RESUMEN
Hepatocellular carcinoma (HCC) poses a significant threat due to its highly aggressive and high recurrence characteristics, necessitating urgent advances in diagnostic and therapeutic approaches. Long non-coding RNAs exert vital roles in HCC tumorigenesis, however the mechanisms of their expression regulation and functions are not fully elucidated yet. Herein, we identify that a novel tumor suppressor 'lnc-PIK3R1' was significantly downregulated in HCC tissues, which was correlated with poor prognosis. Functionally, lnc-PIK3R1 played tumor suppressor roles to inhibit the proliferation and mobility of HCC cells, and to impede the distant implantation of xenograft in mice. Mechanistic studies revealed that lnc-PIK3R1 interacted with miR-1286 and alleviated the repression on GSK3B by miR-1286. Notably, pharmacological inhibition of GSK3ß compromised the tumor suppression effect by lnc-PIK3R1, confirming their functional relevance. Moreover, we identified that oncogenic YY1 acts as a specific transcriptional repressor to downregulate the expression of lnc-PIK3R1 in HCC. In summary, this study highlights the tumor-suppressive effect of lnc-PIK3R1, and provides new insights into the regulation of GSK3ß expression in HCC, which would benefit the development of innovative intervention strategies for HCC.
Asunto(s)
Carcinoma Hepatocelular , Fosfatidilinositol 3-Quinasa Clase Ia , Regulación Neoplásica de la Expresión Génica , Glucógeno Sintasa Quinasa 3 beta , Neoplasias Hepáticas , MicroARNs , ARN Largo no Codificante , Factor de Transcripción YY1 , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Glucógeno Sintasa Quinasa 3 beta/genética , MicroARNs/genética , MicroARNs/metabolismo , Animales , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Factor de Transcripción YY1/metabolismo , Factor de Transcripción YY1/genética , Ratones , Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Fosfatidilinositol 3-Quinasa Clase Ia/genética , Progresión de la Enfermedad , Proliferación Celular/genética , Línea Celular Tumoral , Masculino , Ratones Desnudos , FemeninoRESUMEN
Soft-tissue sarcomas (STS) emerges as formidable challenges in clinics due to the complex genetic heterogeneity, high rates of local recurrence and metastasis. Exploring specific targets and biomarkers would benefit the prognosis and treatment of STS. Here, we identified RCC1, a guanine-nucleotide exchange factor for Ran, as an oncogene and a potential intervention target in STS. Bioinformatics analysis indicated that RCC1 is highly expressed and correlated with poor prognosis in STS. Functional studies showed that RCC1 knockdown significantly inhibited the cell cycle transition, proliferation and migration of STS cells in vitro, and the growth of STS xenografts in mice. Mechanistically, we identified Skp2 as a downstream target of RCC1 in STS. Loss of RCC1 substantially diminished Skp2 abundance by compromising its protein stability, resulting in the upregulation of p27Kip1 and G1/S transition arrest. Specifically, RCC1 might facilitate the nucleo-cytoplasmic trafficking of Skp2 via direct interaction. As a result, the cytoplasmic retention of Skp2 would further protect it from ubiquitination and degradation. Notably, recovery of Skp2 expression largely reversed the phenotypes induced by RCC1 knockdown in STS cells. Collectively, this study unveils a novel RCC1-Skp2-p27Kip1 axis in STS oncogenesis, which holds promise for improving prognosis and treatment of this formidable malignancy.
Asunto(s)
Sarcoma , Animales , Humanos , Ratones , Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Quinasas Asociadas a Fase-S/genética , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Sarcoma/genética , Sarcoma/patología , Ubiquitinación , Regulación hacia ArribaRESUMEN
Aim: This research aimed to explore the causal impact of blood metabolites on oral cancer using a two-sample Mendelian randomization (MR) analysis. The study endeavored to identify potential biomarkers for oral cancer's clinical management. Materials and methods: Based on the large individual-level datasets from UK Biobank as well as GWAS summary datasets, we first constructed genetic risk scores (GRSs) of 486 human blood metabolites and evaluated the effect on oral cancer. Various statistical methods, including inverse variance weighted (IVW), MR-Egger, and weighted median, among others, were employed to analyze the potential causal relationship between blood metabolites and oral cancer. The sensitivity analyses were conducted using Cochran's Q tests, funnel plots, leave-one-out analyses, and MR-Egger intercept tests. Results: 29 metabolites met the stringent selection criteria. Out of these, 14 metabolites demonstrated a positive association with oral cancer risk, while 15 metabolites indicated a protective effect against oral cancer. The IVW-derived estimates were significant, and the results were consistent across different statistical methodologies. Both the Cochran Q test and the MR-Egger intercept test indicated no heterogeneity and pleiotropy. Conclusion: This MR study offers evidence of the role specific blood metabolites play in oral cancer, pinpointing several with potential risk or protective effects. These findings could be helpful for new diagnostic tools and treatments for oral cancer. While the results are promising, additional research is necessary to fully validate and refine these conclusions. This study serves as a foundational step towards more comprehensive understandings in the future.