PDF(Pubmed)
Abstract：
BACKGROUND: Hepatocellular carcinoma (HCC) is a highly prevalent and deadly cancer, with limited treatment options for advanced-stage patients. Disulfidptosis is a recently identified mechanism of programmed cell death that occurs in SLC7A11 high-expressing cells due to glucose starvation-induced disintegration of the cellular disulfide skeleton. We aimed to explore the potential of disulfidptosis, as a prognostic and therapeutic marker in HCC.
METHODS: We classified HCC patients into two disulfidptosis subtypes (C1 and C2) based on the transcriptional profiles of 31 disulfrgs using a non-negative matrix factorization (NMF) algorithm. Further, five genes (NEIL3, MMP1, STC2, ADH4 and CFHR3) were screened by Cox regression analysis and machine learning algorithm to construct a disulfidptosis scoring system (disulfS). Cell proliferation assay, F-actin staining and PBMC co-culture model were used to validate that disulfidptosis occurs in HCC and correlates with immunotherapy response.
RESULTS: Our results suggests that the low disulfidptosis subtype (C2) demonstrated better overall survival (OS) and progression-free survival (PFS) prognosis, along with lower levels of immunosuppressive cell infiltration and activation of the glycine/serine/threonine metabolic pathway. Additionally, the low disulfidptosis group showed better responses to immunotherapy and potential antagonism with sorafenib treatment. As a total survival risk factor, disulfS demonstrated high predictive efficacy in multiple validation cohorts. We demonstrated the presence of disulfidptosis in HCC cells and its possible relevance to immunotherapeutic sensitization.
CONCLUSIONS: The present study indicates that novel biomarkers related to disulfidptosis may serve as useful clinical diagnostic indicators for liver cancer, enabling the prediction of prognosis and identification of potential treatment targets.
METHODS: We classified HCC patients into two disulfidptosis subtypes (C1 and C2) based on the transcriptional profiles of 31 disulfrgs using a non-negative matrix factorization (NMF) algorithm. Further, five genes (NEIL3, MMP1, STC2, ADH4 and CFHR3) were screened by Cox regression analysis and machine learning algorithm to construct a disulfidptosis scoring system (disulfS). Cell proliferation assay, F-actin staining and PBMC co-culture model were used to validate that disulfidptosis occurs in HCC and correlates with immunotherapy response.
RESULTS: Our results suggests that the low disulfidptosis subtype (C2) demonstrated better overall survival (OS) and progression-free survival (PFS) prognosis, along with lower levels of immunosuppressive cell infiltration and activation of the glycine/serine/threonine metabolic pathway. Additionally, the low disulfidptosis group showed better responses to immunotherapy and potential antagonism with sorafenib treatment. As a total survival risk factor, disulfS demonstrated high predictive efficacy in multiple validation cohorts. We demonstrated the presence of disulfidptosis in HCC cells and its possible relevance to immunotherapeutic sensitization.
CONCLUSIONS: The present study indicates that novel biomarkers related to disulfidptosis may serve as useful clinical diagnostic indicators for liver cancer, enabling the prediction of prognosis and identification of potential treatment targets.
摘要：
背景：肝细胞癌（HCC）是一种非常普遍和致命的癌症，对晚期患者的治疗选择有限。二硫键凋亡是最近发现的程序性细胞死亡机制，由于葡萄糖饥饿诱导的细胞二硫键骨架的崩解，该机制发生在SLC7A11高表达细胞中。我们的目的是探索二硫化物沉积的潜力，作为肝癌的预后和治疗标志物。
方法：我们使用非负矩阵分解（NMF）算法，根据31个双硫蛋白的转录谱，将HCC患者分为两种双硫蛋白亚型（C1和C2）。Further,通过Cox回归分析和机器学习算法筛选了5个基因（NEIL3，MMP1，STC2，ADH4和CFHR3），以构建二硫下垂评分系统（disulfisms）。细胞增殖试验,使用F-肌动蛋白染色和PBMC共培养模型来验证二硫化物下垂发生在HCC中并与免疫疗法反应相关。
结果：我们的结果表明，低二硫上清液亚型（C2）表现出更好的总生存期（OS）和无进展生存期（PFS）预后，伴随着较低水平的免疫抑制细胞浸润和甘氨酸/丝氨酸/苏氨酸代谢途径的激活。此外,低二硫键下垂组显示出更好的免疫治疗反应和索拉非尼治疗的潜在拮抗作用.作为总生存风险因素，disurfS在多个验证队列中表现出很高的预测功效。我们证明了HCC细胞中二硫键的存在及其与免疫治疗致敏的可能相关性。
结论：本研究表明，与二硫键凋亡相关的新型生物标志物可作为肝癌的有用临床诊断指标，能够预测预后和识别潜在的治疗目标。
方法：我们使用非负矩阵分解（NMF）算法，根据31个双硫蛋白的转录谱，将HCC患者分为两种双硫蛋白亚型（C1和C2）。Further,通过Cox回归分析和机器学习算法筛选了5个基因（NEIL3，MMP1，STC2，ADH4和CFHR3），以构建二硫下垂评分系统（disulfisms）。细胞增殖试验,使用F-肌动蛋白染色和PBMC共培养模型来验证二硫化物下垂发生在HCC中并与免疫疗法反应相关。
结果：我们的结果表明，低二硫上清液亚型（C2）表现出更好的总生存期（OS）和无进展生存期（PFS）预后，伴随着较低水平的免疫抑制细胞浸润和甘氨酸/丝氨酸/苏氨酸代谢途径的激活。此外,低二硫键下垂组显示出更好的免疫治疗反应和索拉非尼治疗的潜在拮抗作用.作为总生存风险因素，disurfS在多个验证队列中表现出很高的预测功效。我们证明了HCC细胞中二硫键的存在及其与免疫治疗致敏的可能相关性。
结论：本研究表明，与二硫键凋亡相关的新型生物标志物可作为肝癌的有用临床诊断指标，能够预测预后和识别潜在的治疗目标。
