RESUMO
Background: Experimental and epidemiologic evidence supports the role of circulating insulin-like growth factor-1 (IGF-1) levels with the risk of prostate cancer. Most circulating IGF-1 is bound to specific binding proteins, and only about 5% circulates in a free form. We explored the relation of free IGF-1 and other components of the IGF system with lethal prostate cancer. Methods: Using prospectively collected samples, we undertook a nested case-only analysis among 434 men with lethal prostate cancer and 524 men with indolent, nonlethal prostate cancer in the Physicians' Health Study and the Health Professionals Follow-up Study. Prediagnostic plasma samples were assayed for free IGF-1 and total IGF-1, acid labile subunit, pregnancy-associated plasma protein A (PAPP-A), and intact and total IGF binding protein 4. We estimated odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the associations between IGF-1-related biomarkers and lethal prostate cancer using unconditional logistic regression models adjusted for age, height, and body mass index. Results: Men in the highest quartile of PAPP-A levels had 42% higher odds of lethal prostate cancer (pooled adjusted OR = 1.42, 95% CI = 1.04 to 1.92) compared with men in the lowest 3 quartiles. There were no statistically significant differences in the other plasma analytes. The positive association between PAPP-A and lethal prostate cancer was present among men with intact PTEN but not among those with tumor PTEN loss (2-sided P interaction = .001). Conclusions: Our study provides suggestive evidence that among men who later develop prostate cancer, higher plasma PAPP-A levels measured prior to diagnosis are associated with increased risk of lethal compared with indolent disease.
Assuntos
Biomarcadores Tumorais/sangue , Fator de Crescimento Insulin-Like I/análise , Proteína Plasmática A Associada à Gravidez/análise , Neoplasias da Próstata/sangue , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estatura , Índice de Massa Corporal , Estudos de Casos e Controles , Intervalos de Confiança , Ensaio de Imunoadsorção Enzimática , Seguimentos , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , PTEN Fosfo-Hidrolase/sangue , Proteína Plasmática A Associada à Gravidez/metabolismo , Neoplasias da Próstata/classificação , Neoplasias da Próstata/mortalidade , RiscoRESUMO
Osteoporosis is characterized by osteopenia and bone tissue microstructure degradation. Adipose-derived stem cells (ADSCs) are multipotent adult stem cells that have the ability to yield mesenchymal stem cells and have the potential to undergo osteogenesis and bone regeneration. Therefore, ADSCs have the potential to treat osteoporosis, but the molecular mechanism of these cells in the process of osteogenesis and osteoclasts is still not clear. In the present study, we collected serum samples from 10 clinical osteoporosis patients to detect long noncoding RNA-neighboring enhancer of FOXA2 (lncRNA-NEF) and miR-155 expression levels. Half of these patients were senile and half were postmenopausal women, and nine of them have used steroids for a long time, in which ADSCs were cultured and induced to adipogenic and osteogenic differentiations. Quantitative real-time polymerase chain reaction was used to detect the expression of genes in ADSCs. Overexpression of lncRNA-NEF in ADSCs were undertaken to verify its regulatory function on cell osteogenic and adipogenic differentiations. A luciferase activity experiment was performed to determine the relationship between miR-155 and phosphatase and tensin homologue deleted on chromosome 10 (PTEN). The level of lncRNA-NEF was downregulated, and miR-155 was upregulated, in serum samples from patients with clinical osteoporosis. LncRNA-NEF showed different expression levels in the induction of osteogenic or adipogenic differentiation, which increased during osteogenic induction and decreased during adipogenic induction. Overexpression of lncRNA-NEF or downregulation of miR-155 in ADSCs promoted osteogenic differentiation and inhibited adipogenesis progression. PTEN was the direct target of miR-155 and was involved in the regulation of osteogenic differentiation. Overexpression of lncRNA-NEF regulated the miR-155/PTEN axis to inhibit adipogenesis and promote osteogenesis in ADSCs.
