RESUMO
BACKGROUND: Approximately 25-30% of patients with acute myeloid leukemia (AML) have FMS-like receptor tyrosine kinase-3 (FLT3) mutations that contribute to disease progression and poor prognosis. Prolonged exposure to FLT3 tyrosine kinase inhibitors (TKIs) often results in limited clinical responses due to diverse compensatory survival signals. Therefore, there is an urgent need to elucidate the mechanisms underlying FLT3 TKI resistance. Dysregulated sphingolipid metabolism frequently contributes to cancer progression and a poor therapeutic response. However, its relationship with TKI sensitivity in FLT3-mutated AML remains unknown. Thus, we aimed to assess mechanisms of FLT3 TKI resistance in AML. METHODS: We performed lipidomics profiling, RNA-seq, qRT-PCR, and enzyme-linked immunosorbent assays to determine potential drivers of sorafenib resistance. FLT3 signaling was inhibited by sorafenib or quizartinib, and SPHK1 was inhibited by using an antagonist or via knockdown. Cell growth and apoptosis were assessed in FLT3-mutated and wild-type AML cell lines via Cell counting kit-8, PI staining, and Annexin-V/7AAD assays. Western blotting and immunofluorescence assays were employed to explore the underlying molecular mechanisms through rescue experiments using SPHK1 overexpression and exogenous S1P, as well as inhibitors of S1P2, ß-catenin, PP2A, and GSK3ß. Xenograft murine model, patient samples, and publicly available data were analyzed to corroborate our in vitro results. RESULTS: We demonstrate that long-term sorafenib treatment upregulates SPHK1/sphingosine-1-phosphate (S1P) signaling, which in turn positively modulates ß-catenin signaling to counteract TKI-mediated suppression of FLT3-mutated AML cells via the S1P2 receptor. Genetic or pharmacological inhibition of SPHK1 potently enhanced the TKI-mediated inhibition of proliferation and apoptosis induction in FLT3-mutated AML cells in vitro. SPHK1 knockdown enhanced sorafenib efficacy and improved survival of AML-xenografted mice. Mechanistically, targeting the SPHK1/S1P/S1P2 signaling synergizes with FLT3 TKIs to inhibit ß-catenin activity by activating the protein phosphatase 2 A (PP2A)-glycogen synthase kinase 3ß (GSK3ß) pathway. CONCLUSIONS: These findings establish the sphingolipid metabolic enzyme SPHK1 as a regulator of TKI sensitivity and suggest that combining SPHK1 inhibition with TKIs could be an effective approach for treating FLT3-mutated AML.
Assuntos
Glicogênio Sintase Quinase 3 beta , Leucemia Mieloide Aguda , Fosfotransferases (Aceptor do Grupo Álcool) , Proteína Fosfatase 2 , beta Catenina , Tirosina Quinase 3 Semelhante a fms , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Glicogênio Sintase Quinase 3 beta/genética , beta Catenina/metabolismo , beta Catenina/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Animais , Camundongos , Proteína Fosfatase 2/metabolismo , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/antagonistas & inibidores , Linhagem Celular Tumoral , Sorafenibe/farmacologia , Apoptose/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genéticaRESUMO
Hepatic stellate cell (HSC) activation is the essential pathological process of liver fibrosis (LF). The molecular mechanisms regulating HSC activation and LF are incompletely understood. Here, we explored the effect of transcription factor SRY-related high mobility group box 7 (SOX7) on HSC activation and LF, and the underlying molecular mechanism. We found the expression levels of SOX7 were decreased in human and mouse fibrotic livers, particularly at the fibrotic foci. SOX7 was also downregulated in primary activated HSCs and TGF-ß1 stimulated LX-2 cells. SOX7 knockdown promoted activation and proliferation of LX-2 cells while inhibiting their apoptosis. On the other hand, overexpression of SOX7 suppressed the activation and proliferation of HSCs. Mechanistically, SOX7 attenuates HSC activation and LF by decreasing the expression of ß-catenin and phosphorylation of Smad2 and Smad3 induced by TGF-ß1. Furthermore, overexpression of SOX7 using AAV8-SOX7 mouse models ameliorated the extent of LF in response to CCl4 treatment in vivo. Collectively, SOX7 suppressed HSC activation and LF. Targeting SOX7, therefore, could be a potential novel strategy to protect against LF.
