鉴定肝癌中与细胞坏死相关的预后特征和相关调控轴。
Identification of a Necroptosis-Related Prognostic Signature and Associated Regulatory Axis in Liver Hepatocellular Carcinoma.
机构信息
Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China.
Department of Emergency, Second Affiliated Hospital of Nanchang University, Nanchang, China.
出版信息
Dis Markers. 2022 Jul 9;2022:3968303. doi: 10.1155/2022/3968303. eCollection 2022.
BACKGROUND
Liver hepatocellular carcinoma (LIHC) ranks the sixth in global cancer incidence with poor prognosis. Necroptosis is a kind of regulated cell death and has been proved to be of significance in cancer occurrence and progression. However, few studies comprehensively discuss the potential applications of necroptosis-related genes (NRGs) in the prognostic evaluation and immunotherapy of LIHC.
METHODS
The prognostic signature in the present study was built up using LASSO Cox regression analysis. Integrated bioinformatics tools were utilized to explore the potential mRNA-miRNA-lncRNA regulatory axis in LIHC. Furthermore, qRT-PCR method was used to verify the EZH2 expression in LIHC tissues. Furthermore, prognostic performance of EZH2 in LIHC was assessed by Kaplan-Meier method.
RESULTS
A total of 14 NRGs were differentially expressed in LIHC tissues. The overall genetic mutation status of these NRGs in LIHC was also shown. NRGs were significantly correlated with programmed necrotic cell death, as well as Toll-like receptor signaling pathway in GO and KEGG pathway analysis. Kaplan-Meier analysis revealed that ALDH2, EZH2, NDRG2, PGAM5, RIPK1, and TRAF2 were related to the prognosis. A prognostic signature was constructed by these six genes and showed medium to high accuracy in the prediction of LIHC patients' prognosis. Further analysis revealed that NRGs were correlated with pathological stage, immune infiltration, and drug resistance in LIHC. Moreover, we identified a potential lncRNA TUG1/miR-26b-5p/EZH2 regulatory axis in LIHC, which might affect the progression of LIHC. qRT-PCR suggested a higher mRNA level of EZH2 in LIHC tissues. And a poor overall survival rate was detected in LIHC patients with high EZH2 expression. Moreover, EZH2 expression and cancer stage were identified as the independent risk factors affecting LIHC patients' prognosis.
CONCLUSION
In the present study, we conducted comprehensive bioinformatic analyses and built up a necroptosis-related prognostic signature containing four genes (ALDH2, EZH2, NDRG2, and PGAM5) for patients with LIHC, and this prognostic signature showed a medium to high predictive accuracy. And our study also identified a lncRNA TUG1/miR-26b-5p/EZH2 regulatory axis, which might be of great significance in LIHC progression. In addition, based on the data from our center, the result of qRT-PCR and survival analysis showed a higher mRNA level of EZH2 in LIHC tissues and an unfavorable prognosis in high EZH2 expression group, respectively.
背景
肝肝细胞癌（LIHC）在全球癌症发病率中排名第六，预后不良。细胞坏死是一种受调控的细胞死亡方式，已被证明在癌症的发生和发展中具有重要意义。然而，很少有研究全面探讨细胞坏死相关基因（NRGs）在 LIHC 的预后评估和免疫治疗中的潜在应用。
方法
本研究使用 LASSO Cox 回归分析构建了预后特征。利用综合的生物信息学工具，探讨了 LIHC 中潜在的 mRNA-miRNA-lncRNA 调控轴。此外，通过 qRT-PCR 方法验证了 LIHC 组织中 EZH2 的表达。进一步采用 Kaplan-Meier 法评估 EZH2 在 LIHC 中的预后性能。
结果
在 LIHC 组织中，有 14 个 NRGs 存在差异表达。还显示了这些 NRGs 在 LIHC 中的整体遗传突变状态。GO 和 KEGG 通路分析表明，NRGs 与程序性坏死细胞死亡以及 Toll 样受体信号通路显著相关。Kaplan-Meier 分析表明，ALDH2、EZH2、NDRG2、PGAM5、RIPK1 和 TRAF2 与预后相关。由这 6 个基因构建的预后特征在预测 LIHC 患者的预后方面具有中等到较高的准确性。进一步分析表明，NRGs 与 LIHC 的病理分期、免疫浸润和耐药性相关。此外，我们在 LIHC 中鉴定了一个潜在的 lncRNA TUG1/miR-26b-5p/EZH2 调控轴，可能影响 LIHC 的进展。qRT-PCR 表明，在 LIHC 组织中 EZH2 的 mRNA 水平较高。EZH2 高表达的 LIHC 患者总生存率较低。此外，EZH2 表达和癌症分期被确定为影响 LIHC 患者预后的独立危险因素。
结论
在本研究中，我们进行了全面的生物信息学分析，并构建了一个包含四个基因（ALDH2、EZH2、NDRG2 和 PGAM5）的 LIHC 细胞坏死相关预后特征，该预后特征具有中等到较高的预测准确性。此外，我们还鉴定了一个 lncRNA TUG1/miR-26b-5p/EZH2 调控轴，这可能对 LIHC 的进展具有重要意义。此外，基于我们中心的数据，qRT-PCR 和生存分析的结果分别显示，在 LIHC 组织中 EZH2 的 mRNA 水平较高，在 EZH2 高表达组中预后不良。
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