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Braz. j. med. biol. res ; 54(9): e10390, 2021. graf
Article in English | LILACS | ID: biblio-1249337


Sorafenib (SOR) resistance is still a significant challenge for the effective treatment of hepatocellular carcinoma (HCC). The mechanism of sorafenib resistance remains unclear. Several microRNAs (miRNAs) have been identified as playing a role in impairing the sensitivity of tumor cells to treatment. We examined the mechanism behind the role of miR-92b in mediating sorafenib resistance in HCC cells. We detected that miR-92b expression was significantly upregulated in SOR-resistant HepG2/SOR cells compared to parental HepG2/WT cells. After transfection with miR-92b inhibitor, the proliferation of HepG2/SOR cells was remarkably weakened and rates of apoptosis significantly increased. PTEN was considered to be a functional target of miR-92b according to a luciferase reporter assay. Knockdown of PTEN significantly impaired the ability of miR-92b inhibitor on increasing sorafenib sensitivity of HepG2/SOR cells. Furthermore, we confirmed by western blotting and immunofluorescence that miR-92b can mediate sorafenib resistance by activating the PI3K/AKT/mTOR pathway in HCC cells by directly targeting PTEN. These findings further validate the mechanism of miR-92b in SOR resistance in HCC treatment.

Humans , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/drug therapy , Drug Resistance, Neoplasm , MicroRNAs/genetics , Sorafenib/pharmacology , Liver Neoplasms/genetics , Liver Neoplasms/drug therapy , Signal Transduction , Gene Expression Regulation, Neoplastic , Phosphatidylinositol 3-Kinases/metabolism , Cell Line, Tumor , Cell Proliferation , PTEN Phosphohydrolase/genetics , TOR Serine-Threonine Kinases
Article in Chinese | WPRIM | ID: wpr-888186


This study explored the effects of resveratrol(Res) on the expression of phosphatase and tensin homolog deleted on chromosome ten(PTEN) and the fibrosis of rat renal tubular epithelial cells in a high-glucose environment and the possible mechanism underlying the fibrosis reduction. After the pretreatment of rat renal tubular epithelial cells(NRK-52 E) cultured in a high-glucose condition with Res or PTEN inhibitor SF1670, they were divided into several groups, i.e., normal glucose(NG), normal glucose + SF1670(NS), high glucose(HG), high glucose + SF1670(HS), high glucose + Res at different concentrations(5, 10, 25 μmol·L~(-1)). The expression and distribution of E-cadherin and α-SMA in renal tubular epithelial cells were observed by immunofluorescence cytochemistry. The protein expression levels of PTEN, E-cadherin, α-SMA, p-Akt~((Thr308)) and collagen Ⅳ were determined by Western blot. Real-time PCR was employed to detect the expression of PTEN mRNA. Compared with the NG group, the HG group witnessed the reduced expression of PTEN mRNA, PTEN protein and E-cadherin protein, but saw the increased expression of α-SMA, p-Akt~((Thr308)) and collagen Ⅳ proteins. Besides, with the increase in Res concentration, the expression levels of PTEN mRNA, PTEN protein and E-cadherin protein gradually increased, while those of α-SMA, collagen Ⅳ, p-Akt~((Thr308)) proteins gradually decreased in the Res groups, showing a dose-effect dependence, compared with the HG group. No distinct difference was found between the NS group and the NG group. The expression level of E-cadherin was even lower and those of α-SMA, p-Akt~((Thr308)), and collagen Ⅳ were higher in the HS group than in the HG group, with no marked difference shown in the two groups in terms of PTEN mRNA and protein. Although the PTEN inhibitor did not affect PTEN, the expression changes of the other proteins were opposite to the results after Res treatment and the fibrosis was aggravated, which suggested that SF1670 promoted the fibrosis by inhibiting PTEN, activating Akt and increasing the synthesis of collagen Ⅳ and other extracellular matrix. The results show that Res can antagonize the high glucose-mediated fibrosis of renal tubular epithelial cells. This may be achieved via the up-regulation of PTEN and the inhibition of PI3 K/Akt signaling pathway.

Animals , Epithelial Cells , Fibrosis , Glucose , PTEN Phosphohydrolase/genetics , Rats , Resveratrol/pharmacology
Braz. j. med. biol. res ; 53(4): e8882, 2020. tab, graf
Article in English | LILACS | ID: biblio-1100927


Hepatocellular carcinoma (HCC) is one of the most common primary malignant tumors of the liver worldwide. Liver resection and transplantation are currently the only effective treatments; however, recurrence and metastasis rates are still high. Previous studies have shown that the epithelial-mesenchymal transition (EMT) is a key step in HCC invasion and metastasis. Inhibition of EMT has become a new therapeutic strategy for tumors. Recently, puerarin, a well-characterized component of traditional Chinese medicine, has been isolated from Pueraria radix and exerts positive effects on many diseases, particularly cancers. In this study, CCK-8, EdU immunofluorescence, colony formation, wound healing, and migration assays were used to detect the effects of puerarin on HCC cells. We further analyzed the relationship between puerarin and miR-21/PTEN/EMT markers in HCC cell lines. Our results showed that HCC cell proliferation, migration, invasion, tumor formation, and metastasis were reduced by puerarin in vitro and in vivo. Additionally, puerarin inhibited the EMT process of HCC by affecting the expression of Slug and Snail. Moreover, oncogenic miR-21 was inhibited by puerarin, coupled with an increase in the tumor suppressor gene PTEN. Increasing miR-21 expression or decreasing PTEN expression reversed the inhibition effects of puerarin in HCC. These data confirmed that puerarin affects HCC through the miR-21/PTEN/EMT regulatory axis. Overall, puerarin may represent a chemopreventive and/or chemotherapeutic agent for HCC treatment.

