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<p>Disulfidptosis, a recently identified form of cell death, plays a crucial role in cancer progression, specifically by altering intracellular disulfide bonds within the actin cytoskeleton. Our research centres on developing a prognostic model based on disulfidptosis-<i>rela</i>ted long noncoding RNAs (DRLRs) to differentiate high-grade (G3-G4) from low-grade (G1-G2) Hepatocellular Carcinoma (HCC). Utilizing transcriptomic data from The Cancer Genome Atlas (TCGA), we employed univariate Cox regression analysis, Least Absolute Shrinkage and Selection Operator(LASSO) regression, and multivariate Cox regression to ultimately identify nine key drlncRNAs (<i>AL442125.2</i>,<i> AC018529.2</i>,<i> AL031985.3</i>,<i> AC119150.1</i>,<i> LINC02256</i>,<i> AC026979.4</i>,<i> POLH-AS1</i>,<i> MED8-AS1</i>, and <i>AC026356.1</i>). These were subsequently used to construct a prognostic risk signature model. This 9-DRLR model demonstrated robust discriminative capacity, achieving Area Under the Curve(AUCs) of 0.845, 0.841, and 0.885 for 1-, 3-, and 5-year overall survival prediction in G3-G4 HCC patients, respectively. The model provides strong prognostic stratification of HCC patients by grade and cor<i>rela</i>tes with biological processes linked to tumour aggressiveness and immune evasion, as shown by Gene Ontology (GO) and gene set enrichment analyses (GSEA). High-risk groups exhibited markers of immune dysfunction, elevated tumour mutation burden (TMB), and increased sensitivity to targeted therapies including 5-Fluorouracil and Dasatinib. <i>AL031985.3</i> emerged as a key lncRNA within this model, with its significant overexpression in HCC tissues versus adjacent controls (<i>p</i> &lt; 0.001) validated through quantitative Real-Time PCR (qRT-PCR). Functional analyses revealed <i>AL031985.3</i> as a critical oncogenic driver, where its knockdown significantly suppressed colony formation (<i>p</i> &lt; 0.01) and reduced invasive capacity (<i>p</i> &lt; 0.01) in vitro. These findings were corroborated in vivo, with orthotopic implantation and experimental pulmonary metastasis models demonstrating attenuated tumour growth and modulated epithelial-mesenchymal transition markers following <i>AL031985.3</i> silencing. Our findings underscore the prognostic value of the DRLR signature and establish <i>AL031985.3</i> as a potential therapeutic target for advanced HCC.</p>

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A prognostic model utilizing disulfidptosis-related long noncoding RNAs to differentiate pathological grades in hepatocellular carcinoma: functional analysis of AL031985.3

  • 期刊论文

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  • 发表日期：

    2026年3月30日

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  • Ling Yang,
  • Fei Li,
  • Hailin Yu,
  • Xuefeng Gu,
  • Wei You

摘要

Disulfidptosis, a recently identified form of cell death, plays a crucial role in cancer progression, specifically by altering intracellular disulfide bonds within the actin cytoskeleton. Our research centres on developing a prognostic model based on disulfidptosis-related long noncoding RNAs (DRLRs) to differentiate high-grade (G3-G4) from low-grade (G1-G2) Hepatocellular Carcinoma (HCC). Utilizing transcriptomic data from The Cancer Genome Atlas (TCGA), we employed univariate Cox regression analysis, Least Absolute Shrinkage and Selection Operator(LASSO) regression, and multivariate Cox regression to ultimately identify nine key drlncRNAs (AL442125.2, AC018529.2, AL031985.3, AC119150.1, LINC02256, AC026979.4, POLH-AS1, MED8-AS1, and AC026356.1). These were subsequently used to construct a prognostic risk signature model. This 9-DRLR model demonstrated robust discriminative capacity, achieving Area Under the Curve(AUCs) of 0.845, 0.841, and 0.885 for 1-, 3-, and 5-year overall survival prediction in G3-G4 HCC patients, respectively. The model provides strong prognostic stratification of HCC patients by grade and correlates with biological processes linked to tumour aggressiveness and immune evasion, as shown by Gene Ontology (GO) and gene set enrichment analyses (GSEA). High-risk groups exhibited markers of immune dysfunction, elevated tumour mutation burden (TMB), and increased sensitivity to targeted therapies including 5-Fluorouracil and Dasatinib. AL031985.3 emerged as a key lncRNA within this model, with its significant overexpression in HCC tissues versus adjacent controls (p < 0.001) validated through quantitative Real-Time PCR (qRT-PCR). Functional analyses revealed AL031985.3 as a critical oncogenic driver, where its knockdown significantly suppressed colony formation (p < 0.01) and reduced invasive capacity (p < 0.01) in vitro. These findings were corroborated in vivo, with orthotopic implantation and experimental pulmonary metastasis models demonstrating attenuated tumour growth and modulated epithelial-mesenchymal transition markers following AL031985.3 silencing. Our findings underscore the prognostic value of the DRLR signature and establish AL031985.3 as a potential therapeutic target for advanced HCC.