间皮瘤,一种罕见但高度侵袭性的恶性肿瘤,对当前治疗方法的有效性提出了挑战。Ferroptosis,细胞死亡的非凋亡机制,表现出与多种癌症形式的进展有实质性的关联。重要的是要认识到铁性死亡与各种形式的癌症的进展之间存在显著的关联。然而,在间皮瘤的背景下,铁凋亡调节因子的确切作用仍然是一个谜。在我们的调查中,我们最初研究了间皮瘤领域24种铁凋亡调节因子的预后意义.我们的观察结果揭示了CARS1,CDKN1A的表达水平升高,TFRC,FANCD2,FDFT1,HSPB1,SLC1A5,SLC7A11,与DPP4表达减少,提示预后不良。建立在之前讨论的九个预后基因上,铁性凋亡预后模型提供了一种可靠的方法来预测间皮瘤患者的生存率,并具有相当高的精确度.此外,这些预后铁凋亡调节因子与免疫细胞浸润等参数之间出现了显着的相关性,肿瘤突变负荷,微卫星不稳定,间皮瘤中PD-L1的表达。在这9个具有预后相关性的铁死亡调节因子中,FANCD2表现出最明显的预后影响,正如我们的分析所阐明的。随后,我们使用来自我们机构的临床标本执行了验证过程,因此证实FANCD2表达升高是间皮瘤不良预后的可辨别的预兆.体外实验表明,敲低FANCD2可以明显抑制增殖,迁移,间皮瘤细胞吸引免疫细胞的能力。此外,我们的研究结果还表明,降低FANCD2水平会增加间皮瘤细胞对铁性凋亡诱导物的脆弱性。此外,广泛的泛癌症分析揭示了FANCD2和与免疫检查点相关的基因表达之间的强烈关联,从而表明在广泛的癌症类型中的不良预后。需要额外的研究来验证这些发现。
Mesothelioma, an uncommon yet highly aggressive malignant neoplasm, presents challenges in the effectiveness of current therapeutic approaches. Ferroptosis, a non-apoptotic mechanism of cellular demise, exhibits a substantial association with the progression of diverse cancer forms. It is important to acknowledge that there exists a significant association between ferroptosis and the advancement of various forms of cancer. Nevertheless, the precise role of ferroptosis regulatory factors within the context of mesothelioma remains enigmatic. In our investigation, we initially scrutinized the prognostic significance of 24 ferroptosis regulatory factors in the realm of mesothelioma. Our observations unveiled that heightened expression levels of CARS1, CDKN1A, TFRC, FANCD2, FDFT1, HSPB1, SLC1A5, SLC7A11, coupled with reduced DPP4 expression, were indicative of an unfavorable prognosis. Built upon the nine previously discussed prognostic genes, the ferroptosis prognostic model offers a reliable means to forecast mesothelioma patients\' survival with a substantial degree of precision. Furthermore, a notable correlation emerged between these prognostic ferroptosis regulators and parameters such as immune cell infiltration, tumor mutation burden, microsatellite instability, and PD-L1 expression in the context of mesothelioma. Within this cadre of nine ferroptosis regulatory factors with prognostic relevance, FANCD2 exhibited the most pronounced prognostic influence, as elucidated by our analyses. Subsequently, we executed a validation process employing clinical specimens sourced from our institution, thus confirming that heightened FANCD2 expression is a discernible harbinger of an adverse prognosis in the context of mesothelioma. In vitro experiments revealed that knocking down FANCD2 markedly suppressed the proliferation, migration, and ability of mesothelioma cells to attract immune cells. Furthermore, our findings also showed that reducing FANCD2 levels heightened the vulnerability of mesothelioma cells to inducers of ferroptosis. Furthermore, an extensive pan-cancer analysis uncovered a robust association between FANCD2 and the gene expression linked to immune checkpoints, thereby signifying an adverse prognosis across a broad spectrum of cancer types. Additional research is warranted to validate these findings.