ABSTRACT
Background: The clinical behavior and molecular mechanisms of hepatocellular carcinoma (HCC) are complex and highly variable, limiting the discovery of new targets and therapies in clinical research. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is one of the tumor suppressor genes. It is of great interest to discover the role of unexplored correlation among PTEN, the tumor immune microenvironment, and autophagy-related signaling pathways and to construct a reliable risk model for prognosis during HCC progression. Method: We first performed differential expression analysis on the HCC samples. By using Cox regression and LASSO analysis, we determined the DEGs contributing to the survival benefit. In addition, the gene set enrichment analysis (GSEA) was performed to identify potential molecular signaling pathways regulated by the PTEN gene signature, autophagy, and autophagy-related pathways. ESTIMATE was also employed for evaluating the composition of immune cell populations. Results: We found a significant correlation between PTEN expression and the tumor immune microenvironment. The low-PTEN expression group had higher immune infiltration and lower expression of immune checkpoints. In addition, PTEN expression was found to be positively correlated with autophagy-related pathways. Then, differentially expressed genes between tumor and tumor-adjacent samples were screened, and 2895 genes were significantly associated with both PTEN and autophagy. Based on PTEN-related genes, we identified 5 key prognostic genes, including BFSP1, PPAT, EIF5B, ASF1A, and GNA14. The 5-gene PTEN-autophagy risk score (RS) model was demonstrated to have favorable performance in the prediction of prognosis. Conclusion: In summary, our study showed the importance of the PTEN gene and its correlation with immunity and autophagy in HCC. The PTEN-autophagy.RS model we established could be used to predict the prognosis of HCC patients and showed significantly higher prognostic accuracy than the TIDE score in response to immunotherapy.
ABSTRACT
Inorganic arsenic (iAs) is a common carcinogen that exists in the environment. Liver, as the main target organ of arsenic metabolism, long-term exposure to iAs can ultimately lead to carcinogenesis through two stages: liver fibrosis and cirrhosis. Ferroptosis is a type of programmed cell death caused by the accumulation of iron dependent lipid peroxides that affects the normal function of mitochondria. It has been found that ferroptosis occurs during liver fibrosis. Liver fibrosis caused by iAs has been a global health problem for a long time, but so far there is no effective treatment. The discovery of ferroptosis provides a new way to solve this problem. Therefore, this article will review the research progress of the mechanism of liver injury caused by iAs and ferroptosis.
ABSTRACT
Objective:To analyze DNA methylation sites related to fibrosis and autophagy in human hepatic stellate cells (LX-2 cells) induced by sodium arsenite (NaAsO 2), and to screen specific methylation genes related to fibrosis and autophagy. Methods:Genome-wide DNA detection was performed using Illumina Infinium Methylation EPIC BeadChips (850K methylation chip) to derive differential methylation sites in LX-2 cells (control group) and the fibrosis and autophagy models of LX-2 cells induced by NaAsO 2(low, medium and high dose groups: the final concentrations were 5, 10, 15 μmol/L NaAsO 2, respectively, after 48 h intervention). Gene ontology (GO) function enrichment analysis and Kyoto encyclopedia of genes and genomes (KEGG) signaling pathway enrichment analysis were used to explore gene function. Results:The model of cell fibrosis and autophagy was established successfully in high dose group. The results of 850K methylation chip detection showed that there were 25 817 significant different methylation sites between the high dose group and the control group, including 12 083 hypermethylation sites and 13 734 hypomethylation sites. GO function enrichment analysis showed that the molecular functions of differentially methylated genes mainly included protein binding, ion binding, catalytic activity, enzyme binding. KEGG signaling pathway enrichment analysis showed that the pathways involved in differentially methylated genes mainly included metabolic pathway, cancer pathway, phosphatidylinositol-3-kinase-protein kinase B (PI3K-Akt) signaling pathway, endocytosis, and mitogen activated protein kinase (MAPK) signaling pathway. In the promoter region, 11 and 29 differentially methylated genes related to fibrosis and autophagy were screened, respectively.Conclusions:A large number of differential methylation sites exist in the process of NaAsO 2 induced fibrosis and autophagy of LX-2 cells. Specific methylation genes related to fibrosis and autophagy are screened out.
