HNRNPL facilitates ferroptosis in hepatocellular carcinoma cells by promoting S100A9 expression.

OBJECTIVE: This study probed into the effect of HNRNPL on ferroptosis in hepatocellular carcinoma (HCC) cells and related molecular mechanisms. METHODS: Expression patterns of HNRNPL, Recombinant S100 Calcium Binding Protein A9 (S100A9) were analyzed in HCC tissues or cells. Following transfection, HCC cell activity was analyzed, followed by detection of levels of ROS, iron content, LPO, MDA, and GSH as well as the expression of ferroptosis-related proteins. For molecular mechanism, RIP, RNA pull-down assay and actinomycin D assay were implemented to verify the binding relationship between HNRNPL and S100A9. Finally, in vivo nude mouse xenograft tumor experiments were performed for further validate the crucial role of HNENPL expression in HCC. RESULTS: HNRNPL and S100A9 were significantly overexpressed in HCC. sh-HNRNPL treatment led to a significant decrease in cellular activity, GSH content, and expression of GPX4 and SLC7A11, and a significant increase in iron content, LPO level, MDA, ROS content, and expression of ACSL4 and TFR1. In addition, after sh-HNRNPL was combined with oe-S100A9 or Fer-1, a ferroptosis inhibitor, both oe-S100A9 and Fer-1 reversed the promotional effect of sh-HNRNPL on ferroptosis of HCC cells when sh-HNRNPL acted alone. Mechanically, HNRNPL promoted S100A9 mRNA stability and expression through RBP. Furthermore, low expression of HNRNPL in vivo delayed the growth of xenograft tumors and the expression of ferroptosis-related proteins. CONCLUSION: HNRNPL promotes S100A9 mRNA stability and expression through RBP action, thereby promoting ferroptosis in HCC cells.

Transcatheter arterial chemoembolisation combined with lenvatinib plus camrelizumab as conversion therapy for unresectable hepatocellular carcinoma: a single-arm, multicentre, prospective study.

Background: The synergistic effect of locoregional therapy in combination with systemic therapy as a conversion therapy for unresectable hepatocellular carcinoma (uHCC) is unclear. The purpose of this study was to evaluate the efficacy and safety of transcatheter arterial chemoembolisation (TACE) combined with lenvatinib and camrelizumab (TACE + LEN + CAM) as conversion therapy for uHCC. Methods: This single-arm, multicentre, prospective study was conducted at nine hospitals in China. Patients (aged 18-75 years) diagnosed with uHCC, an Eastern Cooperative Oncology Group performance score (ECOG-PS) of 0-1 and Child-Pugh class A received camrelizumab (200 mg, every 3 weeks) and lenvatinib (bodyweight ≥60 kg: 12 mg/day; <60 kg: 8 mg/day) after TACE treatment. Surgery was performed after tumour was assessed as meeting the criteria for resection. Patients who did not meet the criteria for surgery continued to receive triple therapy until disease progression or intolerable toxicity. Primary endpoints were objective response rate (ORR) according to the modified Response Evaluation Criteria in Solid Tumours (mRECIST) and safety. Secondary endpoints included the surgical conversion rate, radical (R0) resection rate, and disease control rate (DCR). This study was registered with Chinese Clinical Trial Registry (ChiCTR2100050410). Findings: Between Oct 25, 2021, and July 20, 2022, 55 patients were enrolled. As of the data cutoff on June 1, 2023, the median follow-up was 13.3 months (IQR 10.6-15.9 months). The best tumour response to triple therapy was complete response (CR) in 9 (16.4%) patients, partial response (PR) in 33 (60.0%) patients, stable disease (SD) in 5 (9.1%) patients, or progressive disease (PD) in 7 (12.7%) patients. The ORR was 76.4% (42/55, 95% CI, 65.2-87.6%), and the DCR was 85.5% (47/55, 95% CI, 76.2-94.8%) per mRECIST. Twenty-four (43.6%) of the 55 patients suffered from grade 3-4 treatment-related adverse events (TRAEs). No grade 5 TRAEs occurred. A total of 30 (30/55, 54.5%) patients were converted to resectable HCC and 29 (29/55, 52.7%) patients underwent resection. The R0 resection rate was 96.6% (28/29). The major pathologic response (MPR) and pathologic complete response (pCR) rates in the surgery population were 65.5% (19/29) and 20.7% (6/29), respectively. Only one patient developed a Clavien-Dindo IIIa complication (abdominal infection). No Clavien-Dindo IIIb-V complications occurred. The median OS and median PFS were not reached. Interpretation: The triple therapy (TACE + LEN + CAM) is promising active for uHCC with a manageable safety. Moreover, triple therapy has good conversion efficiency and the surgery after conversion therapy is feasible and safe. To elucidate whether patients with uHCC accepting surgical treatment after the triple therapy can achieve better survival benefits than those who receive triple therapy only, well-designed randomised controlled trials are needed. Funding: This study was funded by the Natural Science Foundation of Fujian Province, China (2022J01691) and the Youth Foundation of Fujian Province Health Science and Technology Project, China (2022QNA035).