Assuntos
Doença de Alzheimer/genética , MicroRNAs/genética , Osteogênese/genética , Osteoporose/genética , PTEN Fosfo-Hidrolase/genética , RNA Longo não Codificante/genética , Adipócitos/citologia , Adipócitos/metabolismo , Adipogenia/genética , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Adulto , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/patologia , Animais , Diferenciação Celular , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/sangue , Pessoa de Meia-Idade , Osteoblastos/citologia , Osteoblastos/metabolismo , Osteoporose/sangue , Osteoporose/patologia , PTEN Fosfo-Hidrolase/sangue , Pós-Menopausa/sangue , Pós-Menopausa/genética , RNA Longo não Codificante/sangue , Ratos , Ratos Sprague-Dawley , Transdução de SinaisRESUMO
The aim of this study was to investigate the role and potential mechanism of miR-193a-3p in fracture healing. The 70 fragility fracture patients and 45 healthy controls were enrolled in this study. Quantitative real-time PCR (qRT-PCR) was used for the measurement of the expression levels of miR-193a-3p and PTEN. MTT assay and flow cytometry were used to detect cell viability and apoptosis in the mouse osteoblastic cell line MC3T3-E1. Luciferase reporter assay was performed to confirm the correlation of miR-193a-3p with PTEN. The serum expression level of miR-193a-3p showed no significant change in fracture patients 7 days after fixation treatment, but over time, there was a significant decrease in the expression at 14 days and 21 days after treatment (P < 0.01). Overexpression of miR-193a-3p significantly enhanced cell viability and inhibited cell apoptosis in MC3T3-E1 cells (P < 0.001). Serum PTEN level in fracture patients was increased gradually during the fracture healing process (P < 0.01). PTEN was demonstrated to be a target gene of miR-9-5p and reversed the effect of miR-193a-3p on cell viability and apoptosis (P < 0.001). miR-193a-3p promoted fracture healing via regulating PTEN and may serve as a novel potential target for enhancing bone repair of fragility fracture.
Assuntos
Consolidação da Fratura , Fraturas Ósseas/cirurgia , MicroRNAs/genética , PTEN Fosfo-Hidrolase/genética , Animais , Estudos de Casos e Controles , Linhagem Celular , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Fraturas Ósseas/sangue , Fraturas Ósseas/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , MicroRNAs/sangue , Procedimentos Ortopédicos , PTEN Fosfo-Hidrolase/sangue , Regulação para CimaRESUMO
BACKGROUND: To find new diagnostic markers for idiopathic membranous nephropathy (IMN) and also conduct preliminary explorations into the possible pathogenesis of IMN by comparing the expression of microRNA-451a (miR-451a), miR-106a, miR-19b, miR-17, and phosphatase and tensin homolog (PTEN) protein in the serum of patients with IMN and healthy controls. METHODS: The expression levels of miR-451a, miR-106a, miR-19b, and miR-17 in the serum of patients in the IMN group (n = 55, age: 50.2 ± 12.1 years) and the control group (n = 58, age 47.4 ± 13.1 years) were measured by quantitative real-time polymerase chain reaction (qRT-PCR), and the concentration of serum PTEN protein was determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with the control group, the expression of miR-106a, miR-19b, and miR-17 was decreased significantly in the IMN group, whereas PTEN protein concentration was increased significantly in the IMN group. The areas under the receiver operating characteristic curve (AUC) of serum miR-106a, miR-19b, miR-17, and PTEN were 0.66 (95% confidence interval [CI], 0.56-0.76), 0.81 (95% CI, 0.73-0.89), 0.69 (95% CI, 0.59-0.79), and 0.86 (95% CI, 0.79-0.93), respectively. The level of serum PTEN protein was negatively correlated with the expression of miR-106a and miR-19b. PTEN concentration was positively correlated with serum urea (Urea), creatinine (Crea), cystatin C (Cysc), 24 h urine total protein (24 h-UP) and negatively correlated with albumin (Alb) and estimated glomerular filtration rate (eGFR). CONCLUSIONS: MiR-106a, miR-19b, miR-17, and PTEN are involved in the pathogenesis of IMN and may become new biomarkers for the diagnosis of IMN.
Assuntos
Regulação da Expressão Gênica , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/genética , MicroRNAs/sangue , PTEN Fosfo-Hidrolase/sangue , Albuminas/metabolismo , Estudos de Casos e Controles , Creatinina/sangue , Cistatina C/sangue , Feminino , Taxa de Filtração Glomerular , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/fisiopatologia , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/genética , Proteinúria/sangue , Proteinúria/complicações , Ureia/sangueRESUMO
The silence of lncRNA small nucleolar RNA host gene 16 (SNHG16) suppressed acute lymphoblastic leukemia (ALL) cell proliferation and migration, whereas its role in acute myeloid leukemia (AML) still lacks clarity. This study showed that SNHG16 was upregulated in AML patients and cells. And SNHG16 overexpression remarkably enhanced the proliferation and migration capacities of HL60 and AML-193 cells, while SNHG16 knockdown acted the opposite way. Subsequently, we revealed that SNHG16 directly bound to CELF2 (CUGBP Elav-like family member 2) protein, and caused CELF2 mRNA unstably and proteins reducing. CELF2 was decreased both in AML patients and cells. CELF2 overexpression or interference weakened the effect of overexpressing or silencing SNHG16 on proliferation and migration. Moreover, the transfection of pcDNA-CELF2 elevated PTEN (phosphatase and tensin homolog) activity and hindered the phosphoinositide 3-kinase (PI3K)/AKT signaling. And SNHG16 reduced PTEN activity and promoted the PI3K/AKT pathway activation by restraining CELF2. Furthermore, GDC-0941 (a specific inhibitor of the PI3K/AKT pathway) impeded the effect of SNHG16 increase, and bpV(pic) (a specific PTEN inhibitor) declined the effect of SNHG16 decrease on cell proliferation and migration. Taken together, the present study indicated that SNHG16 promoted proliferation and migration of AML cells via PTEN/PI3K/AKT axis through suppressing CELF2 protein.
