Zhang Kangnan, Zhu Zhenhua, Zhou Jingyi, Shi Min, Wang Na, Yu Fudong, Xu Ling
Department of Gastroenterology, Shanghai Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200336, China.
Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, 200001, China.
Transl Oncol. 2024 Nov;49:102091. doi: 10.1016/j.tranon.2024.102091. Epub 2024 Aug 14.
The onset of drug resistance in advanced cancer patients markedly diminishes their prognosis. Recently, disulfidptosis, a novel form of cell death, has been identified, triggered by excessive disulfide formation leading to cell shrinkage and F-actin contraction. Previous studies have identified 15 essential genes (FLNA, FLNB, MYH9, TLN1, ACTB, MYL6, MYH10, CAPZB, DSTN, IQGAP1, ACTN4, PDLIM1, CD2AP, INF2, SLC7A11) associated with disulfidptosis. This study sourced pan-cancer mRNA expression data from Xena to thoroughly evaluate the molecular and clinical characteristics of disulfidptosis-related genes. Through unsupervised clustering, mRNA expression data identified the expression levels of disulfidptosis-related genes and potential clusters related to this form of cell death. Kaplan-Meier survival curves illustrated the correlation between different clusters and overall survival. The findings reveal that high expression of disulfidptosis-related genes is linked to poor survival in liver cancer. The GDSC database was utilized to analyze the relationship between disulfidptosis-related genes and the AUC of 198 drugs. The results demonstrate that 12 disulfidptosis-related genes influence sorafenib resistance, as revealed by the intersection of differential genes related to sorafenib resistance from the GSE109211 dataset. Among them, the MYH9 gene was found to play a crucial role in both. Finally, experimental evidence confirmed that MYH9 mitigates sorafenib resistance in hepatocellular carcinoma through disulfidptosis-like changes. This study identifies disulfidptosis as a promising avenue for enhancing the sensitivity of tumor cells to drugs, offering new therapeutic perspectives for future research on disulfidptosis and drug resistance in cancer patients.
晚期癌症患者耐药性的出现显著降低了他们的预后。最近，一种新型细胞死亡形式——二硫键介导的细胞焦亡被发现，它由过量二硫键形成引发，导致细胞收缩和F-肌动蛋白收缩。先前的研究已经确定了15个与二硫键介导的细胞焦亡相关的必需基因（FLNA、FLNB、MYH9、TLN1、ACTB、MYL6、MYH10、CAPZB、DSTN、IQGAP1、ACTN4、PDLIM1、CD2AP、INF2、SLC7A11）。本研究从Xena获取泛癌mRNA表达数据，以全面评估二硫键介导的细胞焦亡相关基因的分子和临床特征。通过无监督聚类，mRNA表达数据确定了二硫键介导的细胞焦亡相关基因的表达水平以及与这种细胞死亡形式相关的潜在聚类。Kaplan-Meier生存曲线说明了不同聚类与总生存期之间的相关性。研究结果表明，二硫键介导的细胞焦亡相关基因的高表达与肝癌患者的不良生存相关。利用GDSC数据库分析二硫键介导的细胞焦亡相关基因与198种药物的AUC之间的关系。结果表明，12个二硫键介导的细胞焦亡相关基因影响索拉非尼耐药性，这是通过来自GSE109211数据集的与索拉非尼耐药相关的差异基因的交集揭示的。其中，发现MYH9基因在两者中都起着关键作用。最后，实验证据证实MYH9通过类似二硫键介导的细胞焦亡的变化减轻肝细胞癌中的索拉非尼耐药性。本研究将二硫键介导的细胞焦亡确定为增强肿瘤细胞对药物敏感性的一个有前景的途径，为未来癌症患者中二硫键介导的细胞焦亡和耐药性研究提供了新的治疗视角。
