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1.
Acta Physiologica Sinica ; (6): 157-166, 2020.
Article in Chinese | WPRIM | ID: wpr-827072

ABSTRACT

This study was aimed to investigate the regulatory mechanism of heat shock protein 90 (Hsp90) on transcription factor EB (TFEB) during autophagy in liver cancer cells. Human hepatocellular carcinoma cell line HepG2 was treated with Hsp90 N- and C-terminal inhibitors (STA9090 and Novobiocin), respectively. Western blot and RT-PCR were used to detect the expression levels of TFEB and autophagy-related proteins. Chromatin immunoprecipitation (ChIP) assay was used to observe the ability of Hsp90α binding to the TFEB proximal promoter region. The double-luciferase gene reporter experiment was used to determine the activity of TFEB promoter. The results showed that hypoxia induced up-regulation of TFEB protein and mRNA expression levels in the HepG2 cells. The protein expression levels of TFEB, LC3 and P62 were down-regulated significantly by either STA9090 or Novobiocin, under both normoxic and hypoxic conditions. Transfection of Hsp90α-overexpressing plasmids up-regulated TFEB protein levels in either wild-type or Hsp90α knockout HepG2 cells. Hsp90 bound to the TFEB proximal promoter region and was involved in regulating TFEB transcriptional process. Whereas both STA9090 and Novobiocin inhibited Hsp90 to bind to the TFEB proximal promoter region, and decreased the activity of TFEB promoter. These results suggest that Hsp90 promotes TFEB transcription in human hepatocellular carcinoma cells by binding to the proximal promoter region, thereby up-regulating the expression levels of autophagy-related proteins.


Subject(s)
Autophagy , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Metabolism , Carcinoma, Hepatocellular , Metabolism , Pathology , HSP90 Heat-Shock Proteins , Metabolism , Hep G2 Cells , Humans , Liver Neoplasms , Metabolism , Pathology , Promoter Regions, Genetic
2.
Article in English | WPRIM | ID: wpr-773601

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD) and type 2 Diabetes Mellitus (T2DM) are highly prevalent diseases and are closely associated, with NAFLD being present in the majority of T2DM patients. In Asian traditional medicine, Mori Cortex is widely used for the treatment of diabetes and hyperlipidemia. However, whether it has a therapeutic effect on T2DM associated with NAFLD is still unknown. The present study showed that the oral treatment with Mori Cortex extract (MCE; 10 g·kg·d) lowered the blood lipid levels and reversed insulin resistance (IR) in high fat-diet/streptozotocin-induced type 2 diabetes in rats. The expression levels of sterol receptor element-binding protein-1c (SREBP-1c) and carbohydrate-responsive element binding protein (ChREBP), which are involved in steatosis in NAFLD rats, were measured in the liver samples. MCE decreased the protein and mRNA expression levels of SREBP-1c and ChREBP. In conclusion, down-regulation of SREBP-1c and ChREBP might contribute to the protective effect of MCE on hepatic injury and IR in the rats with T2DM associated with NAFLD.


Subject(s)
Alanine Transaminase , Blood , Animals , Aspartate Aminotransferases , Blood , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Genetics , Diabetes Mellitus, Type 2 , Blood , Drug Therapy , Metabolism , Diet, High-Fat , Disease Models, Animal , Down-Regulation , Insulin , Blood , Insulin Resistance , Physiology , Lipid Metabolism , Genetics , Liver , Male , Morus , Non-alcoholic Fatty Liver Disease , Blood , Drug Therapy , Metabolism , Phytotherapy , Plant Extracts , Pharmacology , Therapeutic Uses , Rats , Rats, Sprague-Dawley , Streptozocin
3.
Article in English | WPRIM | ID: wpr-812390

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD) and type 2 Diabetes Mellitus (T2DM) are highly prevalent diseases and are closely associated, with NAFLD being present in the majority of T2DM patients. In Asian traditional medicine, Mori Cortex is widely used for the treatment of diabetes and hyperlipidemia. However, whether it has a therapeutic effect on T2DM associated with NAFLD is still unknown. The present study showed that the oral treatment with Mori Cortex extract (MCE; 10 g·kg·d) lowered the blood lipid levels and reversed insulin resistance (IR) in high fat-diet/streptozotocin-induced type 2 diabetes in rats. The expression levels of sterol receptor element-binding protein-1c (SREBP-1c) and carbohydrate-responsive element binding protein (ChREBP), which are involved in steatosis in NAFLD rats, were measured in the liver samples. MCE decreased the protein and mRNA expression levels of SREBP-1c and ChREBP. In conclusion, down-regulation of SREBP-1c and ChREBP might contribute to the protective effect of MCE on hepatic injury and IR in the rats with T2DM associated with NAFLD.