Animals , Male , Carcinoma, Hepatocellular/drug therapy , PTEN Phosphohydrolase/genetics , Epithelial-Mesenchymal Transition/drug effects , Isoflavones/therapeutic use , Liver Neoplasms/drug therapy , Antineoplastic Agents/therapeutic use , Pyrroles , Drug Screening Assays, Antitumor , Carcinoma, Hepatocellular/genetics , MicroRNAs/genetics , Cell Proliferation/drug effects , Cell Proliferation/genetics , Disease Models, Animal , Isoflavones/pharmacology , Liver Neoplasms/genetics , Neoplasm Invasiveness , Antineoplastic Agents/pharmacology
Braz. j. med. biol. res ; 52(12): e8483, 2019. tab, graf
Article in English | LILACS | ID: biblio-1055462


PTEN is the most commonly inactivated tumor suppressor gene in primary prostate cancer (PCa) and its loss is associated with poor clinical outcomes. ERG rearrangement is a genomic alteration frequently found in PCa and its prognostic significance has yielded mixed results. Although the association of PTEN and ERG biomarkers has potential impact on clinical outcomes, studies examining the two genes simultaneously are scarce in Brazilian populations. In this study, we retrospectively examined the relationship between ERG expression and PTEN loss in 119 surgically treated prostate cancer patients from Northeastern Brazil through immunohistochemical analysis. ERG expression was found in 41.0% (48/117) of cases and the loss of PTEN detected in 38.1% (40/105) of samples. ERG-positive cases were significantly associated with lower prostate weight; ERG negatively correlated with Gleason score above 6. The lack of associations for PTEN loss alone in this cohort is counter to the literature, which shows that PTEN loss is usually associated with more aggressive disease. The overlapping of the two biomarkers revealed that samples with positive ERG expression without PTEN loss were associated with lower Gleason and lower Grade group. This study contributes with the discussion about the development of the molecular profiling of prostate cancer. The further development of similar studies could help in stratifying specific risk groups, leading to a more personalized therapeutic decision for prostate cancer treatment.

Humans , Male , Middle Aged , Aged , Aged, 80 and over , Prostatic Neoplasms/metabolism , Gene Expression Regulation, Neoplastic , PTEN Phosphohydrolase/metabolism , Prognosis , Prostatic Neoplasms/surgery , Prostatic Neoplasms/pathology , Immunohistochemistry , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/blood , Prevalence , Retrospective Studies , Cohort Studies , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/blood , Neoplasm Grading , Transcriptional Regulator ERG/genetics , Transcriptional Regulator ERG/metabolism , Transcriptional Regulator ERG/blood
Mem. Inst. Oswaldo Cruz ; 110(8): 996-1002, Dec. 2015. graf
Article in English | LILACS | ID: lil-769833


Chagas disease, which is caused by the intracellular protozoanTrypanosoma cruzi, is a serious health problem in Latin America. The heart is one of the major organs affected by this parasitic infection. The pathogenesis of tissue remodelling, particularly regarding cardiomyocyte behaviour after parasite infection, and the molecular mechanisms that occur immediately following parasite entry into host cells are not yet completely understood. Previous studies have reported that the establishment of parasitism is connected to the activation of the phosphatidylinositol-3 kinase (PI3K), which controls important steps in cellular metabolism by regulating the production of the second messenger phosphatidylinositol-3,4,5-trisphosphate. Particularly, the tumour suppressor PTEN is a negative regulator of PI3K signalling. However, mechanistic details of the modulatory activity of PTEN on Chagas disease have not been elucidated. To address this question, H9c2 cells were infected with T. cruzi Berenice 62 strain and the expression of a specific set of microRNAs (miRNAs) were investigated. Our cellular model demonstrated that miRNA-190b is correlated to the decrease of cellular viability rates by negatively modulating PTEN protein expression in T. cruzi-infected cells.

Animals , Rats , Down-Regulation , MicroRNAs/physiology , Myocytes, Cardiac/parasitology , Protein Biosynthesis , PTEN Phosphohydrolase/metabolism , Trypanosoma cruzi/metabolism , Blotting, Western , Cell Line , Cell Survival , Formazans , Genes, Reporter , Myocytes, Cardiac/metabolism , Phosphorylation , PTEN Phosphohydrolase/genetics , Reverse Transcriptase Polymerase Chain Reaction , RNA, Messenger/metabolism , Tetrazolium Salts , Trypanosoma cruzi/classification
Int. braz. j. urol ; 41(5): 898-905, Sept.-Oct. 2015. tab, graf
Article in English | LILACS | ID: lil-767056


ABSTRACT NKX3.1 and PTEN genes are involved in the development and progression of prostate cancer (PCa). Here, in line with other studies that correlated the expression of these two genes, we aimed at evaluating the expression pattern of these genes in clinical PCa samples. Collectively, 81 tissue samples including 45 human PCa and 36 benign prostatic hyperplasia (BPH) specimens were included in the study. The tissue samples were subjected to RNA extraction and subsequently to cDNA synthesis according to the kit manufacturer's protocol. Quantitative Real-Time PCR assay was performed for each sample in triplicate reactions. REST and SPSS software were used to statistically analyze PTEN and NKX3.1 gene expression data. Expression level of both NKX3.1 and PTEN genes was down-regulated in PCa samples compared to BPH samples. The relative expression ratio of PTEN and NKX3.1 was decreased to 0.155 and 0.003, respectively (P=0.000). The results of Chi-Square analysis revealed a significant correlation between the expression of these genes in both BPH and cancer groups (P=0.004 and 0.001, respectively). According to previous studies and our data, we concluded that the association between the down-regulation of PTEN and NKX3.1 genes contributed to the prostate tumorigenesis. This might highlight the interaction between the proteins encoded by these genes. Furthermore, this finding might be exploited for the development of innovative diagnostic and therapeutic approaches in PCa.

