RESUMEN
Skeletal muscle fibrosis is defined as the excessive accumulation of extracellular matrix (ECM) components and is a hallmark of muscular dystrophies. Fibro-adipogenic progenitors (FAPs) are the main source of ECM, and thus have been strongly implicated in fibrogenesis. In skeletal muscle fibrotic models, including muscular dystrophies, FAPs undergo dysregulations in terms of proliferation, differentiation, and apoptosis, however few studies have explored the impact of FAPs migration. Here, we studied fibroblast and FAPs migration and identified lysophosphatidic acid (LPA), a signaling lipid central to skeletal muscle fibrogenesis, as a significant migration inductor. We identified LPA receptor 1 (LPA1) mediated signaling as crucial for this effect through a mechanism dependent on the Hippo pathway, another pathway implicated in fibrosis across diverse tissues. This cross-talk favors the activation of the Yes-associated protein 1 (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ), leading to increased expression of fibrosis-associated genes. This study reveals the role of YAP in LPA-mediated fibrotic responses as inhibition of YAP transcriptional coactivator activity hinders LPA-induced migration in fibroblasts and FAPs. Moreover, we found that FAPs derived from the mdx4cv mice, a murine model of Duchenne muscular dystrophy, display a heightened migratory phenotype due to enhanced LPA signaling compared to wild-type FAPs. Remarkably, we found that the inhibition of LPA1 or YAP transcriptional coactivator activity in mdx4cv FAPs reverts this phenotype. In summary, the identified LPA-LPA1-YAP pathway emerges as a critical driver of skeletal muscle FAPs migration and provides insights into potential novel targets to mitigate fibrosis in muscular dystrophies.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Movimiento Celular , Fibroblastos , Fibrosis , Lisofosfolípidos , Músculo Esquelético , Receptores del Ácido Lisofosfatídico , Transducción de Señal , Proteínas Señalizadoras YAP , Lisofosfolípidos/metabolismo , Animales , Proteínas Señalizadoras YAP/metabolismo , Proteínas Señalizadoras YAP/genética , Ratones , Receptores del Ácido Lisofosfatídico/metabolismo , Receptores del Ácido Lisofosfatídico/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Fibroblastos/metabolismo , Fibroblastos/patología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Humanos , Vía de Señalización Hippo , Ratones Endogámicos mdx , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ/metabolismo , Adipogénesis/genética , Distrofias Musculares/metabolismo , Distrofias Musculares/genética , Distrofias Musculares/patologíaRESUMEN
BACKGROUND: NSCLC is one of the most common causes of death. The hypoxia microenvironment contributes to cancer progression. The purpose was to explore the effects and mechanism of melittin on NSCLC cells in the hypoxic microenvironment. METHODS: NSCLC cell lines (A549 and H1299) were cultured in normoxia or hypoxia conditions with or without melittin treatment. The viability of the cells was detected via MTT assay and the proliferation ability was evaluated by EdU assay. QRT-PCR was performed to evaluate GLUT1, LDHA, HK2, VEGF and LATS2 mRNA levels. Glucose transport was assessed by the 2-NBDG uptake assay. The angiogenesis was determined by the tubule formation assay. The protein expressions of GLUT1, LDHA, HK2, VEGF, LATS2, YAP, p-YAP and HIF-1α were detected via western blotting assay. The tumor formation assay was conducted to examine the roles of melittin and LATS2 in vivo. RESULTS: Melittin inhibited hypoxia-induced cell viability, proliferation, glycolysis and angiogenesis as well as suppressed YAP binding to HIF-1α in NSCLC. Melittin inactivated the YAP/HIF-1α pathway via up-regulation of LATS2, ultimately inhibiting cancer progression of NSCLC. Moreover, melittin suppressed tumor growth via up-regulation of LATS2 in vivo. CONCLUSION: Melittin inactivated the YAP/HIF-1α pathway via up-regulation of LATS2 to contribute to the development of NSCLC. Therefore, melittin is expected to become a potential prognostic drug for the therapy of NSCLC.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Proliferación Celular , Glucólisis , Subunidad alfa del Factor 1 Inducible por Hipoxia , Neoplasias Pulmonares , Meliteno , Neovascularización Patológica , Proteínas Serina-Treonina Quinasas , Proteínas Supresoras de Tumor , Regulación hacia Arriba , Proteínas Señalizadoras YAP , Humanos , Proteínas Serina-Treonina Quinasas/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/irrigación sanguínea , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Glucólisis/efectos de los fármacos , Proteínas Supresoras de Tumor/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Proteínas Señalizadoras YAP/metabolismo , Meliteno/farmacología , Meliteno/uso terapéutico , Línea Celular Tumoral , Factores de Transcripción/metabolismo , Animales , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Transducción de Señal/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fosfoproteínas/metabolismo , AngiogénesisRESUMEN
The Hippo pathway, a signaling cascade involved in the regulation of organ size and several other processes, acts as a conduit between extracellular matrix (ECM) cues and cellular responses. We asked whether the basement membrane (BM), a specialized ECM component known to induce quiescence and differentiation in mammary epithelial cells, would regulate the localization, activity, and interactome of YAP, a Hippo pathway effector. To address this question, we used a broad range of experimental approaches, including 2D and 3D cultures of both mouse and human mammary epithelial cells, as well as the developing mouse mammary gland. In contrast to malignant cells, nontumoral cells cultured with a reconstituted BM (rBM) displayed higher concentrations of YAP in the cytoplasm. Incidentally, when in the nucleus of rBM-treated cells, YAP resided preferentially at the nuclear periphery. In agreement with our cell culture experiments, YAP exhibited cytoplasmic predominance in ductal cells of developing mammary epithelia, where a denser BM is found. Conversely, terminal end bud (TEB) cells with a thinner BM displayed higher nucleus-to-cytoplasm ratios of YAP. Bioinformatic analysis revealed that genes regulated by YAP were overrepresented in the transcriptomes of microdissected TEBs. Consistently, mouse epithelial cells exposed to the rBM expressed lower levels of YAP-regulated genes, although the protein level of YAP and Hippo components were slightly altered by the treatment. Mass spectrometry analysis identified a differential set of proteins interacting with YAP in cytoplasmic fractions of mouse epithelial cells in the absence or presence of rBM. In untreated cells, YAP interactants were enriched in processes related to ubiquitin-mediated proteolysis, whereas in cells exposed to rBM YAP interactants were mainly key proteins related to amino acid, amino sugar, and carbohydrate metabolism. Collectively, we unraveled that the BM induces YAP translocation or retention in the cytoplasm of nontumoral epithelial cells and that in the cytoplasm YAP seems to undertake novel functions in metabolic pathways.