1 (CTNNB1) mutational profile among BCA and BCAC cases. RESULTS: In BCA, the expression of TLE1 was confined to luminal cells of glandular structures, in contrast to the expression of ß-catenin in abluminal cells. The BCA cases harbored CTNNB1 gene mutations (12/35). In BCAC, luminal cell staining of TLE1 was identical to BCA in non-invasive areas (4/4) but indistinct in invasive areas (3/4). The BCAC cases were ß-catenin positive for abluminal cells in both areas. The BCAC cases had CTNNB1 mutation (2/4) and the laser-captured microdissection allowed the separate collection of infiltrative and non-infiltrative areas to detect the same mutation. CONCLUSIONS: Immunohistochemical analysis for TLE1 can identify BCA and BCAC by luminal cell staining difference, especially indistinct luminal cell expression for TLE1 in invasive areas of BCAC. Moreover, TLE1 can be luminal/ductal cell markers.


Assuntos
Adenocarcinoma/química , Adenoma/química , Biomarcadores Tumorais/análise , Imuno-Histoquímica , Proteínas Repressoras/análise , Neoplasias das Glândulas Salivares/química , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adenoma/genética , Adenoma/patologia , Adenoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Invasividade Neoplásica , Valor Preditivo dos Testes , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/patologia , Neoplasias das Glândulas Salivares/cirurgia , Adulto Jovem , beta Catenina/análise , beta Catenina/genética
19.
Hum Pathol ; 81: 166-175, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30030118

RESUMO

Aberrant Wnt signaling is a hallmark of solid pseudopapillary neoplasms (SPNs) of the pancreas. Transcription factor E3 (TFE3) plays a critical role in activation and regulation of the Wnt pathway and is predicted to be a candidate gene implicated in SPN by gene regulatory network analysis. The aim of this study was to evaluate TFE3 as a marker for SPN. Paraffin-embedded tissues of SPN (n = 75) and other primary pancreatic tumors were analyzed, including pancreatic neuroendocrine tumors (n = 17), pancreatic ductal adenocarcinomas (n = 14), pancreatic neuroendocrine carcinomas (n = 4), and acinar cell carcinomas (n = 3). The clinicopathological features were summarized as well. Differentiation of specific pancreatic duct or acinus was not found in any SPN tissue. Morphologic and immunohistochemical results indicated that SPN displays certain characteristics of neuroendocrine cells. Overall, 71 (94.67%) cases of SPN showed nuclear accumulation for TFE3, most of which displayed moderate to intense expression. The TFE3 positive rates in pancreatic neuroendocrine tumor, pancreatic ductal adenocarcinoma, and pancreatic neuroendocrine carcinoma were 23.53%, 14.29%, and 25%, respectively. All 3 cases of acinar cell carcinoma were negative for TFE3. We conclude that SPN may originate from primordial pancreatic cells and is accompanied by some characteristics of neuroendocrine tumors. TFE3, besides ß-catenin, can be an additional diagnostic marker of SPN in differential diagnosis.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/análise , Biomarcadores Tumorais/análise , Carcinoma de Células Acinares/química , Carcinoma Neuroendócrino/química , Carcinoma Ductal Pancreático/química , Carcinoma Papilar/química , Neoplasias Pancreáticas/química , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Acinares/patologia , Carcinoma Neuroendócrino/patologia , Carcinoma Ductal Pancreático/patologia , Carcinoma Papilar/patologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Adulto Jovem , beta Catenina/análise
20.
Biochem Biophys Res Commun ; 503(1): 359-364, 2018 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-29894684

RESUMO

Dysregulation of gene expression at RNA and protein level is a hallmark of Huntington's disease (HD). Altered levels of microRNAs and beta catenin in HD were studied earlier; however, any direct involvement of full length, basally-expressing mutant huntingtin (Htt) remained to be elusive. Here we reported that the gain-of-function mutation of full-length basally-expressing Htt in HD cell Q111 (STHdhQ111/HdhQ111) upregulated microRNA-214 and decreased beta catenin & its transcriptional activity in an aggregate-independent manner. The result was quite opposite of the function of aggregate-forming mutant Htt fragment 83Q-DsRed. Here, we also reported an elevated level of beta catenin phosphorylation in Q111 cell compared to Q7 cell (SThdhQ7/HdhQ7). We showed that in Q111 cell (compared to Q7), beta catenin was more localized in the cytosol than that of the plasma membrane. This is significant as Gsk3beta phosphorylates beta catenin in the cytosol. Hence, for the first time, our study identified beta catenin localization and mutant Htt status as two key factors of beta catenin regulation in HD.


Assuntos
Proteína Huntingtina/genética , Doença de Huntington/genética , beta Catenina/metabolismo , Animais , Linhagem Celular , Proteína Huntingtina/metabolismo , Doença de Huntington/metabolismo , Camundongos , MicroRNAs/genética , Mutação , Fosforilação , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/metabolismo , Regulação para Cima , beta Catenina/análise
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