Aged , Aged, 80 and over , Humans , Male , Middle Aged , Down-Regulation , Gene Expression , Homeodomain Proteins/genetics , PTEN Phosphohydrolase/genetics , Prostatic Neoplasms/genetics , Transcription Factors/genetics , Carcinogenesis/genetics , Disease Progression , Electrophoresis, Gel, Two-Dimensional , Genetic Markers , Homeodomain Proteins/analysis , PTEN Phosphohydrolase/analysis , Real-Time Polymerase Chain Reaction , Reference Values , Temperature , Transition Temperature , Transcription Factors/analysis
Arq. bras. cardiol ; 104(2): 136-143, 02/2015. tab, graf
Article in English | LILACS | ID: lil-741141


Background: Ischemic postconditioning (IPost) is a method of protecting the heart against ischemia-reperfusion (IR) injury. However, the effectiveness of IPost in cases of ischemic heart disease accompanied by co-morbidities such as hypothyroidism remains unclear. Objective: The aim of this study was to determine the effect of IPost on myocardial IR injury in hypothyroid male rats. Methods: Propylthiouracil in drinking water (500 mg/L) was administered to male rats for 21 days to induce hypothyroidism. The hearts from control and hypothyroid rats were perfused in a Langendorff apparatus and exposed to 30 min of global ischemia, followed by 120 min of reperfusion. IPost was induced immediately following ischemia. Results: Hypothyroidism and IPost significantly improved the left ventricular developed pressure (LVDP) and peak rates of positive and negative changes in left ventricular pressure (±dp/dt) during reperfusion in control rats (p < 0.05). However, IPost had no add-on effect on the recovery of LVDP and ±dp/dt in hypothyroid rats. Furthermore, hypothyroidism significantly decreased the basal NO metabolite (NOx) levels of the serum (72.5 ± 4.2 vs. 102.8 ± 3.7 μmol/L; p < 0.05) and heart (7.9 ± 1.6 vs. 18.8 ± 3.2 μmol/L; p < 0.05). Heart NOx concentration in the hypothyroid groups did not change after IR and IPost, whereas these were significantly (p < 0.05) higher and lower after IR and IPost, respectively, in the control groups. Conclusion: Hypothyroidism protects the heart from IR injury, which may be due to a decrease in basal nitric oxide (NO) levels in the serum and heart and a decrease in NO after IR. IPost did not decrease the NO level and did not provide further cardioprotection in the hypothyroid group. .

Fundamento: O pós-condicionamento isquêmico (PCI) é um método potente utilizado para proteger o coração contra a lesão de isquemia-reperfusão (I/R). Não está claro se o PCI é eficaz quando a doença cardíaca isquêmica é acompanhada de comorbidades, tais como hipotireoidismo. Objetivo: O objetivo deste estudo foi determinar o efeito do PCI sobre a lesão de I/R do miocárdio em ratos machos com hipotireoidismo. Métodos: O hipotireoidismo foi induzido pela administração de propiltiouracila em água potável na concentração de 500 mg/L durante 21 dias. Os corações de ratos controle e com hipotireoidismo foram perfundidos utilizando o aparelho de Langendorff e expostos a isquemia global por 30 minutos, seguido de reperfusão por 120 minutos. O PCI foi iniciado imediatamente após a isquemia. Resultados: O hipotireoidismo e PCI aumentaram significativamente a pressão ventricular esquerda desenvolvida (PVED) e as taxas máximas de variação positiva (+dp/dt) e negativa (–dp/dt) da pressão ventricular esquerda durante a reperfusão em ratos controle (p < 0,05). No entanto, o PCI não teve efeito aditivo no restabelecimento da PVED e das ±dp/dt em ratos com hipotireoidismo. Além disso, o hipotireoidismo diminuiu significativamente os níveis basais séricos (72,5 ± 4,2 vs. 102,8 ± 3,7 μmol/L; p < 0,05) e cardíacos (7,9 ± 1,6 vs. 18,8 ± 3,2 μmol/L; p < 0,05) de NOx. Os níveis cardíacos de NOx não se alteraram no grupo com hipotireoidismo após I/R e PCI mas foram significativamente maiores e menores (p < 0,05) nos grupos controle após I/R e PCI, respectivamente. Conclusão: O hipotireoidismo protegeu o coração da lesão de I/R, o que pode ser devido à diminuição dos níveis séricos e cardíacos basais de óxido nítrico (NO) e à diminuição dos níveis de NO após I/R. No entanto, o PCI não diminuiu os níveis de NO e não conferiu proteção adicional ao grupo com hipotireoidismo. .

