Integrated analysis reveals an aspartate metabolism-related gene signature for predicting the overall survival in patients with hepatocellular carcinoma.

BACKGROUND: Deregulating cellular metabolism is one of the prominent hallmarks of malignancy, with a critical role in tumor survival and growth. However, the role of reprogramming aspartate metabolism in hepatocellular carcinoma (HCC) are largely unknown. METHODS: The multi-omics data of HCC patients were downloaded from public databases. Univariate and multivariate stepwise Cox regression were used to establish an aspartate metabolism-related gene signature (AMGS) in HCC. The Kaplan-Meier and receiver operating characteristic curve analyses were performed to evaluate the predictive ability for overall survival (OS) in HCC patients. Gene set enrichment analysis and immune infiltration analysis were operated to determine the potential mechanisms underlying the AMGS. Single-cell RNA sequencing (scRNA-seq) data of liver cancer stem cells were visualized by t-SNE algorithm. In vivo and in vitro experiments were implemented to investigate the biological function of CAD in HCC. In addition, a nomogram based on the AMGS and clinicopathologic characteristics was constructed by univariate and multivariate Cox regression analyses. RESULTS: Patients in the high-AMGS subgroup exerted advanced tumor status and poor prognosis. Mechanistically, the high-AMGS subgroup patients had significantly enhanced proliferation and stemness-related pathways, increased infiltration of regulatory T cells and upregulated expression levels of suppressive immune checkpoints in the tumor immune microenvironment. Notably, scRNA-seq data revealed CAD, one of the aspartate metabolism-related gene, is significantly upregulated in liver cancer stem cells. Silencing CAD inhibited proliferative capacity and stemness properties of HCC cells in vitro and in vivo. Finally, a novel nomogram based on the AMGS showed an accurate prediction in HCC patients. CONCLUSIONS: The AMGS represents a promising prognostic value for HCC patients, providing a perspective for finding novel biomarkers and therapeutic targets for HCC.

SMYD4 monomethylates PRMT5 and forms a positive feedback loop to promote hepatocellular carcinoma progression.

Both lysine and arginine methyltransferases are thought to be promising therapeutic targets for malignant tumors, yet how these methyltransferases function in malignant tumors, especially hepatocellular carcinoma (HCC), has not been fully elucidated. Here, we reported that SMYD4, a lysine methyltransferase, acts as an oncogene in HCC. SMYD4 was highly upregulated in HCC and promoted HCC cell proliferation and metastasis. Mechanistically, PRMT5, a well-known arginine methyltransferase, was identified as a SMYD4-binding protein. SMYD4 monomethylated PRMT5 and enhanced the interaction between PRMT5 and MEP50, thereby promoting the symmetrical dimethylation of H3R2 and H4R3 on the PRMT5 target gene promoter and subsequently activating DVL3 expression and inhibiting expression of E-cadherin, RBL2, and miR-29b-1-5p. Moreover, miR-29b-1-5p was found to inversely regulate SMYD4 expression in HCC cells, thus forming a positive feedback loop. Furthermore, we found that the oncogenic effect of SMYD4 could be effectively suppressed by PRMT5 inhibitor in vitro and in vivo. Clinically, high coexpression of SMYD4 and PRMT5 was associated with poor prognosis of HCC patients. In summary, our study provides a model of crosstalk between lysine and arginine methyltransferases in HCC and highlights the SMYD4-PRMT5 axis as a potential therapeutic target for the treatment of HCC.

Application and Resistance Mechanisms of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma.

Lenvatinib, a multitargeted tyrosine kinase inhibitor (TKI), is one of the preferred targeted drugs for the treatment of advanced hepatocellular carcinoma (aHCC). Since the REFLECT study showed that lenvatinib was noninferior to sorafenib in overall survival (OS), lenvatinib monotherapy has been widely used for aHCC. Moreover, lenvatinib combination therapy, especially lenvatinib combined with immune checkpoint inhibitors (ICIs), has shown more encouraging clinical results. However, drug development and comprehensive treatment have not significantly improved the prognosis, and lenvatinib resistance is often encountered in treatment. The underlying molecular mechanism of lenvatinib resistance is still unclear, and studies to solve drug resistance are ongoing. The molecular mechanisms of lenvatinib resistance in patients with aHCC include the regulation of signaling pathways, the regulation of noncoding RNAs, the impact of the immune microenvironment, tumor stem cell activation and other mechanisms. This review aims to (1) summarize the progress of lenvatinib in treating aHCC, (2) delineate the known lenvatinib resistance mechanisms of current therapy, and (3) describe the development of therapeutic methods intended to overcome these resistance mechanisms.

Analysis of the potential association between ferroptosis and immune in hepatocellular carcinoma and their relationship with prognosis.

Background: The development of targeted therapy and immunotherapy has enriched the treatment of hepatocellular carcinoma (HCC), however, have had poor or no reponse, or even no response. Previous research suggested that ferroptosis and tumor immune microenvironment (TIME) may have a fundamental impact on efficacy during HCC immunotherapy and targeted therapy. Therefore, there is a clinical need to develop a signature that categorizes HCC patients in order to make more accurate clinical decisions. Methods: Clinical data and gene expression data of HCC patients were obtained from The Cancer Genome Atlas (TCGA) portal and International Cancer Genome Consortium (ICGC) portal. To identify ferroptosis-related immune-related genes (ferroptosis-related IRGs), Pearson correlation analysis was conducted. The ferroptosis-related IRGs prognostic signature (FIPS) was constructed using Univariate Cox and LASSO Cox algorithms. The predictive effectiveness of FIPS was evaluated using Receiver Operating Characteristic (ROC) curves and survivorship curve. The correlation ship between FIPS and TIME was evaluated using single-sample Gene Set Enrichment Analysis (ssGSEA) and CIBERSORT. The relationship between FIPS and immunotherapy responsiveness was evaluated using immunophenoscore. The expression level of 10 ferroptosis-related IRGs in normal liver tissues and HCC tissues was compared using immunohistochemistry. Finally, we established a nomogram (based on FIPS, TNM stage, and age) for clinical application. Results: The FIPS was established with ten ferroptosis-related IRGs. The high-FIPS subgroup showed a poor clinical prognosis and an obviously higher proportion of HCC patients with advanced TNM stage, high WHO grade and high alpha fetoprotein(AFP) value. Analysis of TIME indicated that patients in the high-FIPS subgroup may be in immunosuppressed state. Meanwhile, we found that ferroptosis may be inhibited in the high-FIPS subgroup and this subgroup may be impervious to immunotherapy and sorafenib. Conclusion: We constructed a novel potential prognostic signature for HCC patients that predicts overall survival, ferroptosis and immune status, sorafenib sensitivity, and immunotherapy responsiveness.