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ATIC inhibits autophagy in hepatocellular cancer through the AKT/FOXO3 pathway and serves as a prognostic signature for modeling patient survival.

ABSTRACT: Background: Autophagy regulates many cell functions related to cancer, ranging from cell proliferation and angiogenesis to metabolism. Due to the close relationship between autophagy and tumors, we investigated the predictive value of autophagy-related genes. Methods: Data from patients with hepatocellular carcinoma were obtained from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) databases. A regression analysis of differentially expressed genes was performed. Based on a prognostic model, patients were divided into a high-risk or low-risk group. Kaplan-Meier survival analyses of patients were conducted. The immune landscapes, as determined using single-sample gene set enrichment analysis (ssGSEA), exhibited different patterns in the two groups. The prognostic model was verified using the ICGC database and clinical data from patients collected at Zhongnan Hospital. Based on the results of multivariate Cox regression analysis, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate (IMP) cyclohydrolase (ATIC) had the largest hazard ratio, and thus we studied the effect of ATIC on autophagy and tumor progression by performing in vitro and in vivo experiments. Results: Fifty-eight autophagy-related genes were differentially expressed (false discovery rate (FDR)<0.05, log₂ fold change (logFC)>1); 23 genes were related to the prognosis of patients. A prognostic model based on 12 genes (ATG10, ATIC, BIRC5, CAPN10, FKBP1A, GAPDH, HDAC1, PRKCD, RHEB, SPNS1, SQSTM1 and TMEM74) was constructed. A significant difference in survival rate was observed between the high-risk group and low-risk group distinguished by the model (P<0.001). The model had good predictive power (area under the curve (AUC)>0.7). Risk-related genes were related to the terms type II IFN response, MHC class I (P<0.001) and HLA (P<0.05). ATIC was confirmed to inhibit autophagy and promote the proliferation, invasion and metastasis of liver cancer cells through the AKT/Forkhead box subgroup O3 (FOXO3) signaling pathway in vitro and in vivo. Conclusions: The prediction model effectively predicts the survival time of patients with liver cancer. The risk score reflects the immune cell features and immune status of patients. ATIC inhibits autophagy and promotes the progression of liver cancer through the AKT/FOXO3 signaling pathway.

SUBMITTER: Zhang H

PROVIDER: S-EPMC8579461 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:Nasopharyngeal carcinoma (NPC) is a common epithelial carcinoma with high occurrence and metastatic rates in Southern China. To date, the molecular mechanisms of metastasis for NPC remains unclear. The aim of this study was to discover the underlying mechanism of NPC and to elucidate novel genes that may play important roles in NPC progression and metastasis. Methods:We carry out mRNA expression profiling, Arraystar Human mRNA Expression Profiling Service Report based on polymerase chain reaction (PCR) using four pairs of tumor tissues and their corresponding benign adjacent tissues from NPC patients. Results:We found that 1,787 genes were differentially expressed, among them, 8 genes were identified as highly upregulated in NPC patients. Within these 8 genes, only TSPAN8 was consistently over-expressed in poorly differentiated CNE2 cell line and highly-metastatic subclone S18 cell line. TSPAN8 mRNA and protein levels were increased in primary carcinoma tissues compared to their corresponding adjacent benign tissues. Knockdown of TSPAN8 by siRNA resulted in inhibition of NPC cell migration and invasion, while overexpression of TSPAN8 promoted NPC cell migration, invasion and proliferation. To explore the potential metastasis pathway mechanism for NPC, TSPAN8 were silenced in CNE2 cell. From the Tumor Metastasis Pathway Finder PCR array, knockdown of TSPAN8 led to the down-regulation of IL-1?, which showed the most down-regulation among identified genes. IL-1? is a regulating factor of the Akt/MAPK pathway, which is involved in the cancer cell migration regulation. Furthermore, the down-regulation of TSPAN8 in CNE2 cell was associated with inhibition of the Akt/MAPK pathway. Immunohistochemistry (IHC) indicated that TSPAN8 level was increased in NPC tumors, which was associated with shorter overall survival and metastasis free survival (MFS). Conclusions:The data indicated that TSPAN8 acting as a tumor migration marker and may be a prognostic factor or therapeutic target for NPC.

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ATIC inhibits autophagy in hepatocellular cancer through the AKT/FOXO3 pathway and serves as a prognostic signature for modeling patient survival.

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