Adult , Humans , Male , Antineoplastic Agents/pharmacology , Drug Resistance, Neoplasm/genetics , Melanoma/genetics , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Skin Neoplasms/genetics , Antineoplastic Agents/therapeutic use , DNA Mutational Analysis , Genome, Human , GTP-Binding Protein alpha Subunits/genetics , High-Throughput Nucleotide Sequencing , Mutation, Missense , Melanoma/drug therapy , Melanoma/secondary , Polymorphism, Single Nucleotide , Precision Medicine , PTEN Phosphohydrolase/genetics , Proto-Oncogene Proteins B-raf/genetics , Sequence Deletion , Signal Transduction , Skin Neoplasms/drug therapy , Skin Neoplasms/pathology , Treatment Outcome , Tumor Cells, Cultured
Rev. bras. ginecol. obstet ; 36(8): 340-346, 08/2014. tab, graf
Article in English | LILACS | ID: lil-720496


PURPOSE: To examine the expression of AKT and PTEN in a series of HER2-positive primary invasive breast tumors using immunohistochemistry, and to associate these expression profiles with classic pathologic features such as tumor grade, hormone receptor expression, lymphatic vascular invasion, and proliferation. METHODS: A total of 104 HER2-positive breast carcinoma specimens were prepared in tissue microarrays blocks for immunohistochemical detection of PTEN and phosphorylated AKT (pAKT). Original histologic sections were reviewed to assess pathological features, including HER2 status and Ki-67 index values. The associations between categorical and numeric variables were identified using Pearson's chi-square test and the Mann-Whitney, respectively. RESULTS: Co-expression of pAKT and PTEN was presented in 59 (56.7%) cases. Reduced levels of PTEN expression were detected in 20 (19.2%) cases, and these 20 tumors had a lower Ki-67 index value. In contrast, tumors positive for pAKT expression [71 (68.3%)] were associated with a higher Ki-67 index value. CONCLUSION: A role for AKT in the proliferation of HER2-positive breast cancers was confirmed. However, immunohistochemical detection of PTEN expression did not correlate with an inhibition of cellular proliferation or control of AKT phosphorylation, suggesting other pathways in these mechanisms of control. .

OBJETIVOS: Avaliar a expressão imuno-histoquímica de AKT e PTEN em uma série de carcinomas mamários invasivos HER2-positivos, e associar seus padrões de expressão com variáveis anatomopatológicas clássicas, como grau histológico, expressão de receptores hormonais, embolização vascular linfática e atividade proliferativa. MÉTODOS: Um total de 104 amostras de carcinomas mamários invasivos HER2-positivos foram preparadas em blocos de microarranjos de tecido para detecção imuno-histoquímica de PTEN e AKT fosforilada (pAKT). Cortes histológicos originais foram revistos para avaliação das características anatomopatológicas, incluindo o estado do HER2 e a avaliação da expressão de Ki-67. As associações entre as variáveis categóricas e as numéricas foram feitas com o uso dos testes do chi-quadrado de Pearson e Mann-Whitney, respectivamente. RESULTADOS: Co-expressão de pAKT e PTEN foi identificada em 59 (56,7%) casos. Expressão reduzida de PTEN foi detectada em 20 (19,2%) casos, e esses 20 tumores mostraram menores valores de Ki-67. Por outro lado, tumores positivos para pAKT [71 (68,3%)] apresentaram células positivas para valores mais altos de Ki-67. CONCLUSÕES: O papel de AKT na proliferação de carcinomas mamários HER-2 positiva foi confirmada. Entretanto, a detecção imuno-histoquímica de PTEN não se correlacionou com inibição da proliferação celular ou controle da fosforilação de AKT, sugerindo outras vias nesses mecanismos de controle. .

Adult , Aged , Aged, 80 and over , Female , Humans , Middle Aged , Breast Neoplasms/genetics , Gene Expression Regulation, Neoplastic , /genetics , Oncogene Protein v-akt/physiology , PTEN Phosphohydrolase/genetics
Rev. bras. ginecol. obstet ; 36(5): 205-210, 05/2014. tab, graf
Article in English | LILACS | ID: lil-712755


PURPOSE: To investigate protein expression and mutations in phosphatase and tensin homolog (PTEN) in patients with stage IB cervical squamous cell carcinoma (CSCC) and the association with clinical-pathologic features, tumor p53 expression, cell proliferation and angiogenesis. METHODS: Women with stage IB CSCC (n=20 - Study Group) and uterine myoma (n=20 - Control Group), aged 49.1±1.7 years (mean±standard deviation, range 27-78 years), were prospectively evaluated. Patients with cervical cancer were submitted to Piver-Rutledge class III radical hysterectomy and pelvic lymphadenectomy and patients in the Control Group underwent vaginal hysterectomy. Tissue samples from the procedures were stained with hematoxylin and eosin for histological evaluation. Protein expression was detected by immunohistochemistry. Staining for PTEN, p53, Ki-67 and CD31 was evaluated. The intensity of PTEN immunostaining was estimated by computer-assisted image analysis, based on previously reported protocols. Data were analyzed using the Student's t-test to evaluate significant differences between the groups. Level of significance was set at p<0.05. RESULTS: The PTEN expression intensity was lower in the CSCC group than in the Control (benign cervix) samples (150.5±5.2 versus 204.2±2.6; p<0.001). Our study did not identify any mutations after sequencing all nine PTEN exons. PTEN expression was not associated with tumor expression of p53 (p=0.9), CD31 (p=0.8) or Ki-67 (p=0.3) or clinical-pathologic features in patients with invasive carcinoma of the cervix. CONCLUSIONS: Our findings demonstrate that the PTEN protein expression is significantly diminished in CSCC. .