Assuntos
Células Estreladas do Fígado , Cirrose Hepática , Fatores de Transcrição SOXF , Células Estreladas do Fígado/metabolismo , Animais , Cirrose Hepática/metabolismo , Cirrose Hepática/genética , Cirrose Hepática/patologia , Camundongos , Humanos , Masculino , Fatores de Transcrição SOXF/metabolismo , Fatores de Transcrição SOXF/genética , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/genética , Proliferação de Células , Camundongos Endogâmicos C57BL , beta Catenina/metabolismo , beta Catenina/genética , Apoptose , Proteína Smad2/metabolismo , Proteína Smad2/genética , Linhagem Celular , Proteína Smad3/metabolismo , Proteína Smad3/genéticaAssuntos
Neoplasias da Mama , Movimento Celular , Proliferação de Células , Proteínas de Membrana , MicroRNAs , Invasividade Neoplásica , Via de Sinalização Wnt , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Feminino , Movimento Celular/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Animais , Linhagem Celular Tumoral , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Camundongos , beta Catenina/metabolismo , beta Catenina/genéticaRESUMO
Gastrointestinal cancers (GICs) are highly prevalent cancers that threaten human health worldwide. The Wnt/ß-catenin signaling pathway has been reported to play a pivotal role in the carcinogenesis of GICs. Numerous interventions targeting the Wnt/ß-catenin signaling in GICs are currently being tested in clinical trials with promising results. Unfortunately, there are no clinically approved drugs that effectively target this pathway. This comprehensive review aims to evaluate the impact of clinical therapies targeting the Wnt/ß-catenin signaling pathway in GICs. By integrating data from bioinformatics databases and recent literature from the past five years, we examine the heterogeneous expression and regulatory mechanisms of Wnt/ß-catenin pathway genes and proteins in GICs. Specifically, we focus on expression patterns, mutation frequencies, and clinical prognoses to understand their implications for treatment strategies. Additionally, we discuss recent clinical trial efforts targeting this pathway. Understanding the inhibitors currently under clinical investigation may help optimize foundational research and clinical strategies. We hope that elucidating the current status of precision therapeutic stratification for patients targeting the Wnt/ß-catenin pathway will guide future innovations in precision medicine for GICs.
Assuntos
Antineoplásicos , Neoplasias Gastrointestinais , Via de Sinalização Wnt , Humanos , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/fisiologia , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Animais , beta Catenina/metabolismo , beta Catenina/antagonistas & inibidores , beta Catenina/genética , Terapia de Alvo Molecular/métodosAssuntos
Carcinoma de Células Escamosas , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glipicanas , Neoplasias Pulmonares , beta Catenina , Glipicanas/genética , Glipicanas/metabolismo , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proliferação de Células/genética , beta Catenina/metabolismo , beta Catenina/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Regulação para Cima , Carcinogênese/genética , Carcinogênese/patologia , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Animais , Masculino , FemininoRESUMO
Objective: To explore the gene mutation characteristics and the relationship between gene mutations and long-term prognosis in clinical stage â A lung adenocarcinoma patients. Methods: A retrospective analysis was conducted on 63 clinical stage â A lung adenocarcinoma patients who underwent surgical resection at the Cancer Hospital of the Chinese Academy of Medical Sciences from January 2007 to October 2012, with documented postoperative recurrence or metastasis, as well as those who had a follow-up duration of 10 years or more without recurrence or metastasis. Whole exome sequencing (WES) technology was used to analyze the gene mutation profiles in tumor tissues and univariate and multivariate Cox regression analysis were used to clarify the influencing factors for patient prognosis. Results: After long term follow-up, 13 out of the 63 patients (21%) experienced recurrence or metastasis. WES technology analysis revealed that the most common tumor related gene mutations occurred in epidermal growth factor receptor (EGFR), with a mutation rate of 65.1% (41/63), followed by tumor protein p53 (TP53), fatatypical cadherin 1 (FAT1), low density lipoprotein receptor-related protein 1B (LRP1B), mechanistic target of rapamycin (MTOR), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG), and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4 (SMARCA4), with mutation rates of 30.2% (19/63), 20.6% (13/63), 15.9% (10/63), 15.9% (10/63), 15.9% (10/63), and 15.9% (10/63), respectively. Multivariate Cox regression analysis showed that PIK3CG mutations (HR=21.52, 95% CI: 3.19-145.01),smoothened (SMO) mutations (HR=35.28, 95% CI: 3.12-398.39), catenin beta 1 (CTNNB1) mutations (HR=332.86, 95% CI: 15.76-7 029.05), colony stimulating factor 1 receptor (CSF1R) mutations (HR=8 109.60, 95% CI: 114.19-575 955.17), and v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutations (HR=23.65, 95% CI: 1.86-300.43) were independent risk factors affecting the prognosis of clinical stage â A lung adenocarcinoma patients. Conclusions: PIK3CG, SMO, CTNNB1, CSF1R, BRAF gene mutations are closely related to long-term recurrence or metastasis in clinical stage â A lung adenocarcinoma. Patients with these gene mutations should be given closer clinical attention.
