Relationships of Cuproptosis-Related Genes With Clinical Outcomes and the Tumour Immune Microenvironment in Hepatocellular Carcinoma

Abstract

Background: Cuproptosis is a recently identified form of regulated cell death that plays a critical role in the onset and progression of various cancers. However, the effects of cuproptosis-related genes (CRGs) on hepatocellular carcinoma (HCC) are poorly understood. This study aimed to identify the cuproptosis subtypes and established a novel prognostic signature of HCC.Methods: We collected gene expression data and clinical outcomes from the TCGA, ICGC, and GEO datasets, analysed and identified 16 CRGs and the different subtypes of cuproptosis related to overall survival (OS), and further examined the differences in prognosis and immune infiltration among the subtypes. Subtypes-related differentially expressed genes (DEGs) were employed to build a prognostic signature. The relationship of the signature with the immune landscape as well as the sensitivity to different therapies was explored. Moreover, a nomogram was constructed to predict the outcome based on different clinicopathological characteristics.Results: Three cuproptosis subtypes were identified on the basis of 16 CRGs, and subtype B had an advanced clinical stage and worse OS. The immune response and function in subtype B were significantly suppressed, which may be an important reason for its poor prognosis. Based on the DEGs among the three subtypes, a prognostic model of five CRGs was constructed in the training set, and its predictive ability was validated in two external validation sets. HCC patients were classified into high and low-risk subgroups according to the risk score, and found that patients in the low-risk group showed significantly higher survival possibilities than those in the high-risk group (p < 0.001). The independent predictive performance of the risk score was assessed and verified by multivariate Cox regression analysis (p < 0.001). We further created an accurate nomogram to improve the clinical applicability of the risk score, showing good predictive ability and calibration. Low- and high-risk patients exhibit distinct immune cell infiltration and immune checkpoint changes. By further analyzing the risk score, patients in the high-risk group were found to be resistant to immunotherapy and a variety of chemotherapy drugs.Conclusion: Our study identified three cuproptosis subtypes and established a novel prognostic model that provides new insights into HCC subtype prognostic assessment and guides more effective treatment regimens.

Identification and validation of potential diagnostic signature and immune cell infiltration for HIRI based on cuproptosis-related genes through bioinformatics analysis and machine learning

“…The combined datasets encompassed 75 cases of HIRI and 80 control cases. Thirty-eight CRGs were recovered from the previous literature ( ATP7A, ATP7B, ACO2, CDKN2A, DBT, DLAT, DLD, DLST, DPYD, FDX1, GCSH, GLRX5, GLS, ISCA2, LIAS, LIPA, LIPT1, LIPT2, LIPM, MTF1, NDUFA1, NDUFA8, NDUFB10, NDUFB2, NDUFB6, NLRP3, NDUFC1, NDUFC2, NDUFV2, NFE2L2, PDHA1, PLAT, PDHB, POLD1, PPAT, SLC31A1, SDHB, and TIMMDC1 ) ( 11 , 12 ). ATP7A mutations cause Menkes disease, Hence, ATP7A was excluded from further consideration.…”

“…This mutation has been reported to potentially involve cuproptosis ( 8 ). Some studies have also hinted at an underlying connection between cuproptosis and other liver diseases such as hepatocellular carcinoma and nonalcoholic fatty liver disease; cuproptosis has also attracted great interest in its therapy ( 11 , 12 ). However, research on the role of copper or cuproptosis in HIRI remains relatively limited.…”

Immunomodulation of cuproptosis and ferroptosis in liver cancer

“…SLC31A1 is equivalent to the input of copper. The inhibition of SLC31A1-dependent copper transport leads to anti-cell-death effects in cancer cells [ 18 ]. Studies have found that the expression of SLC31A1 in liver cancer samples has changed, which is related to the increase in copper content in liver tissues; liver cancer cell lines rely on CTR1 to transport copper for proliferation, colony formation, and growth.…”

Ferroptosis and cuproptosis prognostic signature for prediction of prognosis, immunotherapy and drug sensitivity in hepatocellular carcinoma: development and validation based on TCGA and ICGC databases

“…We compared our own model to 12 other published HCC prognostic models to better show its predictive power (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Multivariate analysis was used to calculate the risk value and prognostic evaluation for each dataset, leveling the playing field amongst the four models.…”