OBJETIVO: O objetivo do estudo foi investigar a expressão e mutações do PTEN em pacientes com Carcinoma de Células Escamosas (CCE) de Colo do Útero com estadiamento IB e sua associação com fatores prognósticos, expressão do p53, proliferação celular e angiogênese. MÉTODOS: Mulheres com diagnóstico de CCE de colo uterino em estágio IB (n=20) (casos) e mioma uterino (n=20) (controle) com idade de 49.1±1.7 foram acompanhadas. As pacientes com câncer de colo do útero foram submetidas a histerectomia Piver-Rutledge classe III associada a linfadenectomia pélvica e aquelas com mioma uterino a histerectomia vaginal. Amostras de tumor e colo normal foram retiradas para avaliação histológica e marcação imuno-histoquímica das proteínas PTEN, p53, ki-67 e CD 3. A intensidade imuno-histoquímica do PTEN foi estimada por processamento de imagem digital a partir de protocolos pré-estabelecidos. Os dados foram analisados através do teste de qui - quadrado (χ2). O nível de significância foi considerado quando p < 0,05. RESULTADOS: A expressão do PTEN estava diminuída no grupo de pacientes com CCE em comparação ao grupo controle (150.5±5.2 versus 204.2±2.6; p<0.001). Nenhuma mutação no seqüenciamento genético dos nove exons do PTEN foi encontrada. Não houve associação estatisticamente significativa entre a expressão do PTEN e a expressão do p53 (p=0,969), Ki-67 (p=0.283) e CD 31 (p=0.817) ou fatores prognósticos anátomo-clínicos nas pacientes com carcinoma invasor do colo uterino. CONCLUSÕES: Este estudo demonstrou que o PTEN estava significativamente diminuído nas pacientes com CCE. .

Adult , Aged , Female , Humans , Middle Aged , /biosynthesis , Carcinoma, Squamous Cell/genetics , PTEN Phosphohydrolase/biosynthesis , PTEN Phosphohydrolase/genetics , Uterine Cervical Neoplasms/genetics , Gene Expression Regulation, Neoplastic , /biosynthesis , Mutation , Prospective Studies , /biosynthesis , Uterine Cervical Neoplasms/pathology
Acta cir. bras ; 29(supl.1): 34-38, 2014. tab
Article in English | LILACS | ID: lil-720408


PURPOSE: To analyze Pten and Smad4 gene expression in the urogenital system of Wistar rats in differents ages. METHODS: Pten and Smad4 mRNA expression was assessed in the bladder, ventral prostate, testis, ovaries, and uterus by real-time PCR. Statistical analysis using the ANOVA (p<0.05). RESULTS: Pten levels showed a progressive age-dependent increase in the bladder (male and female) and prostate and were elevated in the ovaries of the middle-aged. In the uterus, no statistically significant differences were observed; in the testis, increased and decreased levels were seen in young adult and middle-aged rats, respectively. Smad4 expression was downregulated in the ovaries of the pubertal group but increased in the middle age group. In the uterus, Smad4 expression in the oldest group was higher than the others groups. In the testis, Smad4 expression steadily declined with age; in the prostate, it was higher in middle-aged rats than in younger rats. A similar trend was observed in the bladder of male and female middle-aged rats, compared with the pubertal group. CONCLUSION: The changes in phosphatase tensin homologue and Smad4 mRNA expression in Wistar rats appear to be associated with hormonal modifications in puberty and may be related to early follicular and testicular development. .

Animals , Female , Male , Gene Expression/genetics , PTEN Phosphohydrolase/genetics , /genetics , Urogenital System/enzymology , Age Factors , Rats, Wistar , Real-Time Polymerase Chain Reaction , Reference Values , RNA, Messenger/genetics , Time Factors
Article in English | WPRIM | ID: wpr-95306


Cowden syndrome is an uncommon, autosomal dominant disease which is characterized by multiple hamartomas of the skin, mucous membrane, brain, breast, thyroid, and gastrointestinal tract. The diagnosis of Cowden syndrome implicates an increased risk of developing breast cancer. We report a case of a 22-year-old woman with Cowden syndrome that presented as breast cancer with concomitant bilateral exuberant benign masses in both breasts.

Arteriovenous Malformations/diagnostic imaging , Breast Neoplasms/complications , DNA/analysis , DNA Mutational Analysis , Diagnosis, Differential , Female , Hamartoma Syndrome, Multiple/complications , Humans , PTEN Phosphohydrolase/genetics , Thyroid Neoplasms/diagnostic imaging , Tomography, X-Ray Computed , Young Adult
Rev. Col. Bras. Cir ; 40(6): 471-475, nov.-dez. 2013. ilus, graf, tab
Article in Portuguese | LILACS | ID: lil-702656


OBJETIVO: avaliar a frequência de deleção do gene PTEN no carcinoma de células renais e o impacto da deleção nas taxas de sobrevida global e livre de doença. MÉTODOS: foram analisados 110 pacientes portadores de carcinoma de células renais submetidos à nefrectomia radical ou parcial entre os anos de 1980 e 2007. Em 53 casos foi possível a análise do gene PTEN pelo método de hibridização in situ fluorescente através da técnica de "tissue microarray". Para a análise estatística, os pacientes foram classificados em dois grupos, de acordo com a presença ou ausência de deleção. RESULTADOS: o tempo médio de seguimento foi de 41,9 meses. Deleção hemizigótica foi identificada em 18 pacientes (33,9%), ao passo que deleção homozigótica esteve presente em três (5,6%). Em aproximadamente 40% dos casos analisados havia deleção. Monossomia e trissomia foram detectadas, respectivamente, em nove (17%) e dois pacientes (3,8%). Em 21 pacientes (39,6%), a análise por hibridização in situ do gene PTEN foi normal. Não houve diferenças estatisticamente significativas nas taxas de sobrevida global (p=0,468) e livre de doença (p=0,344) entre os pacientes portadores ou não de deleção. Foram fatores independentes para a sobrevida global: estádio clínico TNM, sintomatologia ao diagnóstico, alto grau de Fuhrmann performance status (Ecog) e recorrência tumoral. A livre de doença foi influenciada unicamente pelo estádio clínico TNM. CONCLUSÃO: deleção do gene PTEN no CCR foi detectada com frequência de aproximadamente 40% e sua presença não foi determinante de menores taxas de sobrevida, permanecendo os fatores prognósticos tradicionais como determinantes da evolução dos pacientes.

