ABSTRACT
BACKGROUND: Liver hepatocellular cancer (LIHC) and stomach adenocarcinoma (STAD) are common malignancies with high lethal ratios worldwide. Great progress has been achieved by using diverse therapeutic strategies; however, these diseases still have an unfavourable prognosis. Ferroptosis inducer drugs, unlike apoptosis-related drugs, can overcome the resistance to cancer therapy caused by traditional chemicals. However, the relationship between overall survival (OS) and ferroptosis-related genes, as well as the mechanisms involved, are largely unclear. METHODS: The expression levels of AIFM2, GPX4, ACSL4, FTH1, NOS1, and PTGS2 in LIHC and STAD were obtained from UALCAN. The correlations of OS with these gene expression levels were obtained using the Kaplan-Meier Plotter database. The OS associated with genetic mutations of those genes compared to that of unchanged genes was analysed using the TIMER website. GO and KEGG enrichment analyses of ferroptosis-related genes and their coexpressed genes in LIHC and STAD were conducted using the STRING and DAVID databases. The relationship of PTGS2 and ACSL4 to immune cell infiltration was analysed using the TIMER website. The viability and GPX5 expression levels in LIHC cells treated with RSL3 and As2O3 were detected by MTT methods and western blotting, respectively. RESULTS: Our results showed that GPX4, FTH1 and AIFM2 were overexpressed in LIHC and STAD. High levels of GPX4, FTH1 and AIFM2 were prominently correlated with better prognosis in LIHC. However, GPX and FTH1 in STAD did not show significant correlations with OS. AIFM2 in STAD had the opposite trend with OS compared with that in LIHC. Moreover, a high mutation rate of these genes (35.74%) was also observed in LIHC patients, and genetic mutation of these genes was correlated with shorter OS. In contrast, the genetic mutation of these genes did not change OS in STAD. Enrichment analysis showed that the respiratory electron transport chain, cell chemotaxis and T-cell migration were related to ferroptosis. ASCL4 and PTGS2 coexpressed with cytokines associated with immune cell infiltration. Compared to RSL3 or As2O3 alone, As2O3 plus RSL3 significantly inhibited the growth of Huh7 cells. GPX4 was downregulated to an undetectable level when in combination with RSL3. CONCLUSIONS: Our results indicated that ferroptosis-related genes might play an important role in LIHC and STAD and might be risk factors for overall survival in LIHC and STAD.
Subject(s)
Adenocarcinoma , Carcinoma, Hepatocellular , Ferroptosis , Liver Neoplasms , Stomach Neoplasms , Humans , Ferroptosis/genetics , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Stomach Neoplasms/mortality , Stomach Neoplasms/metabolism , Stomach Neoplasms/drug therapy , Prognosis , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Liver Neoplasms/mortality , Liver Neoplasms/metabolism , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/metabolism , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Adenocarcinoma/metabolism , Adenocarcinoma/drug therapy , Adenocarcinoma/mortality , Gene Expression Regulation, Neoplastic , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolismABSTRACT
BACKGROUND: DFNA5 (GSDME) belongs to Gasdermin familily that is involved in a variety of cancers and triggers cell pyroptosis after chemical treatment. However, the relationship in DFNA5 between prognosis and immune cells in diverse cancers has been receiving little attention. Tumor immune cells infiltration and exhaustion may associate with patients prognosis. The roles of DFNA5 in tumor immune cells infiltration and exhaustion have not been clarified. METHODS: The expression level of DFNA5 was determined by the Tumour Immune Estimation Resource and the Oncomine database. Then the impacts of DFNA5 in prognosis were assessed by Kaplan-Meier plotter and ULACAN. The correlations between DFNA5 and tumour-infiltrating lymphocytes were explored by TIMER. In addition, the relationships in the expression levels of DFNA5 and typical genes combination of tumour-infiltrating lymphocytes were analysed by GEPIA and TIMER. In this study, we screened the chemokine and immune related proteins interacted with DFNA5 using TurboID system to explore the instantaneous or weak interactions. RESULTS: DFNA5 significantly influences the prognosis in different cancers according to The Cancer Genome Atlas (TCGA). The expression levels of DFNA5 showed positive correlations to the infiltration of macrophages, CD8 + T cells, CD4 + T cells in liver hepatocellular carcinoma (LIHC), colon adenocarcinoma (COAD), and lung adenocarcinoma (LUAD). DFNA5 expression displayed obvious correlations with multiple lymphocytes gene makers in COAD, LIHC and LUAD. DFNA5 expression has effects on the prognosis of liver hepatocellular carcinoma and LUAD. DFNA5 upregulated the expression levels of PDCD1 and CD274 in a dose-dependent manner. Chemokine and immune related proteins interact with DFNA5. CONCLUSIONS: These results indicate that DFNA5 is related to patient prognosis and immune cells, consisting of macrophages, CD4 + T cells, and CD8 + T cells, in diverse cancers. In addition, DFNA5 expression might contribute to the regulation of T cell exhaustion, tumour-associated macrophages (TAMs), and Tregs in COAD, LIHC and LUAD. DFNA5 may regulate immune infiltration via EIF2AK2. IFNGR1 was related to the functions of PD-L1 expression and PD-1 checkpoint pathway. These results indicate that DFNA5 levels may be act as a prognostic factor and predict the degrees of immune cells infiltration in LIHC and LUAD.