Assuntos
Adenocarcinoma de Pulmão , Receptores ErbB , Neoplasias Pulmonares , Mutação , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Proteína Supressora de Tumor p53 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Estudos Retrospectivos , Prognóstico , Receptores ErbB/genética , Proteína Supressora de Tumor p53/genética , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/genética , Caderinas/genética , Caderinas/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Sequenciamento do Exoma , Seguimentos , Masculino , Feminino , Pessoa de Meia-Idade , Proteínas de Ligação a DNA , Receptores de LDL , Fatores de TranscriçãoRESUMO
The two types of craniopharyngioma, adamantinomatous (ACP) and papillary (PCP), are clinically relevant tumours in children and adults. Although the biology of primary craniopharyngioma is starting to be unravelled, little is known about the biology of recurrence. To fill this gap in knowledge, we have analysed through methylation array, RNA sequencing and pERK1/2 immunohistochemistry a cohort of paired primary and recurrent samples (32 samples from 14 cases of ACP and 4 cases of PCP). We show the presence of copy number alterations and clonal evolution across recurrence in 6 cases of ACP, and analysis of additional whole genome sequencing data from the Children's Brain Tumour Network confirms chromosomal arm copy number changes in at least 7/67 ACP cases. The activation of the MAPK/ERK pathway, a feature previously shown in primary ACP, is observed in all but one recurrent cases of ACP. The only ACP without MAPK activation is an aggressive case of recurrent malignant human craniopharyngioma harbouring a CTNNB1 mutation and loss of TP53. Providing support for a functional role of this TP53 mutation, we show that Trp53 loss in a murine model of ACP results in aggressive tumours and reduced mouse survival. Finally, we characterise the tumour immune infiltrate showing differences in the cellular composition and spatial distribution between ACP and PCP. Together, these analyses have revealed novel insights into recurrent craniopharyngioma and provided preclinical evidence supporting the evaluation of MAPK pathway inhibitors and immunomodulatory approaches in clinical trials in against recurrent ACP.
Assuntos
Evolução Clonal , Craniofaringioma , Sistema de Sinalização das MAP Quinases , Recidiva Local de Neoplasia , Neoplasias Hipofisárias , Proteína Supressora de Tumor p53 , Animais , Feminino , Humanos , Masculino , Camundongos , beta Catenina/genética , beta Catenina/metabolismo , Evolução Clonal/genética , Craniofaringioma/genética , Craniofaringioma/patologia , Craniofaringioma/metabolismo , Progressão da Doença , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
The effect and mechanism of Huangqin Qingre Chubi Capsules(HQC) on rheumatoid arthritis(RA) were studied.Seventy male SPF rats were randomly divided into normal group, model group, low-(0. 18 g·kg~(-1)), middle-(0. 36 g·kg~(-1)), and high-(0. 72 g·kg~(-1)) dose groups of HQC, methotrexate group(MTX, 0. 75 mg·kg~(-1)), and negative control group(NC group, model +saline). Adjuvant arthritis fibroblast-like synoviocytes(AA-FLS) were divided into normal group, model group, low-, middle-, and high-dose groups of HQC, and negative control group. RT-qPCR and Western blot were used to detect the m RNA and protein expressions of METTL3, SFRP4, ß-catenin, CCND1, c-Myc, MMP3, and fibronectin. The protein expression of MMP3 and ß-catenin was detected by immunofluorescence. The gene expression level of METTL3 on AA-FLS was knocked down to further examine the expression of each gene. ELISA measured the levels of IL-1ß, IL-6, and IL-8. The results showed that compared with the normal group, rats in the model group found redness and swelling in their limbs and significantly increased joint swelling. Compared with the model group, the joint swelling degree of each treatment group significantly decreased(P<0. 05). The paw retraction threshold and body weight mass index both significantly increased(P<0. 05). METTL3 was highly expressed on AA and negatively correlated with the expression of SFRP4. After treatment, the m RNA and protein expression of METTL3, ß-catenin, CCND1, c-Myc, fibronectin, and MMP3 were significantly decreased on AA-FLS(P< 0. 05). Compared with the model group, knocking down METTL3 resulted in reduced m RNA and protein expression of ß-catenin, CCND1, c-Myc, fibronectin, and MMP3(P< 0. 05). At the same time, the m RNA and protein expressions of ß-catenin, CCND1, c-Myc, fibronectin, and MMP3 in the HQC+METTL3 knockdown group were significantly lower than those in the METTL3 knockdown group(P<0. 05). HQC could reduce the levels of IL-1ß, IL-6, and IL-8 to varying degrees(P<0. 05). The results indicate that HQC has a significant improvement effect on arthritis in AA rats. The expression of METTL3 is significantly increased in synovial tissue and AA-FLS of AA rats, which may be a potential target for the diagnosis and treatment of RA. HQC improves RA through the METTL3-SFRP4/Wnt/ß-catenin signaling pathway and has significant antiinflammatory and anti-rheumatic effects.
