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1.
Aging (Albany NY) ; 11(5): 1389-1403, 2019 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-30853664

RESUMO

Mounting evidences have indicated that long noncoding RNAs (lncRNAs) play pivotal roles in human diseases, especially in cancers. Recently, TINCR was proposed to be involved in tumor progression. However, its role in colorectal cancer (CRC) remains elusive. In our study, we found that SP1-induced TINCR was significantly upregulated in CRC tissues and cell lines. Moreover, cox multivariate survival analysis revealed that high TINCR was an independent predictor of poor overall survival (OS). Functionally, knockdown of TINCR obviously suppressed CRC cells proliferation, migration and invasion in vitro, and inhibited CRC cells growth and metastasis in vivo. Mechanistically, we identified TINCR could act as a miR-7-5p sponge using RNA pull down, luciferase reporter and RIP assays. Furthermore, we showed that TINCR might promote CRC progression via miR-7-5p-mediated PI3K/Akt/mTOR signaling pathway. Lastly, we revealed that plasma TINCR expression was upregulated in CRC when compared to healthy controls and could be a promising diagnostic biomarker for CRC. Based on above results, our data indicated that TINCR might serve as a potential diagnostic and prognostic biomarker for CRC.

2.
Pathol Res Pract ; 215(5): 900-904, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30732916

RESUMO

BACKGROUND: Gastric cancer (GC) is one of the most common cancers globally leading to 850,000 deaths each year. GC patients are often diagnosed at advanced stages which results in poor prognosis. This study aimed to identify a novel circulating miRNA as the diagnostic biomarker of GC and further explore its regulatory mechanisms in GC. MATERIALS AND METHODS: First, the candidate serum miRNA was selected after analysis of microarray data. Then, the levels of candidate miRNA in the serum of GC patients were validated in an independent cohort. The diagnostic utility of miRNA was evaluated by using receiver operating characteristic curve (ROC) analysis. The functional and pathways enrichment analysis of targets of candidate miRNA were explored by online tool DAVID. RESULTS: After comprehensive analysis of Gene Expression Omnibus (GEO) dataset, miR-551b-5p was selected as candidate due to its highest differential fold-change. Another independent cohort showed that serum miR-551b-5p could differentiate GC patients from healthy controls (HCs) with area under the curve (AUC) of 0.84 (95%CI: 0.75-0.93). The functional and pathways enrichment analysis revealed that targets of miR-551b-5p mainly located in cytoplasm and significantly associated with regulation of ubiquitin-dependent protein catabolic process, cell division, and mRNA stability. CONCLUSIONS: Circulating miR-551b-5p was a novel promising biomarker for the detection of GC and exploration of the molecular mechanisms of miR-551b-5p is useful to search for new therapeutic strategies of GC.


Assuntos
Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , MicroRNAs/sangue , Neoplasias Gástricas/sangue , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Humanos , Sensibilidade e Especificidade
3.
Oncol Rep ; 40(2): 1093-1102, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29845201

RESUMO

Recent studies have revealed that overexpression of long non­coding RNA (lncRNA) PVT1 is correlated with several types of cancer. However, its role in pancreatic cancer development remains to be clarified. In the present study, we found that PVT1 promoted the growth and the epithelial­mesenchymal transition (EMT) of pancreatic cancer cells. We first determined that PVT1 was upregulated in pancreatic cancer tissues compared with adjacent normal tissues. Knockdown of PVT1 inhibited viability, adhesion, migration and invasion. Furthermore, PVT1 knockdown reduced the expression of mesenchymal markers including Snail, Slug, ß­catenin, N­cadherin and vimentin, while it increased epithelial marker expression of E­cadherin. Finally, knockdown of PVT1 inhibited the TGF­ß/Smad signaling, including p­Smad2/3 and TGF­ß1 but enhanced the expression of Smad4. In contrast, overexpression of PVT1 reversed the process. These findings revealed that PVT1 acts as an oncogene in pancreatic cancer, possibly through the regulation of EMT via the TGF­ß/Smad pathway and PVT1 may serve as a potential target for diagnostics and therapeutics in pancreatic cancer.