Subject(s)
Alanine Transaminase , Blood , Animals , Aspartate Aminotransferases , Blood , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Genetics , Diabetes Mellitus, Type 2 , Blood , Drug Therapy , Metabolism , Diet, High-Fat , Disease Models, Animal , Down-Regulation , Insulin , Blood , Insulin Resistance , Physiology , Lipid Metabolism , Genetics , Liver , Male , Morus , Non-alcoholic Fatty Liver Disease , Blood , Drug Therapy , Metabolism , Phytotherapy , Plant Extracts , Pharmacology , Therapeutic Uses , Rats , Rats, Sprague-Dawley , Streptozocin
4.
ABCD arq. bras. cir. dig ; 29(4): 227-231, Oct.-Dec. 2016. tab
Article in English | LILACS | ID: biblio-837532

ABSTRACT

ABSTRACT Background: Gastric cancer is the fifth most frequent cancer and the third most common cause of cancer-related deaths worldwide.It has been reported that Wnt/ betacatenin pathway is activated in 30-50% of these tumors. However,the deregulation of this pathway has not been fully elucidated. Aim: To determine the expression of E-cadherin, betacatenin, APC, TCF-4 and survivin proteins in gastric adenocarcinoma tissues and correlate with clinical and pathological parameters. Method: Seventy-one patients with gastric adenocarcinoma undergoing gastrectomy were enrolled. The expression of E-cadherin, betacatenin, APC, TCF-4 and survivin proteins was detected by immunohistochemistryand related to the clinical and pathological parameters. Results: The expression rates of E-cadherin in the membrane was 3%; betacatenin in the cytoplasm and nucleus were 23,4% and 3,1% respectively; APC in the cytoplasm was 94,6%; TCF-4 in the nucleus was 19,4%; and survivin in the nucleus 93,9%. The expression rate of E-cadherin was correlated with older patients (p=0,007), while betacatenin with tumors <5 cm (p=0,041) and APC with proximal tumors (p=0,047). Moreover, the expression of TCF-4 was significantly higher in the diffuse type (p=0,017) and T4 tumors (p=0,002). Conclusion: The Wnt/betacatenin is not involved in gastric carcinogenesis. However, the high frequency of survivin allows to suggest that other signaling pathways must be involved in the transformation of gastric tissue.


RESUMO Racional: O câncer gástrico encontra-se entre as principais neoplasias malignas do mundo sendo o quinto mais incidente e o terceiro em relação ao índice de mortalidade. Acredita-se que a via Wnt/betacatenina esteja ativada em 30-50% desses tumores, porém a desregulação dela ainda não está completamente esclarecida. Objetivo: Avaliar a imunoexpressão das proteínas E-caderina, betacatenina, APC, TCF-4 e survivina em tecidos de adenocarcinoma gástrico e correlacioná-las com as variáveis clínicas dos doentes e anatomopatológicas do tumor. Método: Foram coletados os dados clínicos e anatomopatológicos dos prontuários de 71 doentes com adenocarcinoma gástrico submetidos à gastrectomia. O material obtido na operação foi submetido à análise imunoistoquímica e a frequência da expressão de cada proteína pôde ser analisada de acordo com a sua localização na célula e relacionada com as variáveis clinicopatológicas. Resultados: A graduação percentualda expressão e da localização das proteínas foi a seguinte: E-caderina em 3% na membrana; betacatenina em 23,4% no citoplasma e 3,1% no núcleo; APC em 94,6% no citoplasma; TCF-4 em19,4% no núcleo; e survivina em 93,9% no núcleo. Houve relação entre expressão da proteína E-caderina com a idade mais avançada (p=0,007); betacatenina com tumores <5 cm de diâmetro (p=0,041);APC com tumores proximais (p=0,047); e TCF-4 com tipo difuso da classificação de Lauren (p=0,017) e com o grau de penetração tumoral (p=0,002). Conclusão: A via Wnt/betacatenina não está envolvida na carcinogênese gástrica. Porém, a frequência elevada de survivina permite sugerir que outras vias sinalizadoras devam estar envolvidas na transformação do tecido gástrico.


Subject(s)
Humans , Male , Female , Middle Aged , Stomach Neoplasms/metabolism , Adenocarcinoma/metabolism , Cadherins/biosynthesis , Wnt Proteins/biosynthesis , Transcription Factors/biosynthesis , Antigens, CD , Adenomatous Polyposis Coli Protein/biosynthesis , Inhibitor of Apoptosis Proteins/biosynthesis , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/biosynthesis , Wnt Signaling Pathway , Transcription Factor 4 , Survivin
5.
Chinese Journal of Pathology ; (12): 16-20, 2016.
Article in Chinese | WPRIM | ID: wpr-278567

ABSTRACT

<p><b>OBJECTIVE</b>To study the clinicopathologic features and differential diagnosis of alveolar soft part sarcoma (ASPS).</p><p><b>METHODS</b>The clinical data and pathologic features of 48 cases of ASPS were evaluated. Immunohistochemical study, PAS staining and fluorescence in-situ hybridization (FISH) were carried out in selected examples. Relevant literature was reviewed.</p><p><b>RESULTS</b>Amongst the 48 cases studied, there were 17 males and 31 females, with male-to-female ratio of 1.0∶1.8. The age of patients ranged from 2 to 60 years (median=26 years). The tumor was most commonly located in deep soft tissue, especially that of lower extremities. Histologically, the tumor cells were arranged in alveolar or solid patterns and separated by sinusoidal vessels. They were large and contained abundant eosinophilic granules or crystals in cytoplasm. The nuclei were round to polygonal and vesicular, often with prominent nucleoli. Intravascular tumor extension was common. Some cases showed necrosis, hemorrhage and cystic changes. Immunohistochemical study showed that the tumor cells were positive for TFE3 (100%, 33/33). FISH assay was carried out in 4 cases and all of them had TFE3-ASPL gene fusion.</p><p><b>CONCLUSIONS</b>ASPS is a rare malignant neoplasm, often occurs in young patients. TFE3 is a useful immunohistochemical marker for diagnosis. The diagnosis is further confirmed by other markers.</p>