Assuntos
Proteínas CELF/genética , Leucemia Mieloide Aguda/sangue , Proteínas do Tecido Nervoso/genética , PTEN Fosfo-Hidrolase/genética , RNA Longo não Codificante/genética , Proteínas CELF/sangue , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Regulação Leucêmica da Expressão Gênica/genética , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Proteínas do Tecido Nervoso/sangue , Proteína Oncogênica v-akt/sangue , Proteína Oncogênica v-akt/genética , PTEN Fosfo-Hidrolase/sangue , Fosfatidilinositol 3-Quinases/sangue , Fosfatidilinositol 3-Quinases/genética , RNA Longo não Codificante/sangue , Transdução de Sinais/genéticaRESUMO
PURPOSE: DNA damage repair (DDR) defects are common across cancer types and can indicate therapeutic vulnerability. Optimal exploitation of DDR defects in prostate cancer requires new diagnostic strategies and a better understanding of associated clinical genomic features. EXPERIMENTAL DESIGN: We performed targeted sequencing of 1,615 plasma cell-free DNA samples from 879 patients with metastatic prostate cancer. Depth-based copy-number calls and heterozygous SNP imbalance were leveraged to expose DDR-mutant allelic configuration and categorize mechanisms of biallelic loss. We used split-read structural variation analysis to characterize tumor suppressor rearrangements. Patient-matched archival primary tissue was analyzed identically. RESULTS: BRCA2, ATM, and CDK12 were the most frequently disrupted DDR genes in circulating tumor DNA (ctDNA), collectively mutated in 15% of evaluable cases. Biallelic gene disruption via second somatic alteration or mutant allele-specific imbalance was identified in 79% of patients. A further 2% exhibited homozygous BRCA2 deletions. Tumor suppressors TP53, RB1, and PTEN were controlled via disruptive chromosomal rearrangements in BRCA2-defective samples, but via oncogene amplification in context of CDK12 defects. TP53 mutations were rare in cases with ATM defects. DDR mutations were re-detected across 94% of serial ctDNA samples and in all available archival primary tissues, indicating they arose prior to metastatic progression. Loss of BRCA2 and CDK12, but not ATM, was associated with poor clinical outcomes. CONCLUSIONS: BRCA2, ATM, and CDK12 defects are each linked to distinct prostate cancer driver genomics and aggression. The consistency of DDR status in longitudinal samples and resolution of allelic status underscores the potential for ctDNA as a diagnostic tool.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína BRCA2/genética , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Quinases Ciclina-Dependentes/genética , Mutação , Neoplasias de Próstata Resistentes à Castração/patologia , Idoso , Idoso de 80 Anos ou mais , Proteínas Mutadas de Ataxia Telangiectasia/sangue , Proteína BRCA2/sangue , Biomarcadores Tumorais/sangue , DNA Tumoral Circulante/análise , Terapia Combinada , Quinases Ciclina-Dependentes/sangue , Reparo do DNA , Seguimentos , Deleção de Genes , Rearranjo Gênico , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/sangue , PTEN Fosfo-Hidrolase/genética , Prognóstico , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/classificação , Neoplasias de Próstata Resistentes à Castração/genética , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
This study investigates whether the circulating miR-155, let-7c, miR-21, and PTEN levels to be used in the differential diagnosis of patients with idiopathic granulomatous mastitis (IGM) and breast cancer (BC). Forty-five patients with BC, 50 patients with IGM, and 48 healthy volunteers were included in the study. Serum miR-21 expression was significantly higher in BC (fold change = 2.42) and IGM group (fold change = 1.33) compared to control (p < .001). Serum miR-155 and let-7c expression levels were significantly lower in both groups compared to the control group (p < .001). miR-21 expression in BC was significantly higher than IGM (fold change = 1.976; p < .001). PTEN levels in BC were significantly higher than IGM (p < .001) and significantly lower than the control group (p < .001); the IGM group was significantly lower than the control group (p < .001). In addition to radiological data, serum miR-21 and PTEN levels may be noninvasive biomarkers that can help differentiate IGM from BC. The results of the study will lead to future studies in the differential diagnosis of IGM and BC.
