背景:异质组织硬化促进肿瘤进展和耐药,并预测肝细胞癌(HCC)患者的临床预后不良。Ferroptosis,先天性肿瘤抑制机制,介导各种肿瘤抑制剂的抗癌活性,包括免疫检查点抑制剂,其诱导目前被认为是一种有前途的治疗策略。然而,细胞外基质(ECM)刚度在调节HCC中铁凋亡和铁凋亡靶向耐药中的作用尚不清楚。
目的:本研究旨在探讨细胞外基质硬度如何影响HCC的铁凋亡及其治疗效果。
方法:通过细胞活性证实了铁凋亡分析,胞内亚铁铁,和线粒体病理学测定。基线PD-L2,SMYD3和SLC7A11(xCT)在67例索拉非尼治疗的HCC患者(46例无应答者和21例应答者)中进行了评估。shPD-L2,索拉非尼,和抗PD-1抗体在肝癌的体内研究。
结果:这里,我们发现,基质僵硬诱导的PD-L2作为xCT介导的铁细胞凋亡的抑制因子,可促进HCC患者的癌症生长和索拉非尼耐药.机械上,基质硬化通过激活SMYD3/H3K4me3诱导PD-L2的表达,SMYD3/H3K4me3充当RNA结合蛋白,以增强FTL的mRNA稳定性并提高其蛋白水平。PD-L2的敲低能显著促进RSL3或索拉非尼通过FTL诱导的xCT介导的铁性凋亡,而它的过度表达消除了这些上升趋势。值得注意的是,PD-L2缺失与索拉非尼和抗PD-1抗体组合显著致敏HCC细胞并在体内抑制癌症生长。此外,我们发现,与PD-L2,SLC7A11和SYMD3结合的铁毒性和免疫检查点相关的预后基因可以很好地预测索拉非尼在HCC患者中的临床疗效.
结论:这些发现扩展了我们对依赖力学的PD-L2在铁中毒中的作用的理解,癌症进展和耐药性,为PD-L2作为治疗靶标或诊断生物标志物的临床翻译提供基础。
BACKGROUND: Heterogeneous tissue stiffening promotes tumor progression and resistance, and predicts a poor clinical outcome in patients with hepatocellular carcinoma (HCC). Ferroptosis, a congenital tumor suppressive mechanism, mediates the anticancer activity of various tumor suppressors, including immune checkpoint inhibitors, and its induction is currently considered a promising treatment strategy. However, the role of extracellular matrix (ECM) stiffness in regulating ferroptosis and ferroptosis-targeted resistance in HCC remains unclear.
OBJECTIVE: This research aimed to explore how extracellular matrix stiffness affects ferroptosis and its treatment efficacy in HCC.
METHODS: Ferroptosis analysis was confirmed via cell activity, intracellular ferrous irons, and mitochondrial pathology assays. Baseline PD-L2, SMYD3, and SLC7A11 (xCT) were evaluated in 67 sorafenib-treated patients with HCC (46 for non-responder and 21 for responder) from public data. The combined efficacy of shPD-L2, sorafenib, and anti-PD-1 antibody in HCC was investigated in vivo.
RESULTS: Here, we revealed that matrix stiffness-induced PD-L2 functions as a suppressor of xCT-mediated ferroptosis to promote cancer growth and sorafenib resistance in patients with HCC. Mechanically, matrix stiffening induced the expression of PD-L2 by activating SMYD3/H3K4me3, which acts as an RNA binding protein to enhance the mRNA stability of FTL and elevate its protein level. Knockdown of PD-L2 significantly promoted xCT-mediated ferroptosis induced by RSL3 or sorafenib on stiff substrate via FTL, whereas its overexpression abolished these upward trends. Notably, PD-L2 deletion in combination with sorafenib and anti-PD-1 antibody significantly sensitized HCC cells and blunted cancer growth in vivo. Additionally, we found the ferroptosis- and immune checkpoint-related prognostic genes that combined PD-L2, SLC7A11 and SYMD3 well predict the clinical efficacy of sorafenib in patients with HCC.
CONCLUSIONS: These findings expand our understanding of the mechanics-dependent PD-L2 role in ferroptosis, cancer progression and resistance, providing a basis for the clinical translation of PD-L2 as a therapeutic target or diagnostic biomarker.