OBJECTIVE: To evaluate the frequency of deletion of the PTEN gene in renal cell carcinoma (RCC) and its impact on the rates of overall and disease-free survival. METHODS: We analyzed 110 patients with renal cell carcinoma who underwent radical or partial nephrectomy between 1980 and 2007. In 53 cases it was possible to analyse the PTEN gene by the method of fluorescent in situ hybridization using the technique of tissue microarray. For statistical analysis, patients were classified in two groups according to the presence or absence of the deletion. RESULTS: The mean follow-up time was 41.9 months. Hemizygous deletion was detected in 18 patients (33.9%), while the homozygous one was present in three (5.6%). Deletion was present in approximately 40% of the analyzed cases. Monosomy and trisomy were detected in nine (17%) and two patients (3.8%), respectively. In 21 patients (39.6%) the analysis of the PTEN gene by in situ hybridization was normal. There were no statistically significant differences in overall (p = 0.468) and disease-free (p = 0.344) survival rates between patients with or without deletion. Factors which were independent for overall survival: TNM clinical stage, symptoms at diagnosis, high Fuhrmann grade, performance status (ECoG) and tumor recurrence. Disease-free survival was influenced only by the clinical TNM stage. CONCLUSION: Deletion of the PTEN gene in RCC was detected with a frequency of approximately 40% and its presence was not determinant of lower survival rates, the traditional prognostic factors remaining as determinants of outcome.

Female , Humans , Male , Middle Aged , Carcinoma, Renal Cell/genetics , Gene Deletion , Kidney Neoplasms/genetics , PTEN Phosphohydrolase/genetics , Carcinoma, Renal Cell/mortality , Disease-Free Survival , In Situ Hybridization, Fluorescence , Kidney Neoplasms/mortality , Retrospective Studies , Survival Rate , Tissue Array Analysis
An. bras. dermatol ; 88(6,supl.1): 52-52, Nov-Dec/2013. tab, graf
Article in English | LILACS | ID: lil-696828


We present the case of a female patient with facial cutaneous lesions, a cobblestone-like pattern of the oral mucosa, and verruciform lesions on the hand since her youth. She reported a history of breast cancer, endometrial cancer, melanoma and multiple benign tumors and cysts. PTEN gene analysis was performed and confirmed Cowden Syndrome, a rare genodermatosis with an autosomal dominant pattern of inheritance, characterized by multiple hamartomas. The phosphatase and tensin homolog (PTEN) gene negatively regulates cell proliferation and cell cycle progression. Loss of PTEN function contributes to an increased risk of cancer. We emphasize the importance of early detection and accurate management of Cowden Syndrome.

Apresentamos o caso de uma paciente com lesões cutâneas faciais, mucosa oral com aparência de paralelepípedo, e lesões de aspecto verrucoso na mão desde a sua juventude. Ela relatou uma história de câncer de mama, câncer de endométrio, melanoma e múltiplos tumores benignos e cistos. A análise genética PTEN foi realizada e confirmou a Síndrome de Cowden, uma genodermatose rara, com um padrão de herança autossômica dominante, caracterizada por múltiplos hamartomas. O gene homólogo de fosfatase e angiotensina (PTEN) regula negativamente a proliferação celular e a progressão do ciclo celular. A perda da função PTEN contribui para um aumento do risco de câncer. Ressaltamos a importância da detecção precoce e tratamento preciso da Síndrome de Cowden.

Female , Humans , Middle Aged , Hamartoma Syndrome, Multiple/pathology , Skin Neoplasms/pathology , Biopsy , Breast Neoplasms/complications , Early Diagnosis , Hamartoma Syndrome, Multiple/genetics , PTEN Phosphohydrolase/genetics , Risk Factors , Skin Neoplasms/genetics , Skin/pathology
An. bras. dermatol ; 88(6): 982-985, Nov-Dec/2013. graf
Article in English | LILACS | ID: lil-698997


Bannayan-Riley-Ruvalcaba Syndrome is a rare condition caused by mutations in the PTEN gene. It displays association of multiple lipomas, macrocephaly, hemangiomas, hamartomatous intestinal polyposis, developmental delay and speckled pigmented maculae on the male genitalia. We report the case of a nine-month-old boy who had fast growing and progressive tumors for three months, macrocephaly and lentigines on the penis. Imaging tests showed extensive lipomatosis with invasion of paraspinal muscles, enlargement of the spinal canal and spinal cord compression; after surgical excision of the mass, the pathology was consistent with lipoma. Adipocyte culture karyotype demonstrated PTEN mutation. We present this case for its rarity and exuberance.

A síndrome de Bannayan-Riley-Ruvalcaba é afecção rara, causada por mutações no gene PTEN. Apresenta associação de múltiplos lipomas, macrocefalia, hemangiomas, polipose hamartomatosa intestinal, atraso do desenvolvimento e máculas salpicadas na genitália masculina. Relatamos o caso de um menino de nove meses com lesões tumorais de crescimento rápido e progressivo em três meses de evolução, macrocefalia e lentigos no pênis. Exames de imagem demonstraram extensa lipomatose com invasão da musculatura paraespinhal, alargamento do canal vertebral e compressão medular. Depois da excisão cirúrgica da massa, o anatomopatológico foi compatível com lipoma. A análise do cariótipo em cultura de adipócitos demonstrou mutação do PTEN. Apresentamos este caso por sua exuberância e raridade.

