RESUMO
Memories already consolidated when reactivated return to a labile state and can be modified, this process is known as reconsolidation. It is known the Wnt signaling pathways can modulate hippocampal synaptic plasticity as well as learning and memory. Yet, Wnt signaling pathways interact with NMDA (N-methyl-D-aspartate) receptors. However, whether canonical Wnt/ß-catenin and non-canonical Wnt/Ca2 + signaling pathways are required in the CA1 region of hippocampus for contextual fear memory reconsolidation remains unclear. So, here we verified that the inhibition of canonical Wnt/ß-catenin pathway with DKK1 (Dickkopf-1) into CA1 impaired the reconsolidation of contextual fear conditioning (CFC) memory when administered immediately and 2 h after reactivation session but not 6 h later, while the inhibition of non-canonical Wnt/Ca2+ signaling pathway with SFRP1 (Secreted frizzled-related protein-1) into CA1 immediately after reactivation session had no effect. Moreover, the impairment induced by DKK1 was blocked by the administration of the agonist of the NMDA receptors glycine site, D-Serine, immediately and 2 h after reactivation session. We found that hippocampal canonical Wnt/ß-catenin is necessary to the reconsolidation of CFC memory at least two hours after reactivation, while non-canonical Wnt/Ca2+ signaling pathway is not involved in this process and, that there is a link between Wnt/ß-catenin signaling pathway and NMDA receptors. In view of this, this study provides new evidence regarding the neural mechanisms underlying contextual fear memory reconsolidation and contributes to provide a new possible target for the treatment of fear related disorders.
Assuntos
Memória , Via de Sinalização Wnt , Memória/fisiologia , beta Catenina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Hipocampo/metabolismo , Medo/fisiologiaRESUMO
PURPOSE: The de novo lipogenesis has been a longstanding observation in hepatocellular carcinoma (HCC). However, the prognostic value and carcinogenic roles of the enzyme Acetyl-CoA carboxylase alpha (ACACA) in HCC remains unknown. METHODS: The proteins with remarkable prognostic significance were screened out from The Cancer Proteome Atlas Portal (TCPA) database. Furthermore, the expression characteristics and prognostic value of ACACA were evaluated in multiple databases and the local HCC cohort. The loss-of-function assays were performed to uncover the potential roles of ACACA in steering malignant behaviors of HCC cells. The underlying mechanisms were conjectured by bioinformatics and validated in HCC cell lines. RESULTS: ACACA was identified as a crucial factor of HCC prognosis. Bioinformatics analyses showed that HCC patients with higher expression of ACACA protein or mRNA levels had poor prognosis. Knockdown of ACACA remarkably crippled the proliferation, colony formation, migration, invasion, epithelial-mesenchymal transition (EMT) process of HCC cells and induced the cell cycle arrest. Mechanistically, ACACA might facilitate the malignant phenotypes of HCC through aberrant activation of Wnt/ß-catenin signaling pathway. In addition, ACACA expression was associated with the dilute infiltration of immune cells including plasmacytoid DC (pDC) and cytotoxic cells by utilization of relevant database analysis. CONCLUSION: ACACA could be a potential biomarker and molecular target for HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , beta Catenina/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/patologia , Prognóstico , Proteínas/metabolismoRESUMO
BACKGROUND: Ewing's sarcoma is the second most common bone and soft tissue malignancy in children and adolescents. Tumor necrosis factor-α-induced protein 8-like 1 (TIPE1) functions as a tumor suppressor in several cancers. Activation of Wnt/ß-catenin signaling in subpopulations of tumor cells contributes to phenotypic heterogeneity and disease progression in Ewing's sarcoma. The exact role of TIPE1 in Ewing's sarcoma remains to be elucidated. PURPOSE: This study aimed to assess the expression and function of TIPE1 in Ewing's sarcoma. METHODS: TIPE1 expression in Ewing's sarcoma cells was determined by qPCR and western blotting. Furthermore, the Ewing's sarcoma cell line RD-ES was transfected with a lentivirus-based TIPE1 expression system to upregulate the expression of TIPE1. The Cell Counting Kit 8 was used to assess the effect of TIPE1 on cell proliferation. The effects of TIPE1 on cell migration and invasion was detected by Transwell assay. Flow cytometry was performed to detect apoptosis. RESULTS: Our results suggested lower TIPE1 expression in Ewing's sarcoma cell lines compared with normal osseous cells. TIPE1 remarkably inhibited the growth and proliferation of Ewing's sarcoma cell; TIPE1 also induced apoptosis and inhibited invasion in vitro. TIPE1 inhibited Ewing's sarcoma growth, motility, and survival through regulation of Wnt/ß-catenin signaling. CONCLUSIONS: Our results demonstrated the anti-tumor function of TIPE1 in Ewing's sarcoma and reveal a novel therapeutic target.