Subject(s)
Adolescent , Adult , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Genetics , Child , Child, Preschool , Diagnosis, Differential , Female , Gene Fusion , Humans , In Situ Hybridization, Fluorescence , Male , Middle Aged , Oncogene Proteins, Fusion , Genetics , Sarcoma, Alveolar Soft Part , Diagnosis , Pathology , Young Adult
6.
Protein & Cell ; (12): 417-433, 2016.
Article in English | WPRIM | ID: wpr-757122

ABSTRACT

Microglia play a pivotal role in clearance of Aβ by degrading them in lysosomes, countering amyloid plaque pathogenesis in Alzheimer's disease (AD). Recent evidence suggests that lysosomal dysfunction leads to insufficient elimination of toxic protein aggregates. We tested whether enhancing lysosomal function with transcription factor EB (TFEB), an essential regulator modulating lysosomal pathways, would promote Aβ clearance in microglia. Here we show that microglial expression of TFEB facilitates fibrillar Aβ (fAβ) degradation and reduces deposited amyloid plaques, which are further enhanced by deacetylation of TFEB. Using mass spectrometry analysis, we firstly confirmed acetylation as a previously unreported modification of TFEB and found that SIRT1 directly interacted with and deacetylated TFEB at lysine residue 116. Subsequently, SIRT1 overexpression enhanced lysosomal function and fAβ degradation by upregulating transcriptional levels of TFEB downstream targets, which could be inhibited when TFEB was knocked down. Furthermore, overexpression of deacetylated TFEB at K116R mutant in microglia accelerated intracellular fAβ degradation by stimulating lysosomal biogenesis and greatly reduced the deposited amyloid plaques in the brain slices of APP/PS1 transgenic mice. Our findings reveal that deacetylation of TFEB could regulate lysosomal biogenesis and fAβ degradation, making microglial activation of TFEB a possible strategy for attenuating amyloid plaque deposition in AD.


Subject(s)
Alzheimer Disease , Metabolism , Pathology , Amyloid beta-Peptides , Metabolism , Amyloid beta-Protein Precursor , Genetics , Metabolism , Animals , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Chemistry , Genetics , Metabolism , Brain , Metabolism , Cells, Cultured , Chloride Channels , Genetics , Metabolism , Disease Models, Animal , HEK293 Cells , Humans , Lysosomes , Genetics , Metabolism , Mice , Mice, Transgenic , Microglia , Cell Biology , Metabolism , Mutagenesis, Site-Directed , Peptides , Chemistry , Protein Binding , RNA Interference , Sirtuin 1 , Genetics , Metabolism
7.
Chinese Journal of Pathology ; (12): 895-899, 2015.
Article in Chinese | WPRIM | ID: wpr-278505

ABSTRACT

<p><b>OBJECTIVE</b>To study the clinicopathologic features, immunophenotype, differential diagnosis and prognosis of renal cell carcinoma (RCC) associated with t(6;11)(p21.2;q13)/MALAT1-TFEB gene fusion.</p><p><b>METHODS</b>A total of 9 cases of such rare tumor were selected for clinicopathologic, immunohistochemical and molecular analysis, with review of literature.</p><p><b>RESULTS</b>The age of the patients ranged from 21 to 42 years (mean=31.3 years). The patients included four men and five women. Histologically, 4 of the 9 cases studied showed classic morphologic features of TFEB RCC, with hyaline material, pigments and psammoma bodies frequently identified. The remaining 5 cases demonstrated uncommon morphology, mimicking perivascular epithelioid cell neoplasm, clear cell RCC, chromophobe RCC or papillary RCC. Immunohistochemical study showed that TFEB and vimentin were positive in all cases. Most of the tumors studied also expressed Ksp-cadherin, E-cadherin, CD117, HMB45, Melan A and Cathepsin K. CKpan showed immunostaining in only 1 case. The staining for TFE3, CD10 and CK7 were all negative. TFEB gene rearrangement was detected in all the 9 cases studied using fluorescence in-situ hybridization. MALAT1-TFEB fusion gene was identified in 2 cases by polymerase chain reaction and direct sequencing. TFEB RCC seemed to be an indolent tumor. During a mean follow-up of 31 months, none developed tumor recurrence, progression, or metastasis.</p><p><b>CONCLUSIONS</b>TFEB fusion-associated RCC is a rare neoplasm, tends to occur in young age group and carries an indolent behavior. Diagnosis relies on clinicopathologic findings and immunohistochemical analysis. TFEB break-apart FISH assay is a reliable tool in confirming the diagnosis.</p>


Subject(s)
Adult , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Genetics , Carcinoma, Renal Cell , Genetics , Pathology , Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 6 , Diagnosis, Differential , Female , Gene Fusion , Gene Rearrangement , Genes, Neoplasm , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Kidney Neoplasms , Genetics , Pathology , Male , Prognosis , RNA, Long Noncoding , Genetics , Translocation, Genetic , Young Adult
8.
Article in Chinese | WPRIM | ID: wpr-815260