Assuntos
Neoplasias da Mama/sangue , Mastite Granulomatosa/sangue , MicroRNAs/sangue , PTEN Fosfo-Hidrolase/sangue , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Diagnóstico Diferencial , Feminino , Mastite Granulomatosa/genética , Humanos , MicroRNAs/genética , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/genética , PrognósticoRESUMO
BACKGROUND: To investigate the association between phosphatase and tension homologue deleted on chromosome ten (PTEN) gene polymorphisms and non-small-cell lung cancer (NSCLC) and further identify whether these polymorphisms influence serum PTEN levels. METHODS: A total of 152 NSCLC patients and 124 healthy controls were included in the study. PTEN gene rs11202586 (T > C) and rs1903858 (A > G) polymorphisms were detected using the multiple single-base extension technique (SNaPshot). The serum PTEN levels were determined using an enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: The rs1903858 AG, GG genotypes, and G allele were associated with a higher risk of NSCLC (odds ratio (OR) =2.079, 95% confidence interval (CI) = 1.087-3.974, P = .027; OR = 1.897, 95%CI = 1.053-3.419, P = .033; OR = 1.505, 95%CI = 1.065-2.126, P = .020). Stratified analysis reveal that the rs1903858 GG genotype and G allele were associated with an increased risk of squamous cell carcinoma (SCC) (OR = 3.226, 95%CI = 1.075-9.678, P = .037; OR = 1.873, 95%CI = 1.092-3.212, P = .023). Among smokers, the rs1903858 G allele carriers have an increased risk of NSCLC (OR = 1.916, 95%CI = 1.023-3.589, P = .042), but a decreased risk of NSCLC was found with the AT haplotype. With respect to the serum PTEN levels, no significant difference was noted between NSCLC patients and healthy controls in this study. CONCLUSIONS: The study indicated that the rs1903858 gene polymorphism is associated with increased risk of NSCLC, particularly in SCC and smoker, and the haplotype AT was a protective factor for NSCLC. The serum PTEN levels were not associated with NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , PTEN Fosfo-Hidrolase , Polimorfismo de Nucleotídeo Único/genética , Idoso , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Estudos de Casos e Controles , Feminino , Haplótipos/genética , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/sangue , PTEN Fosfo-Hidrolase/genéticaRESUMO
Objectives: Studies have shown that human and peripheral blood mononuclear cells (PBMCs) are mostly used for research purposes to study several biochemical endpoints. The effects of the flavonoids, genistein, kaempferol, and quercetin on phospho tensin homolog (PTEN) levels in cancer cells (i.e., breast [BT549], lung [A549]), human embryonic kidney cells (HEK293), and the levels of lipid peroxides (LP) in PBMCs were respectively investigated.Materials and methods: Cancer, kidney, and PBMCs from several donors were each exposed to each of the flavonoids at concentrations of 0, 5, 10, 15, 20, and 25 µM. Our hypotheses were that exposure of cancer and kidney cells to genistein, kaempferol, and quercetin can increase PTEN and decrease lipid peroxides in PBMCs levels respectively to better cope with oxidative stress.Results: The results indicate that the flavonoids increased total PTEN levels in a dose-dependent manner. The effect of quercetin was more pronounced followed by genistein and kaempferol. Furthermore, decreases in lipid peroxides were observed in the PBMCs for the flavonoid-treated samples compared to those exposed to flavonoids and with oxidative stress as described by Fenton's chemistry. Levels of LP in quercetin-treated samples were lower compared to kaempferol and genistein.Conclusions: The findings suggest that the flavonoids play an important role in controlling oxidative stress in several human cells.
Assuntos
Flavonoides/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Peróxidos Lipídicos/sangue , PTEN Fosfo-Hidrolase/sangue , Células A549 , Neoplasias da Mama , Linhagem Celular Tumoral , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Genisteína/farmacologia , Células HEK293 , Humanos , Quempferóis/farmacologia , Leucócitos Mononucleares/química , Estresse Oxidativo/efeitos dos fármacos , Quercetina/farmacologiaRESUMO
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.