Assuntos
Neoplasias Ósseas , Sarcoma de Ewing , Adolescente , Criança , Humanos , Apoptose , beta Catenina/genética , beta Catenina/metabolismo , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Proliferação de Células , Perfilação da Expressão Gênica , Sarcoma de Ewing/tratamento farmacológico , Sarcoma de Ewing/genética , Transdução de Sinais , Proteínas Wnt/genética , Proteínas Wnt/metabolismoRESUMO
PURPOSE: SMEK1, also known as PP4R3α, the regulatory subunit 3α of serine and threonine phosphatase PP4, participates in diversely critical biological processes such as the integration of centromere, deacetylation of histones, asymmetric divisions of neuroblast, and other crucial cellular activities. SMEK1 was formerly reported to play a part in carcinogenesis. This study aims to reveal the role of SMEK1 in lung adenocarcinoma and the underlying molecular mechanism. METHODS: Using immunohistochemical (IHC) staining, the protein level of SMEK1 in lung adenocarcinoma and adjacent non-tumor tissue was detected. The functional role of SMEK1 in cell proliferation and invasion was explored using cell counting kit-8 and Transwell assay, respectively. Xenograft tumor experiment was used to investigate the effect of SMEK1 on tumor growth in vivo. The alteration of Wnt/ß-catenin signaling pathway was detected by Western blotting, quantitative PCR, and dual-luciferase reporter assays. RESULTS: SMEK1 was highly expressed at the protein level in lung adenocarcinoma compared to the adjacent non-tumor tissue. In vitro, suppression of SMEK1 significantly decreased the proliferation, migration, and invasion of lung adenocarcinoma cell lines, while overexpression of SMEK1 enhanced above abilities. The xenograft model demonstrated that down-regulation of SMEK1 significantly inhibited tumor growth in vivo. In addition, we found that SMEK1 could positively regulate Wnt/ß-catenin signaling in lung adenocarcinoma cell lines. CONCLUSIONS: SMEK1 exerts a cancer-promoting effect in lung adenocarcinoma by activating Wnt/ß-catenin signaling.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Via de Sinalização Wnt/fisiologia , Linhagem Celular Tumoral , beta Catenina/metabolismo , Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/genética , Proliferação de Células , Movimento Celular , Regulação Neoplásica da Expressão GênicaRESUMO
BACKGROUND: Colorectal cancer (CRC) is one of the most common malignant cancers in human, and its incidence increases gradually every year. Metastasis is an important factor leading to tumor development. The epithelial-mesenchymal transition (EMT) has been proved to be closely related to tumor metastasis, yet its related mechanism in CRC remains to be explored. METHODS: We obtained the differentially expressed gene C5aR1 with SETDB1 stable overexpression and knockdown cells by RNA-seq. Cell proliferation was tested by CCK8 and colony formation assay. Migration and invasion of CRC cells were determined by the wound healing and transwell invasion assay. The potential pathway of C5aR1 in CRC was preliminarily studied by western blotting. RESULTS: Sequencing results showed that C5aR1 was the most differentially expressed gene. By changing the expression of C5aR1 in CRC cells, this study found that C5aR1 promoted the proliferation, colony formation, migration and invasion of CRC cells in vitro. C5aR1 accelerated the EMT process and the expression of C5aR1 altered the molecular expression of key proteins in the Wnt/ß-catenin pathway. CONCLUSION: C5aR1 promotes the development of CRC and accelerates the EMT process. Furthermore, C5aR1 may involve in the regulation of Wnt/ß-catenin pathway in CRC.
