The potential of lncRNAs to regulate cuproptosis in hepatocellular carcinoma: establishment and validation of a novel risk model

Abstract

Abstract Background Recently, a novel, different from the known mechanisms, copper-dependent cell death-"cuproptosis" was demonstrated. However, the regulation of cuproptosis, especially in malignancy, remains unclear. This study aimed to identify the hepatocellular carcinoma-long noncoding RNAs (HCC-lncRNAs) closely related to cuproptosis. Methods First, we identified lncRNAs that are associated with cuproptosis-related genes and abnormally expressed in HCC. Subsequently, the comprehensive methods of Univariate cox regression analysis, multivariate cox regression analysis and LASSO regression analysis were used to further screen targets and establish a risk models in the training group and test group with no clinical difference in TCGA. ssGSEA was used to estimate the contents of immune cells in the tumor microenvironment. In vitro elesclomol-CuCl2 shock test verified the correlation between the lncRNAs targets and copper toxicity. Results We successfully constructed a cuproptosis-related risk model: risk score = 0.82 * AC018690.1 + 0.65 * AL050341.2 + 0.61 * LINC02038, which could accurately reflect the prognosis of HCC patients. Further, we added clinical factors to optimize the model. Meanwhile, the tumor immune microenvironment was observably different between high and low risk groups, in which the infiltration levels of T helper 2 cells, T helper cells 17 and dendritic cells were significantly related to the risk scores. Interestingly, the patients in the high-risk group are more sensitive to immunotherapy, while sorafenib and dasatinib are less effective. Finally, we confirmed that knocking down these lncRNAs targets could significantly weaken the resistance to cuproptosis in vitro. Conclusions Based on three novel HCC-lncRNAs, we established an accurate risk model with potential value for clinical application. Given these lncRNAs dramatically regulate the response of HCC to copper toxicity, it raises hope for the development of copper-related therapy, even “sorafenib -copper ionophores -immunotherapy”, on HCC.