RESUMO
OBJECTIVES: Cuproptosis represents an innovative type of cell death, distinct from apoptosis, driven by copper dependency, yet the involvement of copper apoptosis-associated long non-coding RNAs (CRLncRNAs) in hepatocellular carcinoma (HCC) remains unclear. This study is dedicated to unveiling the role and significance of these copper apoptosis-related lncRNAs within the context of HCC, focusing on their impact on both the development of the disease and its prognosis. METHODS: We conducted an analysis of gene transcriptomic and clinical data for HCC cases by sourcing information from The Cancer Genome Atlas database. By incorporating cuproptosis-related genes, we established prognostic features associated with cuproptosis-related lncRNAs. Furthermore, we elucidated the mechanism of cuproptosis-related lncRNAs in the prognosis and treatment of HCC through comprehensive approaches, including Lasso and Cox regression analyses, survival analyses of samples, as well as examinations of tumor mutation burden and immune function. RESULTS: We developed a prognostic model featuring six cuproptosis-related lncRNAs: AC026412.3, AC125437.1, AL353572.4, MKLN1-AS, TMCC1-AS1, and SLC6A1-AS1. This model demonstrated exceptional prognostic accuracy in both training and validation cohorts for patients with tumors, showing significantly longer survival times for those categorized in the low-risk group compared to the high-risk group. Additionally, our analyses, including tumor mutation burden, immune function, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway enrichment, and drug sensitivity, further elucidated the potential mechanisms through which cuproptosis-associated lncRNAs may influence disease outcome. CONCLUSIONS: The model developed using cuproptosis-related long non-coding RNAs (lncRNAs) demonstrates promising predictive capabilities for both the prognosis and immunotherapy outcomes of tumor patients. This could play a crucial role in patient management and the optimization of immunotherapeutic strategies, offering valuable insights for future research.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Prognóstico , Cobre , Apoptose/genética , Masculino , Biomarcadores Tumorais/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Transcriptoma , Análise de SobrevidaRESUMO
Hepatocellular carcinoma (HCC) is the fifth most frequently diagnosed cancer and ranks third in cancer-related fatalities. The recognized involvement of long noncoding RNAs (lncRNAs) in several cancer types, including HCC, inspired this study to explore a novel lncRNA's functional importance in the progression of HCC. To achieve this, lncRNA microarray analysis was conducted on three distinct sets of HCC tissues, revealing LINC00707 as the most significantly upregulated lncRNA. Further research into its biological functions has revealed that LINC00707 acts as an oncogene, driving HCC progression by enhancing the proliferation, migration and invasion of HCC cells. Mechanistic insights were provided, demonstrating that LINC00707 interacts with YTH N6-methyladenosine RNA-binding protein 2 (YTHDF2), thus facilitating the ubiquitination-dependent degradation of the YTHDF2 protein. Furthermore, LINC00707 was found to influence the cytotoxicity of NK-92MI cells against HCC cells through its interactions with YTHDF2. These findings significantly contribute to a deeper understanding of the role played by LINC00707 in the progression of HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , RNA Longo não Codificante , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Células Matadoras Naturais/metabolismo , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Movimento Celular/genética , Linhagem Celular Tumoral , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismoRESUMO
Accumulating evidence indicates that circular RNAs (circRNAs) can interact with microRNAs to modulate gene expression in various cancers, including hepatocellular carcinoma (HCC). Although the significant role of circRNAs has been well documented in HCC, the complex mechanisms of circRNAs still need to be elucidated. Our current study is aimed at investigating the function of circ_0001588 in HCC, which was observed to significantly increase in HCC tissues and cells. We demonstrated that the knockdown of circ_0001588 resulted in repressed cell proliferation, migration, and invasion. In vivo studies using a nude mouse model showed that circ_0001588 downregulation reduced tumor size. Moreover, miR-874 was predicted as a target of circ_0001588. Using luciferase binding assays, we proved that circ_0001588 functions as a molecular ceRNA of miR-874 and that CDK4 acts as a downstream target of miR-874 in HCC. It was confirmed that overexpression of miR-874 decreased the proliferation, migration, and invasion triggered by the increase in circ_0001588. In summary, our results indicate that circ_0001588 acts as a ceRNA and promotes HCC progression by targeting the miR-874/CDK4 signaling pathway. Hence, we propose that circ_0001588 may be a promising target for HCC treatment.
Assuntos
Carcinoma Hepatocelular/genética , Quinase 4 Dependente de Ciclina/genética , Neoplasias Hepáticas/genética , MicroRNAs/metabolismo , RNA Circular/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Hepáticas/patologia , Camundongos , RNA Circular/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Hepatocellular carcinoma (HCC) is a common malignant liver tumor worldwide. Tumor recurrence and metastasis contribute to the bad clinical outcome of HCC patients. Substantial studies have displayed lncRNAs modulate various tumorigenic processes of many cancers. Our current work was aimed to investigate the function of LINC00675 in HCC and to recognize the potential interactions between lncRNAs and microRNAs. GFI1 can exhibit a significant role in the progression of human malignant tumors. Firstly, GFI1 was identified using real-time PCR in HCC tissues and cells. In this work, we indicated GFI1 was remarkably reduced in HCC tissues and cells. Meanwhile, GFI1 specifically interacted with the promoter of LINC00675. Up-regulation of LINC00675 obviously repressed the migration and invasion capacity of SMCC-7721 and QGY-7703 cells in vitro. Moreover, decrease of LINC00675 competitively bound to miR-942-5p that contributed to the miRNA-mediated degradation of GFI1, thus facilitated HCC metastasis. The ceRNA function of LINC00675 in HCC cells was assessed and confirmed using RNA immunoprecipitation assay and RNA pull-down assays in our work. Additionally, we proved overexpression of miR-942-5p promoted HCC progression, which was reversed by the up-regulation of GFI1. In summary, LINC00675 might act as a prognostic marker for HCC, which can inhibit HCC development via regulating miR-942-5p and GFI1.