Assuntos
Transição Epitelial-Mesenquimal/genética , Neoplasias Pancreáticas/genética , RNA Longo não Codificante/genética , Proteínas Smad/genética , Fator de Crescimento Transformador beta/genética , Biomarcadores Tumorais/genética , Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Neoplasias Pancreáticas/patologia , Regulação para Cima/genética
4.
Mol Cell Biochem ; 431(1-2): 161-168, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28281184

RESUMO

Although the function of miR-200a has been discussed in many cancers and fibrotic diseases, its role in pancreatic fibrosis is still poorly understood. In this study, we for the first time confirm that miR-200a attenuates TGF-ß1-induced pancreatic stellate cells activation and extracellular matrix formation. First, we find that TGF-ß1 induces activation and extracellular matrix (ECM) formation in PSCs, and the effects are blocked by the inhibitor of PI3K (LY294002). Furthermore, we identify that miR-200a is down-regulated in TGF-ß1-activated PSCs, and up-regulation of miR-200a inhibits PSCs activation induced by TGF-ß1. Meanwhile, TGF-ß1 inhibits the expression of the epithelial marker E-cadherin, and increases the expression of mesenchymal markers vimentin, and the expression of ECM proteins a-SMA and collagen I, while miR-200a mimic reversed the above effects in PSCs, indicating that miR-200a inhibits TGF-ß1-induced activation and epithelial-mesenchymal transition (EMT). In addition, overexpression of miR-200a promotes the expression of PTEN and decreases the expression of matrix proteins and attenuates phosphorylation of Akt and mTOR. Taken together, our study uncovers a novel mechanism that miR-200a attenuates TGF-ß1-induced pancreatic stellate cells activation and ECM formation through inhibiting PTEN /Akt/mTOR pathway.


Assuntos
Transição Epitelial-Mesenquimal , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Células Estreladas do Pâncreas/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , Animais , Cromonas/farmacologia , Matriz Extracelular/metabolismo , Fibrose , Masculino , Morfolinas/farmacologia , Células Estreladas do Pâncreas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley
5.
Cancer Lett ; 369(1): 124-33, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26276718

RESUMO

Drug resistance in gastric cancer largely results from the gastric cancer stem cells (GCSCs), which could be targeted to improve the efficacy of chemotherapy. In this study, we identified a subpopulation of GCSCs enriched in holoclones that expressed CD44(+)/Musashi-1(+) stem cell biomarkers, capable of self-renewal and proliferation. Enriched CD44(+)/Musashi-1(+) GCSCs demonstrated elevated expression of sonic hedgehog (SHH) and glioma-associated oncogene homolog 1 (GLI1), the well-known signaling pathway molecules involved in the drug resistance. Further, CD44(+)/Musashi-1(+) cells exhibited high drug efflux bump activity and were resistant to doxorubicin (Dox)-induced apoptosis, and unregulated the ATP-binding cassette sub-family G member 2 (ABCG2) expression,. The above effects on apoptosis were reversed in the presence of GLI inhibitors, GANT61 and GDC-0449, or by the knockdown of GLI1/SHH. Upon knockdown of GLI1, expression of ABCG2 was downregulated the antitumor effects were significantly improved as observed in the gastric cancer xenograft. Collectively, our study revealed that co-expression of CD44(+)/Musashi-1(+) could be used to identify GCSCs, which also accounts for the drug resistance in gastric cancer. SHH-GLI and its downstream effector ABCG2 could be better targeted to possibly improve the efficacy of chemotherapy in drug-resistant gastric cancers.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Proteínas Hedgehog/metabolismo , Receptores de Hialuronatos/metabolismo , Células-Tronco Neoplásicas/fisiologia , Neoplasias Gástricas/tratamento farmacológico , Fatores de Transcrição/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Anilidas/farmacologia , Animais , Antibióticos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Autorrenovação Celular , Doxorrubicina/farmacologia , Feminino , Expressão Gênica , Células HEK293 , Humanos , Camundongos Nus , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Piridinas/farmacologia , Transdução de Sinais , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína GLI1 em Dedos de Zinco
6.
Mol Endocrinol ; 28(1): 116-26, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24264575