Assuntos
Neoplasias Colorretais , Transição Epitelial-Mesenquimal , Receptor da Anafilatoxina C5a , Via de Sinalização Wnt , Humanos , beta Catenina/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/genética , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Receptor da Anafilatoxina C5a/genéticaRESUMO
PURPOSE: To elucidate the underlying mechanism of HIF-1α in migration and invasion of choriocarcinoma. METHODS: Cell proliferation was determined by CCK-8 assay when cell invasion was detected by transwell assay. The protein expression was detected by western blotting, immunohistochemistry, and qPCR assay. RESULT: HIF-1α was shown to be strongly expressed in both clinical tumour tissues and cell lines in choriocarcinoma. When HIF-1α was efficiently knocked down in JEG3 cells, the proliferation rate was reduced by approximately 50% and the number of cells that migrated through the transwell insert was greatly decreased. The cell invasion rate was also significantly reduced. Moreover, typical markers of epithelial-mesenchymal transition such as E-cadherin, were increased, while vimentin and α-SMA were decreased after HIF-1α knockdown. In contrast, overexpression of DEC1 reversed the effects of HIF-1α knockdown. Cell proliferation, migration, and invasion were partially recovered. The level of E-cadherin was decreased, while the level of vimentin and α-SMA was increased. In addition, the level of ß-catenin and LEF1 was downregulated after HIF-1α knockdown. The expression of MMP2 and MMP9 also declined. However, overexpression of DEC1 after HIF-1α knockdown partially reversed the expression pattern of these molecules. CONCLUSION: HIF-1α contributed to EMT and metastasis through activation of canonical ß-catenin signalling in choriocarcinoma and this process was dependent on DEC1. This study provides a new mechanism of HIF-1α in choriocarcinoma and suggests that intervention with DEC1 might be a promising therapeutic choice for choriocarcinoma.
Assuntos
Coriocarcinoma , beta Catenina , Gravidez , Feminino , Humanos , beta Catenina/genética , beta Catenina/metabolismo , Linhagem Celular Tumoral , Vimentina/metabolismo , Caderinas/genética , Caderinas/metabolismo , Coriocarcinoma/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Transição Epitelial-Mesenquimal , Movimento Celular , Regulação Neoplásica da Expressão GênicaRESUMO
The Wnt/ß-Catenin pathway alterations present in colorectal cancer (CRC) are of special interest in the development of new therapeutic strategies to impact carcinogenesis and the progression of CRC. In this context, different polyphenols present in natural products have been reported to have modulatory effects against the Wnt pathway in CRC. In this study, we evaluate the effect of two polyphenol-rich coffee extracts and chlorogenic acid (CGA) against SW480 and HT-29 CRC cells. This involved the use of MTT and SRB techniques for cell viability; wound healing and invasion assay for the evaluation of the migration and invasion process; T cell factor (TCF) reporter plasmid for the evaluation of transciption factor (TCF) transcriptional activity; polymerase chain reaction (PCR) of target genes and confocal fluorescence microscopy for ß-Catenin and E-Cadherin protein fluorescence levels; and subcellular localization. Our results showed a potential modulatory effect of the Wnt pathway on CRC cells, and we observed a reduction in the transcriptional activity of ß-catenin. All the results were prominent in SW480 cells, where the Wnt pathway deregulation has more relevance and implies a constitutive activation of the signaling pathway. These results establish a starting point for the discovery of a mechanism of action associated with these effects and corroborate the anticancer potential of polyphenols present in coffee, which could be explored as chemopreventive molecules or as adjunctive therapy in CRC.
Assuntos
Neoplasias Colorretais , beta Catenina , Humanos , beta Catenina/genética , beta Catenina/metabolismo , Via de Sinalização Wnt , Ácido Clorogênico/farmacologia , Ácido Clorogênico/uso terapêutico , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Neoplasias Colorretais/metabolismoRESUMO
PURPOSE: Gastric carcinoma (GC) is a common malignant disease with high morbidity and mortality. MiR-507 has been confirmed as a tumor inhibitor which can suppress the progression of multiple cancers while its role in GC remains unknown. METHODS: In this study, the expression levels of miR-507 in the GC tissues and cells were observed by qRT-PCR, and CCK-8 assay, transwell asssay and TUNEL assay were used to observe the function of miR-507 on GC. The miRNA database and dual-luciferase reporter assay were used to investigate the downstream target of miR-507. Moreover, the activities of Wnt/ß-catenin and HIF-1α pathways were observed by western blot. RESULTS: The results showed that miR-507 was significantly downregulated in GC tissues and cell lines, and miR-507 upregulation effectively inhibited the proliferation and invasion and induced the apoptosis of GC cells. CBX4 was a downstream target of miR-507, and CBX4 could reverse the effects of miR-507 on the GC cells. Moreover, it was determined that miR-507 could inhibit CBX4 expression to suppress the activation of Wnt/ß-catenin and HIF-1α pathways. CONCLUSIONS: In conclusion, it suggests that miR-507 could inhibit the progression of GC via regulating CBX4-mediated activation of Wnt/ß-catenin and HIF-1α pathways.