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Membrana Basal , Citoplasma , Células Epiteliales , Factores de Transcripción , Proteínas Señalizadoras YAP , Animales , Humanos , Ratones , Células Epiteliales/metabolismo , Proteínas Señalizadoras YAP/metabolismo , Femenino , Citoplasma/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Membrana Basal/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Glándulas Mamarias Animales/metabolismo , Glándulas Mamarias Animales/citología , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Glándulas Mamarias Humanas/metabolismo , Glándulas Mamarias Humanas/citología , Núcleo Celular/metabolismo , Transducción de SeñalRESUMEN
Hyperactivation of YAP/TAZ, the Hippo pathway downstream effectors, is common in human cancer. The requirement of YAP/TAZ for cancer cell survival in preclinical models, prompted the development of pharmacological inhibitors that suppress their transcriptional activity. However, systemic YAP/TAZ inhibition may sometimes have unpredictable patient outcomes, with limited or even adverse effects because YAP/TAZ action is not simply tumor promoting but also tumor suppressive in some cell types. Here, we review the role of the Hippo pathway in distinct tumor cell populations, discuss the impact of inhibiting Hippo output on tumor growth, and examine current developments in YAP/TAZ inhibitors.
Asunto(s)
Neoplasias , Transducción de Señal , Humanos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Factores de Transcripción/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Señalizadoras YAP , Neoplasias/tratamiento farmacológico , Neoplasias/genéticaRESUMEN
OBJECTIVE: To analyze the immunohistochemical expression of YAP and its correlation with markers involved in cell proliferation and apoptosis in benign epithelial odontogenic lesions. STUDY DESIGN: The sample consisted of 95 cases of odontogenic lesions (25 dentigerous cysts, 30 non-syndromic odontogenic keratocysts, 30 conventional ameloblastomas, and 10 unicystic ameloblastomas) and 10 dental follicles used as normal odontogenic tissue. The histological sections were submitted to immunohistochemistry with YAP, cyclin D1, Ki-67, and Bcl-2 antibodies. Immunoexpression was analyzed qualitatively and quantitatively using an adapted method. The collected data were analyzed descriptively and statistically (p ≤ 0.05). RESULTS: The highest YAP expression was observed in odontogenic keratocysts, followed by unicystic ameloblastomas and conventional ameloblastomas, which exhibited moderate immunoreactivity predominantly in peripheral cells. Furthermore, significant differences in YAP immunoexpression were observed between the groups analyzed, with significant positive correlations between YAP and cyclin D1 in dentigerous cysts and unicystic ameloblastomas and between YAP and Ki-67 in unicystic ameloblastomas (p < 0.05). However, there were no statistically significant correlations between YAP and Bcl-2 immunoexpression in the groups studied. CONCLUSION: YAP may influence epithelial cell proliferation in odontogenic cysts and tumors, suggesting its possible participation in the progression of the odontogenic lesions studied.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Ameloblastoma , Apoptosis , Proliferación Celular , Ciclina D1 , Quiste Dentígero , Antígeno Ki-67 , Quistes Odontogénicos , Proteínas Proto-Oncogénicas c-bcl-2 , Proteínas Señalizadoras YAP , Humanos , Ameloblastoma/patología , Ameloblastoma/metabolismo , Quistes Odontogénicos/patología , Quistes Odontogénicos/metabolismo , Quiste Dentígero/patología , Quiste Dentígero/metabolismo , Antígeno Ki-67/metabolismo , Antígeno Ki-67/análisis , Ciclina D1/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/análisis , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Factores de Transcripción/análisis , Saco Dental/patología , Saco Dental/metabolismo , Inmunohistoquímica , Tumores Odontogénicos/patología , Tumores Odontogénicos/metabolismo , Células Epiteliales/patología , Células Epiteliales/metabolismoRESUMEN
Introdução: Os cistos e tumores odontogênicos são lesões que apresentam comportamento biológico heterogêneo e patogênese ainda não totalmente esclarecida. A Yes-associated protein (YAP) atua como um regulador transcricional de genes envolvidos na proliferação celular e na apoptose, participando da ativação de vias associadas ao crescimento cístico e à progressão neoplásica. Objetivo: Analisar a expressão imuno-histoquímica da proteína YAP e correlacioná-la com marcadores envolvidos na proliferação celular e na apoptose em lesões odontogênicas epiteliais benignas. Metodologia: A amostra consistiu de 95 casos de lesões odontogênicas - 25 cistos dentígeros (CDs), 30 CO não sindrômicos (COs), 30 AMB convencionais (AMB-Cs) e 10 AMB unicísticos (AMB-Us) -, além de 10 espécimes de folículo dentários (FD). Foi realizada coleta dos dados clinico-demográficos dos casos, bem como análise morfológica para melhor caracterização da amostra. Os cortes histológicos foram submetidos à técnica imuno-histoquímica através da utilização dos anticorpos YAP, ciclina D1, Ki-67 e Bcl-2, e a análise da expressão destes foi realizada quali-quantitativamente, mediante metodologia adaptada. Os dados coletados seguiram para análise descritiva e estatística (p ≤ 0,05). Resultados: Houve discreta predileção por mulheres (n = 55; 57,6%) e por indivíduos na faixa etária dos 21 aos 40 anos (n = 50; 47,6%), sendo a região posterior de mandíbula mais afetada (64%). A análise da imunoexpressão de YAP revelou maiores níveis de expressão em COs, especialmente nas camadas basal e parabasal, seguido dos AMB-Us e AMB-Cs, que demonstraram moderada imunorreatividade, predominantemente nas células periféricas. Além disso, houve diferenças significativas quanto à imunoexpressão de YAP entre os grupos analisados, com existência de correlações positivas e estatisticamente significativas entre YAP e ciclina D1 em CDs e AMB-Us, e entre YAP e Ki-67 em AMB-Us (p < 0,05). Todavia, entre a imunoexpressão YAP e Bcl-2, foi verificada ausência de correlação estatisticamente significativa. Conclusões: A YAP pode exercer influência sobre a proliferação celular do epitélio de cistos e tumores odontogênicos, auxiliando, assim, na progressão das diferentes lesões odontogênicas (AU).