RESUMO

Liver glycogen metabolism plays an important role in glucose homeostasis. Glycogen synthesis is mainly regulated by glycogen synthase that is dephosphorylated and activated by protein phosphatase 1 (PP1) in combination with glycogen-targeting subunits or G subunits. There are seven G subunits (PPP1R3A to G) that control glycogenesis in different organs. PPP1R3G is a recently discovered G subunit whose expression is changed along the fasting-feeding cycle and is proposed to play a role in postprandial glucose homeostasis. In this study, we analyzed the physiological function of PPP1R3G using a mouse model with liver-specific overexpression of PPP1R3G. PPP1R3G overexpression increases hepatic glycogen accumulation, stimulates glycogen synthase activity, elevates fasting blood glucose level, and accelerates postprandial blood glucose clearance. In addition, the transgenic mice have a reduced fat composition, together with decreased hepatic triglyceride level. Fasting-induced hepatic steatosis is relieved by PPP1R3G overexpression. In addition, PPP1R3G overexpression is able to elevate glycogenesis in primary hepatocytes. The glycogen-binding domain is indispensable for the physiological activities of PPP1R3G on glucose metabolism and triglyceride accumulation in the liver. Cumulatively, these data indicate that PPP1R3G plays a critical role in postprandial glucose homeostasis and liver triglyceride metabolism via its regulation on hepatic glycogenesis.


Assuntos
Glucose/metabolismo , Homeostase , Metabolismo dos Lipídeos , Glicogênio Hepático/biossíntese , Fígado/metabolismo , Proteína Fosfatase 1/metabolismo , Animais , Sítios de Ligação , Glicemia , Células Cultivadas , Metabolismo Energético , Hepatócitos/metabolismo , Resistência à Insulina , Camundongos , Camundongos Transgênicos , Especificidade de Órgãos , Cultura Primária de Células , Proteína Fosfatase 1/genética , Triglicerídeos/metabolismo
7.
Zhonghua Zhong Liu Za Zhi ; 36(12): 897-902, 2014 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-25623762

RESUMO

OBJECTIVE: To investigate the reversal effect of targeted modulation of bcl-2 expression by miR-15a and miR-16 on drug resistance of human colon cancer cells. METHODS: Mimics or inhibitors of miR-15a and miR-16 were transfected into HCT8 or HCT8/VCR cells with the help of Lipofectamine 2000. The expressions of miR-15a and miR-16 mRNA were detected by RT-qPCR. The levels of bcl-2 and P-gp proteins were measured by Western blot. The inhibitory effects of VCR on growth of HCT8 and HCT8/VCR cells were detected by CCK8. RESULTS: After transfection of the mimics, the expression of miR-15a in the blank control group, negative control group and miR-15a mimic group was 1.00, 0.87 ± 0.24, and 223.44 ± 59.07, respectively, and miR-15a was increased significantly (P < 0.001). The expression of miR-16 in the blank control group, negative control group and miR-16 mimic group was 1.00, 0.66 ± 0.19, and 107.32 ± 22.58, respectively, and miR-16 expression was increased significantly (P < 0.001). The Western blot assay showed that the relative expressions of bcl-2 protein in the blank control group, negative control group, miR-15a mimic group and miR-16 mimic group were 1.00, 0.97 ± 0.02, 0.51 ± 0.06, and 0.65 ± 0.03, respectively, and the expression of bcl-2 protein was decreased significantly (P < 0.05), however, the expressions of P-gp protein showed no significant difference. The CCK8 test showed that at 1, 5, 25 and 125 µg/ml concentration of VCR, the survival rates of HCT8/VCR cells were basically the same in the blank control group, negative control group, miR-15a mimic group and miR-16 mimic group, but the survival rate of HCT8/VCR cells was significantly decreased after transfection of mimics (P < 0.05). After transfection of the inhibitors, the expressions of both miR-15a and miR-16 were decreased significantly (P < 0.001). The Western blot showed that the expression of bcl-2 protein was increased (P < 0.05), while the expression of P-gp protein showed no significant difference. The CCK8 test showed that the survival rate of HCT8 cells which were transfected with inhibitors was significantly higher than that of the blank control group (P < 0.05). CONCLUSIONS: miR-15a and miR-16 may reverse the drug resistance in human colon cancer cells. A possible mechanism is regulating the expression of bcl-2.


Assuntos
MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo , Resistência a Medicamentos , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Mensageiro , Transfecção
8.
J Biol Chem ; 287(47): 39653-63, 2012 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-23027871