Assuntos
Artrite Reumatoide , Cápsulas , Medicamentos de Ervas Chinesas , Via de Sinalização Wnt , beta Catenina , Animais , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Artrite Reumatoide/genética , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacologia , Ratos , Masculino , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , beta Catenina/genética , Metiltransferases/genética , Metiltransferases/metabolismo , Humanos , Ratos Sprague-Dawley , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo , Proteínas Proto-OncogênicasRESUMO
Colorectal cancer (CRC) is a common gastrointestinal malignancy. Long noncoding RNAs (lncRNAs) are associated with the progression of various cancers, including CRC. Herein, we explored the function of lncRNA LINC01550 in CRC. LINC01550 expression in CRC was analyzed using The Cancer Genome Atlas (TCGA). The diagnostic value of LINC01550 was evaluated using ROC curves. The relationship between clinicopathological variables and LINC01550 expression was explored, and its prognostic value was assessed using Kaplan-Meier and Cox regression analyses. The relationship between LINC01550 expression and immune cell infiltration was analyzed using CIBERSORT. Tumor-associated mutations and drug sensitivity were compared between high and low LINC01550 expression groups. The effects of LINC01550 overexpression on CRC cells were investigated using CCK-8, flow cytometry, wound healing, Transwell, qRT-PCR, and western blot assays. LINC01550 was downregulated in CRC tissues, and the low expression of LINC01550 was correlated with advanced stage and metastasis. CRC patients with low LINC01550 expression had poorer overall survival. LINC01550 expression was an independent risk factor for CRC prognosis. APC and TP53 mutations were more frequent in the low LINC01550 expression group, while the high LINC01550 expression group was significantly more sensitive to 5-fluorouracil, irinotecan, trametinib, gemcitabine, rapamycin, and XAV939. LINC01550 overexpression suppressed the proliferation, migration, invasion, and epithelial-mesenchymal transition of HCT-116 and HT-29 cells and promoted apoptosis. LINC01550 exerted these effects by inhibiting Wnt/ß-catenin signaling. Our results suggest LINC01550 as a diagnostic and prognostic predictor in CRC that acts as a tumor suppressor and a potential therapeutic target.
Assuntos
Neoplasias Colorretais , RNA Longo não Codificante , Via de Sinalização Wnt , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Linhagem Celular Tumoral , Prognóstico , Proliferação de Células/efeitos dos fármacos , beta Catenina/metabolismo , beta Catenina/genética , Transição Epitelial-Mesenquimal , Movimento CelularRESUMO
Heart failure (HF) prognosis depends on various regulatory factors; microRNA-128 (miR-128) is identified as a regulator of cardiac fibrosis, contributing to HF. MyoD family inhibitor (MDFI), which is reported to be related with Wnt/ß-catenin pathway, is supposed to be regulated by miR-128. This study investigates the interaction between miR-128 and MDFI in cardiomyocyte development and elucidates its role in heart injury. Gene expression profiling assessed miR-128's effect on MDFI expression in HF using qPCR and Western blot analysis. Luciferase assays studied the direct interaction between miR-128 and MDFI. MTT, transwell, and immunohistochemistry evaluated the effects of miR-128 and MDFI on myocardial cells in mice HF. Genescan and luciferase assays validated the interaction between miR-128 and MDFI sequences. miR-128 mimics significantly reduced MDFI expression at mRNA and protein levels with decrease rate of 55%. Overexpression of miR-128 promoted apoptosis with the increase rate 65% and attenuated cardiomyocyte proliferation, while MDFI upregulation significantly enhanced proliferation. Elevated miR-128 levels upregulated Wnt1 and ß-catenin expression, whereas increased MDFI levels inhibited these expressions. Histological analysis with haematoxylin and eosin staining revealed that miR-128 absorption reduced MDFI expression, hindering cell proliferation and cardiac repair, with echocardiography showing corresponding improvements in cardiac function. Our findings suggest miR-128 interacts with MDFI, playing a crucial role in HF management by modulating the Wnt1/ß-catenin pathway. Suppression of miR-128 could promote cardiomyocyte proliferation, highlighting the potential value of the miR-128/MDFI interplay in HF treatment.
Assuntos
Apoptose , Cardiomegalia , Proliferação de Células , Insuficiência Cardíaca , MicroRNAs , Miócitos Cardíacos , MicroRNAs/genética , MicroRNAs/metabolismo , Animais , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Apoptose/genética , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Proliferação de Células/genética , Camundongos , Masculino , Humanos , Via de Sinalização Wnt/genética , Regulação da Expressão Gênica , Camundongos Endogâmicos C57BL , beta Catenina/metabolismo , beta Catenina/genética , Proteína Wnt1/metabolismo , Proteína Wnt1/genéticaRESUMO
OBJECTIVE: To investigate the protective effect of the Chinese herbal formula of Jiedu Huayu decoction (, JHD) on oral mucosa of rats with oral submucosal fibrosis (OSF) and its potential mechanism of action. METHODS: Sprague-Dawley male OSF model rats were constructed by injection of betaine and topical rubbing and were randomly grouped and administered by gavage for 4 weeks. Mouth opening and buccal mucosa scores interleukin levels and the expression of Axin and ß-catenin proteins or genes were measured before and after drug administration. RESULTS: After treatment with JHD the buccal mucosal lesions of rats were significantly reduced Axin protein and mRNA expression were significantly increased ß-catenin protein and mRNA expression were significantly decreased interleukin-1ß and interleukin-6 levels were decreased and interleukin-10 levels were increased. CONCLUSION: The mechanism of action of JHD can effectively alleviate the pathological damage of buccal mucosa in OSF rats which may be related to the promotion of Axin expression and inhibition of ß-catenin expression.