Assuntos
Carcinoma , Regulação Neoplásica da Expressão Gênica , MicroRNAs , Neoplasias Gástricas , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Ligases , MicroRNAs/genética , Proteínas do Grupo Polycomb/genética , Neoplasias Gástricas/genética , Via de Sinalização Wnt , beta Catenina/metabolismoRESUMO
The Wnt/ß-catenin signaling pathway is frequently activated in hepatocellular carcinoma (HCC). A number of studies have focused on the aberrant hypermethylation of the DKK family proteins and its role in regulating the activation of specific signaling pathways. However, the exact way by which DKK regulates the signaling pathway caused by Core protein of HCV has not been reported. In the present study, we evaluated the expression level of DKK and its aberrant promoter methylation to investigate the involvement of epigenetic regulation in hepatoma cell lines. The transcription and protein expression of DKK1 was significantly increased, whereas the transcription and protein expression levels of DKK2, DKK3, and DKK4 were significantly decreased following overexpression of Core protein. Pyrosequencing indicated that hypermethylation of DKK3 was increased. This was associated with increased expression of Dnmt1. The investigation of the molecular mechanism indicated that HCV Core protein interacted with Dnmt1, which combined with the promoter of DKK3, leading to methylation of DKK3. Functional studies indicated that Core protein promoted the growth, migration and invasion of cancer cells. However, upregulation of the expression of DKK3 and/or the knockdown of the expression of Dnmt1 inhibited the growth, migration and invasion of cancer cells. Taken together, the data indicated that epigenetic silencing of DKK3 caused by Dnmt1 activated the Wnt/ß-catenin pathway in HCV Core-mediated HCC. Therefore, DKK3 may be a potential diagnostic and therapeutic target for HCC.
Assuntos
Carcinoma Hepatocelular , Hepatite C , Neoplasias Hepáticas , Proteínas Adaptadoras de Transdução de Sinal , Linhagem Celular Tumoral , Proliferação de Células , Epigênese Genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Proteínas Wnt , Via de Sinalização Wnt , beta CateninaRESUMO
Wnt proteins activate different signaling pathways, such as the canonical Wnt/ß-catenin signaling pathway and non-canonical ß-catenin-independent signaling pathway and have been related to several functions in central nervous system, including learning and memory. However, whether these signaling pathways are required in the medial prefrontal cortex (mPFC) for fear memory acquisition, consolidation and retrieval remains unclear. To address this question, we submitted male rats to a contextual fear conditioning (CFC) paradigm, and administered canonical Wnt/ß-catenin and non-canonical Wnt/Ca2+ signaling pathways inhibitors, DKK1 and SFRP1, respectively, into the prelimbic (PrL) subdivision of the mPFC at different moments and evaluated short-term and long-term memory acquisition, consolidation and retrieval. We found that blocking canonical Wnt/ß-catenin and non-canonical Wnt/Ca2+ signaling pathways 15 min before or immediately after CFC training had no effect on STM and LTM of CFC, while their blockade 15 min before the retention test prevented the retrieval of STM and LTM of CFC. These results highlight the importance of the mPFC in fear memory retrieval demonstrating that both canonical Wnt/ß-catenin and non-canonical Wnt/Ca2+ signaling pathways participate in this process. To understand how brain systems act on fear memories could provide a new target for the treatment of fear related disorders such as post-traumatic stress disorder and other anxiety disorders.
