Chen Xiaomin, Hu Shunfeng, Han Yang, Cai Yiqing, Lu Tiange, Hu Xinting, Chu Yurou, Zhou Xiangxiang, Wang Xin
Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China.
Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Road, Jinan, 250021, Shandong, China.
Clin Exp Med. 2023 Oct;23(6):2601-2617. doi: 10.1007/s10238-023-00996-4. Epub 2023 Jan 22.
Diffuse large B cell lymphoma (DLBCL) is a usual-seen hematological malignant tumor possessing molecular and genetic heterogeneity. Ferroptosis induction has been increasingly acknowledged to be an advantageous therapeutic method in tumor treatment by triggering cell death of tumor cells. However, studies on the function of ferroptosis in DLBCL remain scarce, especially the interaction with the tumor immune microenvironment (TIME). The clinical and biological functions of ferroptosis-related genes in DLBCL were still warranted to be explored. A ferroptosis-related risk model was constructed, followed by functional enrichment analyses and evaluation of immune profile. Quantitative real-time PCR, western blotting, and immunohistochemistry were conducted to examine the RNA and protein levels. Dysregulated expression of the major ferroptosis-related genes was found in DLBCL. A prognostic risk model based on 10 ferroptosis-related genes was constructed. The risk score served as an independent prognostic indicator for DLBCL patients in univariate and multivariate Cox regression analysis. Patients with low-risk scores presented a more favorable prognosis. Functional enrichment analysis revealed that immune-related pathways were significantly enriched, and the high-risk group exhibited less immunocyte infiltration, lower immunoscore, and downregulated PD-L1 expression relative to the low-risk group. Two molecular subtypes were determined through consensus clustering of the expression of ferroptosis-related genes. Cluster 1 was relevant to favorable prognosis, higher immunoscore, and elevated PD-L1 expression. More importantly, STEAP3 was screened as a reliable biomarker for DLBCL, and its enhanced expression levels of mRNA and protein were verified in public databases and clinical specimens. Our study demonstrated the crucial role of ferroptosis-related genes including STEAP3 in the TIME of DLBCL and identified promising novel molecular targets for DLBCL treatment.
弥漫性大B细胞淋巴瘤（DLBCL）是一种常见的血液系统恶性肿瘤，具有分子和基因异质性。诱导铁死亡已越来越被认为是一种通过触发肿瘤细胞死亡来进行肿瘤治疗的有效方法。然而，关于铁死亡在DLBCL中的作用的研究仍然很少，尤其是与肿瘤免疫微环境（TIME）的相互作用。DLBCL中铁死亡相关基因的临床和生物学功能仍有待探索。构建了一个铁死亡相关风险模型，随后进行功能富集分析和免疫特征评估。采用定量实时PCR、蛋白质印迹法和免疫组织化学法检测RNA和蛋白质水平。发现DLBCL中主要铁死亡相关基因表达失调。构建了基于10个铁死亡相关基因的预后风险模型。在单因素和多因素Cox回归分析中，风险评分作为DLBCL患者的独立预后指标。低风险评分的患者预后更佳。功能富集分析显示免疫相关通路显著富集，与低风险组相比，高风险组免疫细胞浸润较少、免疫评分较低且PD-L1表达下调。通过对铁死亡相关基因表达的一致性聚类确定了两种分子亚型。聚类1与良好预后、较高免疫评分和升高的PD-L1表达相关。更重要的是，筛选出STEAP3作为DLBCL的可靠生物标志物，并在公共数据库和临床标本中验证了其mRNA和蛋白质表达水平的升高。我们的研究证明了包括STEAP3在内的铁死亡相关基因在DLBCL的TIME中的关键作用，并为DLBCL治疗确定了有前景的新型分子靶点。