RESUMO

Upon activation, TGF-ß type I receptor (TßRI) undergoes active ubiquitination via recruitment of E3 ligases to the receptor complex by Smad7. However, how ubiquitination of TßRI is coupled to intracellular trafficking, and protein degradation remains unclear. We report here that Tollip, an adaptor protein that contains both ubiquitin-associated domains and endosome-targeting domain, plays an important role in modulating trafficking and degradation of TßRI. Tollip was previously demonstrated to possess a functional role in modulating the signaling of interleukin-1 and Toll-like receptors. We identify here that Tollip interacts with Smad7, a major modulatory protein involved in the negative regulation of TGF-ß signaling. Overexpression of Tollip antagonizes TGF-ß-stimulated transcriptional response, Smad2 phosphorylation, and epithelial-mesenchymal transition. Tollip also interacts with ubiquitinated TßRI, and such interaction requires ubiquitin-associated domains of Tollip. The interaction and intracellular colocalization of Tollip with TßRI is enhanced by Smad7. Overexpression of Tollip accelerates protein degradation of activated TßRI. In addition, Tollip alters subcellular compartmentalization and endosomal trafficking of activated TßRI. Collectively, our studies reveal that Tollip cooperates with Smad7 to modulate intracellular trafficking and degradation of ubiquitinated TßRI, whereby negatively regulates TGF-ß signaling pathway.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteólise , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Ubiquitinação/fisiologia , Animais , Endossomos/genética , Endossomos/metabolismo , Células HeLa , Células Hep G2 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Camundongos , Estrutura Terciária de Proteína , Transporte Proteico/fisiologia , Proteínas Serina-Treonina Quinases/genética , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/genética , Proteína Smad7/genética , Proteína Smad7/metabolismo , Fator de Crescimento Transformador beta/genética
9.
J Biol Chem ; 287(45): 37973-85, 2012 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-22969086

RESUMO

Liver X receptors (LXRs) are nuclear receptors that function to modulate lipid metabolism as well as immune and inflammatory responses. Upon activation by their ligands, LXRs up-regulate a spectrum of gene transcription programs involved in cholesterol and fatty acid homeostasis. However, the mechanisms by which LXR-mediated transcriptional activation is regulated remain incompletely understood. Here, we show that PIAS1, a member of the protein inhibitor of the activated STAT family of proteins with small ubiquitin-like modifier (SUMO) E3 ligase activity, acts to suppress LXR ligand-dependent transcriptional activation of the lipogenic program in hepatocytes. We found that liver mRNA expression levels of Pias1 and Pias3 were inversely associated with those of genes involved in lipogenesis in mouse models with diet-induced or genetic obesity. Overexpression of PIAS1 in primary hepatocytes resulted in a reduction of LXR ligand-induced fatty acid synthesis and suppression of the expression of lipogenic genes, including Srebp1c and Fas. Moreover, PIAS1 was able to interact with LXRß and repress its transcriptional activity upon ligand stimulation, which did not require PIAS1-promoted SUMO modification of LXRß. In addition, PIAS1 could also interact with PGC-1ß and attenuate its association with LXRß, blunting the ability of PGC-1ß to co-activate LXRß. Importantly, PIAS1 impaired LXRß binding to its target DNA sequence. Taken together, our results suggest that PIAS1 may serve as a lipogenic regulator by negatively modulating LXRs in a SUMOylation-independent manner.


Assuntos
Lipogênese/genética , Receptores Nucleares Órfãos/genética , Proteínas Inibidoras de STAT Ativados/genética , Ativação Transcricional/genética , Animais , Western Blotting , Células Cultivadas , Ácidos Graxos/biossíntese , Células HEK293 , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Hidrocarbonetos Fluorados/farmacologia , Ligantes , Fígado/citologia , Fígado/metabolismo , Receptores X do Fígado , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/etiologia , Obesidade/genética , Obesidade/metabolismo , Receptores Nucleares Órfãos/agonistas , Receptores Nucleares Órfãos/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Ligação Proteica/efeitos dos fármacos , Proteínas Inibidoras de STAT Ativados/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sulfonamidas/farmacologia , Sumoilação , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição , Ativação Transcricional/efeitos dos fármacos
10.
Cell Res ; 22(4): 661-76, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21968647

