RESUMO
Fibroblast growth factor receptor 2 (FGFR2) is a membrane-spanning tyrosine kinase that mediates FGF signaling. Various FGFR2 alterations are detected in breast cancer, yet it remains unclear if activation of FGFR2 signaling initiates tumor formation. In an attempt to answer this question, a mouse model berrying an activation mutation of FGFR2 (FGFR2-S252W) in the mammary gland is generated. It is found that FGF/FGFR2 signaling drives the development of triple-negative breast cancer accompanied by epithelial-mesenchymal transition that is regulated by FGFR2-STAT3 signaling. It is demonstrated that FGFR2 suppresses BRCA1 via the ERK-YY1 axis and promotes tumor progression. BRCA1 knockout in the mammary gland of the FGFR2-S252W mice significantly accelerated tumorigenesis. It is also shown that FGFR2 positively regulates PD-L1 and that a combination of FGFR2 inhibition and immune checkpoint blockade kills cancer cells. These data suggest that the mouse models mimic human breast cancers and can be used to identify actionable therapeutic targets.
Assuntos
Proteína BRCA1/metabolismo , Inibidores de Checkpoint Imunológico/uso terapêutico , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/fisiologia , Neoplasias de Mama Triplo Negativas/terapia , Animais , Antígeno B7-H1/metabolismo , Proteína BRCA1/antagonistas & inibidores , Proteína BRCA1/genética , Progressão da Doença , Transição Epitelial-Mesenquimal , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Imunoterapia , Glândulas Mamárias Animais/metabolismo , Camundongos , Camundongos Transgênicos , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Fator de Transcrição STAT3/metabolismo , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Fator de Transcrição YY1/metabolismoRESUMO
HDL normally transports about 50-70% of plasma sphingosine 1-phosphate (S1P), and the S1P in HDL reportedly mediates several HDL-associated biological effects and signaling pathways. The HDL receptor, SR-BI, as well as the cell surface receptors for S1P (S1PRs) may be involved partially and/or completely in these HDL-induced processes. Here we investigate the nature of the HDL-stimulated interaction between the HDL receptor, SR-BI, and S1PR1 using a protein-fragment complementation assay and confocal microscopy. In both primary rat aortic vascular smooth muscle cells and HEK293 cells, the S1P content in HDL particles increased intracellular calcium concentration, which was mediated by S1PR1. Mechanistic studies performed in HEK293 cells showed that incubation of cells with HDL led to an increase in the physical interaction between the SR-BI and S1PR1 receptors that mainly occurred on the plasma membrane. Model recombinant HDL (rHDL) particles formed in vitro with S1P incorporated into the particle initiated the internalization of S1PR1, whereas rHDL without supplemented S1P did not, suggesting that S1P transported in HDL can selectively activate S1PR1. In conclusion, these data suggest that S1P in HDL stimulates the transient interaction between SR-BI and S1PRs that can activate S1PRs and induce an elevation in intracellular calcium concentration.
Assuntos
Lipoproteínas HDL/metabolismo , Lisofosfolipídeos/metabolismo , Receptores de Lisoesfingolipídeo/metabolismo , Receptores Depuradores Classe B/metabolismo , Esfingosina/análogos & derivados , Animais , Aorta/metabolismo , Transporte Biológico/genética , Cálcio/metabolismo , Células HEK293 , Humanos , Lipoproteínas HDL/genética , Técnicas de Cultura de Órgãos , Ratos , Receptores de Lisoesfingolipídeo/genética , Receptores Depuradores Classe B/genética , Transdução de Sinais , Esfingosina/metabolismo , Receptores de Esfingosina-1-FosfatoRESUMO
Disruption of the TGF-ß pathway is associated with liver fibrosis and suppression of liver tumorigenesis, conditions associated with low Vitamin D (VD) levels. However, potential contributions of VD to liver tumor progression in the context of TGF-ß signaling remain unexplored. Our analyses of VD deprivation (VDD) in in vivo models of liver tumor formation revealed striking three-fold increases in tumor burden in Smad3(+/-) mice, with a three-fold increase in TLR7 expression compared to controls. ChIP and transcriptional assays confirm Smad3 binding at two TLR7 promoter SBE sites. Molecular interactions between TGF-ß pathway and VDD were validated clinically, where an absence of VD supplementation was associated with low TGF-ß pathway member expression levels and ß-catenin activation in fibrotic/cirrhotic human liver tissues. Subsequent supplementing VD led to restoration of TGF-ß member expression with lower ß-catenin levels. Bioinformatics analysis provides positive supportive correlation between somatic mutations for VD-related genes and the TGF-ß pathway. We conclude that VDD promotes tumor growth in the context of Smad3 disruption, potentially through regulation of TLR7 expression and ß-catenin activation. VD could therefore be a strong candidate for liver cancer prevention in the context of aberrant Smad3 signaling.