Humans , Infant , Male , Hamartoma Syndrome, Multiple/pathology , Lipoma/pathology , Skin Neoplasms/pathology , Disease Progression , Mutation , PTEN Phosphohydrolase/genetics , Skin/pathology
Article in English | WPRIM | ID: wpr-159658


The acquisition of metastasis potential is a critical point for malignant tumors. Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) is a potential tumor suppress gene and frequently down-regulated in malignant tumors. It has been implicated that overexpression of MDA-7 led to proliferation inhibition in many types of human tumor. Invasion is an important process which is potential to promote tumor metastasis. However, the role and potential molecular mechanism of mda-7/IL-24 to inhibit the invasion of human melanoma cancer is not fully clear. In this report, we identified a solid role for mda-7/IL-24 in invasion inhibition of human melanoma cancer LiBr cells, including decreasing of adhesion and invasion in vitro, blocking cell cycle, down-regulating the expression of ICAM-1, MMP-2/9, CDK1, the phosphorylation of ERK and Akt, NF-kappaB and AP-1 transcription activity. Meanwhile, there was an increased expression of PTEN in mda-7/IL-24 over-expression LiBr cells. Our results demonstrated that mda-7/IL-24 is a potential invasion suppress gene, which inhibits the invasion of LiBr cells by the down-regulation of ICAM-1, MMP-2/9, PTEN, and CDK1 expression. The molecular pathways involved were the MAPK/ERK, PI3K-Akt, NF-kappaB, and AP-1. These findings suggest that mda-7/IL-24 may be used as a possible therapeutic strategy for human melanoma cancer.

CDC2 Protein Kinase/genetics , Cell Line, Tumor , Cell Movement , Down-Regulation , G2 Phase Cell Cycle Checkpoints , Humans , Intercellular Adhesion Molecule-1/genetics , Interleukins/genetics , M Phase Cell Cycle Checkpoints , Matrix Metalloproteinase 2/genetics , Matrix Metalloproteinase 9/genetics , Melanoma/metabolism , NF-kappa B/genetics , PTEN Phosphohydrolase/genetics , Phosphorylation , Proto-Oncogene Proteins c-akt/genetics , Transcription Factor AP-1/genetics , Up-Regulation
Arq. bras. endocrinol. metab ; 56(8): 592-596, Nov. 2012. ilus, tab
Article in English | LILACS | ID: lil-660272


Cowden syndrome is characterized by hamartomatous polyps, trichilemmomas, increased risk of developing neoplasms, and is associated with germline mutations in the PTEN gene. We searched for germline mutations in PTEN in a 49-year-old female patient who presented trichilemmoma with previous history of breast carcinoma, and thyroidectomy for a thyroid nodule. We also searched for somatic mutations in breast and thyroid tumoral tissues. DNA was extracted from peripheral leukocytes, paraffin samples of breast carcinoma, and cytological smears of thyroid nodule fine-needle aspiration biopsy, whose final histopathological diagnosis was adenomatous goiter. PTEN was amplified and sequenced. We identified a novel mutation, due to a T>A inversion at position 159 and A>T inversion at position 160, leading to valine-to-aspartic acid substitution at position 53. The p.Val53Asp was also found in homozygous state in samples obtained from adenocarcinoma breast and thyroid biopsy, denoting loss of heterozygosity. Here, we demonstrated a novel germline mutation in PTEN, as well as somatic loss of the wild-type PTEN allele in breast and thyroid tumors in a patient with Cowden syndrome. Arq Bras Endocrinol Metab. 2012;56(8):592-6.

A síndrome de Cowden é caracterizada por pólipos de hamartoma, triquelomomas, risco aumentado em desenvolver neoplasias e está associada a mutações germinativas no gene PTEN. Procuramos por mutação germinativa no PTEN de uma paciente de 49 anos que apresentou triquilemomas com história pregressa de carcinoma de mama e realizou tireoidectomia devido a nódulo de tireoide. Investigamos também uma mutação somática em tecidos tumorais de mama e tireoide. O DNA foi extraído de leucócitos periféricos, de amostras de parafina de carcinoma de mama e exame citológico de nódulo de tireoide obtido de biópsia por agulha fina, cujo diagnóstico histopatológico foi de bócio adenomatoso. O PTEN foi amplificado e sequenciado. Identificou-se uma nova mutação em decorrência de uma inversão de T>A na posição 159 e A>T na posição 160, levando à substituição de valina para ácido aspártico na posição 53. A mutação p.Val53Asp também foi encontrada em estado homozigoto em amostras obtidas do adenocarcinoma de mama e da biópsia de nódulo tireoidiano, denotando perda de heterozigosidade. Portanto, demonstramos uma mutação germinativa no PTEN e também a perda somática do alelo selvagem PTEN no tumor de mama e da tireoide de uma paciente com síndrome de Cowden. Arq Bras Endocrinol Metab. 2012;56(8):592-6.

Female , Humans , Middle Aged , Breast Neoplasms/genetics , Hamartoma Syndrome, Multiple/genetics , Mutation/genetics , PTEN Phosphohydrolase/genetics , Thyroid Neoplasms/genetics , Genetic Markers
IBJ-Iranian Biomedical Journal. 2009; 13 (2): 79-86
in English | IMEMR | ID: emr-91139


