RESUMEN
Senile skin hyperpigmentation displays remarkable histopathological features of dermal aging. The crosstalk between melanocytes and dermal fibroblasts plays crucial roles in aging-related pigmentation. While senescent fibroblasts can upregulate pro-melanogenic factors, the role of anti-melanogenic factors, such as dickkopf1 (DKK1), and the upstream regulatory mechanism during aging remain obscure. This study investigated the roles of yes-associated protein (YAP) and DKK1 in the regulation of dermal fibroblast senescence and melanogenesis. Our findings demonstrated decreased YAP activity and DKK1 levels in intrinsic and extrinsic senescent fibroblasts. YAP depletion induced fibroblast senescence and downregulated the expression and secretion of DKK1, whereas YAP overexpression partially reversed the effect. The transcriptional regulation of DKK1 by YAP was supported by dual-luciferase reporter and chromatin immunoprecipitation assays. Moreover, YAP depletion in fibroblasts upregulated Wnt/ß-catenin in melanocytes and stimulated melanogenesis, which was partially rescued by the re-supplementation of DKK1. Conversely, overexpression of YAP in senescent fibroblasts decreased Wnt/ß-catenin levels in melanocytes and inhibited melanogenesis. Additionally, reduced levels of YAP and DKK1 were verified in the dermis of solar lentigines. These findings suggest that, during skin aging, epidermal pigmentation may be influenced by YAP in the dermal microenvironment via the paracrine effect of DKK1.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Senescencia Celular , Fibroblastos , Péptidos y Proteínas de Señalización Intercelular , Melaninas , Melanocitos , Comunicación Paracrina , Envejecimiento de la Piel , Factores de Transcripción , Proteínas Señalizadoras YAP , Fibroblastos/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Humanos , Melanocitos/metabolismo , Proteínas Señalizadoras YAP/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Melaninas/metabolismo , Melaninas/biosíntesis , Vía de Señalización Wnt , Dermis/citología , Células Cultivadas , MelanogénesisRESUMEN
The Brother of the Regulator of Imprinted Sites (BORIS), as a specific indicator of hepatocellular carcinoma, exhibits a significant increase in expression. However, its upstream regulatory network remains enigmatic. Previous research has indicated a strong correlation between the Hippo pathway and the progression of hepatocellular carcinoma. It is well established that the Activator Protein-1 (AP-1) frequently engages in interactions with the Hippo pathway. Thus, we attempt to prove whether Jun and Fos, a major member of the AP-1 family, are involved in the regulation of BORIS expression. Bioinformatics analysis revealed the existence of binding sites for Jun and Fos within the BORIS promoter. Through a series of overexpression and knockdown experiments, we corroborated that Jun and Fos have the capacity to augment BORIS expression, thereby fostering the migration and invasion of hepatocellular carcinoma cells. Moreover, Methylation-Specific PCR and Bisulfite Sequencing PCR assays revealed that Jun and Fos do not have a significant impact on the demethylation of the BORIS promoter. However, luciferase reporter and chromatin immunoprecipitation experiments substantiated that Jun and Fos could directly bind to the BORIS promoter, thereby enhancing its transcription. In conclusion, these results suggest that Jun and Fos can promote the development of hepatocellular carcinoma by directly regulating the expression of BORIS. These findings may provide experimental evidence positioning BORIS as a novel target for the clinical intervention of hepatocellular carcinoma.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Factor de Transcripción AP-1/genética , Factor de Transcripción AP-1/metabolismo , Neoplasias Hepáticas/patología , Línea Celular , Regiones Promotoras Genéticas/genéticaRESUMEN
The underlying mechanisms of metastasis and recurrence of liver cancer remain largely unknown. Here, we found that Brother of the Regulator of Imprinted Sites (BORIS) variant SF2(C2/A4) was highly expressed in high metastatic potential hepatocellular carcinoma (HCC) cells and clinical tumor samples, related to the formation of satellite nodules. Its over expression promoted self-renewal, the expression of tumor stem cell markers, chemoresistance, wound healing rate, invasion and metastasis of HepG2 and Hep3B cells; reinforced epithelial-mesenchymal transition (EMT), decreased the expression of E-cadherin and increased N-cadherin and Vimentin. Subcellular localization experiment showed that BORIS SF2(C2/A4) was localized in nucleus and cytoplasm. Further double luciferase reporter gene experiment confirmed that it bound to TWIST1 gene promoter and significantly increased latter expression. BORIS SF2(C2/A4) knock down induced apoptosis of HCCLM3 and PLC/PRF/5 cells, and increased the protein content of cleaved caspase 3. Additionally, BORIS SF2(C2/A4) over expression increased the expression of fibroblast growth factor 2 (FGF2) in HepG2 and Hep3B cells. FGF2 expressed higher in HCC tumor tissues than in paired peri-tumor tissues, and its expression was positively correlated with BORIS SF2(C2/A4). Interestingly, high expression of FGF2 is also associated with the formation of satellite nodules. Moreover, using the medium from BORIS SF2(C2/A4) overexpressed cell lines to coculture hepatic stellate cell (HSCs) line LX-2, the latter could be activated and increased the expression of CD90 and PIGF, which is consistent with the effect of adding bFGF alone. These results indicate that BORIS SF2(C2/A4) plays a role in deterioration of liver cancer by regulating TWIST1 to induce EMT, and by FGF2 to activate HSCs.