Assuntos
Neoplasias Hepáticas Experimentais/patologia , Glicoproteínas de Membrana/metabolismo , Proteína Smad3/genética , Receptor 7 Toll-Like/metabolismo , Fator de Crescimento Transformador beta/genética , Deficiência de Vitamina D/complicações , Proteínas Wnt/metabolismo , Animais , Humanos , Neoplasias Hepáticas Experimentais/complicações , Masculino , Camundongos , Camundongos Transgênicos , Transdução de Sinais , Vitamina D/administração & dosagemRESUMO
BACKGROUND: Laser toning using low-fluence 1064-nm Q-switched neodymium-doped yttrium aluminum laser (QSNY) has gained popularity in the treatment of photoaging-associated mottled pigmentation (PMP). However, hypopigmentation or lack of efficacy has been reported depending on the fluences used. OBJECTIVE: To compare a novel fractional 1064-nm QSNY with conventional 1064-nm QSNY for the treatment of photoaging-associated mottled pigmentary lesions except epidermal lesions of lentigines and freckles through a randomized, split-face, double-blind study. MATERIALS AND METHODS: Thirteen Asian women were treated every week for 6 weeks with fractional 1064-nm QSNY on one side of the face and conventional 1064-nm QSNY on the other side. We evaluated the pigmentation area and severity index (PSI), melanin index, erythema index, and the patient's global assessment of improvement. RESULTS: At three months post-treatment, the PSI score improved compared with baseline, by 14.48% on the conventional 1064-nm QSNY side and 21.81% on the fractional 1064-nm QSNY side. Both groups showed improvements in the melanin index. CONCLUSION: Both fractional 1064-nm QSNY and strictly low-fluence conventional 1064-nm QSNY are moderately effective against PMP and other photoaging signs. Fractional laser toning shows better subjective outcomes than conventional toning.
Assuntos
Epidermólise Bolhosa Simples/terapia , Terapia a Laser/métodos , Lasers de Estado Sólido/uso terapêutico , Terapia com Luz de Baixa Intensidade/métodos , Luz Solar/efeitos adversos , Adulto , Povo Asiático , Terapia Combinada , Método Duplo-Cego , Feminino , Humanos , Satisfação do Paciente , Estudos Prospectivos , Resultado do TratamentoRESUMO
This study was conducted to evaluate the effects of guided imagery on stress and fatigue in patients undergoing radioactive iodine therapy after thyroidectomy in Korea. Participants were 84 individuals (44 for experimental group and 40 for control group) with thyroid cancer. The experimental group listened to a guided imagery CD once a day for 4 weeks. Global Assessment of Recent Stress and Revised Piper Fatigue Scale were self-administered, and heart rate variability was measured at three time points; prior to intervention (T1), just before intervention (T2) and 1 week later after intervention (T3). Heart rate variability was consisted of Standard Deviation of all NN interval (SDNN), Total Power (TP), Low Frequency (LF), and High Frequency (HF). There were significant decreases in stress (F = 28.45, P < 0.001) and fatigue (F = 26.17, P < 0.001) over time in the experimental group compared to the control group. Heart rate variability changed over time in the experimental group relative to the control group; SDNN (F = 6.68, P = 0.002), TP (F = 5.29, P = 0.006), LF (F = 4.58, P = 0.012), and HF (F = 3.71, P = 0.026). From the results of this study guided imagery can be recommended as an effective intervention to thyroid cancer patients with stress and fatigue.
RESUMO
The quality (Q)-switched neodymium:yttrium-aluminum-garnet (Nd:YAG) laser is one of the first non-ablative lasers to be used for facial resurfacing and photorejuvenation. Recently, the method of low-fluence Q-switched Nd:YAG lasers known as 'laser toning' has been used for non-ablative skin rejuvenation and for the treatment of melasma in Asian countries. We report our experience of using a novel Q-switched Nd:YAG laser that was operated as a dual pulse at half fluence and 140-µs intervals compared with conservative mode laser.