Assuntos
Proteína Axina , Medicamentos de Ervas Chinesas , Mucosa Bucal , Ratos Sprague-Dawley , beta Catenina , Animais , Medicamentos de Ervas Chinesas/administração & dosagem , Masculino , beta Catenina/metabolismo , beta Catenina/genética , Ratos , Proteína Axina/genética , Proteína Axina/metabolismo , Mucosa Bucal/metabolismo , Mucosa Bucal/efeitos dos fármacos , Humanos , Fibrose Oral Submucosa/tratamento farmacológico , Fibrose Oral Submucosa/metabolismo , Fibrose Oral Submucosa/genética , Modelos Animais de DoençasRESUMO
Objective: Detecting oral lesions at high risk of becoming cancer may enable early interventions to prevent oral cancer. The diagnosis of dysplasia in an oral lesion is used to predict this risk but is subject to interobserver and intraobserver variability. Studying biomarkers or molecular markers that reflect underlying molecular alterations can serve as an additional and objective method of risk assessment. E-cadherin and beta-catenin, molecular markers of epithelial-mesenchymal transition (EMT), potentially contribute to early malignant progression in oral tissue. This narrative review provides an overview of EMT, its relation to oral cancer, and the interaction among E-cadherin, beta-catenin, and the Wnt pathway in malignant progression of oral tissue. Methods: Full-text literature on EMT, E-cadherin, beta-catenin, oral epithelial dysplasia, and oral cancer was retrieved from PubMed and Google Scholar. Results: Sixty original research articles, reviews, and consensus statements were selected for review. Discussion: EMT, a biological mechanism characterized by epithelial and mesenchymal changes, can contribute to cancer development. Molecular markers of EMT including TWIST, vimentin, and N-cadherin may serve as prognostic markers of oral cancer. Dependent on Wnt pathway activity and the loss of membranous E-cadherin, E-cadherin and beta-catenin can play various roles along the spectrum of malignant progression, including tumour inhibition, early tumour progression, and late-stage tumour progression. Cross-sectional immunohistochemical research has found changes in expression patterns of E-cadherin and beta-catenin from normal oral tissue, oral epithelial dysplasia, to oral squamous cell carcinoma. Conclusion: Future research should explore the longitudinal role of EMT markers in predicting malignant progression in oral tissue.
Objectif: La détection de lésions buccales présentant un risque élevé d'évoluer en cancer peut permettre des interventions précoces pour prévenir le cancer de la bouche. Le diagnostic de dysplasie dans le cas de lésions buccales sert à prédire ce risque, mais il est soumis à une variabilité d'un observateur à l'autre et avec le même observateur. L'étude de marqueurs biologiques ou de marqueurs moléculaires correspondant à des altérations moléculaires sous-jacentes peut constituer une méthode objective supplémentaire d'évaluation des risques. L'E-cadhérine et la bêta-caténine, des marqueurs moléculaires de la transition épithélio-mésenchymateuse (TEM), pourraient contribuer aux premières étapes de l'évolution maligne du tissu buccal. Cette revue narrative donne un aperçu de la TEM, de ses liens avec le cancer de la bouche et de l'interaction entre l'E-cadhérine, la bêta-caténine et la voie de signalisation Wnt dans l'évolution maligne du tissu buccal. Méthodes: On a obtenu le texte intégral d'études portant sur la TEM, l'E-cadhérine, la bêta-caténine, la dysplasie épithéliale buccale et le cancer de la bouche sur PubMed et Google Scholar. Résultats: Soixante articles sur des études originales, des revues et des déclarations de consensus ont été sélectionnés aux fins d'examen. Discussion: La TEM, un mécanisme biologique caractérisé par des changements épithéliaux et mésenchymateux, peut contribuer à l'apparition d'un cancer. Les marqueurs moléculaires de la TEM, notamment TWIST, la vimentine et la N-cadhérine, peuvent servir de marqueurs pronostiques du cancer de la bouche. En fonction de l'activité de la voie de signalisation Wnt et de la perte de l'E-cadhérine membraneuse, l'E-cadhérine et la bêta-caténine peuvent jouer divers rôles dans le spectre de l'évolution maligne, notamment l'inhibition tumorale, la progression tumorale précoce et l'évolution tumorale avancée. Des études transversales d'immunohistochimie ont révélé des changements dans les modèles d'expression de l'E-cadhérine et de la bêta-caténine avec le passage du tissu buccal normal, de la dysplasie épithéliale buccale au carcinome squameux de la bouche. Conclusion: À l'avenir, des études devraient explorer le rôle longitudinal des marqueurs de la TEM dans la prévision de l'évolution maligne dans les tissus buccaux.
