Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China; Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
Gene. 2024 Aug 15;919:148498. doi: 10.1016/j.gene.2024.148498. Epub 2024 Apr 24.
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.
间皮瘤是一种罕见但高度侵袭性的恶性肿瘤，目前的治疗方法效果有限。铁死亡是一种非凋亡性的细胞死亡机制，与多种癌症形式的进展有很大关联。需要注意的是，铁死亡与各种癌症形式的进展之间存在显著关联。然而，铁死亡调节因子在间皮瘤中的具体作用仍然是一个谜。在我们的研究中，我们首先研究了 24 个铁死亡调节因子在间皮瘤中的预后意义。我们的观察结果表明，CARS1、CDKN1A、TFRC、FANCD2、FDFT1、HSPB1、SLC1A5、SLC7A11 的表达水平升高，同时 DPP4 的表达降低，与不良预后相关。基于之前讨论的九个预后基因，铁死亡预后模型可以提供一种可靠的方法来预测间皮瘤患者的生存，具有较高的准确性。此外，在间皮瘤中，这些预后铁死亡调节剂与免疫细胞浸润、肿瘤突变负担、微卫星不稳定性和 PD-L1 表达等参数之间存在显著相关性。在这九个具有预后意义的铁死亡调节因子中，FANCD2 的预后影响最为显著，这是我们的分析结果所揭示的。随后，我们使用我们机构提供的临床标本进行了验证实验，证实了 FANCD2 表达升高是间皮瘤不良预后的一个明显标志。体外实验表明，敲低 FANCD2 显著抑制了间皮瘤细胞的增殖、迁移和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死亡诱导剂的敏感性。此外，广泛的泛癌症分析发现 FANCD2 与免疫检查点相关的基因表达之间存在强烈关联，表明在多种癌症类型中存在不良预后。需要进一步的研究来验证这些发现。