Background: Odontogenic cysts and tumors present heterogeneous biological behavior, and their etiopathogenesis is not fully understood yet. Yes-associated protein (YAP) acts as a transcriptional regulator of genes involved in cell proliferation and apoptosis, activating pathways associated with cystic growth and neoplastic progression. Objective: To analyze the immunohistochemical expression of YAP protein and correlate it with markers involved in cell proliferation and apoptosis in benign epithelial odontogenic lesions. Methods: The sample consisted of 95 cases of odontogenic lesions - 25 dentigerous cysts (DCs), 30 non-syndromic odontogenic keratocyst (OKCs), 30 conventional AMB (C-AMBs), and 10 unicystic AMB (UAMBs) -, in addition to 10 specimens of dental follicles (DF). Clinicodemographic data collection was carried out, as well as morphological analysis for better characterization of the sample. The histological sections were submitted to the immunohistochemical technique using YAP, cyclin D1, Ki-67, and Bcl-2 antibodies, and their immunoexpression analysis was performed qualitatively and quantitatively, through an adapted methodology. The collected data were submitted for descriptive and statistical analysis (p ≤ 0.05). Results: There was a slight predilection for women (n = 55; 57.6%) and individuals aged between 21 and 40 years (n = 50; 47.6%), with the posterior region of the mandible as the most affected site (64%). Analysis of YAP immunoexpression revealed higher expression levels in OKCs, especially in the basal and parabasal layers, followed by U-AMBs and C-AMBs, which showed moderate immunoreactivity, predominantly in peripheral cells. In addition, there were significant differences in YAP immunoexpression between the analyzed groups, with positive and statistically significant correlations between YAP and cyclin D1 in DCs and U-AMBs, and between YAP and Ki-67 in U-AMBs (p < 0.05). However, between YAP and Bcl-2 immunoexpression, there was no statistically significant correlation. Conclusions: YAP may influence on the cell proliferation of odontogenic cysts and tumors epithelium, thus helping with the progression of the different odontogenic lesions (AU) .
Asunto(s)
Proliferación Celular , Proteínas Señalizadoras YAP/metabolismo , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ/metabolismo , Quiste Dentígero/patología , Biomarcadores de Tumor , Registros Médicos , Estudios Retrospectivos , Interpretación Estadística de Datos , Apoptosis , Quiste Odontogénico Calcificado/patología , Estadísticas no Paramétricas , Proteínas Inhibidoras de la Diferenciación , Estudio Observacional , Hallazgos Morfológicos y MicroscópicosRESUMEN
O carcinoma de células escamosas de língua oral (CCELO) apresenta altas taxas de morbidade e mortalidade. Apesar dos progressos alcançados nesta área, os pesquisadores continuam em busca de biomarcadores moleculares que tenham valor preditivo no prognóstico dos pacientes e que possibilitem o desenvolvimento de novas estratégias terapêuticas. Neste contexto, várias pesquisas têm destacado o papel da via Hippo com esta finalidade. Portanto, esta pesquisa teve como objetivo avaliar se as proteínas relacionadas à Via Hippo, LATS2 e YAP1, exercem alguma influência sobre o comportamento biológico dos CCELOs. A amostra foi constituída por 26 casos de CCELO e 8 casos de mucosa oral normal como controle. Para avaliar a morfologia dos CCELOs foram utilizadas as gradações propostas pela OMS (2005) e por Almangush et al. (2014). O perfil imunoistoquímico de LATS2 e YAP1 foi avaliado por escores (0-3), com base na sua imunoexpressão em localização intracelular (núcleo e/ou citoplasma) e distribuição epitelial. Para a análise entre os parâmetros estudados foram realizados os testes estatísticos Qui-quadrado de Pearson e Exato de Fisher. A análise de sobrevida foi realizada através do método de Kaplan Meier e do teste log-rank. Para todas as avaliações foram considerados valores significativos com p<0,05. Foi observada alta expressão da LATS2 tanto em mucosa oral normal (100%) quanto na maioria dos CCELOs (73,1%), sem diferença estatística significativa (p=0,160). Foi possível evidenciar o aumento da imunoexpressão da YAP nos casos de CCELO em comparação à mucosa oral normal (p<0,001). Verificou-se ainda que a baixa expressão da LATS2 foi associada com menores taxas de sobrevida livre da doença (p=0,039). Além disso, constatou-se que a elevada expressão da YAP foi associada à classificação de alto risco do modelo BD (p=0,034), sugerindo que a imunoexpressão desta proteína pode estar associada a TEM e invasão celular em CCELO. A elevada expressão de ambas as proteínas, na maioria dos CCELOs, sugere que outras vias de sinalização, além da regulação através da LATS2, podem estar induzindo a expressão nuclear de YAP nestes tumores. Portanto, conclui-se que a via Hippo pode influenciar o comportamento biológico dos CCELOs (AU).