Assuntos
Hiperpigmentação/radioterapia , Lasers de Estado Sólido/uso terapêutico , Terapia com Luz de Baixa Intensidade/métodos , Adulto , Feminino , Humanos , Adulto JovemRESUMO
Hepatocyte growth factor (HGF) and c-Met have recently attracted a great deal of attention as prognostic indicators of patient outcome, and they are important in the control of tumor growth and invasion. Epigallocatechin-3-gallate (EGCG) has been shown to modulate multiple signal pathways in a manner that controls the unwanted proliferation and invasion of cells, thereby imparting cancer chemopreventive and therapeutic effects. In this study, we investigated the effects of EGCG in inhibiting HGF-induced tumor growth and invasion of oral cancer in vitro and in vivo. We examined the effects of EGCG on HGF-induced cell proliferation, migration, invasion, induction of apoptosis and modulation of HGF/c-Met signaling pathway in the KB oral cancer cell line. We investigated the antitumor effect and inhibition of c-Met expression by EGCG in a syngeneic mouse model (C3H/HeJ mice, SCC VII/SF cell line). HGF promoted cell proliferation, migration, invasion and induction of MMP (matrix metalloproteinase)-2 and MMP-9 in KB cells. EGCG significantly inhibited HGF-induced phosphorylation of Met and cell growth, invasion and expression of MMP-2 and MMP-9. EGCG blocked HGF-induced phosphorylation of c-Met and that of the downstream kinases AKT and ERK, and inhibition of p-AKT and p-ERK by EGCG was associated with marked increases in the phosphorylation of p38, JNK, cleaved caspase-3 and poly-ADP-ribose polymerase. In C3H/HeJ syngeneic mice, as an in vivo model, tumor growth was suppressed and apoptosis was increased by EGCG. Our results suggest that EGCG may be a potential therapeutic agent to inhibit HGF-induced tumor growth and invasion in oral cancer.
Assuntos
Catequina/análogos & derivados , Fator de Crescimento de Hepatócito/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Animais , Catequina/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimioprevenção , Progressão da Doença , Feminino , Humanos , Células KB , Metaloproteinase 2 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/biossíntese , Camundongos , Neoplasias Bucais/patologia , Invasividade Neoplásica , Proteínas Proto-Oncogênicas c-met/biossíntese , Transdução de Sinais/efeitos dos fármacos , CháRESUMO
Development of vitiligo-like hypopigmentary lesions associated with topical imiquimod has been reported. We hypothesized that mode of action of imiquimod in melanocytes may include triggering of apoptosis resulted in loss of cells, which may be a possible mechanism of imiquimod-induced hypopigmentary lesions. Therefore, we investigated whether imiquimod induces apoptosis of human melanocytes and also whether it modulates expression of apoptosis-related molecules in human melanocytes. Imiquimod treatment induced apoptosis of melanocytes, which was observed by TUNEL assay and Hoechst 33258 staining. Imiquimod-induced apoptosis was further shown by measuring mitochondrial membrane potential in melanocytes. The apoptotic activity of imiquimod was associated with caspase-3, Bcl-2 and mitogen-activated protein kinase expression in melanocytes. These results indicated that imiquimod induces apoptosis of melanocytes. These findings may provide a clue to understand pathogenesis of imiquimod-induced vitiligo-like hypopigmentary lesions.
Assuntos
Aminoquinolinas/efeitos adversos , Melanócitos/efeitos dos fármacos , Vitiligo/induzido quimicamente , Adjuvantes Imunológicos/efeitos adversos , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Células Cultivadas , Humanos , Hipopigmentação , Imiquimode , Marcação In Situ das Extremidades Cortadas , Melanócitos/metabolismo , Melanócitos/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Vitiligo/metabolismo , Vitiligo/patologia , Vitiligo/fisiopatologiaRESUMO
Mammalian physiological processes can distinguish between dietary cholesterol and non-cholesterol, retaining very little of the non-cholesterol in their bodies. We have recently identified two genes, ABCG5 and ABCG8, encoding sterolin-1 and -2 respectively, mutations of which cause the human disease sitosterolemia. We report here the mouse cDNAs and genomic organization of Abcg5 and Abcg8. Both genes are arranged in an unusual head-to-head configuration, and only 140 bases separate their two respective start-transcription sites. A single TATA motif was identified, with no canonical CCAT box present between the two genes. The genes are located on mouse chromosome 17 and this complex spans no more than 40 kb. Expression of both genes is confined to the liver and intestine. For both genes, two different sizes of transcripts were identified which differ in the lengths of their 3' UTRs. Additionally, alternatively spliced forms for Abcg8 were identified, resulting from a CAG repeat at the intron 1 splice-acceptor site, causing a deletion of a glutamine. We screened 20 different mouse strains for polymorphic variants. Although a large number of polymorphic variants were identified, strains reported to show significant differences in cholesterol absorption rates did not show significant genomic variations in Abcg5 or Abcg8.