肝细胞癌中铁中毒相关亚型的鉴定和验证及其预测特征。

IF 1.8 4区 医学 Q3 PHARMACOLOGY & PHARMACY Pharmacogenomics & Personalized Medicine Pub Date : 2023-01-01 DOI:10.2147/PGPM.S397892
Chunlan Zheng, Yanan Peng, Haizhou Wang, Youwei Wang, Lan Liu, Qiu Zhao
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引用次数: 2

摘要

背景:肝细胞癌(HCC)是世界上最常见的恶性肿瘤之一,具有免疫抑制肿瘤微环境(TME)。铁下垂在肿瘤的增殖、侵袭和转移中起着重要的作用。然而,铁下垂与肝癌TME之间的关系尚不明确。方法:从癌症基因组图谱(TCGA)中获取正常肝组织与HCC组织间差异表达的铁中毒相关基因(DE FRGs)。在此基础上,我们确定了DE FRGs和TME细胞浸润介导的分子亚型。接下来,通过执行最小绝对收缩和选择算子Cox回归分析,建立了预测特征,以量化铁衰相关特征。单因素和多因素COX分析确定了独立的预后因素。最后,我们验证了3个铁中毒相关特征基因在HCC癌及癌旁正常组织中的表达稳定性。结果:我们鉴定出三种不同的分子亚型,发现预后较好的亚型与TME中免疫和代谢相关标志信号通路的高富集和免疫细胞的高浸润有关。该特征被认为是一个独立的预后因素。我们还发现该特征可以反映TME中不同免疫细胞的浸润特征。免疫抑制细胞,如髓源性抑制细胞(MDSCs)、调节性T细胞和17型T辅助细胞在高危组中显著富集。免疫检查点和肿瘤突变负荷的分析数据表明,该标记在预测免疫治疗反应和化疗敏感性方面具有很大的潜力。此外,在HCC组织和HCC细胞系中证实了3个铁中毒相关特征基因的过表达。铁下垂诱导剂RSL3可抑制肝癌细胞的增殖,是一种潜在的肿瘤免疫治疗药物。结论:这些发现增强了我们对肝癌铁下垂的调控机制的认识,为肝癌预后评估和制定更有效的免疫治疗和化疗策略提供了新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Identification and Validation of Ferroptosis-Related Subtypes and a Predictive Signature in Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world with an immunosuppressive Tumor microenvironment (TME). Ferroptosis plays an essential role in tumor proliferation, invasion, and metastasis. However, the relationship between ferroptosis and TME of HCC has remained elusive.

Methods: Differentially expressed ferroptosis-related genes (DE FRGs) between normal liver tissues and HCC tissues were obtained from The Cancer Genome Atlas (TCGA). On this basis, we identified the molecular subtypes mediated by DE FRGs and TME cell infiltration. Next, a predictive signature was established to quantity the ferroptosis-related characteristics by performing the least absolute shrinkage and selection operator Cox regression analyses. Univariate and multivariate COX analyses determined the independent prognostic factors. Finally, the expression stability of 3 ferroptosis-related signature genes was verified in cancer and paracancerous normal tissues of HCC.

Results: We identified three different molecular subtypes and found that the subtype with the better prognosis was associated with high enrichment of immune- and metabolic-related hallmark signaling pathways and high infiltration of immune cells in TME. The signature was considered to be an independent prognostic factor. We also found that the signature can reflect the infiltration characteristics of different immune cells in TME. Immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs), regulatory T cells, and type 17 T helper cells were significantly enriched in the high-risk group. The analysis data of immune checkpoints and tumor mutation load indicated that the signature had great potential in predicting Immunotherapy response and chemotherapeutic sensitivity. In addition, the overexpression of 3 ferroptosis-related signature genes was confirmed in HCC tissues and HCC cell lines. Ferroptosis inducer RSL3 inhibited the proliferation of HCC cells and was a potential cancer immunotherapy agent.

Conclusion: These findings enhanced our understanding of the regulatory mechanism of ferroptosis in HCC and provided new insights into evaluating prognosis and developing more effective Immunotherapy and chemotherapy strategies.

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来源期刊
Pharmacogenomics & Personalized Medicine
Pharmacogenomics & Personalized Medicine Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
3.30
自引率
5.30%
发文量
110
审稿时长
16 weeks
期刊介绍: Pharmacogenomics and Personalized Medicine is an international, peer-reviewed, open-access journal characterizing the influence of genotype on pharmacology leading to the development of personalized treatment programs and individualized drug selection for improved safety, efficacy and sustainability. In particular, emphasis will be given to: Genomic and proteomic profiling Genetics and drug metabolism Targeted drug identification and discovery Optimizing drug selection & dosage based on patient''s genetic profile Drug related morbidity & mortality intervention Advanced disease screening and targeted therapeutic intervention Genetic based vaccine development Patient satisfaction and preference Health economic evaluations Practical and organizational issues in the development and implementation of personalized medicine programs.
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