Assuntos
Regulação Neoplásica da Expressão Gênica , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias da Próstata/metabolismo , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Estudos de Coortes , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , PTEN Fosfo-Hidrolase/sangue , PTEN Fosfo-Hidrolase/genética , Prevalência , Prognóstico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Estudos Retrospectivos , Regulador Transcricional ERG/sangue , Regulador Transcricional ERG/genética , Regulador Transcricional ERG/metabolismoRESUMO
Experiments were conducted to determine if the follicle-stimulating hormone (FSH) receptor binding inhibitor (FRBI) impacts the expression levels of AT-rich interactive domain-containing protein 1A (ARID1A) and phosphatase and tensin homolog (PTEN) in ovaries and blood, as well as expressions of follicle-stimulating hormone cognate receptor (FSHR) gene and proteins. Mice in FRBI-10, FRBI-20, FRBI-30, and FRBI-40 groups were intramuscularly injected with 10, 20, 30, and 40 mg FRBI/kg, respectively, for five consecutive days. Western blotting and qRT-PCR were utilized to determine expression levels of ARID1A and PTEN proteins and mRNAs. Serum ARID1A and PTEN concentrations of the FRBI-40 group were higher than the control group (CG) and FSH group (P<0.05). FSHR mRNA levels of FRBI-20, FRBI-30, and FRBI-40 groups were lower than that of CG and FSH groups on day 15 (P<0.05 or P<0.01). Expression levels of FSHR proteins of FRBI-30 and FRBI-40 groups were lower than those of CG and FSH groups (P<0.05). Levels of ARID1A and PTEN proteins of the FRBI-30 group were greater than CG on days 20 and 30 (P<0.05). FRBI doses had significant positive correlations to levels of ARID1A and PTEN proteins. Additionally, ARID1A and PTEN had negative correlations to FSHR mRNAs and proteins. A high dose of FRBI could promote the expression levels of ARID1A and PTEN proteins in ovarian tissues. FRBI increased serum concentrations of ARID1A and PTEN. However, FRBI depressed expression levels of FSHR mRNAs and proteins in mouse ovaries.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Hormônio Foliculoestimulante/metabolismo , Proteínas Nucleares/sangue , Neoplasias Ovarianas/metabolismo , PTEN Fosfo-Hidrolase/sangue , Receptores do FSH/antagonistas & inibidores , Animais , Western Blotting , Proteínas de Ligação a DNA/sangue , Feminino , Camundongos , Proteínas Nucleares/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosforilação , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Transcrição , Ativação Transcricional/genética , Regulação para CimaRESUMO
Coronary artery disease (CAD) is primarily caused by atherosclerosis, which is a series of chronic inflammatory processes leading to the initiation and progression of vascular endothelial cell injury enhancing plaque formation. As critical components of the immune system, peripheral blood mononuclear cells (PBMCs) actively cross-talk with pathophysiological conditions induced by endothelial cell injury, reflecting in altered PBMC expression pattern. This study explored PBMC expression levels of miR-21, miR-25 and PTEN in patients with angiographically proven significant coronary stenosis (the CAD group), patients with insignificant coronary stenosis (the ICAD group) and healthy subjects, and assessed potentials of PBMC expressions in discriminating groups of study subjects. In-silico analysis was also performed to obtain insights into CAD-related pathways and biological processes that may be influenced by altered miRNA expressions. A reduced level of PBMC miR-21 was observed in the ICAD group compared to the CAD group (P: 0.004) or healthy controls (P: 0.0001). PBMC miR-21 level was negatively correlated with the PTEN expression (Spearman r: -0.43, P: 3.9e-09). The PTEN expression was increased in the CAD or ICAD group compared to the control group (CAD vs. controls P: 0.0003, ICAD vs. controls P: 0.03). A stepwise increase in PBMC miR-25 levels was observed from healthy controls to ICADs and CAD patients (Kruskal-Wallis P: 7.68e-12). PBMC gene expressions had reasonable power to discriminate between pairs of study groups. PBMC miR-21 levels were able to discriminate ICADs from both CADs and controls and miR-25 levels had potentials to differentiate among all pairs of study groups (i.e. CADs-ICADs, CADs-controls, CADs-all other subjects, ICADs-controls). PBMC PTEN expression was able to discriminate patients with CAD or ICAD from control subjects. Overrepresentation enrichment analysis of experimentally validated targets of miR-21 and miR-25 highlighted key biological processes and pathways, such as "angiogenesis" and "leukocyte cell-cell adhesion", that may be influenced by dysregulation of PBMC miR-21 and miR-25. In conclusion, these findings suggest that patients with insignificant coronary stenosis may have a distinct PBMC miRNA expression profile than those with significant stenosis or healthy controls.
Assuntos
Estenose Coronária/genética , MicroRNAs/biossíntese , PTEN Fosfo-Hidrolase/biossíntese , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Estenose Coronária/sangue , Células Endoteliais/metabolismo , Feminino , Humanos , Leucócitos/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , MicroRNAs/sangue , MicroRNAs/genética , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/sangue , PTEN Fosfo-Hidrolase/genéticaRESUMO