Oral tongue squamous cell carcinoma (OTSCC) has high morbidity and mortality rates. Despite the progress made in this area, researchers continue to search for molecular biomarkers that have predictive value in the prognosis of patients and allow the development of new therapeutic strategies. In this context, several studies have highlighted the role of the Hippo pathway for this purpose. Therefore, this research aimed to evaluate whether the proteins related to the Hippo pathway, LATS2 and YAP1, have some influence on the OTSCC biological behavior. The sample consisted of 26 OTSCC cases and 8 normal oral mucosa cases as control. For the morphological assessment of OTSCC, the gradations proposed by the WHO (2005) and by Almangush et al. (2014) were performed. The immunohistochemical profile of LATS2 and YAP1 was evaluated by scores (0-3), based on their immunoexpression in intracellular location (nucleus and/or cytoplasm) and epithelial distribution. Pearson's Chi-square and Fisher's Exact statistical tests were performed for the analysis of the studied parameters. Survival analysis was performed using the Kaplan-Meier method and the log-rank test. For all evaluations, values with p<0.05 were considered significant. High expression of LATS2 was observed both in normal oral mucosa (100%) and in most OTSCC (73,1%), with no statistically significant difference (p=0,160). It was possible to observe the increase in YAP immunoexpression in cases of OTSCC compared to the normal oral mucosa (p<0.001). It was also found that the LATS2 low expression was associated with lower rates of disease-free survival (p=0.039). Furthermore, YAP high expression was found associated with the BD model's high-risk classification (p=0.034), suggesting this protein immunoexpression may be associated with EMT and cell invasion in OTSCC. The high expression of both proteins in most OTSCC suggests that other signaling pathways, in addition to regulating through LATS2, may be inducing the nuclear YAP expression in these tumors. Therefore, it is concluded that the Hippo pathway can influence the OTSCC biological behavior (AU).
Asunto(s)
Lengua/lesiones , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Vía de Señalización Hippo , Proteínas Señalizadoras YAP/metabolismo , Pronóstico , Distribución de Chi-Cuadrado , Análisis de Supervivencia , Registros Médicos , Estudios Transversales/métodos , Estudios Retrospectivos , Interpretación Estadística de Datos , Estudio ObservacionalRESUMEN
CONTEXT: The establishment of pregnancy in cows requires uterine activity regulation of the main Hippo signalling effector yes-associated protein 1 (YAP). It remains unknown (1) how YAP activity at the corpus luteum (CL) correlates with early pregnancy-related events in ruminants; and (2) if YAP activity in the uterus and CL can be affected by metabolic disorders that may lead to pregnancy failure in ruminants. AIMS AND METHODS: To determine the effect of early pregnancy on total and phospho-YAP expression and its transcriptional activity in the CL, we compared non-pregnant vs pregnant ewes. To understand the YAP activity dysregulation with disorders that may result in pregnancy loss, we induced negative energy balance in pregnant ewes. KEY RESULTS AND CONCLUSIONS: Our main results indicate that early pregnancy alters the expression and activity patterns of YAP in the ovine CL but not in the endometrium. In addition, while our NEB-induced model fails to alter YAP activity at the endometrium level, we found that fasting during the first but not second week of pregnancy affects YAP activity in the CL of pregnant ewes. IMPLICATIONS: The data presented herein provide considerable insight into the activity of a signalling pathway that may be a key player in pregnancy recognition and establishment in ewes.
Asunto(s)
Preñez , Proteínas Señalizadoras YAP , Animales , Bovinos , Cuerpo Lúteo/metabolismo , Endometrio/metabolismo , Femenino , Embarazo , Ovinos , Útero/metabolismoRESUMEN
OBJECTIVE: To investigate the effects of resveratrol (RSVL) on epithelial-mesenchymal transition (EMT) and biological behaviors of gastric cancer cells. METHODS: SGC-7901 cells were treated with RSVL, followed by TGF-ß1 treatment for induction of EMT. Cell proliferation was tested by MTT assay, migration and invasion by Transwell and scratch assays, and Hippo-YAP signaling pathway activation by immunofluorescence. The RNA and protein expressions of E-cadherin, Vimentin, N-cadherin, and Snail were detected by qPCR and Western blot. A tumor model was constructed to examine the effect of RSVL on gastric tumor growth. RESULTS: RSVL inhibited the migration, invasion, and growth of gastric cancer cells in concentration- and time-dependent manners. RSVL inhibited TGF-ß1-induced EMT of gastric cancer cells, which might relate to inactivation of the Hippo-YAP pathway. In the mouse tumor model, RSVL inhibited the EMT process by suppressing the Hippo-YAP pathway. CONCLUSION: RSVL inhibited EMT of gastric cancer cells probably by weakening the Hippo-YAP signaling pathway.
