AUTHOR=Zhao Shuai , Chen Shuxian , Liu Wangrui , Wei Shiyin , Wu Xinrui , Cui Dan , Jiang Lifeng , Chen Siyu , Wang Jian 

TITLE=Integrated machine learning and bioinformatic analyses used to construct a copper-induced cell death-related classifier for prognosis and immunotherapeutic response of hepatocellular carcinoma patients

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1188725

DOI=10.3389/fphar.2023.1188725

ISSN=1663-9812

ABSTRACT=Background: Copper, as a phytonutrient, exhibits potent activity against numerous diseases. Recently, a novel mechanism of cell death, termed “cuproptosis,” has been discovered and found to impact energy metabolism through copper, resulting in the induction of multiple cuproptosis-related genes. Hepatocellular carcinoma (HCC) is a widely prevalent cancer with a poor prognosis and frequent metastasis. Hence, early diagnosis followed by targeted therapy is imperative for improving these patients’ outcomes. In this study, we present a novel scoring system based on ten cuproptosis-related genes (CRGs) to more accurately predict tumor progression and metastasis.
Methods: We comprehensively evaluated cuproptosis patterns in HCC specimens obtained from two databases and a real-world cohort. Then 10 CRGs were analyzed in conjunction with immune cell infiltration signatures in the tumor microenvironment (TME), and we constructed risk signatures to assess the impact of cuproptosis on HCC and investigated the functional effects of these genes on HCC cells, as well as their potential influence on the efficacy of immunotherapy and targeted therapy drugs.
Results: Our analysis revealed two unique cuproptosis-associated mutational patterns that exhibited distinct immune cell infiltration characteristics and survival probabilities. Previous studies demonstrated that assessing cuproptosis-induced tumor mutational patterns provided valuable insights into tumor stage, phenotype, stromal activity, genetic diversity, and patient prognosis. Herein, our high-risk scores were associated with poorer survival rates and reduced efficacy of anti-PD-L1/CTLA4 immunotherapy, and first-line targeted drugs. Moreover, cytological functional assays revealed that CDKN2A and GLS promoted the proliferation and migration of HCC cells while inhibiting copper-dependent cell death.
Conclusions: HCC patients with high-risk scores had significantly poorer treatment outcomes and survival rates, thereby highlighting the significant role of cuproptosis in HCC development. Thus, accurately quantifying cuproptosis-related tumor characteristics can aid in phenotypic categorization, thereby enabling personalized and targeted therapeutic approaches, as well as precise prediction of prognosis and metastasis.