ABSTRACT

OBJECTIVE@#To determine the time course and potential mechanism of fibroblast growth factor-1 (FGF-1) in the regulation of adipogenesis.
@*METHODS@#We cultured human Simpson-Golabi-Behmel syndrome (SGBS) pre-adipocytes with recombinant FGF-1 and harvested cells at various stages prior to and during differentiation; at cell proliferation (D-3), confluence (D0), early (D3), middle (D7) and mature (D14) stages of differentiation. We determined lipid accumulation in mature adipocytes by morphological observation and quantitative measurement of oil red O staining. We also examined the expression of adipogenic genes and related markers involved in the Wnt/β-catenin pathway using quantitative Real-time PCR and Western blot.
@*RESULTS@#Compared to control SGBS cells, treatment with FGF-1 increased lipid accumulation; induced a sustained increase in the mRNA for peroxisome proliferater-activated receptor γ (PPARγ), glyceraldehyde-3-phosphate dehydrogenase (G3PDH), adiponectin and glucose transporter type 4 (GLUT4); and promoted a sustained decrease in expression of markers of the Wnt/β-catenin pathway, β-catenin and transcription factor 4 (TCF4).
@*CONCLUSION@#The adipogenic effects of FGF-1 are apparent throughout the whole priming and differentiation period in human SGBS pre-adipocytes. Furthermore, our results suggest that FGF-1 
promotes adipogenesis, at least in part, via a sustained decrease in activity of the Wnt/β-catenin pathway.


Subject(s)
Adipocytes , Metabolism , Adipogenesis , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Metabolism , Cell Differentiation , Cells, Cultured , Fibroblast Growth Factor 1 , Pharmacology , Humans , Recombinant Proteins , Pharmacology , Transcription Factor 4 , Transcription Factors , Metabolism , Wnt Signaling Pathway , beta Catenin , Metabolism
9.
Korean Journal of Urology ; : 212-217, 2015.
Article in English | WPRIM | ID: wpr-60932

ABSTRACT

PURPOSE: Xp11.2 translocation renal cell carcinoma (RCC) is characterized by various translocations of the TFE3 transcription factor gene. These rare cancers occur predominantly in children and young adults. Here, we review the clinicopathological features of Xp11.2 translocation RCC. MATERIALS AND METHODS: We identified 21 patients with Xp11.2 translocation RCC. We retrospectively analyzed patient characteristics, clinical manifestations, and specific pathological features to assess definitive diagnosis, surgical and systemic treatments, and clinical outcomes. RESULTS: The mean age at diagnosis was 43.4+/-20.0 years (range, 8-80 years; 8 males and 13 females). Eleven patients were incidentally diagnosed, nine patients presented with local symptoms, and one patient presented with systemic symptoms. The mean tumor size was 6.2+/-3.8 cm (range, 1.9-14 cm). At the time of diagnosis, 11, 1, and 5 patients showed stage I, II, and III, respectively. Four patients showed distant metastasis. At analysis, 15 patients were disease-free after a median follow-up period of 30.0 months. Four patients received target therapy but not effectively. CONCLUSIONS: Xp11 translocation RCC tends to develop in young patients with lymph node metastasis. Targeted therapy did not effectively treat our patients. Surgery is the only effective therapy for Xp11 translocation RCC, and further studies are needed to assess systemic therapy and long-term prognosis.


Subject(s)
Adolescent , Adult , Aged , Aged, 80 and over , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics , Biomarkers , Carcinoma, Renal Cell/diagnosis , Child , Chromosomes, Human, X/chemistry , Female , Humans , Kidney Neoplasms/diagnosis , Lymphatic Metastasis , Male , Middle Aged , Prognosis , Retrospective Studies , Translocation, Genetic , Young Adult
10.
Article in Chinese | WPRIM | ID: wpr-329206

ABSTRACT

<p><b>OBJECTIVE</b>To study the effect of Biejiajian Pills on Wnt signal pathway and the mechanisms underlying its action to suppress the invasiveness of hepatocellular carcinoma.</p><p><b>METHODS</b>HepG2 cells cultured in the serum of rats fed with Biejiajian Pills for 48 h were examined for β-catenin expression using immunofluorescence, β-catenin/TCF4 complex activity with luciferase, and expressions of the downstream proteins cyclin D1 and MMP-2 using qRT-PCR.</p><p><b>RESULTS</b>Biejiajian Pills-treated sera significantly reduced the expressions of cytoplasmic and nuclear β-catenin protein, cyclin D1 and MMP-2 proteins and lowered the activities of β-catenin/TCF4 complex.</p><p><b>CONCLUSION</b>Biejiajian Pills may serve as a potential anti-tumor agent, whose effect might be mediated by inhibiting the Wnt/β-catenin pathway.</p>


Subject(s)
Animals , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Metabolism , Carcinoma, Hepatocellular , Metabolism , Cyclin D1 , Metabolism , Drugs, Chinese Herbal , Pharmacology , Hep G2 Cells , Humans , Liver Neoplasms , Metabolism , Matrix Metalloproteinase 2 , Metabolism , Rats , Transcription Factor 4 , Transcription Factors , Metabolism , Wnt Proteins , Wnt Signaling Pathway , beta Catenin , Metabolism
11.
Chinese Journal of Biotechnology ; (12): 182-193, 2014.
Article in Chinese | WPRIM | ID: wpr-279531

ABSTRACT

To clarify the function and molecular mechanism of miR-155 in myogenic differentiation of C2C12, we constructed adenovirus over-expression vector of miR-155, then C2C12 cells were infected by adenovirus and induced myogenic differentiation. First, we observed the morphology of C2C12 after differentiation. Then the mRNA and protein expressions of myogenic markers (MyoD, MyoG and MyHC) were detected by qPCR and western blotting. Subsequently, the dual luciferase reporter gene assay was carried out to validate putative target gene (TCF4) of miR-155. Meanwhile, mRNA level of TCF4 was analyzed after over-expressing miR-155. The results show that over-expressed miR-155 reduced myotubes formation. Moreover, the mRNA and protein expression of MyoG and MyHC decreased significantly (P < 0.01). Further research demonstrated miR-155 bound the one (4532-4538) of three putative sites (1487-1493,1516-1522, 4532-4583) of TCF4 by luciferase reporter gene assay and the mRNA level of TCF4 decreased notably (P < 0.05). The data suggest that miR-155 inhibited myogenic differentiation of C2C12 through targeted TCF4.


