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基于液-液相分离和铁死亡相关基因的肝细胞癌机器学习诊断模型

Machine Learning Diagnostic Model for Hepatocellular Carcinoma Based on Liquid-Liquid Phase Separation and Ferroptosis-Related Genes.

作者信息

Chen Wenchao, Zhu Ting, Pu Xiaofan, Zhao Linlin, Zhou Senhao, Zhong Xin, Wang Suihan, Lin Tianyu

机构信息

Department of General Surgery, Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou, China.

Department of Thoracic Surgery, Shaoxing People's Hospital, Shaoxing, China.

出版信息

Turk J Gastroenterol. 2024 Oct 7;36(2):89-99. doi: 10.5152/tjg.2024.24101.

DOI:10.5152/tjg.2024.24101
PMID:39635757
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11843271/
Abstract

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) represents a primary liver malignancy with a multifaceted molecular landscape. The interplay between liquid-liquid phase separation (LLPS) and ferroptosis-a regulated form of cell death-has garnered interest in tumorigenesis. However, the precise role of LLPS and ferroptosis-related genes in HCC progression and prognosis remains obscure. Unraveling this connection could pave the way for innovative diagnosis and therapeutic strategies.

MATERIALS AND METHODS

The differentially expressed genes (DEGs) were identified based on 3 GEO datasets, followed by overlapping with LLPS-related and ferroptosis-related genes. Based on central hub genes, a diagnostic model was developed through LASSO regression and validated using KM survival analysis and real-time quantitative polymerase chain reaction (RT-qPCR). Then the effects of NRAS on the development of HCC and ferroptosis were also detected.

RESULTS

We identified 24 DEGs overlapping among HCC-specific, LLPS, and ferroptosis-related genes. A diagnostic model, centered on 5 hub genes, was developed and validated. Lower expression of these genes corresponded with enhanced patient survival rates, and they were distinctly overexpressed in HCC cells. NRAS downregulation significantly inhibited HepG2 cell proliferation and migration (P < .01). Fe2+ content and ROS levels were both significantly increased in the si-NRAS group when compared to those in the si-NC group (P < .01), while opposite results were observed for the protein level of GPX4 and GSH content.

CONCLUSION

The diagnostic model with 5 hub genes (EZH2, HSPB1, NRAS, RPL8, and SUV39H1) emerges as a potential innovative tool for the diagnosis of HCC. NRAS promotes the carcinogenesis of HCC cells and inhibits ferroptosis.

摘要

背景/目的：肝细胞癌（HCC）是一种具有多方面分子格局的原发性肝脏恶性肿瘤。液-液相分离（LLPS）与铁死亡（一种受调控的细胞死亡形式）之间的相互作用已引起人们对肿瘤发生的关注。然而，LLPS和铁死亡相关基因在HCC进展和预后中的精确作用仍不清楚。阐明这种联系可能为创新的诊断和治疗策略铺平道路。

材料与方法

基于3个基因表达综合数据库（GEO）数据集鉴定差异表达基因（DEG），然后与LLPS相关基因和铁死亡相关基因进行重叠。基于中心枢纽基因，通过套索回归建立诊断模型，并使用KM生存分析和实时定量聚合酶链反应（RT-qPCR）进行验证。然后还检测了NRAS对HCC发生发展和铁死亡的影响。

结果

我们在HCC特异性、LLPS和铁死亡相关基因中鉴定出24个重叠的DEG。建立并验证了一个以5个枢纽基因为中心的诊断模型。这些基因的低表达与患者生存率提高相关，并且它们在HCC细胞中明显过表达。NRAS下调显著抑制HepG2细胞增殖和迁移（P <.01）。与si-NC组相比，si-NRAS组的Fe2+含量和ROS水平均显著升高（P <.01），而GPX4蛋白水平和GSH含量则观察到相反的结果。

结论

具有5个枢纽基因（EZH2、HSPB1、NRAS、RPL8和SUV39H1）的诊断模型成为诊断HCC的潜在创新工具。NRAS促进HCC细胞的癌变并抑制铁死亡。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/516b/11843271/a99871cf6020/tjg-36-2-89_S002.jpg
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本文引用的文献

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Smad2/3/4 complex could undergo liquid liquid phase separation and induce apoptosis through TAT in hepatocellular carcinoma.Smad2/3/4复合物可发生液-液相分离，并通过TAT在肝细胞癌中诱导细胞凋亡。
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EphA2 as a phase separation protein associated with ferroptosis and immune cell infiltration in colorectal cancer.
EphA2 作为一种相分离蛋白，与结直肠癌中的铁死亡和免疫细胞浸润有关。
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Cytoskeleton remodeling mediated by circRNA-YBX1 phase separation suppresses the metastasis of liver cancer.环状 RNA-YBX1 相分离介导的细胞骨架重构抑制肝癌转移。
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Gluconeogenic enzyme PCK1 supports S-adenosylmethionine biosynthesis and promotes H3K9me3 modification to suppress hepatocellular carcinoma progression.糖异生酶 PCK1 支持 S- 腺苷甲硫氨酸的生物合成，并促进 H3K9me3 的修饰，以抑制肝癌的进展。
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