Asunto(s)
Transición Epitelial-Mesenquimal , Neoplasias Gástricas , Animales , Cadherinas/metabolismo , Línea Celular Tumoral , Movimiento Celular , Vía de Señalización Hippo , Ratones , Proteínas Serina-Treonina Quinasas , ARN , Resveratrol/farmacología , Neoplasias Gástricas/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Vimentina/metabolismo , Proteínas Señalizadoras YAPRESUMEN
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is recognized as a main mediator bridging innate and adaptive immunity, recent advances have expanded its roles to anti-tumor immunity and carcinogenesis. Loss of cGAS-STING signaling in non-small cell lung cancer (NSCLC) leads to enhanced tumorigenicity and decreased cytotoxic T lymphocyte infiltration. Apart from its anticancer response, persistent overreaction of cGAS-STING signaling promotes progression of certain inflammation-aggravated cancers. Activation of the pro-inflammatory nucleic acid sensing pathway can trigger Hippo pathway, which mediates the inactivation of Yes-associated protein 1 (YAP1) and its paralogue transcriptional co-regulators with PDZ-binding motif (TAZ, also known as WWTR1), and subsequent suppression of tumorigenesis. Active YAP acts as a transcriptional driver in bolstering immunosuppressive cytokines to evade immune surveillance and promote occurrence of preneoplasia. It is reasonable that aggressive tumors co-opt these regulators to generate few immunogenic antigens and drive tumorigenic behaviors via a highly cooperative manner. Given their multifaced roles, we profile the molecular biology characteristic and current status underpinning oncogenic YAP, review its crosstalk roles with cGAS/STING pathway in NSCLC, and summarize the major clinical investigations in NSCLC with TCGA database.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Proteínas de la Membrana , Nucleotidiltransferasas , Transducción de Señal , Proteínas Señalizadoras YAP , Carcinogénesis , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Proteínas Señalizadoras YAP/genética , Proteínas Señalizadoras YAP/metabolismoRESUMEN
OBJECTIVE: Accumulating evidence has been revealed that miR-590 is involved in the progression and carcinogenesis of various cancers. However, the molecular mechanism of miR-590 in non-small-cell lung cancer (NSCLC) remains unclear. METHODS: Quantitative reverse transcription-PCR (qRT-PCR), western blot, MTT, and transwell assay were applied to investigate the functional role of miR-590 in this study. Dual luciferase reporter assay was utilized to investigate the interaction between YAP1 and miR-590 expression. Cells transfected with miR-590 mimic or inhibitor were subjected to western blot to investigate the role of Wnt/ß-catenin signaling in NSCLC modulated by miR-590. RESULTS: MiR-590 was down-regulated in NSCLC tissues and cells. Kaplan-Meier analysis found that the higher expression of miR-590 in NSCLC patients, the more improved survival rate of NSCLC patients. Over-expression of miR-590 inhibited NSCLC cell proliferation, migration, and invasion. Moreover, increasing miR-590 suppressed Yes-associated protein 1 (YAP1) expression and inhibited the Wnt/ß-catenin pathway in NSCLC cells. Furthermore, miR-590 was negatively correlated with YAP1 expression. CONCLUSION: These findings demonstrated that the miR-590/YAP1 axis exerted an important role in the progression of NSCLC, suggesting that miR-590 might be the appealing prognostic marker for NSCLC treatment.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , MicroARNs/fisiología , Vía de Señalización Wnt/fisiología , Proteínas Señalizadoras YAP/fisiología , Progresión de la Enfermedad , Humanos , Células Tumorales CultivadasRESUMEN
The Hippo and mTOR signaling cascades are major regulators of cell growth and division. Aberrant regulation of these pathways has been demonstrated to contribute to gliomagenesis and result in enhanced glioblastoma proliferation and invasive characteristics. Several crosstalk mechanisms have been described between these two pathways, although a complete picture of these signaling interactions is lacking and is required for effective therapeutic targeting. Here we report the ability of mTORC2 to directly phosphorylate YAP at serine 436 (Ser436) positively regulating YAP activity. We show that mTORC2 activity enhances YAP transcriptional activity and the induction of YAP-dependent target gene expression while its ablation via genetic or pharmacological means has the opposite affects on YAP function. mTORC2 interacts with YAP via Sin1 and mutational analysis of serine 436 demonstrates that this phosphorylation event affects several properties of YAP leading to enhanced transactivation potential. Moreover, YAP serine 436 mutants display altered glioblastoma growth, migratory capacity and invasiveness both in vitro and in xenograft experiments. We further demonstrate that mTORC2 is able to regulate a Hippo pathway resistant allele of YAP suggesting that mTORC2 can regulate YAP independent of Hippo signaling. Correlative associations between the expression of these components in GBM patient samples also supported the presence of this signaling relationship. These results advance a direct mTORC2/YAP signaling axis driving GBM growth, motility and invasiveness.
Asunto(s)
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Carga Tumoral/fisiología , Proteínas Señalizadoras YAP/metabolismo , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Femenino , Glioblastoma/genética , Glioblastoma/patología , Vía de Señalización Hippo/fisiología , Humanos , Diana Mecanicista del Complejo 2 de la Rapamicina/genética , Ratones , Ratones SCID , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Fosforilación/fisiología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Proteínas Señalizadoras YAP/genéticaRESUMEN
The yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ) are transcriptional coactivators, members of the Hippo signaling pathway, which play a critical role in cell growth regulation, embryonic development, regeneration, proliferation, and cancer origin and progression. The mechanism involves the nuclear binding of the un-phosphorylated YAP/TAZ complex to release the transcriptional enhanced associate domain (TEAD) from its repressors. The active ternary complex is responsible for the aforementioned biological effects. Overexpression of YAP/TAZ has been reported in cancer stem cells and tumor resistance. The resistance involves chemotherapy, targeted therapy, and immunotherapy. This review provides an overview of YAP/TAZ pathways' role in carcinogenesis and tumor microenvironment. Potential therapeutic alternatives are also discussed.