Subject(s)
Animals , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Genetics , Cell Differentiation , Cell Line , Genetic Vectors , Mice , MicroRNAs , Genetics , Myoblasts , Cell Biology , Myogenin , Genetics , Metabolism , Myosin Heavy Chains , Genetics , Metabolism , RNA, Messenger , Genetics , Transcription Factor 4
12.
Chinese Journal of Pathology ; (12): 381-385, 2013.
Article in Chinese | WPRIM | ID: wpr-233442

ABSTRACT

<p><b>OBJECTIVE</b>To study the clinicopathologic features, immunophenotype and genetic changes of perivascular epithelioid cell neoplasms (PEComa).</p><p><b>METHODS</b>A total of 25 cases of PEComa located in various anatomic sites were selected for immunohistochemical staining (SP or EnVision method). TFE3 fluorescence in-situ hybridization was also performed to determine the TFE3 gene status.</p><p><b>RESULTS</b>The age of patient ranged from 21 to 61 years (mean = 43 years). The male-to-female ratio was 1: 1.3. Histologically, 22 cases represented conventional angiomyolipomas, composed of a mixture of adipose tissue, spindle element, epithelioid smooth muscle cells and abnormal thick-walled blood vessels in various proportions. Three cases involving lung, soft tissue and broad ligament had subtle but distinctive morphologic features. Nested or sheet-like architecture with epithelioid or spindle cells was observed. Immunohistochemical study showed that HMB 45, melan A, smooth muscle actin and cathepsin K were expressed in 80% (20/25), 88% (22/25), 88% (22/25) and 100% (25/25) of PEComa, respectively. Within positive cases, the average proportion of positive tumor cells was 36%, 41%, 35% and 90% respectively for HMB 45, melan A, smooth muscle actin and cathepsin K. TFE3 was negative in all of the 22 renal and hepatic PEComa studied, while it was positive in the 3 cases of extra-hepatorenal PEComa. None of the 25 cases exhibited evidence of TFE3 gene fusion or amplification.</p><p><b>CONCLUSIONS</b>Extra-hepatorenal PEComa have distinctive morphologic features and are associated with TFE3 overexpression. Cathepsin K immunostaining demonstrates high sensitivity and specificity in PEComa, better than other commonly employed immunomarkers. This marker is thus useful in diagnosis of PEComa and distinction with other neoplasms.</p>


Subject(s)
Actins , Metabolism , Adult , Angiomyolipoma , Metabolism , Pathology , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Genetics , Metabolism , Cathepsin K , Metabolism , Female , Humans , Immunohistochemistry , Kidney Neoplasms , Metabolism , Pathology , Liver Neoplasms , Metabolism , Pathology , MART-1 Antigen , Metabolism , Male , Melanoma-Specific Antigens , Metabolism , Middle Aged , Perivascular Epithelioid Cell Neoplasms , Metabolism , Pathology , Young Adult
13.
Article in English | WPRIM | ID: wpr-159137

ABSTRACT

TCF4 (transcription factor 4; E2-2, ITF2) is a transcription factor that when haplo-insufficient causes Pitt-Hopkins Syndrome (PTHS), an autism-spectrum disorder that is associated with pervasive developmental delay and severe intellectual disability. The TCF4 gene is also a risk factor with highly significant linkage to schizophrenia, presumably via overexpression of the TCF4 gene product in the central nervous system. This review will present an overview of the clinical manifestations of PTHS and relate those clinical attributes to the underlying molecular genetics of TCF4. In order to provide a molecular biological context for the loss of function of TCF4 in PTHS, the review will also present a brief overview of the basic biochemistry of TCF4-mediated regulation of cellular and neuronal gene expression. In the final section of this review, I will discuss and speculate upon possible roles for the TCF4 transcription factor in neuronal function and comment upon how understanding these roles may give new insights into the molecular neurobiology of human cognition.


Subject(s)
Animals , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics , Disease Models, Animal , Facies , Humans , Hyperventilation/diagnosis , Intellectual Disability/diagnosis , Neurons/metabolism , Transcription, Genetic
14.
Chinese Medical Journal ; (24): 3336-3339, 2012.
Article in English | WPRIM | ID: wpr-316513

ABSTRACT

<p><b>BACKGROUND</b>The tendency of tumor cells to disperse throughout the liver is a distinct feature of hepatocellular carcinoma (HCC). Nck family adaptor proteins function to regulate actin cytoskeletal reorganization that leads to cell motility. We previously found that Max binding protein (MNT) was differentially expressed in HCC, and interacted with Nck1 by 2-DE. MNT is a protein member of the Myc/Max/Mad network which plays roles in cell proliferation, differentiation, and death. We investigated the effects of MNT on migration of human liver cancer SK-HEP-1 cells to study the migration regulatory role of MNT in HCC cells.</p><p><b>METHODS</b>Interaction between MNT and Nck1 was further validated in hepatoma cells by GST-pull down assay and immunoprecipitation. siRNAs specific to MNT (MNT siRNA) were used to knockdown MNT expression. Western blotting, transwell assay were used to determine the migration potential of cells.</p><p><b>RESULTS</b>Interaction between MNT and Nck1 was validated in hepatoma cells. MNT knockdown promoted the migration of human liver cancer SK-HEP-1 cells (P < 0.01).</p><p><b>CONCLUSION</b>The results suggest that MNT, via interaction with Nck1, inhibits hepatoma cell migration.</p>