Assuntos
Medo , beta Catenina , Animais , Cálcio/metabolismo , Medo/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Memória/fisiologia , Córtex Pré-Frontal/metabolismo , Ratos , Via de Sinalização Wnt , beta Catenina/metabolismoRESUMO
Knockout (ko) mice for the ß2 adrenoceptor (Adrß2) have impaired skeletal muscle regeneration, suggesting that this receptor is important for muscle stem cell (satellite cell) function. Here, we investigated the role of Adrß2 in the function of satellite cells from ß2ko mice in the context of muscle regeneration, through in vivo and in vitro experiments. Immunohistochemical analysis showed a significant reduction in the number of self-renewed Pax7+ satellite cells, proliferating Pax7+/MyoD+ myogenic precursor cells, and regenerating eMHC+ myofibers in regenerating muscle of ß2ko mice at 30, 3, and 10 days post-injury, respectively. Quiescent satellite cells were isolated by fluorescence-activated cell sorting, and cell cycle entry was assessed by EdU incorporation. The results demonstrated a lower number of proliferating Pax7+/EdU+ satellite cells from ß2ko mice. There was an increase in the gene expression of the cell cycle inhibitor Cdkn1a and Notch pathway components and the activation of Notch signaling in proliferating myoblasts from ß2ko mice. There was a decrease in the number of myogenin-positive nuclei in myofibers maintained in differentiation media, and a lower fusion index in differentiating myoblasts from ß2ko mice. Furthermore, the gene expression of Wnt/ß-catenin signaling components, the expression of nuclear ß-catenin and the activation of Wnt/ß-catenin signaling decreased in differentiating myoblasts from ß2ko mice. These results indicate that Adrß2 plays a crucial role in satellite cell self-renewal, as well as in myoblast proliferation and differentiation by regulating Notch and Wnt/ß-catenin signaling, respectively.
Assuntos
Células Satélites de Músculo Esquelético , Animais , Camundongos , Camundongos Knockout , Músculos/metabolismo , Miogenina/metabolismo , Receptores Adrenérgicos/metabolismo , Células Satélites de Músculo Esquelético/metabolismo , Via de Sinalização Wnt/genética , beta Catenina/genética , beta Catenina/metabolismoRESUMO
INTRODUCTION AND OBJECTIVES: Hepatocellular carcinoma (HCC) is one of the most malignant digestive tumors, and its insidious onset and rapid progression are the main reasons for the difficulty in effective treatment. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) is a key enzyme that regulates phospholipid metabolism of the cell membrane. However, the mechanism by which LPCAT1 regulates HCC metastasis remains unknown. This study aimed to explore its biological function and potential mechanisms concerning migration and invasion in HCC. MATERIALS AND METHODS: LPCAT1 expression in HCC tissues and its association with clinical outcomes were investigated by western blotting and bioinformatic methods, respectively. The role of LPCAT1 in migration and invasion was assessed via Transwell assays. The expression pattern of epithelial-mesenchymal transition (EMT) markers was quantified by western blotting. The biological behaviors of LPCAT1 in vivo were evaluated using xenograft tumor models and caudal vein metastatic models. Signaling pathways related to LPCAT1 were predicted using gene set enrichment analysis (GSEA) and further confirmed by western blotting. RESULTS: LPCAT1 expression was significantly upregulated in HCC tissues and indicated a poor prognosis of HCC patients. Several EMT-related markers were found to be regulated by LPCAT1. HCC cells overexpressing LPCAT1 exhibited remarkably high migration and invasion capacities, upregulated expression of mesenchymal markers and reduced E-cadherin expression. In vivo, LPCAT1 promoted HCC pulmonary metastasis. Furthermore, the Wnt/ß-catenin signaling pathway was confirmed to be activated by LPCAT1. CONCLUSIONS: LPCAT1 could serve as a promising biomarker of HCC and as a novel therapeutic target for the treatment of metastatic HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , 1-Acilglicerofosfocolina O-Aciltransferase/genética , 1-Acilglicerofosfocolina O-Aciltransferase/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/patologia , Via de Sinalização Wnt/genéticaRESUMO
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.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , MicroRNAs/fisiologia , Via de Sinalização Wnt/fisiologia , Proteínas de Sinalização YAP/fisiologia , Progressão da Doença , Humanos , Células Tumorais CultivadasRESUMO
