System analysis based on the cuproptosis-related genes identifies LIPT1 as a novel therapy target for liver hepatocellular carcinoma

Abstract

Background Liver hepatocellular carcinoma (LIHC) ranks sixth among the most common types of cancer with a high mortality rate. Cuproptosis is a newly discovered type of cell death in tumor, which is characterized by accumulation of intracellular copper leading to the aggregation of mitochondrial lipoproteins and destabilization of proteins. Thus, understanding the exact effects of cuproptosis-related genes in LIHC and determining their prognosticvalue is critical. However, the prognostic model of LIHC based on cuproptosis-related genes has not been reported. Methods Firstly, we downloaded transcriptome data and clinical information of LIHC patients from TCGA and GEO (GSE76427), respectively. We then extracted the expression of cuproptosis-related genes and established a prognostic model by lasso cox regression analysis. Afterwards, the prediction performance of the model was evaluated by Kaplan–Meier survival analysis and receiver operating characteristic curve (ROC). Then, the prognostic model and the expression levels of the three genes were validated using the dataset from GEO. Subsequently, we divided LIHC patients into two subtypes by non-negative matrix factorization (NMF) classification and performed survival analysis. We constructed a Sankey plot linking different subtypes and prognostic models. Next, we calculate the drug sensitivity of each sample from patients in the high-risk group and low-risk group by the R package pRRophetic. Finally, we verified the function of LIPT1 in LIHC. Results Using lasso cox regression analysis, we developed a prognostic risk model based on three cuproptosis-related genes (GCSH, LIPT1 and CDKN2A). Both in the training and in the test sets, the overall survival (OS) of LIHC patients in the low-risk group was significantly longer than that in the high-risk group. By performing NMF cluster, we identified two molecular subtypes of LIHC (C1 and C2), with C1 subtype having significantly longer OS and PFS than C2 subtype. The ROC analysis indicated that our model had a precisely predictive capacity for patients with LIHC. The multivariate Cox regression analysis indicated that the risk score is an independent predictor. Subsequently, we identified 71 compounds with IC50 values that differed between the high-risk and low-risk groups. Finally, we determined that knockdown of LIPT1 gene expression inhibited proliferation and invasion of hepatoma cells. Conclusion In this study, we developed a novel prognostic model for hepatocellular carcinoma based on cuproptosis-related genes that can effectively predict the prognosis of LIHC patients. The model may be helpful for clinicians to make clinical decisions for patients with LIHC and provide valuable insights for individualized treatment. Two distinct subtypes of LIHC were identified based on cuproptosis-related genes, with different prognosis and immune characteristics. In addition, we verified that LIPT1 may promote proliferation, invasion and migration of LIHC cells. LIPT1 might be a new potential target for therapy of LIHC.

A cuproptosis-related LncRNA signature: Integrated analysis associated with biochemical recurrence and immune landscape in prostate cancer

“…Lipoyltransferase 1, encoded by LIPT1, is a vital enzyme that transfers lipoate to the E2 subunits of the 2-ketoacid dehydrogenase complexes, and the deficiency of it had already been confirmed to suppress TCA cycle metabolism (Solmonson et al, 2022). Studies have shown that LIPT1 is closely linked to a favorable outcome in patients with urothelial cancer, hepatocellular carcinoma, and melanoma (Chen et al, 2021;Lv et al, 2022;Yan et al, 2022). In this study, we found that LIPT1 was upregulated in PCa, but not correlated with the BCR.…”

FNBP4 is a Potential Biomarker Associated with Cuproptosis and Promotes Tumor Progression in Hepatocellular Carcinoma

“… 51 A recent study showed that the expression of LIPT1 not only effectively predicts the prognosis of patients with HCC but also may become a therapeutic target for HCC. 52 DLAT, a key gene that catalyzes the conversion of pyruvate to acetyl CoA, can enhance ATP production and promote tumor cell proliferation. 53 CDKN2A, encoding the cyclin inhibitor p16, binds to cyclin and cyclin-dependent kinases 4 and 6 to inhibit proliferation in normal cells.…”

Identification of Cuproptosis-Related Genes in Nonalcoholic Fatty Liver Disease

“…Copper, a cofactor for various enzymes, is an essential micronutrient required for normal cell function, and the cuproptosis is related to various cancer progressions, such as HCC [ 19 , 20 ]. Recent studies have determined that serum and liver copper are related to NAFLD, but the specific mechanism is still unclear [ 21 ].…”