Subject(s)
Adaptor Proteins, Signal Transducing , Genetics , Metabolism , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Genetics , Metabolism , Blotting, Western , Cell Differentiation , Genetics , Physiology , Cell Line, Tumor , Cell Movement , Genetics , Physiology , Humans , Immunoprecipitation , Liver Neoplasms , Oncogene Proteins , Genetics , Metabolism , Protein Binding , Genetics , Physiology , Repressor Proteins , Genetics , Metabolism , Reverse Transcriptase Polymerase Chain Reaction
15.
Article in Chinese | WPRIM | ID: wpr-814603

ABSTRACT

OBJECTIVE@#To compare the difference in gene expression profiles between parental cell line and drug resistant cell line (CNE-1 and CNE-1/taxol) pre-treated or treated by drugs, and search for genes related to taxol resistance and reversal of taxol resistance phenotype.@*METHODS@#cDNA microarray was used to detect the difference in gene expression profiles between 6 groups of cells. Combination of multiple filtering genes and detailed analysis of documented resistance genes were used to analyze the data.@*RESULTS@#Through multiple filtering, 297 differentially expressed genes were screened. The expression of 17 genes was increased or decreased more than 5 folds in CNE-1/taxol compared with CNE-1.Through analyzing documented drug-resistant genes, MDR1 expression was not detected in each group. CYP1A1, one of P450 family members, was not expressed in CNE-1, but significantly increased expressions was found in CNE-1/taxol and these increased expressions were restored by cisplatin. The expression level of some members of tumor necrosis factor family was decreased in CNE-1/taxol and restored by cisplatin, including TNFAIP1, 3 and TNFRSF12A, 21. The differentially expressed members in the caspase family were caspase-4 and caspase-6. The expression of β-tubulin II was down-regulated in CNE-1/taxol. TSP1 was obviously down-regulated in CNE- 1/taxol compared with CNE-1, and a more significant down-regulation of TSP1 was found when treated by taxol. However, it was greatly up-regulated after cisplatin treatment in CNE-1/taxol.@*CONCLUSION@#Some genes are probably related to taxol resistance and reversal of taxol resistance in NPC cells: 297 differentially expressed genes detected by multiple filing, CYP1A1, some members of TNF family and another 17 genes whose differential expression is more than 5 folds between parental cell line and drug resistant cell line. Combination of multiple filtering genes and detailed analysis of documented resistance genes is a good method to study drug resistance and reversal of drug resistance in carcinoma cells.


Subject(s)
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Genetics , Cell Line, Tumor , Cytochrome P-450 CYP1A1 , Genetics , Drug Resistance, Neoplasm , Genetics , Gene Expression Regulation, Neoplastic , Humans , Nasopharyngeal Neoplasms , Pathology , Oligonucleotide Array Sequence Analysis , Paclitaxel , Pharmacology , Proteins , Genetics , Receptors, Tumor Necrosis Factor , Genetics , TWEAK Receptor
16.
Chinese Journal of Pathology ; (12): 35-39, 2010.
Article in Chinese | WPRIM | ID: wpr-273426

ABSTRACT

<p><b>OBJECTIVE</b>To study the expression and clinical significance of kidney injury molecule-1 (KIM-1) in primary and metastatic renal epithelial neoplasms.</p><p><b>METHODS</b>A total of 136 cases of kidney neoplasms were retrospectively reviewed including 63 primary clear cell renal cell carcinomas (RCCs), 22 papillary RCCs, 13 chromophobe RCCs, 7 oncocytomas, 7 RCCs associated with Xp11.2 translocation/TFE3 gene fusions and 24 metastatic clear cell RCCs. Immunostaining for KIM-1 and kidney-specific-protein (Ksp)-cadherin were performed and the relationship to tumor stage and grade in clear cell RCCs was investigated.</p><p><b>RESULTS</b>Expression of KIM-1 was detected in 77.8% (49/63) of clear cell RCCs, 90.9% (20/22) of papillary RCCs, 1/13 of chromophobe RCCs, 7/7 of RCCs associated with Xp11.2 translocation/TFE3 gene fusions and 87.5%(21/24) of the metastatic RCCs, but not detected in 7 cases of oncocytomas. A diffuse expression of KIM-1 was more frequently observed in Furhman nuclear grade III/IV clear cell RCCs (P = 0.010). Ksp-cadherin expression was mainly observed in chromophobe RCCs and oncocytomas.</p><p><b>CONCLUSIONS</b>KIM-1 is a specific biomarker for injuried kidney proximal tubules and the corresponding neoplasms, and has a high specificity and sensitivity for primary or metastatic clear cell RCCs, papillary RCCs and RCCs associated with Xp11.2 translocation/TFE3 gene fusions. Combination of KIM-1 and Ksp-cadherin immunostaining can lead to a more precise histological classification of primary kidney epithelial neoplasms and improve the diagnostic accuracy of metastatic RCCs.</p>


