RESUMO
Exposure to inorganic arsenic remains a global public health problem. The liver is the main target organ, leading to arsenic-induced liver fibrosis. Phosphatase and tensin homology deleted on chromosome ten (PTEN) may participate in arsenic-induced liver fibrosis by regulating autophagy, but the exact mechanisms remain unclear. We established a mouse model of arsenic poisoning through their drinking water and a fibrosis model using the human hepatic stellate cell line LX-2 through NaAsO2 exposure for 24 h. Masson staining measured liver fibrosis. The cells were transfected with a PTEN overexpression plasmid. Western blot and qRT-PCR determined the levels of protein/mRNA expression. Fibrosis was evident in both the mouse model and arsenic-exposed LX-2 cells. NaAsO2 upregulated expression of autophagic markers microtubule-associated protein light chain A/B (LC3), recombinant human autophagy effector protein (Beclin-1), and hairy and enhancer of split homolog-1 (HES1), but downregulated PTEN. Alongside this, α-smooth muscle actin (α-SMA) expression was significantly upregulated by NaAsO2. PTEN overexpression altered NaAsO2-induced autophagy and downregulated LC3 and Beclin-1. While Notch1, HES1, α-SMA, and collagen I expression were all downregulated in the NaAsO2 groups. Therefore, PTEN overexpression might decrease autophagy and inhibit fibrosis progression caused by arsenic, and the NOTCH1/HES1 pathway is likely involved.
RESUMO
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.