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Carcinogénesis/metabolismo , Carcinogénesis/patología , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ/metabolismo , Microambiente Tumoral , Proteínas Señalizadoras YAP , Animales , Resistencia a Antineoplásicos , Humanos , Mecanotransducción CelularRESUMEN
PURPOSE: Increasing evidence suggested that microRNA plays an important role in ovarian cancer. In this study, the role of miR-92 in ovarian cancer was investigated. METHODS: In this study, miR-92 expression in clinical sample was evaluated, role of miR-92 was investigated in vitro, and underlying mechanism was investigated using Chip, co-IP, and western blot. RESULTS: In this study, we show that miR-92 is overexpressed in ovarian cancer tissue compared with normal cancer tissue. Transfection of miR-92 increased proliferation of ovarian cancer cell, and increased migration capacity and colony formation were observed after miR-92 transfection; we found that expression of LATS2 was decreased by miR-92, and this was further confirmed by luciferase assay, which proved that miR-92 is targeting 3' of the endogenous LATS2 gene. Downregulation of LATS2 resulted in increased translocation of YAP1 and upregulation of PD-L1, which subsequently suppressed NK cell function and promoted T cell apoptosis. Moreover, co-transfection of YAP1-targeted shRNA could relieve miR-92-induced immune suppression effect. Mechanically, immunoprecipitation (IP) was used to show that LATS2 interacted with YAP1 and subsequently limited nuclear translocation of YAP1; chromatin immunoprecipitation (ChIP) was used to confirm that YAP1 could bind to enhancer region of PD-L1 to enhance transcription activity of PD-L1. CONCLUSIONS: Our data revealed a novel mechanism which finally resulted in immune suppression in ovarian cancer.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Antígeno B7-H1/metabolismo , Células Asesinas Naturales/inmunología , MicroARNs/metabolismo , Neoplasias Ováricas/inmunología , Proteínas Serina-Treonina Quinasas/metabolismo , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Apoptosis , Línea Celular Tumoral , Movimiento Celular , Núcleo Celular/metabolismo , Proliferación Celular , Regulación hacia Abajo , Elementos de Facilitación Genéticos , Femenino , Silenciador del Gen , Humanos , Inmunidad Celular , Inmunoprecipitación , Células Madre Neoplásicas , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Proteínas Serina-Treonina Quinasas/genética , ARN Interferente Pequeño , Transducción de Señal , Linfocitos T/fisiología , Proteínas Supresoras de Tumor/genética , Regulación hacia Arriba , Proteínas Señalizadoras YAPRESUMEN
ANKHD1 (ankyrin repeat and KH domain containing 1) is a large protein characterized by the presence of multiple ankyrin repeats and a K-homology domain. Ankyrin repeat domains consist of widely existing protein motifs in nature, they mediate protein-protein interactions and regulate fundamental biological processes, while the KH domain binds to RNA or ssDNA and is associated with transcriptional and translational regulation. In recent years, studies containing relevant information on ANKHD1 in cancer biology and its clinical relevance, as well as the increasing complexity of signaling networks in which this protein acts, have been reported. Among the signaling pathways of interest in oncology regulated by ANKHD1 are Hippo signaling, JAK/STAT, and STMN1. The scope of the present review is to survey the current knowledge and highlight future perspectives for ANKHD1 in the malignant phenotype of cancer cells, exploring biological, functional, and clinical reports of this protein in cancer. [BMB Reports 2020; 53(8): 413-418].
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Neoplasias/genética , Neoplasias/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Secuencias de Aminoácidos , Sitios de Unión/genética , Fenómenos Biológicos , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Janus Quinasa 1/metabolismo , Dominios Proteicos/fisiología , ARN/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/fisiología , Factores de Transcripción STAT/metabolismo , Transducción de Señal/genética , Transducción de Señal/fisiología , Estatmina/metabolismo , Factores de Transcripción/metabolismo , Proteínas Señalizadoras YAPRESUMEN
BACKGROUND: Polycystic ovary syndrome is the most common endocrine disorder affecting women of reproductive age. A number of criteria have been developed for clinical diagnosis of polycystic ovary syndrome, with the Rotterdam criteria being the most inclusive. Evidence suggests that polycystic ovary syndrome is significantly heritable, and previous studies have identified genetic variants associated with polycystic ovary syndrome diagnosed using different criteria. The widely adopted electronic health record system provides an opportunity to identify patients with polycystic ovary syndrome using the Rotterdam criteria for genetic studies. OBJECTIVE: To identify novel associated genetic variants under the same phenotype definition, we extracted polycystic ovary syndrome cases and unaffected controls based on the Rotterdam criteria from the electronic health records and performed a discovery-validation genome-wide association study. STUDY DESIGN: We developed a polycystic ovary syndrome phenotyping algorithm on the basis of the Rotterdam criteria and applied it to 3 electronic health record-linked biobanks to identify cases and controls for genetic study. In the discovery phase, we performed an individual genome-wide association study using the Geisinger MyCode and the Electronic Medical Records and Genomics cohorts, which were then meta-analyzed. We attempted validation of the significant association loci (P<1×10-6) in the BioVU cohort. All association analyses used logistic regression, assuming an additive genetic model, and adjusted for principal components to control for population stratification. An