RESUMO

Ras plays a pivotal role in many cellular activities, and its subcellular compartmentalization provides spatial and temporal selectivity. Here we report a mode of spatial regulation of Ras signaling in the Golgi apparatus by two highly homologous proteins PAQR10 and PAQR11 of the progestin and AdipoQ receptors family. PAQR10 and PAQR11 are exclusively localized in the Golgi apparatus. Overexpression of PAQR10/PAQR11 stimulates basal and EGF-induced ERK phosphorylation and increases the expression of ERK target genes in a dose-dependent manner. Overexpression of PAQR10/PAQR11 markedly elevates Golgi localization of HRas, NRas and KRas4A, but not KRas4B. PAQR10 and PAQR11 can also interact with HRas, NRas and KRas4A, but not KRas4B. The increased Ras protein at the Golgi apparatus by overexpression of PAQR10/PAQR11 is in an active state. Consistently, knockdown of PAQR10 and PAQR11 reduces EGF-stimulated ERK phosphorylation and Ras activation at the Golgi apparatus. Intriguingly, PAQR10 and PAQR11 are able to interact with RasGRP1, a guanine nucleotide exchange protein of Ras, and increase Golgi localization of RasGRP1. The C1 domain of RasGRP1 is both necessary and sufficient for the interaction of RasGRP1 with PAQR10/PAQR11. The simulation of ERK phosphorylation by overexpressed PAQR10/PAQR11 is abrogated by downregulation of RasGRP1. Furthermore, differentiation of PC12 cells is significantly enhanced by overexpression of PAQR10/PAQR11. Collectively, this study uncovers a new paradigm of spatial regulation of Ras signaling in the Golgi apparatus by PAQR10 and PAQR11.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Complexo de Golgi/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptores de Superfície Celular/metabolismo , Comunicação Celular/genética , Compartimento Celular/genética , Diferenciação Celular/genética , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica , Complexo de Golgi/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Células HEK293 , Células HeLa , Humanos , Sistema de Sinalização das MAP Quinases/genética , Células PC12 , Fosforilação , Ligação Proteica , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptores de Superfície Celular/genética
11.
Diabetes ; 60(5): 1435-45, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21471512

RESUMO

OBJECTIVE: Most animals experience fasting-feeding cycles throughout their lives. It is well known that the liver plays a central role in regulating glycogen metabolism. However, how hepatic glycogenesis is coordinated with the fasting-feeding cycle to control postprandial glucose homeostasis remains largely unknown. This study determines the molecular mechanism underlying the coupling of hepatic glycogenesis with the fasting-feeding cycle. RESEARCH DESIGN AND METHODS: Through a series of molecular, cellular, and animal studies, we investigated how PPP1R3G, a glycogen-targeting regulatory subunit of protein phosphatase 1 (PP1), is implicated in regulating hepatic glycogenesis and glucose homeostasis in a manner tightly orchestrated with the fasting-feeding cycle. RESULTS: PPP1R3G in the liver is upregulated during fasting and downregulated after feeding. PPP1R3G associates with glycogen pellet, interacts with the catalytic subunit of PP1, and regulates glycogen synthase (GS) activity. Fasting glucose level is reduced when PPP1R3G is overexpressed in the liver. Hepatic knockdown of PPP1R3G reduces postprandial elevation of GS activity, decreases postprandial accumulation of liver glycogen, and decelerates postprandial clearance of blood glucose. Other glycogen-targeting regulatory subunits of PP1, such as PPP1R3B, PPP1R3C, and PPP1R3D, are downregulated by fasting and increased by feeding in the liver. CONCLUSIONS: We propose that the opposite expression pattern of PPP1R3G versus other PP1 regulatory subunits comprise an intricate regulatory machinery to control hepatic glycogenesis during the fasting-feeding cycle. Because of its unique expression pattern, PPP1R3G plays a major role to control postprandial glucose homeostasis during the fasting-feeding transition via its regulation on liver glycogenesis.


Assuntos
Glicemia/metabolismo , Jejum/sangue , Jejum/fisiologia , Glicogênio Hepático/biossíntese , Fígado/metabolismo , Proteína Fosfatase 1/metabolismo , Animais , Hepatócitos/metabolismo , Immunoblotting , Imunoprecipitação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Período Pós-Prandial , Proteína Fosfatase 1/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
12.
Clin Res Hepatol Gastroenterol ; 35(4): 325-8, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21482220

RESUMO

Glomus tumors, as a type of quite rare neoplasms, originate from modified smooth muscle cells of the glomus body whose function is to regulate blood flow within arteries according to the body temperature. Although these tumors most commonly occur in the peripheral soft tissues, especially in the distal parts of extremities, there have been rare reports of visceral involvement (Lorber et al., 2005) [1]. We report a case of gastric glomus tumor, which was preoperatively diagnosed by ultrasonic endoscopy as a gastric stromal tumor and treated by endoscopic submucosal dissection (ESD).