Six Metabolism Related mRNAs Predict the Prognosis of Patients With Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is one of the most common aggressive solid malignant tumors and current research regards HCC as a type of metabolic disease. This study aims to establish a metabolism-related mRNA signature model for risk assessment and prognosis prediction in HCC patients. Methods: HCC data were obtained from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and Gene Enrichment Analysis (GSEA) website. Least absolute shrinkage and selection operator (LASSO) was used to screen out the candidate mRNAs and calculate the risk coefficient to establish the prognosis model. A high-risk group and low-risk group were separated for further study depending on their median risk score. The reliability of the prediction was evaluated in the validation cohort and the whole cohort. Results: A total of 548 differential mRNAs were identified from HCC samples (n = 374) and normal controls (n = 50), 45 of which were correlated with prognosis. A total of 373 samples met the screening criteria and there were randomly divided into the training cohort (n = 186) and the validation cohort (n = 187). In the training cohort, six metabolism-related mRNAs were used to construct a prognostic model with a LASSO regression model. Based on the risk model, the overall survival rate of the high-risk cohort was significantly lower than that of the low-risk cohort. The results of a time-ROC curve proved that the risk score (AUC = 0.849) had a higher prognostic value than the pathological grade, clinical stage, age or gender. Conclusion: The model constructed by the six metabolism-related mRNAs has a significant value for survival prediction and can be applied to guide the evaluation of HCC and the designation of clinical therapy.

Development of a prognostic model for hepatocellular carcinoma using genes involved in aerobic respiration.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Currently, recent risk stratification has only focused on liver function and tumor characteristics. Thus, the purpose of this study was to develop a prognostic model based on genes involved in aerobic respiration. Matched tumor and normal tissues from TCGA and ICGC cohorts were analyzed to identify 15 overlapping differential expressed genes. Cox univariate analysis of the 15 genes in the TCGA cohort revealed they were all associated with disease-specific survival (DSS) in HCC patients. Using LASSO estimation and the optimal value for penalization coefficient lambda 12 genes were selected for the prognostic model, and then HCC patients in the TCGA cohort were dichotomized into low-risk and high-risk groups. Univariate and multivariate Cox analysis demonstrated patients in low-risk group had better survival. Validation of the risk score model with the ICGC cohort produces results consistent with those of the TCGA cohort. In conclusion, this study developed and validated a prognostic model of HCC through a comprehensive analysis of genes involved in aerobic respiration. This model may help develop personalized treatments for patients with HCC.

Comparison of 2-D Shear Wave Elastography and Point Shear Wave Elastography for Assessing Liver Fibrosis.

Progressive liver fibrosis may result in cirrhosis, portal hypertension and increased risk of hepatocellular carcinoma. We performed a meta-analysis to compare liver fibrosis staging in chronic liver disease patients using 2-D shear wave elastography (2-D SWE) and point shear wave elastography (pSWE). The PubMed, Web of Science and Cochrane Library databases were searched until May 31, 2020 for studies evaluating the diagnostic performance of 2-D SWE and pSWE in assessing liver fibrosis. Pooled sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratios and area under receiver operating characteristic curve were estimated using the bivariate random effects model. As a result, 71 studies with 11,345 patients were included in the analysis. The pooled sensitivities of 2-D SWE and pSWE significantly differed for the detection of significant fibrosis (F ≥ 2; 0.84 vs. 0.76, p < 0.001) and advanced fibrosis (F ≥ 3; 0.90 vs. 0.83, p = 0.003), but not for detection of cirrhosis (F = 4; 0.89 vs. 0.85, p = 0.090). The pooled specificities of 2-D SWE and pSWE did not significantly differ for detection of F ≥ 2 (0.81 vs. 0.79, p = 0.753), F ≥ 3 (0.87 vs. 0.83, p = 0.163) or F = 4 (0.87 vs. 0.84, p = 0.294). Both 2-D SWE and pSWE have high sensitivity and specificity for detecting each stage of liver fibrosis. Two-dimensional SWE has higher sensitivity than pSWE for detection of significant fibrosis and advanced fibrosis.