Subject(s)
Adenoma, Oxyphilic , Metabolism , Pathology , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Genetics , Metabolism , Bone Neoplasms , Metabolism , Cadherins , Metabolism , Carcinoma, Papillary , Metabolism , Pathology , Carcinoma, Renal Cell , Genetics , Metabolism , Pathology , Chromosomes, Human, X , Gene Fusion , Hepatitis A Virus Cellular Receptor 1 , Humans , Kidney Neoplasms , Genetics , Metabolism , Pathology , Lung Neoplasms , Metabolism , Membrane Glycoproteins , Metabolism , Neoplasms, Glandular and Epithelial , Classification , Genetics , Metabolism , Pathology , Receptors, Virus , Metabolism , Retrospective Studies , Translocation, Genetic
17.
Chinese Journal of Pathology ; (12): 582-586, 2010.
Article in Chinese | WPRIM | ID: wpr-333205

ABSTRACT

<p><b>OBJECTIVE</b>To investigate clinicopathological features, molecular genetic characteristics, differential diagnoses and prognosis of renal cell carcinoma in teenagers.</p><p><b>METHODS</b>Microscopic and immunohistochemical features of 46 cases of renal cell carcinomas in teenagers were reviewed along with the clinical follow-up data. Loss of heterozygosity (LOH), analysis of von Hippel-Lindau (VHL) gene and screening for VHL gene mutations were performed in all of the tumors.</p><p><b>RESULTS</b>There were 19 Xp11.2 translocations/TFE3 gene fusions renal clear cell carcinomas (Xp11 RCCs), 9 chromophobe renal cell carcinomas (CCRCCs), 17 papillary renal cell carcinomas (PRCCs), and 1 unclassified renal cell carcinoma (RCC). All of the 19 Xp11.2 translocation RCCs showed a moderate to strong immunoreactivity for TFE, however, no TFEB expression was obtained. There were 4 histological patterns in the Xp11 RCC cases including: 8 tumors possessing a nested to papillary architecture resembling to the t(X;17) ASPL-TFE3 phenotype; 6 tumors possessing a morphologic feature like the t(X;1) PRCC-TFE3 phenotype; 4 cases morphologically resembling to clear cell RCC; and 1 Xp11 RCC case, with a special morphologic feature not searched yet in the literature, including a ground glass appearance of the nuclei accompanying occasionally with grooves on the nuclear surface; nucleoli inconspicuous with accumulation of abundant mucin-like substance in the stroma. VHL gene analysis revealed deletions at 3p25-26 in one clear cell RCC and one papillary type 2 RCC. The papillary type 2 RCC had also a family history of VHL disease, with a germline G→C mutation at a splicing site of position 553+5. There were no VHL mutations detected in the remaining 45 RCCs. Statistical analysis of tumor stage and outcome revealed that TFE+ RCCs of teen-agers were more frequently associated with a higher pT3/pT4 stage and a poorer outcome than that of the TFE-RCCs (P < 0.05).</p><p><b>CONCLUSIONS</b>RCCs of the teenagers have a different morphologic spectrum and genetic background from the RCCs seen in adults. Among RCCs of the teen-agers, Xp11.2 translocation tumors are the most common RCCs and have a poorer prognosis than that of the TFE-RCCs.</p>


Subject(s)
Adolescent , Adult , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Genetics , Metabolism , Carcinoma, Papillary , Genetics , Metabolism , Pathology , Carcinoma, Renal Cell , Genetics , Metabolism , Pathology , Child , Child, Preschool , Chromosomes, Human, Pair 11 , Chromosomes, Human, X , Diagnosis, Differential , Female , Follow-Up Studies , Gene Fusion , Humans , Kidney Neoplasms , Genetics , Metabolism , Pathology , Loss of Heterozygosity , Male , Neoplasm Staging , Neprilysin , Metabolism , Phenotype , Survival Rate , Translocation, Genetic , Von Hippel-Lindau Tumor Suppressor Protein , Genetics , Young Adult , von Hippel-Lindau Disease , Genetics
18.
Chinese Journal of Pathology ; (12): 726-731, 2008.
Article in Chinese | WPRIM | ID: wpr-315082

ABSTRACT

<p><b>OBJECTIVE</b>To study the clinicopathologic features and immunophenotype of renal cell carcinomas, and to discuss their diagnostic value.</p><p><b>METHODS</b>The clinicopathologic features of 114 cases of renal cell carcinoma were reviewed and categorized on the basis of 2004 WHO classification. Immunohistochemical study for a panel of antibodies (including CK, CD10, vimentin, CD117, AMACR, CK7 and TFE3) was carried out. The follow-up data, if available, were also analyzed.</p><p><b>RESULTS</b>The cases were reclassified into 5 subtypes, including 77 cases (67.5%) of clear cell carcinoma (CCRCC), 11 cases (9.6%) of papillary renal cell carcinoma (PRCC), 14 cases (12.3%) of chromophobe renal cell carcinoma (chrRCC), 10 cases (8.8%) of renal carcinoma associated with Xp11.2 translocations/TFE3 gene fusions (Xp11.2RCC) and 2 cases (1.8%) of unclassified renal cell carcinoma (unRCC). Immunohistochemical study showed that the expression rates of CK, CD10 and vimentin in CCRCC were 93.5% (72/77), 93.5% (72/77) and 75.3% (58/77), respectively. On the other hand, all the 11 cases of PRCC studied were positive for AMACR. The expression rate of CD117 in chrRCC was 78.5% (11/14). In the 10 cases of Xp11.2 RCC studied, the expression rates of TFE3, AMACR, CD10 and CK were 100% (10/10), 100% (10/10), 90% (9/10) and 70% (7/10), respectively.</p><p><b>CONCLUSIONS</b>The various subtypes of renal cell carcinomas are heterogeneous in histologic appearance and demonstrate distinctive immunophenotype. The expressions of CD10, vimentin, CD117, AMACR, CK7 and TFE3 are helpful in the differential diagnosis.</p>