Assuntos
Gastroscopia , Tumor Glômico/cirurgia , Neoplasias Gástricas/cirurgia , Feminino , Mucosa Gástrica/cirurgia , Humanos , Pessoa de Meia-Idade
13.
Carcinogenesis ; 29(6): 1157-63, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18515281

RESUMO

Raf kinase trapping to Golgi (RKTG) is a newly characterized negative regulator of the Ras-Raf-mitogen-activated and extracellular signal-regulated kinase kinase (MEK)-extracellular signal-regulated kinase (ERK)-signaling pathway via sequestrating Raf-1 to the Golgi apparatus. Among Raf kinase family members, B-Raf is the most frequently mutated gene in human cancers and an activated B-Raf mutation V600E is associated with >60% of human melanomas. Here, we show that RKTG can also bind and translocate B-Raf to the Golgi apparatus. When overexpressed in A375, a human malignant melanoma cell line with B-Raf(V600E), RKTG inhibits ERK activation, cell proliferation and transformation of A375 cells. In addition, the tumorigenicity of the RKTG-expressing A375 cells is suppressed in nude mice. Consistently, cell proliferation rate was reduced in the tumor xenografts in which RKTG was overexpressed. Collectively, our results suggest that RKTG may play a suppressive role in human melanoma that harbors an oncogenic B-Raf mutation via its antagonistic action on B-Raf.


Assuntos
Complexo de Golgi/enzimologia , Melanoma/enzimologia , Proteínas Proto-Oncogênicas B-raf/metabolismo , Neoplasias Cutâneas/enzimologia , Quinases raf/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Ativação Enzimática/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Immunoblotting , Imunoprecipitação , Melanoma/genética , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Confocal , Mutação , Transporte Proteico/fisiologia , Proteínas Proto-Oncogênicas B-raf/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Cutâneas/genética , Transfecção
14.
Biochem J ; 414(3): 399-406, 2008 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-18547165

RESUMO

RKTG (Raf kinase trapping to Golgi) is exclusively localized at the Golgi apparatus and functions as a spatial regulator of Raf-1 kinase by sequestrating Raf-1 to the Golgi. Based on the structural similarity with adiponectin receptors, RKTG was predicted to be a seven-transmembrane protein with a cytosolic N-terminus, distinct from classical GPCRs (G-protein-coupled receptors). We analysed in detail the topology and functional domains of RKTG in this study. We determined that the N-terminus of RKTG is localized on the cytosolic side. Two short stretches of amino acid sequences at the membrane proximal to the N- and C-termini (amino acids 61-71 and 299-303 respectively) were indispensable for Golgi localization of RKTG, but were not required for the interaction with Raf-1. The three loops facing the cytosol between the transmembrane domains had different roles in Golgi localization and Raf-1 interaction. While the first cytosolic loop was only important for Golgi localization, the third cytosolic loop was necessary for both Golgi localization and Raf-1 sequestration. Taken together, these findings suggest that RKTG is a type III membrane protein with its N-terminus facing the cytosol and multiple sequences are responsible for its localization at the Golgi apparatus and Raf-1 interaction. As RKTG is the first discovered Golgi protein with seven transmembrane domains, the knowledge derived from this study would not only provide structural information about the protein, but also pave the way for future characterization of the unique functions of RKTG in the regulation of cell signalling.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Citosol/metabolismo , Complexo de Golgi/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/análise , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-raf/química , Proteínas Proto-Oncogênicas c-raf/metabolismo , Transfecção
15.
Zhongguo Zhong Xi Yi Jie He Za Zhi ; 27(12): 1123-5, 2007 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-18198649

RESUMO

OBJECTIVE: To evaluate the effect of retention enema with combination of Chinese and Western drugs in treating chronic ulcerative colitis (CUC). METHODS: The therapeutic effects of retention enema with combination of Chinese and Western drugs (as tested group) and with Western drugs alone (as control group) were compared in a randomized controlled trial. RESULTS: The total effective rate of clinical curative in the tested group and the control group was 96.7% and 73.3% respectively, the difference between them was significant (chi2 = 4.71, P < 0.05). Statistical difference in comparing pre- and post-treatment condition and comparing between groups was shown in comparison of symptoms, scores of endoscopic picture (except that of polypus), and routine examination of stool (except pus cell number, all P < 0.05). The total recurrence rate of the tested group was 33.3% and the control group 60.0%, the difference between them was significant (chi2 = 4.286, P < 0.05). CONCLUSION: Retention enema with combination of Chinese and Western drugs has good curative effects in treating CUC.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Dexametasona/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Gentamicinas/uso terapêutico , Administração Retal , Adulto , Idoso , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Dexametasona/administração & dosagem , Quimioterapia Combinada , Medicamentos de Ervas Chinesas/administração & dosagem , Feminino , Gentamicinas/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Fitoterapia , Resultado do Tratamento
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