PURPOSE: The addition of anti-HER2 therapies to neoadjuvant treatment significantly enhances pathological complete response (PCR) rate in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Selecting patients unlikely to benefit from neoadjuvant anti-HER2 therapies is increasingly important. In this study, we proposed to assess the role of the phosphatase and tensin homolog (PTEN) as a biomarker in predicting PCR to neoadjuvant anti-HER2 therapies by conducting meta-analysis. METHODS: Our team searched Embase, Medline, and the Cochrane Library by the end of September 16, 2018, for trials on patients with HER2-positive breast cancer treated with neoadjuvant anti-HER2 therapies. The associations between PTEN expression and PCR rate were then assessed. Odds ratio (ORs) and hazard ratio (HRs) with 95% confidence intervals (CIs) with 2-sided P values were calculated. The Newcastle-Ottawa scale (NOS) was used to estimate the quality of the involved trials. RESULTS: A total of 820 patients from 8 trials were included in this meta-analysis. Overall, the PTEN normal tumors was related to a significant increase in PCR rate (OR 0.55; 95% CIâ=â0.31-0.96; Pâ=â.04; Iâ=â54%). In different anti-HER2 agents analysis, the PTEN normal tumors was related to a significant increase in PCR rate in patients treated with trastuzumab alone (OR 0.40; 95% CIâ=â0.24-0.67; Pâ=â.0005; Iâ=â15%). Besides, no significant association between PTEN status and PCR rate was detected in patients treated with lapatinib alone (OR 1.90; 95% CIâ=â0.78-4.60; Pâ=â.16; Iâ=â0%) or trastuzumab plus lapatinib (OR 1.27; 95% CIâ=â0.27-5.97; Pâ=â.76; Iâ=â73%). CONCLUSION: Based on current evidence, PTEN status could be n suitable biomarker in predicting PCR rate to neoadjuvant anti-HER2 therapies, especially in trastuzumab-treated patients.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante/métodos , PTEN Fosfo-Hidrolase/sangue , Receptor ErbB-2/biossíntese , Biomarcadores Tumorais , Neoplasias da Mama/terapia , Feminino , Humanos , PTEN Fosfo-Hidrolase/biossíntese , Trastuzumab/uso terapêuticoRESUMO
Alzheimer's disease (AD) is one of the most common neurodegenerative diseases in which the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (PKB or Akt) pathway is deregulated in response to phosphatase and tensin homolog (PTEN) overexpression. Lactoferrin (LF), a multifunctional iron-binding glycoprotein, is involved in AD pathology; however, direct evidence of its impact upon AD remains unclear. To elucidate LF's role in AD, the possible protective mechanism post-LF administration for 3 months was investigated in AD patients by observing changes in the p-Akt/PTEN pathway. AD patients showed decreased serum acetylcholine (ACh), serotonin (5-HT), antioxidant and anti-inflammatory markers, and decreased expression of Akt in peripheral blood lymphocytes (PBL), as well as PI3K, and p-Akt levels in PBL lysate; all these parameters were significantly improved after daily LF administration for 3 months. Similarly, elevated serum amyloid ß (Aß) 42, cholesterol, oxidative stress markers, IL-6, heat shock protein (HSP) 90, caspase-3, and p-tau, as well as increased expression of tau, MAPK1 and PTEN in AD patients, were significantly reduced upon LF intake. Improvement in the aforementioned AD surrogate markers post-LF treatment was reflected in enhanced cognitive function assessed by the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-Cognitive Subscale 11-item (ADAS-COG 11) questionnaires as clinical endpoints. These results provide a basis for a possible protective mechanism of LF in AD through its ability to alleviate the AD pathological cascade and cognitive decline via modulation of the p-Akt/PTEN pathway, which affects the key players of inflammation and oxidative stress that are involved in AD pathology.
Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/tratamento farmacológico , Lactoferrina/uso terapêutico , PTEN Fosfo-Hidrolase/sangue , Proteínas Proto-Oncogênicas c-akt/sangue , Transdução de Sinais/efeitos dos fármacos , Idoso , Doença de Alzheimer/patologia , Feminino , Humanos , Lactoferrina/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Masculino , PTEN Fosfo-Hidrolase/antagonistas & inibidores , Projetos Piloto , Proteínas Proto-Oncogênicas c-akt/agonistas , Transdução de Sinais/fisiologia , Resultado do TratamentoRESUMO
Experiments were conducted to determine if the follicle-stimulating hormone (FSH) receptor binding inhibitor (FRBI) impacts the expression levels of AT-rich interactive domain-containing protein 1A (ARID1A) and phosphatase and tensin homolog (PTEN) in ovaries and blood, as well as expressions of follicle-stimulating hormone cognate receptor (FSHR) gene and proteins. Mice in FRBI-10, FRBI-20, FRBI-30, and FRBI-40 groups were intramuscularly injected with 10, 20, 30, and 40 mg FRBI/kg, respectively, for five consecutive days. Western blotting and qRT-PCR were utilized to determine expression levels of ARID1A and PTEN proteins and mRNAs. Serum ARID1A and PTEN concentrations of the FRBI-40 group were higher than the control group (CG) and FSH group (P<0.05). FSHR mRNA levels of FRBI-20, FRBI-30, and FRBI-40 groups were lower than that of CG and FSH groups on day 15 (P<0.05 or P<0.01). Expression levels of FSHR proteins of FRBI-30 and FRBI-40 groups were lower than those of CG and FSH groups (P<0.05). Levels of ARID1A and PTEN proteins of the FRBI-30 group were greater than CG on days 20 and 30 (P<0.05). FRBI doses had significant positive correlations to levels of ARID1A and PTEN proteins. Additionally, ARID1A and PTEN had negative correlations to FSHR mRNAs and proteins. A high dose of FRBI could promote the expression levels of ARID1A and PTEN proteins in ovarian tissues. FRBI increased serum concentrations of ARID1A and PTEN. However, FRBI depressed expression levels of FSHR mRNAs and proteins in mouse ovaries.
