UCHL3 inhibits ferroptosis by stabilizing ß-catenin and maintains stem-like properties of hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is the most common type of primary hepatic liver cancer. Dysregulated Wnt/ß-catenin activation is closely related to the progression of cancer. Nevertheless, the mechanism that sustains the abnormal expression of ß-catenin in HCC has yet to be identified. In this study, we find that UCHL3 is overexpressed in HCC tissues and correlated with ß-catenin protein level. High expression of UCHL3 is associated with poor prognosis. UCHL3 knockdown markedly reduces the protein level of ß-catenin in HCC cells. TOP-luciferase activity and ß-catenin target genes expression are also decreased upon UCHL3 depletion. We find that the ARM domain of ß-catenin is required for the interaction with UCHL3. UCHL3 increases ß-catenin protein stability via removing K48-specific poly-ubiquitin chains from ß-catenin protein. Furthermore, the depletion of UCHL3 induces ferroptosis and hinders the growth, invasion, and stem cell properties of HCC cells. These impacts could be restored by the overexpression of ß-catenin. In addition, the UCHL3 inhibitor TCID inhibits the aggressive phenotype of HCC through the degradation of ß-catenin. In general, our results indicates that UCHL3 increases the stability of ß-catenin, which in turn facilitates tumorigenesis of HCC, suggesting that targeting UCHL3 may be a promising approach for the treatment of HCC.

A robust panel based on genomic methylation sites for recurrence-free survival in early hepatocellular carcinoma.

Purpose: Altered gene methylation precedes altered gene expression and the onset of disease. This study aimed to develop a potential model for predicting recurrence of early to mid-stage hepatocellular carcinoma (HCC) using methylation loci. Methods: We used data from early to mid-stage HCC patients (TNM I-II) in the TCGA-LIHC dataset and lasso-cox regression model to identify an 18-DNA methylation site panel from which to calculate the riskScore of patients. The correlation of high/low riskScore with recurrence-free survival (RFS) and immune microenvironment in HCC patients was analyzed by bioinformatics. It was also validated in the GSE56588 dataset and the final dynamic nomogram was constructed. Results: The results showed that riskScore was significantly correlated with RFS in HCC patients. The differential mutated genes between the two groups of HCC patients with high/low riskScore were mainly enriched in the TP53 signaling pathway. The immune microenvironment was better in HCC patients in the low-riskScore group compared to the high-riskScore group. This was validated in the GSE56588 dataset. Based on the subgroup stratification analysis of the relationship between high/low riskScore and RFS, as well as univariate and multivariate cox analyses, the riskScore was found to be independent of clinical indicators. We found that riskScore, vascular invasion and cirrhosis status could effectively differentiate RFS in HCC patients, and we also constructed prediction model based on these three factors. The model we constructed were validated in the TCGA-LIHC database and a web calculator was built for clinical use. Conclusion: The methylation riskScore is a predictor of RFS independent of clinical factors and can be used as a marker to predict recurrence in HCC patients.

Splenic Volume, an Easy-To-Use Predictor of HCC Late Recurrence for HCC Patients After Hepatectomy.

Purpose: The high recurrence rate of hepatocellular carcinoma (HCC) has a poor impact on the quality of life and survival time of patients. Especially for late recurrence, poor data are available in analysis. We aim to evaluate whether the splenic volume (SV) measured from preoperative CT images could predict late recurrence in HCC patients after hepatectomy. Patients and Methods: A cohort of 300 HCC patients hospitalized at Xiangya Hospital of Central South University between January 2015 and June 2018 was retrospectively analyzed. The SV was calculated by using automated volumetry software from preoperative CT images. A total of 300 HCC patients were separated into the early recurrence cohort (n=167), the late recurrence cohort (n=39), and the no recurrence cohort (n=94) according to whether there is a recurrence and the recurrence time. Univariate and multivariate Cox analyses were performed to identify the independent risk factors of both early and late recurrence. Results: AFP, Microvascular invasion (MVI), satellitosis, and BCLC staging were independent risk factors of HCC early recurrence. Splenic volume (HR=1.003, 95%CI:1.001-1.005, P<0.001) was the only predictor of HCC late recurrence. Based on X-tile software, 133 non-early recurrence patients were divided into two groups according to SV: low SV (<165ml, n=45) and high SV (≥165ml, n= 88). The low SV group had a significantly better RFS compared with the high SV group (P=0.015). Nomogram was built on the base of SV to get the probability of 3-year RFS, 4-year RFS, and 5-year RFS. Conclusion: In our study, we drew a conclusion that splenic volume was the only predictor of HCC late recurrence because of its association with portal hypertension and liver cirrhosis. High splenic volume often indicated a worse recurrence.