Assuntos
Biomarcadores Tumorais , Caderinas , Transformação Celular Neoplásica , Transição Epitelial-Mesenquimal , Neoplasias Bucais , beta Catenina , Humanos , beta Catenina/metabolismo , beta Catenina/genética , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Caderinas/metabolismo , Caderinas/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Neoplasias Bucais/patologia , Neoplasias Bucais/metabolismo , Neoplasias Bucais/diagnóstico , Via de Sinalização WntRESUMO
Mammalian embryos are very vulnerable to environmental toxicants (ETs) exposure. Bisphenol A (BPA), one of the most diffused ETs, exerts endocrine-disrupting effects through estro-gen-mimicking and hormone-like properties, with detrimental health effects, including on reproduction. However, its impact during the peri-implantation stages is still unclear. This study, using gastruloids as a 3D stem cell-based in vitro model of embryonic development, showed that BPA exposure arrests their axial elongation when present during the Wnt/ß-catenin pathway activation period by ß-catenin protein reduction. Gastruloid reshaping might have been impeded by the downregulation of Snail, Slug and Twist, known to suppress E-cadherin expression and to activate the N-cadherin gene, and by the low expression of the N-cadherin protein. Also, the lack of gastruloids elongation might be related to altered exit of BPA-exposed cells from the pluripotency condition and their following differentiation. In conclusion, here we show that the inhibition of gastruloids' axial elongation by BPA might be the result of the concomitant Wnt/ß-catenin perturbation, reduced N-cadherin expression and Oct4, T/Bra and Cdx2 altered patter expression, which all together concur in the impaired development of mouse gastruloids.
Assuntos
Compostos Benzidrílicos , Fenóis , Via de Sinalização Wnt , beta Catenina , Animais , Fenóis/toxicidade , Compostos Benzidrílicos/toxicidade , Camundongos , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , beta Catenina/genética , Caderinas/metabolismo , Caderinas/genética , Organoides/metabolismo , Organoides/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Disruptores Endócrinos/toxicidadeRESUMO
The prevalence of non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers, with the Wnt/ß-catenin signaling pathway exhibiting robust activation in this particular subtype. The expression of FAM83A (family with sequence similarity 83, member A) has been found to be significantly upregulated in lung cancer, leading to the stabilization of ß-catenin and activation of the Wnt signaling pathway. In this study, we conducted a screening of down-regulated miRNAs in lung cancer with FAM83A as the target. Ultimately, we identified miR-1 as a negative regulator of FAM83A and confirmed that FAM83A is a direct target gene of miR-1 through dual luciferase reporter assays. The overexpression of miR-1 significantly attenuated the expression level of FAM83A and suppressed the Wnt signaling pathway, leading to a reduction in the expression levels of downstream target genes AXIN2, CyclinD1, and C-MYC. Additionally, it decreased the nuclear translocation of ß-catenin. In addition, overexpression of miR-1 accelerated the degradation of ß-catenin by inhibiting FAM83A, promoted the assembly of ß-catenin degradation complex, and inhibited the proliferation, migration and invasion of NSCLC cells. In summary, miR-1 may be a potential candidate miRNA for the treatment of NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , MicroRNAs , Proteínas de Neoplasias , Via de Sinalização Wnt , beta Catenina , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Via de Sinalização Wnt/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , beta Catenina/metabolismo , beta Catenina/genética , Linhagem Celular Tumoral , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proliferação de Células/genética , Movimento Celular/genética , Células A549RESUMO
Xenopus embryos provide a favorable material to dissect the sequential steps that lead to dorsal-ventral (D-V) and anterior-posterior (A-P) cell differentiation. Here, we analyze the signaling pathways involved in this process using loss-of-function and gain-of-function approaches. The initial step was provided by Hwa, a transmembrane protein that robustly activates early ß-catenin signaling when microinjected into the ventral side of the embryo leading to complete twinned axes. The following step was the activation of Xenopus Nodal-related growth factors, which could rescue the depletion of ß-catenin and were themselves blocked by the extracellular Nodal antagonists Cerberus-Short and Lefty. During gastrulation, the Spemann-Mangold organizer secretes a cocktail of growth factor antagonists, of which the BMP antagonists Chordin and Noggin could rescue simultaneously D-V and A-P tissues in ß-catenin-depleted embryos. Surprisingly, this rescue occurred in the absence of any ß-catenin transcriptional activity as measured by ß-catenin activated Luciferase reporters. The Wnt antagonist Dickkopf (Dkk1) strongly synergized with the early Hwa signal by inhibiting late Wnt signals. Depletion of Sizzled (Szl), an antagonist of the Tolloid chordinase, was epistatic over the Hwa and Dkk1 synergy. BMP4 mRNA injection blocked Hwa-induced ectopic axes, and Dkk1 inhibited BMP signaling late, but not early, during gastrulation. Several unexpected findings were made, e.g., well-patterned complete embryonic axes are induced by Chordin or Nodal in ß-catenin knockdown embryos, dorsalization by Lithium chloride (LiCl) is mediated by Nodals, Dkk1 exerts its anteriorizing and dorsalizing effects by regulating late BMP signaling, and the Dkk1 phenotype requires Szl.