inverse-variance fixed-effect model was adopted for meta-analysis. In addition, we examined the top variants to evaluate their associations with each criterion in the phenotyping algorithm. We used the STRING database to characterize protein-protein interaction network. RESULTS: Using the same algorithm based on the Rotterdam criteria, we identified 2995 patients with polycystic ovary syndrome and 53,599 population controls in total (2742 cases and 51,438 controls from the discovery phase; 253 cases and 2161 controls in the validation phase). We identified 1 novel genome-wide significant variant rs17186366 (odds ratio [OR]=1.37 [1.23, 1.54], P=2.8×10-8) located near SOD2. In addition, 2 loci with suggestive association were also identified: rs113168128 (OR=1.72 [1.42, 2.10], P=5.2×10-8), an intronic variant of ERBB4 that is independent from the previously published variants, and rs144248326 (OR=2.13 [1.52, 2.86], P=8.45×10-7), a novel intronic variant in WWTR1. In the further association tests of the top 3 single-nucleotide polymorphisms with each criterion in the polycystic ovary syndrome algorithm, we found that rs17186366 (SOD2) was associated with polycystic ovaries and hyperandrogenism, whereas rs11316812 (ERBB4) and rs144248326 (WWTR1) were mainly associated with oligomenorrhea or infertility. We also validated the previously reported association with DENND1A1. Using the STRING database to characterize protein-protein interactions, we found both ERBB4 and WWTR1 can interact with YAP1, which has been previously associated with polycystic ovary syndrome. CONCLUSION: Through a discovery-validation genome-wide association study on polycystic ovary syndrome identified from electronic health records using an algorithm based on Rotterdam criteria, we identified and validated a novel genome-wide significant association with a variant near SOD2. We also identified a novel independent variant within ERBB4 and a suggestive association with WWTR1. With previously identified polycystic ovary syndrome gene YAP1, the ERBB4-YAP1-WWTR1 network suggests involvement of the epidermal growth factor receptor and the Hippo pathway in the multifactorial etiology of polycystic ovary syndrome.
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Síndrome del Ovario Poliquístico/genética , Receptor ErbB-4/genética , Transactivadores/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adulto , Estudios de Casos y Controles , Registros Electrónicos de Salud , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Hiperandrogenismo/genética , Infertilidad Femenina/genética , Persona de Mediana Edad , Oligomenorrea/genética , Quistes Ováricos/genética , Síndrome del Ovario Poliquístico/diagnóstico , Síndrome del Ovario Poliquístico/fisiopatología , Polimorfismo de Nucleótido Simple , Superóxido Dismutasa/genética , Factores de Transcripción/metabolismo , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Proteínas Señalizadoras YAPRESUMEN
BACKGROUND: LincRNAs have been revealed to be tightly associated with various tumorigeneses and cancer development, but the roles of specific lincRNA on tumor-related angiogenesis was hardly studied. Here, we aimed to investigate whether linc-OIP5 in breast cancer cells affects the angiogenesis of HUVECs and whether the linc-OIP5 regulations are involved in angiogenesis-related Notch and Hippo signaling pathways. METHODS: A trans-well system co-cultured HUVECs with linc-OIP5 knockdown breast cancer cell MDA-MB-231 was utilized to study the proliferation, migration and tube formation abilities of HUVECs and alterations of related signaling indicators in breast cancer cells and their conditioned medium through a series of cell and molecular experiments. RESULTS: Overexpressed linc-OIP5, YAP1, and JAG1 were found in breast cancer cell lines MCF7 and MDA-MB-231 and the expression levels of YAP1 and JAG1 were proportional to the breast cancer tissue grades. MDA-MB-231 cells with linc-OIP5 knockdown led to weakened proliferation, migration, and tube formation capacity of co-cultured HUVECs. Besides, linc-OIP5 knockdown in co-cultured MDA-MB-231 cells showed downregulated YAP1 and JAG1 expression, combined with a reduced JAG1 level in conditioned medium. Furthermore, a disrupted DLL4/Notch/NRP1 signaling in co-cultured HUVECs were also discovered under this condition. CONCLUSION: Hence, linc-OIP5 in MDA-MB-231 breast cancer cells may act on the upstream of the YAP1/Notch/NRP1 signaling circuit to affect proliferation, migration, and tube formation of co-cultured HUVECs in a non-cellular direct contact way through JAG1 in conditioned medium. These findings at least partially provide a new angiogenic signaling circuit in breast cancers and suggest linc-OIP5 could be considered as a therapeutic target in angiogenesis of breast cancers.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Neoplasias de la Mama/patología , Células Endoteliales de la Vena Umbilical Humana/citología , Neuropilina-1/metabolismo , Receptores Notch/metabolismo , Factores de Transcripción/metabolismo , Microambiente Tumoral , Western Blotting , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Femenino , Humanos , Inmunohistoquímica , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Proteínas Señalizadoras YAPRESUMEN