Assuntos
Animais , Feminino , Coelhos , Neoplasias Ovarianas/metabolismo , Receptores do FSH/antagonistas & inibidores , Proteínas Nucleares/sangue , Proteínas de Ligação a DNA/metabolismo , PTEN Fosfo-Hidrolase/sangue , Hormônio Foliculoestimulante/metabolismo , Fosforilação , Fatores de Transcrição , Proteínas Nucleares/metabolismo , Ativação Transcricional/genética , Regulação para Cima , Western Blotting , Proteínas de Ligação a DNA/sangue , PTEN Fosfo-Hidrolase/metabolismo , Reação em Cadeia da Polimerase em Tempo RealRESUMO
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.
Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Próstata/metabolismo , Regulação Neoplásica da Expressão Gênica , PTEN Fosfo-Hidrolase/metabolismo , Prognóstico , Neoplasias da Próstata/cirurgia , Neoplasias da Próstata/patologia , Imuno-Histoquímica , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/sangue , Prevalência , Estudos Retrospectivos , Estudos de Coortes , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/sangue , Gradação de Tumores , Regulador Transcricional ERG/genética , Regulador Transcricional ERG/metabolismo , Regulador Transcricional ERG/sangueRESUMO
Phosphatase and tensin homolog (PTEN) is thought to mediate B cell activation by negatively regulating the phosphoinositide 3-kinase (PI3K) signaling pathway. This pathway is important for activation, growth, and proliferation. Although enhanced B cell receptor (BCR) signaling contributes to increased B cell activity in immune thrombocytopenia (ITP), the role of PTEN is unclear. In this study, we analyzed B cells of ITP patients using flow cytometry and found that all B cell subsets, excluding memory B cells, showed lower PTEN expression than cells from healthy controls (HCs). PTEN expression was also positively-correlated with blood platelet count, although levels were lower in patients who were platelet autoantibody-positive compared with those who were negative. We next evaluated the effects of IL-21, anti-IgM, and CD40L on PTEN expression, demonstrating that they were potent inducers of PTEN expression in normal B cells. Induction of PTEN expression was lower in B cells of ITP patients. We also found that IL-21 increased the proportion of plasma cells in peripheral blood mononuclear cells (PBMCs) of ITP patients, independent of BCR signaling. This effect was reproducible using PTEN inhibitors with cells from HCs. In summary, defective PTEN expression, regulation, and function all contribute to the B cell hyper-responsiveness that associates with ITP.
Assuntos
Subpopulações de Linfócitos B/imunologia , PTEN Fosfo-Hidrolase/deficiência , Púrpura Trombocitopênica Idiopática/imunologia , Adolescente , Adulto , Anticorpos Anti-Idiotípicos/farmacologia , Antígenos de Plaquetas Humanas/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Subpopulações de Linfócitos B/metabolismo , Ligante de CD40/farmacologia , Células Cultivadas , Feminino , Humanos , Interleucina-2/farmacologia , Interleucinas/farmacologia , Ativação Linfocitária , Masculino , Compostos Organometálicos/farmacologia , PTEN Fosfo-Hidrolase/antagonistas & inibidores , PTEN Fosfo-Hidrolase/sangue , PTEN Fosfo-Hidrolase/fisiologia , Plasmócitos/efeitos dos fármacos , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , RNA Mensageiro/sangue , Receptores de Antígenos de Linfócitos B/imunologia , Adulto JovemRESUMO
BACKGROUND & AIM: Phosphatase and tensin homologue (PTEN) reduces insulin sensitivity. Since critically ill patients present insulin resistance, we aimed at assessing the role of PTEN expression on glucose homeostasis and clinical outcome in patients admitted to an intensive care unit (ICU) and receiving artificial nutrition. METHODS: Observational, single-center study conducted in one ICU in Rome, Italy on adult patients hospitalized for trauma. Plasma glucose levels and its variability were recorded in patients receiving artificial nutrition. PTEN expression was measured by western blotting analysis and the associations between PTEN, plasma glucose levels and variability, and calories administered were investigated. Parametric and non-parametric tests were used, as appropriate. RESULTS: Twenty consecutive patients (13 men and 7 women, mean age of 37.3 ± 12.7 years) were studied. No correlation between plasma glucose and PTEN was documented (r = -0.15, P = 0.55), neither between glycemic variability and PTEN expression (r = -0.00, P = 0.99). However, total kcal/day administered and PTEN expression significantly correlated (r = 0.56, P = 0.01). Also, patients with PTEN levels below the median received less kcal/day than those with PTEN above the median (P = 0.048). This association was more pronounced when normalized per body weight (P = 0.03) and after adjusting for the average of insulin daily administered (P = 0.02). CONCLUSIONS: PTEN expression might significantly contribute to glucose homeostasis and disposal in critically ill patients receiving artificial nutrition. Larger samples are necessary to confirm our observation. CLINICAL TRIAL REGISTRY NUMBER: NCT01796847 (www.clinicaltrials.gov) submitted on February 11, 2013.