Assuntos
Padronização Corporal , Peptídeos e Proteínas de Sinalização Intercelular , Transdução de Sinais , Proteínas de Xenopus , beta Catenina , Animais , Padronização Corporal/genética , Proteínas de Xenopus/metabolismo , Proteínas de Xenopus/genética , beta Catenina/metabolismo , beta Catenina/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Xenopus laevis/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Gastrulação , Proteína Nodal/metabolismo , Proteína Nodal/genética , Embrião não Mamífero/metabolismo , Embrião não Mamífero/embriologia , Organizadores Embrionários/metabolismo , GlicoproteínasRESUMO
CTNNB1 encodes beta-catenin, which plays a crucial role in Wnt signaling pathway. Mutations in CTNNB1 involve in tumor developing, Primary Aldosteronism, Neurodevelopmental disorders (NDDs), etc. NDDs is a class of disorders that impact brain development and function, manifesting symptom including autism spectrum disorder (ASD), intellectual disability (ID), schizophrenia (SCZ), and epilepsy. Here, we generated an iPSC line (CTUi005-A) from a patient diagnosed with NDDs, carrying a heterozygous mutation of the CTNNB1 gene. CTUi005-A exhibits typical iPSC characteristics, and holds potential as a cellular tool for investigating the pathogenic mechanisms underlying NDDs.
Assuntos
Heterozigoto , Células-Tronco Pluripotentes Induzidas , Mutação , beta Catenina , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Linhagem Celular , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , MasculinoRESUMO
Cribriform morular thyroid carcinoma (CMTC) has been included within the group of thyroid tumors of uncertain histogenesis in the recent World Health Organization classification of endocrine tumors. Most CMTCs occur in young euthyroid women with multiple (and bilateral) thyroid nodules in cases associated with familial adenomatous polyposis (FAP) or as single nodules in sporadic cases. CMTC generally behaves indolently, while aggressiveness and mortality are associated with highgrade CMTC. This tumor histologically displays a distinctive combination of growth patterns with morular structures. Strong diffuse nuclear and cytoplasmic immunostaining for ßcatenin is the hallmark of CMTC. Tumor cells are also positive for thyroid transcription factor1 and for estrogen and progesterone receptors, but negative for thyroglobulin and calcitonin. It is possible that the CMTC phenotype could result from blockage in the terminal/follicular differentiation of follicular cells (or their precursor cells) secondary to the permanent activation of the Wnt/ßcatenin pathway. In CMTC, the activation of the Wnt/ßcatenin pathway is the central pathogenetic event, which in FAPassociated cases results from germline mutations of the APC regulator of WNT signaling pathway (APC) gene, and in sporadic cases from somatic inactivating mutations in the APC, AXIN1 and CTNNB1 genes. Estrogens appear to play a tumorpromoting role by stimulating both the PI3K/AKT/mTOR and the RAS/RAF/MAPK signaling pathways. Additional somatic mutations (i.e. RET rearrangements, or KRAS, phosphatidylinositol4,5bisphosphate 3kinase catalytic subunit α, telomerase reverse transcriptase or tumor protein 53 mutations) may further potentiate the development and progression of CMTC. While hemithyroidectomy would be the treatment of choice for sporadic cases without highrisk data, total thyroidectomy would be indicated in FAPassociated cases. There is insufficient clinical data to propose therapies targeting the Wnt/ßcatenin pathway, but multikinase or selective inhibitors could be used in a manner analogous to that of conventional thyroid tumors. It is also unknown whether adjuvant antiestrogenic therapy could be useful in the subgroup of women undergoing surgery with highrisk CMTC, as well as when there is tumor recurrence and/or metastasis.
Assuntos
Neoplasias da Glândula Tireoide , Humanos , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Feminino , Via de Sinalização Wnt , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , beta Catenina/genética , beta Catenina/metabolismoRESUMO
RATIONALE: Desmoid tumor (DT) is a rare soft tissue tumor that can occur anywhere in the body. Abdominal wall DT presents unique clinical challenges due to its distinctive manifestations, treatment modalities, and the lack of biomarkers for diagnosis and recurrence prediction, making clinical decisions exceedingly complex. PATIENT CONCERNS: A 32-year-old female who underwent radical resection combined with patch reinforcement for rectus abdominis DT, successfully alleviating abdominal discomfort, with no recurrence during the 6-month follow-up after surgery. DIAGNOSES: Based on the imaging studies and medical history, the patient underwent radical surgical resection. Histopathology reveals that the tumor cells predominantly composed of proliferative fibroblasts with local collagen deposition. The lesional cells show positive staining for ß-catenin, indicating a diagnosis of DT. INTERVENTIONS: The patient underwent radical surgical resection with patch reinforcement to repair the abdominal wall defect. Pathology confirmed negative margins, achieving an R0 resection, and genetic testing identified a T41A mutation in CTNNB1. Consequently, no additional adjuvant therapy was administered postoperatively. OUTCOMES: The patient was discharged with the incision healing well after 3 days postoperation. Upon reexamination 6 months later, no recurrence or adverse complications were observed. LESSONS: Abdominal wall DT treatment requires personalized plans from multidisciplinary team discussions. Genetic testing plays a crucial role in identifying novel biomarkers for abdominal wall DT. We have once again demonstrated the significant clinical significance of CTNNB1 mutations in the diagnosis and progression of abdominal wall DT. Additionally, genes such as CCND1, CYP3A4, SLIT1, RRM1, STIM1, ESR2, UGT1A1, among others, may also be closely associated with the progression of abdominal wall DT. Future research should delve deeper into and systematically evaluate the precise impact of these genetic mutations on treatment selection and prognosis for abdominal wall DT, in order to better guide patient management and treatment decisions.