BACKGROUND AND AIMS: Activated hepatocytes are hypothesized to be a major source of signals that drive cirrhosis, but the biochemical pathways that convert hepatocytes into such a state are unclear. We examined the role of the Hippo pathway transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in hepatocytes to facilitate cell-cell interactions that stimulate liver inflammation and fibrosis. APPROACH AND RESULTS: Using a variety of genetic, metabolic, and liver injury models in mice, we manipulated Hippo signaling in hepatocytes and examined its effects in nonparenchymal cells to promote liver inflammation and fibrosis. YAP-expressing hepatocytes rapidly and potently activate the expression of proteins that promote fibrosis (collagen type I alpha 1 chain, tissue inhibitor of metalloproteinase 1, platelet-derived growth factor c, transforming growth factor ß2) and inflammation (tumor necrosis factor, interleukin 1ß). They stimulate expansion of myofibroblasts and immune cells, followed by aggressive liver fibrosis. In contrast, hepatocyte-specific YAP and YAP/TAZ knockouts exhibit limited myofibroblast expansion, less inflammation, and decreased fibrosis after CCl4 injury despite a similar degree of necrosis as controls. We identified cellular communication network factor 1 (CYR61) as a chemokine that is up-regulated by hepatocytes during liver injury but is expressed at significantly lower levels in mice with hepatocyte-specific deletion of YAP or TAZ. Gain-of-function and loss-of-function experiments with CYR61 in vivo point to it being a key chemokine controlling liver fibrosis and inflammation in the context of YAP/TAZ. There is a direct correlation between levels of YAP/TAZ and CYR61 in liver tissues of patients with high-grade nonalcoholic steatohepatitis. CONCLUSIONS: Liver injury in mice and humans increases levels of YAP/TAZ/CYR61 in hepatocytes, thus attracting macrophages to the liver to promote inflammation and fibrosis.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas de Ciclo Celular/metabolismo , Hepatocitos/metabolismo , Cirrosis Hepática/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Estrés Fisiológico , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Proteínas de Ciclo Celular/genética , Cadena alfa 1 del Colágeno Tipo I , Proteína 61 Rica en Cisteína/genética , Proteína 61 Rica en Cisteína/metabolismo , Modelos Animales de Enfermedad , Mutación con Ganancia de Función , Humanos , Cirrosis Hepática/genética , Mutación con Pérdida de Función , Ratones , Enfermedad del Hígado Graso no Alcohólico/genética , Transactivadores/genética , Factores de Transcripción/genética , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Proteínas Señalizadoras YAPRESUMEN
The identification of gene-environment interactions related to breast cancer reveals the biological and molecular mechanisms underlying the disease and allows the distinction of women at high risk from women at lower risk, which could decrease the morbimortality of this neoplasm. The current study evaluated the association between polymorphisms rs1820453 and rs11225161 of the Yes-associated protein (YAP) gene in women with breast cancer exposed to arsenic (As) through drinking water. In total, 182 women were assessed for the frequency of YAP rs1820453 and rs11225161 polymorphisms and As urinary levels. The results demonstrated a positive and significant association between breast cancer and smoking, type of drinking water, and levels of AsIII , AsV and inorganic As (iAs) but not the YAP gene polymorphisms evaluated. In conclusion, our data showed that the source of drinking water and AsV and iAs urinary levels increased the risk for breast cancer, but no interactions between YAP gene polymorphisms and As urinary levels were found.
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Proteínas Adaptadoras Transductoras de Señales/genética , Arsenicales/efectos adversos , Neoplasias de la Mama/genética , Agua Potable/efectos adversos , Interacción Gen-Ambiente , Polimorfismo de Nucleótido Simple , Factores de Transcripción/genética , Contaminantes Químicos del Agua/efectos adversos , Adulto , Arsenicales/orina , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/etnología , Estudios Transversales , Femenino , Predisposición Genética a la Enfermedad , Humanos , México , Persona de Mediana Edad , Fenotipo , Medición de Riesgo , Factores de Riesgo , Fumar/efectos adversos , Contaminantes Químicos del Agua/orina , Proteínas Señalizadoras YAPRESUMEN
BACKGROUND & AIMS: Gastric carcinoma is related mostly to CagA+-Helicobacter pylori infection, which disrupts the gastric mucosa turnover and elicits an epithelial-mesenchymal transition (EMT) and preneoplastic transdifferentiation. The tumor suppressor Hippo pathway controls stem cell homeostasis; its core, constituted by the large tumor suppressor 2 (LATS2) kinase and its substrate Yes-associated protein 1 (YAP1), was investigated in this context. METHODS: Hippo, EMT, and intestinal metaplasia marker expression were investigated by transcriptomic and immunostaining analyses in human gastric AGS and MKN74 and nongastric immortalized RPE1 and HMLE epithelial cell lines challenged by H pylori, and on gastric tissues of infected patients and mice. LATS2 and YAP1 were silenced using small interfering RNAs. A transcriptional enhanced associated domain (TEAD) reporter assay was used. Cell proliferation and invasion were evaluated. RESULTS: LATS2 and YAP1 appear co-overexpressed in the infected mucosa, especially in gastritis and intestinal metaplasia. H pylori via CagA stimulates LATS2 and YAP1 in a coordinated biphasic pattern, characterized by an early transient YAP1 nuclear accumulation and stimulated YAP1/TEAD transcription, followed by nuclear LATS2 up-regulation leading to YAP1 phosphorylation and targeting for degradation. LATS2 and YAP1 reciprocally positively regulate each other's expression. Loss-of-function experiments showed that LATS2 restricts H pylori-induced EMT marker expression, invasion, and intestinal metaplasia, supporting a role of LATS2 in maintaining the epithelial phenotype of gastric cells and constraining H pylori-induced preneoplastic changes. CONCLUSIONS: H pylori infection engages a number of signaling cascades that alienate mucosa homeostasis, including the Hippo LATS2/YAP1/TEAD pathway. In the host-pathogen conflict, which generates an inflammatory environment and perturbations of the epithelial turnover and differentiation, Hippo signaling appears as a protective pathway, limiting the loss of gastric epithelial cell identity that precedes gastric carcinoma development.