Pharmacogenomics is the study of genetic variations among individuals to predict the probability that a patient will respond to single or multidrug chemotherapy. Breast cancer is one of the most common cancers among women worldwide. Treatment of breast cancer by application of biological rationales gives us the ability to match the correct pharmacology to individual tumour genetic profiles. The breast cancers exhibit multiple anomalies in phosphatidylinositol 3 kinase pathways, such as phosphatase and tensin homolog deleted on chromosome TEN loss that can be put in context of therapy with rapamycin analogues. Considering the high incidence of breast cancer in Iran, the potential role of tumor suppressor PTEN/MMAC1gene was investigated in Isfahanian breast cancer patients. In this study, PTEN was evaluated by means of polymerase chain reaction, single strand conformation polymorphism, Heteroduplex mobility assay and direct DNA sequencing in 72 breast cancer tumors for detection and characterization of mutations. According to the results of this research, nucleotide substitutions were found in 5/72 [7%] of samples. The sporadic breast cancer patient was found to be heterozygote for the p.D92N, p.C105W, p.D107N, p.A121P and p.R 130Q mutations. One novel mutation, p.D107N, was found in this study. Loss of PTEN function in breast cancer can occur either by mutation or reduction of PTEN expression in almost half of sporadic breast tumors. This rate of mutations is an important consideration for novel therapeutic in which biological efficacy is influenced by the activity of PTEN

Humans , Female , Pharmacogenetics , PTEN Phosphohydrolase/genetics , Phosphatidylinositol 3-Kinase/genetics , Sirolimus , Polymerase Chain Reaction , Polymorphism, Single-Stranded Conformational , Sequence Analysis, DNA , Mutation
Article in English | IMSEAR | ID: sea-18167


BACKGROUND & OBJECTIVE: Mutation/deletion of PTEN has been known to be involved in the development of many cancers including endometrial carcinoma. NDRG1 (N-myc downstream-regulated gene 1) is reported to be associated with tumourigenesis. PTEN expression has been shown to be correlated with NDRG1 in both prostate and breast cancer. In this study, we explored the possibility that PTEN alteration may cause carcinogenesis of endometrioid carcinoma by regulating the expression of the NDRG1 gene. METHODS: Tissue blocks of 103 patients with pathologically confirmed endometrioid carcinoma were included. All the carcinoma tissues were accompanied with varied degree of necrosis. Using two-step method and avidin-biotin peroxidase complex immunohistochemistry method, the correlation of the two genes expression in ischaemic area and the relationship of NDRG1 expression between ischaemic and non-ischaemic area in endometrioid carcinomas was evaluated. RESULTS: PTEN alteration and NDRG1 expressions were significantly increased in the ischaemic area of endometrioid carcinoma compared with their expressions in the normal endometrium respectively (P<0.001, P<0.001). A positive correlation was found between PTEN alteration and NDRG1 expression in the ischaemic area of endometrioid carcinoma. INTERPRETATION & CONCLUSION: We suggest that NDRG1 may be an important candidate gene in facilitating endometrium carcinogenesis in the adaptation of hypoxia for survival. Alteration of PTEN may upregulate NDRG1 expression, which plays an important role in the process leading to endometrial carcinogenesis.

Carcinoma, Endometrioid/genetics , Cell Cycle Proteins/genetics , Endometrium/cytology , Female , Humans , Intracellular Signaling Peptides and Proteins/genetics , Middle Aged , PTEN Phosphohydrolase/genetics
Iranian Journal of Cancer Prevention. 2008; 1 (4): 141-147
in English | IMEMR | ID: emr-143338


In this study, we evaluated PTEN mutations in Cowden Disease and Juvenile Polyposis syndrome. PTEN mutations were detected, cancer and other phenotypes associated with each of these mutations were characterized and loss of wild type PTEN allele in the associated tumors was demonstrated. Out of 9 patients included in this study, 8 had Juvenile polyposis and 1 had Cowden syndrome. PTEN gene was evaluated by means of polymerase chain reaction, single strand conformation polymorphism [SSCP], Heteroduplex mobility assay [HMA] and direct DNA sequencing. According to the results of this research, nucleotide substitutions in PTEN gene were found in 22% [2/9] of patients. The samples were found to be heterozygote for the c.341T>G and c.389G>A mutations. One novel mutation c.341T>G in Iranian patients with Cowden syndrome was found in this study. The study of these rare patients could provide insight into PTEN driven tumorgenesis

Humans , Female , PTEN Phosphohydrolase/genetics , Mutation/genetics , Adenomatous Polyposis Coli , Polymorphism, Genetic , Polymerase Chain Reaction , Polymorphism, Single-Stranded Conformational
Article in English | WPRIM | ID: wpr-59825


Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a tumor suppressor. Although it is well known to have various physiological roles in cancer, its inhibitory effect on inflammation remains poorly understood. In the present study, a human PTEN gene was fused with PEP-1 peptide in a bacterial expression vector to produce a genetic in-frame PEP-1-PTEN fusion protein. The expressed and purified PEP-1-PTEN fusion protein were transduced efficiently into macrophage Raw 264.7 cells in a time- and dose- dependent manner when added exogenously in culture media. Once inside the cells, the transduced PEP-1-PTEN protein was stable for 24 h. Transduced PEP-1-PTEN fusion protein inhibited the LPS-induced cyclooxygenase 2 (COX-2) and iNOS expression levels in a dose-dependent manner. Furthermore, transduced PEP-1-PTEN fusion protein inhibited the activation of NF-kappa B induced by LPS. These results suggest that the PEP-1-PTEN fusion protein can be used in protein therapy for inflammatory disorders.

Animals , Cell Line , Cyclooxygenase 2/metabolism , Cysteamine/analogs & derivatives , Enzyme Activation , Humans , Lipopolysaccharides/pharmacology , Macrophages/metabolism , Mice , NF-kappa B/metabolism , Nitric Oxide/biosynthesis , Nitric Oxide Synthase Type II/metabolism , PTEN Phosphohydrolase/genetics , Peptides/genetics , Recombinant Fusion Proteins/biosynthesis , Signal Transduction