Subject(s)
Adenocarcinoma, Clear Cell , Pathology , Adolescent , Adult , Aged , Aged, 80 and over , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Genetics , Allergy and Immunology , Metabolism , Biomarkers, Tumor , Genetics , Carcinoma, Papillary , Allergy and Immunology , Pathology , Carcinoma, Renal Cell , Allergy and Immunology , Metabolism , Pathology , Female , Gene Fusion , Humans , Immunophenotyping , Kidney Neoplasms , Allergy and Immunology , Metabolism , Pathology , Male , Middle Aged , Neprilysin , Racemases and Epimerases , Genetics , Translocation, Genetic , Vimentin , World Health Organization , Young Adult
19.
Chinese Journal of Pathology ; (12): 244-246, 2007.
Article in Chinese | WPRIM | ID: wpr-333916

ABSTRACT

<p><b>OBJECTIVE</b>To study the clinicopathologic features, differential diagnosis and prognosis of renal cell carcinoma associated with Xp11.2 translocations/TFE3 gene fusions.</p><p><b>METHODS</b>The histopathologic findings and immunophenotype of 11 cases of renal cell carcinoma associated with Xp11.2 translocations/TFE3 gene fusions were studied. Follow-up data (ranged from 10 to 112 months) were also analyzed.</p><p><b>RESULTS</b>There were a total of 7 females and 4 males. The age of patients ranged from 8 to 26 years (mean = 16.3 years). The diameter of the tumors varied from 2.5 to 6.0 cm. Histologically, two morphologic patterns were seen. The first pattern consisted of alveolar, papillary or nested architecture. The tumor cells contained voluminous, clear to eosinophilic cytoplasm, distinct cell borders, vesicular chromatin, and prominent nucleoli. Psammoma bodies were frequently found and could be abundant. In contrast, the second pattern was composed of nested and compact architecture. The tumor cells possessed less abundant cytoplasm and inconspicuous nucleoli. Few psammoma bodies were detected. Immunohistochemical study showed that all cases strongly expressed TFE3, CD10 and P504s. Variable positivity for pan-cytokeratin, epithelial membrane antigen and vimentin was also noted. None of them expressed CK7, Ksp-cadherin and CD117.</p><p><b>CONCLUSIONS</b>Renal cell carcinoma associated with Xp11.2 translocations/TFE3 gene fusions is a newly described but rarely encountered subtype of renal cell carcinoma. Pathologic diagnosis can be established when taken age of the patients, histopathologic findings and immunoreactivity for TFE3 protein into consideration.</p>


Subject(s)
Adolescent , Adult , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Metabolism , Carcinoma, Renal Cell , Genetics , Metabolism , Child , Chromosomes, Human, X , Female , Follow-Up Studies , Gene Fusion , Humans , Kidney Neoplasms , Genetics , Metabolism , Male , Neprilysin , Metabolism , Racemases and Epimerases , Metabolism , Translocation, Genetic , Young Adult
20.
Chinese Journal of Hematology ; (12): 745-749, 2007.
Article in Chinese | WPRIM | ID: wpr-262954

ABSTRACT

<p><b>OBJECTIVE</b>To investigate the expression and mutation of Mad1, Mxi1 and Rox genes in leukemia cells.</p><p><b>METHODS</b>Expression and mutation of Mad1, Mxi1 and Rox genes in bone marrow mononuclear cells (BMMNC) from 26 de novo acute leukemia (AL) patients, and in peripheral blood mononuclear cells (PBMNC) from 30 healthy volunteers, as well as in 7 human leukemic cell lines were analyzed by reverse transcription-polymerase chain reaction (RT-PCR), single strand conformational polymorphism (SSCP) and DNA sequencing.</p><p><b>RESULTS</b>RT-PCR showed that all the above cells expressed Mad1, Mxi1 and Rox mRNA. SSCP revealed four polymorphisms: two in Mad1, one each in Mxi1 and Rox. DNA sequencing detected nine missense mutations: two in Mad1 in AL patients, four in Mxi1 (three in AL patients and one in KG-1 cell line), and three in Rox in AL patients. The mutations of Mad1, Mxi1 and Rox mRNA were detected in 2, 3 and 3 patients, respectively.</p><p><b>CONCLUSION</b>It is for the first time to demonstrate the mutations of Mad1, Mxi1 and Rox genes in AL patients suggesting these mutated genes involve in the pathogenesis of leukemia.</p>


Subject(s)
Adolescent , Adult , Aged , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Genetics , Metabolism , Basic Helix-Loop-Helix Transcription Factors , Genetics , Metabolism , Cell Cycle Proteins , Genetics , Metabolism , Female , Humans , Leukemia , Genetics , Metabolism , Male , Middle Aged , Mutation , Nuclear Proteins , Genetics , Metabolism , Polymorphism, Single-Stranded Conformational , Repressor Proteins , Genetics , Metabolism , Tumor Suppressor Proteins , Genetics , Metabolism
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