Cui Bing, Xu Chengcheng, Xu Yuan, Chen Aqin, Mao Chaoming, Chen Yuehua
Department of Blood Transfusion, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu Province, China.
Department of Nuclear Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu Province, China.
Zhejiang Da Xue Xue Bao Yi Xue Ban. 2024 Dec 25;53(6):691-698. doi: 10.3724/zdxbyxb-2024-0095.
To explore a causal relationship between ferroptosis-related gene heat shock protein A5 (HSPA5) and hepatocellular carcinoma (HCC).
A two-sample Mendelian randomization (MR) design was employed to evaluate the causal relationships among HSPA5, regulatory T cells (Tregs), and HCC. Single nucleotide polymorphisms (SNPs) associated with HSPA5, Tregs and HCC were selected as instrumental variables through publicly available genome-wide association studies (GWAS) databases. MR analysis was used to assess the direct effect of HSPA5 on HCC, followed by two-step MR to analyze the potential mediating role of Tregs. Reverse MR analysis was conducted with HCC as the exposure and HSPA5 as the outcome. Inverse variance weighting was the primary method for testing causal associations in all MR analyses. Robustness of the results was confirmed through MR-Egger, weighted median, weighted mode, and simple mode methods. Heterogeneity of instrumental variables was evaluated using Cochrane's statistic, while pleiotropy was tested by MR-Egger intercept and MR-PRESSO, with leave-one-out sensitivity analysis performed for robustness. Data from The Cancer Genome Atlas (TCGA) and Human Protein Atlas (HPA) were utilized to verify the expression levels of HSPA5 in HCC tissues and its correlation with Tregs to reveal the interaction mechanisms between HSPA5 and Tregs in HCC progression and their relationship with patient prognosis.
MR analysis showed a positive correlation between elevated HSPA5 expression and HCC risk (all <0.01), while reverse MR analysis found no statistically significant association between HCC and HSPA5 (>0.05). HSPA5 expression was significantly correlated with Tregs function (all <0.05), and the enrichment of Tregs in HCC microenvironment was positively associated with HCC progression (all <0.05). Mediation analysis indicated that Tregs accounted for 5.00% and 7.45% of the mediation effect between HSPA5 and HCC. TCGA and HPA database analysis revealed that both HSPA5 mRNA and protein expression levels were higher in HCC tissues compared to normal tissues, and high HSPA5 expression was significantly associated with poor prognosis. Immune infiltration analysis confirmed a significant positive correlation between HSPA5 and Tregs, with high Tregs infiltration closely related to HCC progression.
Elevated HSPA5 expression is significantly associated with HCC development and poor prognosis. HSPA5 may promote HCC progression by regulating the function of Tregs in the tumor microenvironment.
探讨铁死亡相关基因热休克蛋白A5（HSPA5）与肝细胞癌（HCC）之间的因果关系。
采用两样本孟德尔随机化（MR）设计评估HSPA5、调节性T细胞（Tregs）和HCC之间的因果关系。通过公开的全基因组关联研究（GWAS）数据库选择与HSPA5、Tregs和HCC相关的单核苷酸多态性（SNP）作为工具变量。MR分析用于评估HSPA5对HCC的直接影响，随后进行两步MR分析以分析Tregs的潜在中介作用。以HCC为暴露因素、HSPA5为结局进行反向MR分析。逆方差加权是所有MR分析中检验因果关联的主要方法。通过MR-Egger、加权中位数、加权模式和简单模式方法确认结果的稳健性。使用Cochrane统计量评估工具变量的异质性，通过MR-Egger截距和MR-PRESSO检验多效性，并进行留一法敏感性分析以验证稳健性。利用癌症基因组图谱（TCGA）和人类蛋白质图谱（HPA）的数据验证HSPA5在HCC组织中的表达水平及其与Tregs的相关性，以揭示HSPA5和Tregs在HCC进展中的相互作用机制及其与患者预后的关系。
MR分析显示HSPA5表达升高与HCC风险呈正相关（均<0.01），而反向MR分析发现HCC与HSPA5之间无统计学显著关联（>0.05）。HSPA5表达与Tregs功能显著相关（均<0.05），HCC微环境中Tregs的富集与HCC进展呈正相关（均<0.05）。中介分析表明，Tregs在HSPA5与HCC之间的中介效应中占5.00%和7.45%。TCGA和HPA数据库分析显示，与正常组织相比，HCC组织中HSPA5的mRNA和蛋白表达水平均较高，HSPA5高表达与预后不良显著相关。免疫浸润分析证实HSPA5与Tregs之间存在显著正相关，Tregs高浸润与HCC进展密切相关。
HSPA5表达升高与HCC发生及预后不良显著相关。HSPA5可能通过调节肿瘤微环境中Tregs的功能促进HCC进展。