A Nomogram Based on Preoperative Inflammatory Indices and ICG-R15 for Prediction of Liver Failure After Hepatectomy in HCC Patients.

OBJECTIVE: To establish a nomogram based on inflammatory indices and ICG-R15 for predicting post-hepatectomy liver failure (PHLF) among patients with resectable hepatocellular carcinoma (HCC). METHODS: A retrospective cohort of 407 patients with HCC hospitalized at Xiangya Hospital of Central South University between January 2015 and December 2020, and 81 patients with HCC hospitalized at the Second Xiangya Hospital of Central South University between January 2019 and January 2020 were included in the study. Totally 488 HCC patients were divided into the training cohort (n=378) and the validation cohort (n=110) by random sampling. Univariate and multivariate analysis was performed to identify the independent risk factors. Through combining these independent risk factors, a nomogram was established for the prediction of PHLF. The accuracy of the nomogram was evaluated and compared with traditional models, like CP score (Child-Pugh), MELD score (Model of End-Stage Liver Disease), and ALBI score (albumin-bilirubin) by using receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA). RESULTS: Cirrhosis (OR=2.203, 95%CI:1.070-3.824, P=0.030), prothrombin time (PT) (OR=1.886, 95%CI: 1.107-3.211, P=0.020), tumor size (OR=1.107, 95%CI: 1.022-1.200, P=0.013), ICG-R15% (OR=1.141, 95%CI: 1.070-1.216, P<0.001), blood loss (OR=2.415, 95%CI: 1.306-4.468, P=0.005) and AST-to-platelet ratio index (APRI) (OR=4.652, 95%CI: 1.432-15.112, P=0.011) were independent risk factors of PHLF. Nomogram was built with well-fitted calibration curves on the of these 6 factors. Comparing with CP score (C-index=0.582, 95%CI, 0.523-0.640), ALBI score (C-index=0.670, 95%CI, 0.615-0.725) and MELD score (C-ibasedndex=0.661, 95%CI, 0.606-0.716), the nomogram showed a better predictive value, with a C-index of 0.845 (95%CI, 0.806-0.884). The results were consistent in the validation cohort. DCA confirmed the conclusion as well. CONCLUSION: A novel nomogram was established to predict PHLF in HCC patients. The nomogram showed a strong predictive efficiency and would be a convenient tool for us to facilitate clinical decisions.

The prognostic value of postoperative circulating cell-free DNA in operable hepatocellular carcinoma.

BACKGROUND: Tumor biomarkers are eagerly needed in monitoring the recurrence of operable hepatocellular carcinoma (HCC). Circulating cell-free DNA (cfDNA) is a promising noninvasive molecular biomarker for HCC. The current study aimed to evaluate the clinical significance of the postoperative cfDNA in operable HCC. METHODS: This study enrolled 82 HCC patients from January 2018 to June 2019. All patients underwent liver surgery and were pathologically diagnosed with HCC. Postoperative blood samples were collected from each patient. A fluorometric dsDNA assay was used to measure the concentration of cfDNA. We explore the correlation between cfDNA and recurrence. Kaplan-Meier's curves were used to evaluate the recurrence-free survival (RFS). Univariate and multivariate Cox regression analyses were used for assessing the relative clinical variables in predicting recurrence. RESULTS: Of the 82 HCC patients, 72 (87%) patients are male and the average age was 52.7 ± 12.8 years. The cfDNA-low and cfDNA-high groups had median recurrence times of 19.5 months and 14.0 months, respectively (p = .023). Multivariate analysis showed that postoperative cfDNA, tumour number and microvascular invasion (p < .050) were independent risk factors for recurrence in operable HCC. CONCLUSIONS: Postoperative cfDNA is still a promising marker to predict prognosis in postoperative HCC patients although prospective and large multicenter clinical study is needed to further validate the relationship between cfDNA and HCC recurrence.