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Carcinoma Hepatocelular , Proteínas de Unión al ADN , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/genética , Factor 2 de Crecimiento de Fibroblastos/genética , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Neoplasias Hepáticas/patología , Factor de Crecimiento Placentario/metabolismo , Proteínas de Unión al ADN/genéticaRESUMEN
Introduction: Hepatocellular carcinoma (HCC) has a high mortality rate, with curative resection being the primary treatment. However, HCC patients have a large possibility of recurrence within 5 years after curative resection. Methods: Thus, identifying biomarkers to predict recurrence is crucial. In our study, we analyzed data from CCLE, GEO, and TCGA, identifying eight oncogenes associated with HCC. Subsequently, the expression of 8 genes was tested in 5 cases of tumor tissues and the adjacent non-tumor tissues. Then ATP6AP1, PSMD14 and HSP90AB1 were selected to verify the expression in 63 cases of tumor tissues and the adjacent non-tumor tissues. The results showed that ATP6AP1, PSMD14, HSP90AB1 were generally highly expressed in tumor tissues. A five-year follow-up of the 63 clinical cases, combined with Kaplan-Meier Plotter's relapse-free survival (RFS) analysis, found a significant correlation between PSMD14 expression and recurrence in HCC patients. Subsequently, we analyzed the PSMD14 mutations and found that the PSMD14 gene mutations can lead to a shorter disease-free survival time for HCC patients. Results: The results of enrichment analysis indicated that the differentially expressed genes related to PSMD14 are mainly enriched in the signal release pathway. Conclusion: In conclusion, our research showed that PSMD14 might be related to recurrence in HCC patients, and the expression of PSMD14 in tumor tissue might be a potential prognostic biomarker after tumor resection in HCC patients.
RESUMEN
Increasing evidence has revealed that the invasion and metastasis of HCC are intimately related to the low-glucose microenvironment, but the intrinsic regulatory mechanism remains unclear. It has been well documented that AMPK regulates the transcriptional expression of GLUT4 and its catalytic subunit AMPKα2 can negatively regulate the downstream target molecule HNF4A. Meanwhile, BORIS (Brother of the Regulator of Imprinted Sites) is able to modulate the Warburg effect by regulating the splicing of pyruvate kinase M2 (PKM2), a critical enzyme in glycolysis. Through bioinformatic analysis and a series of overexpression, knockdown, and complementation experiments, we demonstrated that HNF4A can directly act on BORIS and negatively regulate its expression, thereby inhibiting hepatoma cell motility and tumor metastasis, whereas BORIS can directly act on GLUT4 and positively regulate its expression to enhance hepatoma cell motility and tumor metastasis. We also found that HNF4A agonist (Benfluorex) and GLUT4 inhibitor (antiviral drug Ritonavir) can suppress HCC cell proliferation and glucose uptake. Taken together, these results all suggest that activation of the AMPKα2/HNF4A/BORIS/GLUT4 signaling pathway in a low-glucose microenvironment can significantly promote the invasion and metastasis of HCC cells, while HNF4A and GLUT4 may have important potential applications as prognostic or drug target molecules.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Proteínas Quinasas Activadas por AMP/metabolismo , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Proliferación Celular , Proteínas de Unión al ADN/metabolismo , Regulación Neoplásica de la Expresión Génica , Glucosa/metabolismo , Transportador de Glucosa de Tipo 4 , Factor Nuclear 4 del Hepatocito/genética , Factor Nuclear 4 del Hepatocito/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Pronóstico , Microambiente TumoralRESUMEN
Continuous urban development leads to urban heat island effects. Research suggests that urban green spaces can help effectively reduce urban heat island effects in the summer. Previous studies have mainly focused on the influence of different underlying surfaces on air cooling and humidification. There is a lack of in-depth research on the relationship between park structure and microclimatic effects. Here, we examined the main landscape parameters of green spaces in 15 parks located in Suzhou Industrial Park (SIP) with a subtropical maritime monsoon climate zone during the summer to analyze their influence on the microclimate. We adopted a multiple regression method to perform a quantitative analysis of the correlation between the factors and the cooling and humidifying effects. We used one-way ANOVA (analysis of variance) and multiple linear regression statistical analysis methods to study the influence of woodland density and water bodies on the microclimatic effect of the green areas. The result shows that the average cooling and humidifying effect of medium-size green spaces was most significant during high-temperature hours in the daytime. Also, the result shows that the shape and size of water areas within a green space have a significant influence on local cooling and humidification.