Assuntos
Glicemia/análise , Ingestão de Energia/fisiologia , Apoio Nutricional/estatística & dados numéricos , PTEN Fosfo-Hidrolase/sangue , Ferimentos e Lesões , Adulto , Estado Terminal , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Ferimentos e Lesões/epidemiologia , Ferimentos e Lesões/metabolismo , Ferimentos e Lesões/terapia , Adulto JovemRESUMO
PURPOSE: PTEN and KLLN are two tumor suppressor genes located in 10q23, share a bidirectional promoter and have roles in carcinogenesis. Formerly, the role of PTEN mutations and KLLN epimutations were identified in incidence of thyroid lesions in individuals with Cowden syndrome, a rare autosomal dominant inherited disorder. This study is the first of its type to assess PTEN and KLLN circulating levels in patients with sporadic papillary thyroid carcinoma (PTC) and compare to patients with multinodular goiter (MNG) and healthy individuals. METHODS: Plasma levels of PTEN and KLLN were determined by enzyme-linked immunosorbent assay in three groups consisted of PTC (n = 33), MNG (n = 26) and healthy persons (n = 30). The association of demographic/pathological characteristics with the levels of PTEN and KLLN were evaluated. RESULTS: A significant lower plasma levels of PTEN and KLLN were observed in PTC patients compared with those of healthy persons (PTEN, 9.43 ± 3.20 vs. 16.96 ± 1.28 ng/ml, P = 0.000; KLLN, 1.81 ± 0.83 vs. 2.57 ± 1.09 ng/ml, P = 0.005), while no statistical difference was found between PTC and MNG groups. Patients with MNG lesion had significantly lower levels of PTEN/KLLN (PTEN, 9.62 ± 2.97 vs. 16.96 ± 1.28 ng/ml, P = 0.000; KLLN, 1.34 ± 0.86 vs. 2.57 ± 1.09 ng/ml, P = 0.000) compared to the healthy controls. The demographic/pathological characteristics did not demonstrate an association with the levels of PTEN and KLLN. CONCLUSIONS: The study suggests that the lowered levels of PTEN and KLLN are associated with both sporadic PTC and MNG tumorigenesis, but they cannot be considered as circulating biomarkers for differential diagnosis between malignancy and benignity in indeterminate thyroid nodules.
Assuntos
Carcinoma Papilar/sangue , Regulação para Baixo , Bócio Nodular/sangue , PTEN Fosfo-Hidrolase/sangue , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/sangue , Proteínas Supressoras de Tumor/sangue , Adulto , Biomarcadores Tumorais/sangue , Carcinoma Papilar/diagnóstico , Carcinoma Papilar/patologia , Estudos de Casos e Controles , Diagnóstico Diferencial , Ensaio de Imunoadsorção Enzimática , Feminino , Bócio Nodular/diagnóstico , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Distribuição Normal , Estatísticas não Paramétricas , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/patologia , Carga TumoralRESUMO
MicroRNAs are small, endogenous, and non-coding RNAs that play important regulatory roles in multiple biological processes in cancers. Recent evidence has indicated that miR-19a participates in the cancer tumorigenic progression. However, the functional roles of miR-19a in cancer stem cells are still unclear. As the cancer stem cells are considered to be responsible for the tumor recurrence and treatment failure in osteosarcoma, the aim of this study is to investigate the molecular mechanism of miR-19a underlying osteosarcoma tumorigenesis. In this study, we observed significant upregulation of miR-19a in osteosarcoma patients' tumor tissues as well as the osteosarcoma cell lines in vitro. We showed that knockdown of miR-19a by its antisense oligonucleotide (anti-miR-19a) significantly decreased the population of cancer stem cells in osteosarcoma cell lines. Furthermore, we found the miR-19a regulated the cell proliferation, migration, and viability in the human osteosarcoma-cancer stem cells. The gene of phosphatase and tensin homolog deleted on chromosome 10, which is an important tumor suppressor, was found to be directly regulated by miR-19a in human osteosarcoma-cancer stem cells. We demonstrated that knockdown of miR-19a increased the expression of phosphatase and tensin homolog deleted on chromosome 10. As the anti-miR-19a inhibited the phosphatidylinositol 3-kinase/AKT pathway and induced apoptosis of human osteosarcoma-cancer stem cells, the phosphatase and tensin homolog deleted on chromosome 10 small interfering RNA inhibited the effect of it. Meanwhile, the phosphatase and tensin homolog deleted on chromosome 10 small interfering RNA also abolished the effect of anti-miR-19a on inhibiting the cell proliferation, migration, and viability in the human osteosarcoma-cancer stem cells. In conclusion, our findings demonstrated that dysregulation of miR-19a plays critical roles in the osteosarcoma stem cells, at least in part via targeting the phosphatase and tensin homolog deleted on chromosome 10. Knockdown of miR-19a may represent a potential strategy for the osteosarcoma treatment.