TMEM205 Is an Independent Prognostic Factor and Is Associated With Immune Cell Infiltrates in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide despite the availability of diverse treatment strategies. Much research progress has been made regarding immunotherapy but the effects remain unsatisfactory, highlighting the urgent need for novel immune-related therapy targets. In recent years, more and more studies have pointed out the associations between certain transmembrane (TMEM) family proteins and tumor progression, but the role of TMEM205 remains unclear. In this study, we analyzed the RNA-seq and clinical data of 371 patients from The Cancer Genome Atlas (TCGA) and found significant differential expression of TMEM205 between normal and tumor tissues (P < 0.001). Low TMEM205 expression was also found to be independently associated with poor overall survival (OS; p = 0.032) and poor disease-specific survival (DSS; p = 0.002) in multivariate Cox regression analyses. RNA-seq and clinical data from hepatocellular carcinoma patients in the International Cancer Genome Consortium (ICGC) also showed significant differential expression of TMEM205 (P < 0.001) and association between low TMEM205 expression and poor survival (P < 0.001). We also used the Estimate the Proportion of Immune and Cancer cells (EPIC) tool to estimate the proportions of various immune cells in the tumor tissues. A correlation analysis was conducted, and TMEM205 expression in tumor tissues was found to be significantly associated with the proportion of macrophages (Pearson r = 0.45, p < 0.0001). A negative correlation was found between TMEM205 expression and M2 macrophage markers (CD163, EGR2, and MS4A4A) and between TMEM205 expression and regulatory T cell (Treg) markers (CCR8, STAT5B, and IL2RA), while a positive correlation was found between TMEM205 expression and the proportion of CD8+ T cells (Pearson r = 0.26, p < 0.0001). In conclusion, TMEM205 might improve HCC patients' prognosis by reducing the levels of immunosuppressive cells (M2 macrophages and Tregs) and facilitating the infiltration of cytotoxic T cells into the tumor microenvironment. Therefore, TMEM205 has potential as a prognostic biomarker and immunotherapy agent in combination therapy regimens for HCC.

Partial ALPPS versus complete ALPPS for staged hepatectomy.

BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) can induce a stronger regenerative ability than traditional 2-stage hepatectomy (TSH). ALPPS has become popular for achieving fast hypertrophy in patients with an insufficient future liver remnant (FLR). However, ALPPS is associated with high morbidity and mortality. Partial ALPPS is a variation that may decrease the morbidity and mortality. The purpose of this study was to perform a meta-analysis comparing outcomes of ALLPS and partial ALLPS. METHODS: PubMed, Embase, and Cochrane Library databases were searched for studies comparing partial ALPPS and complete ALPPS up to April 2019. Included studies were assessed by the Newcastle-Ottawa Scale (NOS). Weighted mean difference (WMD)/standard mean difference (SMD) and odds ratios (OR) with 95% confidence intervals (CIs) were calculated to compare FLR, time interval between stages, postoperative complications, and mortality between partial and complete ALPPS. RESULTS: Four studies including 124 patients were included. FLR hypertrophy of partial ALPPS was comparable to complete ALPPS (p = 0.09). The time interval between stages was not different between the 2 procedures (p = 0.57). The postoperative complications rate of partial ALPPS was significantly lower than that of complete ALPPS (OR = 0.38; p = 0.03). The mortality rate of partial ALLPS (4.9%) was lower than that of complete ALLPS (18.9%), but the difference was not significant (OR = 0.37; p = 0.12). CONCLUSIONS: Partial ALLPS is associated with similar FLR hypertrophy and time interval between stages as complete ALLPS, and a lower complication rate. Further studies are needed to examine patient selection and outcomes of the 2 procedures.