Assuntos
Fibromatose Agressiva , Reto do Abdome , Humanos , Feminino , Adulto , Fibromatose Agressiva/cirurgia , Fibromatose Agressiva/diagnóstico , Fibromatose Agressiva/genética , Fibromatose Agressiva/patologia , Reto do Abdome/cirurgia , beta Catenina/genética , Neoplasias Abdominais/cirurgia , Neoplasias Abdominais/genética , Neoplasias Abdominais/diagnóstico , Neoplasias Abdominais/patologiaRESUMO
The term type 3 diabetes mellitus (T3DM) has been considered for Alzheimer's disease (AD) due to the common molecular and cellular characteristics found between type 2 diabetes mellitus (T2DM) and cognitive deficits. However, the specific mechanism of T3DM remains elusive, especially the neuroprotective effects of dietary components in hyperglycemic individuals. In this study, a peptide, Leu-Val-Arg-Leu (LVRL), found in walnuts significantly improved memory decline in streptozotocin (STZ)- and high-fat-diet (HFD)-stimulated T2DM mouse models (p < 0.05). The LVRL peptide also mitigated hyperglycemia, enhanced synaptic plasticity, and ameliorated mitochondrial dysfunction, as demonstrated by Morris water maze tests, immunoblotting, immunofluorescence, immunohistochemistry, transmission electron microscopy, and cellular staining. A Wnt3a inhibitor, DKK1, was subsequently used to verify the possible role of the Wnt3a/ß-Catenin/GSK-3ß pathway in glucose-induced insulin resistance in PC12 cells. In vitro LVRL treatment dramatically modulated the protein expression of p-Tau (Ser404), Synapsin-1, and PSD95, elevated the insulin level, increased glucose consumption, and relieved the mitochondrial membrane potential, and MitoSOX (p < 0.05). These data suggested that peptides like LVRL could modulate the relationship between brain insulin and altered cognition status via the Wnt3a/ß-Catenin/GSK-3ß pathway.
Assuntos
Diabetes Mellitus Tipo 2 , Glicogênio Sintase Quinase 3 beta , Juglans , Fármacos Neuroprotetores , Proteína Wnt3A , beta Catenina , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Masculino , Glicogênio Sintase Quinase 3 beta/metabolismo , Glicogênio Sintase Quinase 3 beta/genética , Camundongos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/química , beta Catenina/metabolismo , beta Catenina/genética , Humanos , Ratos , Juglans/química , Proteína Wnt3A/metabolismo , Proteína Wnt3A/genética , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Camundongos Endogâmicos C57BL , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/administração & dosagem , Células PC12 , Transdução de Sinais/efeitos dos fármacosRESUMO
PURPOSE: To investigate the therapeutic effect of atorvastatin on alveolar bone defect model in rats, and to observe the effect of atorvastatin on Wnt/ß-catenin. METHODS: Thirty rats were randomly divided into normal group (group N), model group (group M) and atorvastatin administration group (group ATV). Except group N, bone defects were made in other rats' alveolar bone to construct alveolar bone defect model. After successful modeling, 20 mg/kg atorvastatin suspension was administered by gavage in group ATV, and the same amount of sodium carboxymethyl cellulose solution was administered by gavage in group N and group M for twenty-one days. After the last administration, tail vein blood was collected to detect the concentrations of serum osteoprotegerin (OPG), alkaline phosphatase (ALP) and osteocalcin (BPG). H-E staining was used to observe the pathological changes of maxillary defect area, and lane Sandhu score was performed. Tartrate resistant acid phosphatase(TRAP) staining was used to detect the number of osteoclasts in the defect area. Real time fluorescence quantitative PCR(RT-qPCR) and Western blot(WB) were used to detect Wnt, ß-catenin and Runx2 mRNA protein expression. Statistical analysis was performed with SPSS 23.0 software package. RESULTS: Compared with group N, the concentrations of OPG, ALP, BGP and Lane Sandhu score in group M decreased, and the number of osteoclasts increased. Compared with group M, the concentrations of OPG, ALP and BGP and lane Sandhu score in group ATV increased, and the number of osteoclasts decreased. After H-E staining, the amount of bone formation in maxillary defect area in group N was more,there was fewer bone tissues in the defect area in group M, the amount of bone tissues in the defect area increased in group ATV. Compared with group N, Wnt, ß-catenin and Runx2 mRNA protein decreased. Compared with group M, Wnt, ß-catenin and Runx2 mRNA protein expression increased. CONCLUSIONS: Atorvastatin can promote the healing of alveolar bone defect and accelerate bone reconstruction in rat models. This effect may be related to the activation of Wnt/ß-catenin signaling pathway.