Abstract Colorectal cancer (CRC) one of the leading cause of cancer-related deaths worldwide. With the presently available knowledge on CRC, it is understood that the underlying is a complex process. The complexity of CRC lies in aberrant activation of several cellular signaling pathways that lead to activation and progression of CRC. In this context, recent studies have pointed towards the role of developmental pathways like; hedgehog (HH), wingless-related integration site (WNT/ß-catenin) and Notch pathways that play a crucial role in maintenance and homeostasis of colon epithelium. Moreover, the deregulation of these signaling pathways has also been associated with the pathogenesis of CRC. Therefore, in the search for better therapeutic options, these pathways have emerged as potential targets. The present review attempts to highlight the role of HH, WNT/ß-catenin and Notch pathways in colon carcinogenesis
Assuntos
Neoplasias Colorretais/patologia , Patogenesia Homeopática/classificação , Neoplasias do Colo/patologia , Compreensão , CarcinogêneseRESUMO
Autism spectrum disorders (ASD) is a heterogeneous group of neurodevelopmental disorders characterized by synaptic dysfunction and defects in dendritic spine morphology. In the past decade, an extensive list of genes associated with ASD has been identified by genome-wide sequencing initiatives. Several of these genes functionally converge in the regulation of the Wnt/ß-catenin signaling pathway, a conserved cascade essential for stem cell pluripotency and cell fate decisions during development. Here, we review current information regarding the transcriptional program of Wnt/ß-catenin signaling in ASD. First, we discuss that Wnt/ß-catenin gain and loss of function studies recapitulate brain developmental abnormalities associated with ASD. Second, transcriptomic approaches using patient-derived induced pluripotent stem cells (iPSC) cells, featuring mutations in high confidence ASD genes, reveal a significant dysregulation in the expression of Wnt signaling components. Finally, we focus on the activity of chromatin-remodeling proteins and transcription factors considered high confidence ASD genes, including CHD8, ARID1B, ADNP, and TBR1, that regulate Wnt/ß-catenin-dependent transcriptional activity in multiple cell types, including pyramidal neurons, interneurons and oligodendrocytes, cells which are becoming increasingly relevant in the study of ASD. We conclude that the level of Wnt/ß-catenin signaling activation could explain the high phenotypical heterogeneity of ASD and be instrumental in the development of new diagnostics tools and therapies.
RESUMO
Colorectal cancer (CRC) represents the third most commonly diagnosed cancer and the second leading cause of cancer death worldwide. The modern concept of cancer biology indicates that cancer is formed of a small population of cells called cancer stem cells (CSCs), which present both pluripotency and self-renewal properties. These cells are considered responsible for the progression of the disease, recurrence and tumor resistance. Interestingly, some cell signaling pathways participate in CRC survival, proliferation, and self-renewal properties, and most of them are dysregulated in CSCs, including the Wingless (Wnt)/ß-catenin, Notch, Hedgehog, nuclear factor kappa B (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), peroxisome proliferator-activated receptor (PPAR), phosphatidyl-inositol-3-kinase/Akt/mechanistic target of rapamycin (PI3K/Akt/mTOR), and transforming growth factor-ß (TGF-ß)/Smad pathways. In this review, we summarize the strategies for eradicating CRC stem cells by modulating these dysregulated pathways, which will contribute to the study of potential therapeutic schemes, combining conventional drugs with CSC-targeting drugs, and allowing better cure rates in anti-CRC therapy.
Assuntos
Neoplasias Colorretais , Células-Tronco Neoplásicas , Transdução de Sinais/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismoRESUMO
The cellular processes regulated by WNT signaling have been mainly studied during embryonic development and cancer. In the last two decades, the role of WNT in the adult central nervous system has been the focus of interest in our laboratory. In this chapter, we will be summarized ß-catenin-dependent and -independent WNT pathways, then we will be revised WNT signaling function at the pre- and post-synaptic level. Concerning Alzheimer's disease (AD) initially, we found that WNT/ß-catenin signaling activation exerts a neuroprotective mechanism against the amyloid ß (Αß) peptide toxicity. Later, we found that WNT/ß-catenin participates in Tau phosphorylation and in learning and memory. In the last years, we demonstrated that WNT/ß-catenin signaling is instrumental in the amyloid precursor protein (APP) processing and that WNT/ß-catenin dysfunction results in Aß production and aggregation. We highlight the importance of WNT/ß-catenin signaling dysfunction in the onset of AD and propose that the loss of WNT/ß-catenin signaling is a triggering factor of AD. The WNT pathway is therefore positioned as a therapeutic target for AD and could be a valid concept for improving AD therapy. We think that metabolism and inflammation will be relevant when defining future research in the context of WNT signaling and the neurodegeneration associated with AD.
