Establishment of a circRNA-regulated E3 ubiquitin ligase signature and nomogram to predict immunotherapeutic efficacy and prognosis in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common type of malignant tumor where the prognosis is dismal. Circular RNA (CircRNA) is a novel RNA that regulates downstream gene transcription and translation to influence the progression of HCC. However, the regulatory relationship that exists between E3 ligases, which is a class of post-translational modifying proteins, and circRNA remains unclear. METHODS: Based on the E3 ubiquitin ligase in the competitive endogenous RNA (ceRNA) network, a circRNA-regulated E3 ubiquitin ligase signature (CRE3UL) was developed. A CRE3UL signature was created using the least absolute shrinkage and selection operator (Lasso) and Cox regression analysis and merged it with clinicopathologic characteristics to generate a nomogram for prognosis prediction. The pRRophetic algorithm was utilized and immunological checkpoints were analyzed to compare the responses of patients in the high-risk group (HRG) and low-risk group (LRG) to targeted therapy and immunotherapy. Finally, experimental research will further elucidate the relationship between E3 ubiquitin ligase signature and HCC. RESULTS: HRG patients were found to have a worse prognosis than LRG patients. Furthermore, significant variations in prognosis were observed among different subgroups based on various clinical characteristics. The CRE3UL signature was identified as being an independent prognostic indicator. The nomogram that combined clinical characteristics and the CRE3UL signature was found to accurately predict the prognosis of HCC patients and demonstrated greater clinical utility than the current TNM staging approach. According to anticancer medication sensitivity predictions, the tumors of HRG patients were more responsive to gefitinib and nilotinib. From immune-checkpoint markers analysis, immunotherapy was identified as being more probable to assist those in the HRG. CONCLUSIONS: We found a significant correlation between the CRE3UL signature and the tumor microenvironment, enabling precise prognosis prediction for HCC patients. Additionally, a nomogram was developed that performs well in predicting the overall survival (OS) of HCC patients. This provides valuable guidance for clinicians in devising specific personalized treatment strategies.

TRIM5 as a promising diagnostic biomarker of hepatocellular carcinoma: integrated analysis and experimental validation.

The TRIM family is associated with the membrane, and its involvement in the progression, growth, and development of various cancer types has been researched extensively. However, the role played by the TRIM5 gene within this family has yet to be explored to a great extent in terms of hepatocellular carcinoma (HCC). The data of patients relating to mRNA expression and the survival rate of individuals diagnosed with HCC were extracted from The Cancer Genome Atlas (TCGA) database. UALCAN was employed to examine the potential link between TRIM5 expression and clinicopathological characteristics. In addition, enrichment analysis of differentially expressed genes (DEGs) was conducted as a means of deciphering the function and mechanism of TRIM5 in HCC. The data in the TCGA and TIMER2.0 databases was utilized to explore the correlation between TRIM5 and immune infiltration in HCC. WGCNA was performed as a means of assessing TRIM5-related co-expressed genes. The "OncoPredict" R package was also used for investigating the association between TRIM5 and drug sensitivity. Finally, qRT-PCR, Western blotting (WB) and immunohistochemistry (IHC) were employed for exploring the differential expression of TRIM5 and its clinical relevance in HCC. According to the results that were obtained from the vitro experiments, mRNA and protein levels of TRIM5 demonstrated a significant upregulation in HCC tissues. It is notable that TRIM5 expression levels were found to have a strong association with the infiltration of diverse immune cells and displayed a positive correlation with several immune checkpoint inhibitors. The TRIM5 expression also displayed promising clinical prognostic value for HCC patients.

Causal associations between gut microbiota and primary biliary cholangitis: a bidirectional two-sample Mendelian randomization study.

Background: Previous studies have suggested an association between gut microbiota and primary biliary cholangitis (PBC). Nonetheless, the causal relationship between gut microbiota and PBC risk remains unclear. Methods: A bidirectional two-sample Mendelian Randomization (MR) study was employed using summary statistical data for gut microbiota and PBC from the MiBioGen consortium and Genome-Wide Association Studies (GWAS) database to investigate causal relationships between 211 gut microbiota and PBC risk. Inverse variance weighted (IVW) method was the primary analytical approach to assess causality, and the pleiotropy and heterogeneity tests were employed to verify the robustness of the findings. Additionally, we performed reverse MR analyses to investigate the possibility of the reverse causal association. Results: The IVW method identified five gut microbiota that demonstrated associations with the risk of PBC. Order Selenomonadales [odds ratio (OR) 2.13, 95% confidence interval (CI) 1.10-4.14, p = 0.03], Order Bifidobacteriales (OR 1.58, 95% CI 1.07-2.33, p = 0.02), and Genus Lachnospiraceae_UCG_004 (OR 1.64, 95%CI 1.06-2.55, p = 0.03) were correlated with a higher risk of PBC, while Family Peptostreptococcaceae (OR 0.65, 95%CI 0.43-0.98, p = 0.04) and Family Ruminococcaceae (OR 0.33, 95%CI 0.15-0.72, p = 0.01) had a protective effect on PBC. The reverse MR analysis demonstrated no statistically significant relationship between PBC and these five specific gut microbial taxa. Conclusion: This study revealed that there was a causal relationship between specific gut microbiota taxa and PBC, which may provide novel perspectives and a theoretical basis for the clinical prevention, diagnosis, and treatment of PBC.

A Novel Scoring Model of Deubiquitination Patterns Predicts Prognosis and Immunotherapeutic Response in Hepatocellular Carcinoma.

Aberrant expression of deubiquitinases (DUBs) is significantly associated with tumorigenesis. However, the precise impact of deubiquitination on the tumour microenvironment (TME) and immunotherapy in hepatocellular carcinoma (HCC) remains unclear. In this study, we comprehensively characterized the transcriptional and genetic alterations of 26 overall survival (OS)-related DUBs in HCC. The consensus clustering algorithm was used to identify patients with distinct deubiquitination patterns. We then established a DUBscore model using the principal component analysis (PCA) algorithm to quantify the deubiquitination patterns of individual HCC patients. Finally, we performed weighted gene coexpression network analysis (WGCNA) to identify the key DUBs. Consequently, three distinct deubiquitination patterns were identified, each showing significant differences in the characteristics of the TME, immune response, and clinical prognosis. Further analysis revealed that the DUBscore was an independent prognostic factor and could predict the response to immunotherapy for patients with HCC. Ultimately, BRCC3 was identified as a key DUB based on the DUBscore, which was significantly overexpressed in tumour tissues, as confirmed by qRT‒PCR and immunohistochemistry (IHC). We analysed the distribution and expression of BRCC3 in various types of immune cells using single-cell RNA sequencing (scRNA-seq). In conclusion, our study revealed the crucial role of deubiquitination patterns in shaping TME complexity and diversity. A more personalized and effective antitumour immunotherapy strategy can be developed by utilizing the DUBscore model to identify deubiquitination patterns in individual HCC patients. Our findings also highlight that BRCC3 may serve as a potential therapeutic target in HCC and a predictive marker for immunotherapeutic response.