Assuntos
Doença de Alzheimer , Via de Sinalização Wnt , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide , Humanos , FosforilaçãoRESUMO
OBJECTIVE: Emerging studies highlight the crucial effects of microRNAs on cancer initiation and malignant progression of various tumors. This study focused on the biological effect of miR-377-3p on CUL1 and epithelial-mesenchymal transition (EMT) and Wnt/ß-catenin pathways in osteosarcoma (OS). METHODS: We performed quantitative real-time polymerase chain reaction (qRT-PCR) to analyze miR-377-3p and CUL1 expression levels in OS tissues and MG-63 cells. Then, cell counting kit (CCK)-8 and Transwell assay were used to examine the functions of miR-377-3p in OS cell growth and metastasis abilities. Meanwhile, luciferase reporter assay was used to validate CUL1 as direct target of miR-377-3p. qRT-PCR and Western blot were then carried out to detect the impact of miR-377-3p on EMT and Wnt/ß-catenin pathways. Tumor xenograft models were established to further examine the effects of miR-377-3p on OS tumorigenesis in vivo. RESULTS: miR-377-3p downregulation was frequently identified in OS tissues and cells, which was associated with worse prognosis of OS patients. Functional experiments showed miR-377-3p restoration could dramatically repress OS cell growth and migration by regulation of EMT and Wnt/ß-catenin pathways. Moreover, luciferase reporter assay revealed that CUL1 acted as a functional target of miR-377-3p. Additionally, the elevated CUL1 expressions in OS tissues also indicated poor prognosis of OS patients. Furthermore, the OS tumor growth was also obviously inhibited by miR-377-3p overexpression in vivo. CONCLUSIONS: Collectively, all the above findings revealed that miR-377-3p exerted anti-OS functions via CUL1 and EMT and Wnt/ß-catenin pathways. These results may contribute to the development of clinical OS treatment.
Assuntos
Neoplasias Ósseas/metabolismo , Proteínas Culina/metabolismo , MicroRNAs/metabolismo , Osteossarcoma/metabolismo , Via de Sinalização Wnt , Animais , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Progressão da Doença , Regulação para Baixo , Transição Epitelial-Mesenquimal , Genes Reporter , Xenoenxertos , Humanos , Luciferases/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Osteossarcoma/mortalidade , Osteossarcoma/patologia , Osteossarcoma/secundário , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Cellular senescence is a process that can prevent tumour development in a cell autonomous manner by imposing a stable cell cycle arrest after oncogene activation. Paradoxically, senescence can also promote tumour growth cell non-autonomously by creating a permissive tumour microenvironment that fuels tumour initiation, progression to malignancy and metastasis. In a pituitary tumour known as adamantinomatous craniopharyngioma (ACP), cells that carry oncogenic ß-catenin mutations and overactivate the WNT signalling pathway form cell clusters that become senescent and activate a senescence-associated secretory phenotype (SASP). Research in mouse models of ACP has provided insights into the function of the senescent cell clusters and revealed a critical role for SASP-mediated activities in paracrine tumour initiation. In this review, we first discuss this research on ACP and subsequently explore the theme of paracrine tumourigenesis in other tumour models available in the literature. Evidence is accumulating supporting the notion that paracrine signalling brought about by senescent cells may underlie tumourigenesis across different tumours and cancer models.
Assuntos
Carcinogênese/patologia , Senescência Celular/fisiologia , Craniofaringioma/patologia , Comunicação Parácrina/fisiologia , Animais , Humanos , Transdução de Sinais/fisiologia , Microambiente Tumoral/fisiologiaRESUMO
Geoffroea decorticans (chañar) is commonly used for culinary and medicinal purposes in rural communities. The aim of this work was to chemically characterize three Geoffroea decorticans extracts and determine their capacity to modulate the wnt/ß-catenin pathway. This signaling pathway plays a key role in embryonic development but its overactivation leads to cancer cell growth. Phytochemical analysis of extracts showed presence of major classes of phytochemicals. Gas chromatography-mass spectrometry results revealed the presence of acids, esters and furanic compounds. Using Xenopus embryos as in vivo model organisms, we found that the extracts modulated dorso-ventral axis formation and rescued hyperdorsalized phenotypes produced by LiCl treatment. In agreement with these findings, Geoffroea decorticans extracts decreased ß-catenin levels and suppressed the expression of wnt target genes such as xnr3 and chordin, thus demonstrating an inhibitory regulation of the wnt/ß-catenin signaling pathway. All these results support a new role for Geoffroea decorticans fruit derivatives with possible anti-carcinogenic actions.