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基于二硫键蛋白降解相关长链非编码 RNA 的子宫内膜癌新型预后标志物的建立和治疗反应预测

Disulfidptosis-Related lncRNA for the Establishment of Novel Prognostic Signature and Therapeutic Response Prediction to Endometrial Cancer.

机构信息

Department of Obstetrics and Gynecology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China.

出版信息

Reprod Sci. 2024 Mar;31(3):811-822. doi: 10.1007/s43032-023-01382-x. Epub 2023 Oct 25.

Abstract

Disulfidptosis, a newly discovered cellular death mechanism initiated by disulfide stress, features elevated expression of SLC7A11 and restricted glucose availability, rendering it a possible therapeutic target for cancer. Endometrial cancer of the uterine corpus (ECUC) ranks among prevalent gynecological malignancies. Long non-coding RNAs (lncRNAs) have been implicated in ECUC's metabolic pathways, invasive capabilities, and metastatic processes. Yet, the prognostic implications of Disulfidptosis-Linked lncRNAs (DLLs) in ECUC remain ambiguous. Transcriptome and clinical datasets related to ECUC were sourced from The Cancer Genome Atlas (TCGA), while genes linked with disulfidptosis were identified from existing literature. A panel of ten DLLs was discerned through least absolute shrinkage and selection operator (LASSO) coupled with Cox regression methods to formulate and validate risk prognostic models. We engineered a nomogram for ECUC patient prognosis forecasting and further examined the model via gene set enrichment analysis (GSEA), principal component analysis (PCA), gene set analysis (GSA), immune profiling, and sensitivity to antineoplastic agents. Prognostic models employing a set of ten DLLs (including AC005034.2, AC020765.2, AL158071.4, AL161663.2, AP000787.1, CR392039.3, EMSLR, SEC24B-AS1, Z69733.1, Z94721.3) were established. Based on median risk values, patient samples were stratified into high- and low-risk cohorts, revealing notable differences in survival across both training and validation datasets. The risk scores, when amalgamated with clinical variables, acted as standalone predictors of prognosis. GSEA findings indicated that the high-risk category predominantly aligned with pathways like extracellular matrix interactions and cell adhesion molecules, suggesting a likely association with metastatic potential. Concurrently, we scrutinized disparities in immune function and tumor mutational burden across risk categories and identified anticancer drugs with likely efficacy. In summary, a set of ten DLLs proved useful in forecasting patient outcomes and holds potential for informing targeted therapeutic approaches in ECUC.

摘要

二硫键程序性细胞死亡,一种新发现的由二硫键应激引发的细胞死亡机制,其特征是 SLC7A11 表达升高和葡萄糖供应受限,使其成为癌症的潜在治疗靶点。子宫内膜癌是常见的妇科恶性肿瘤之一。长链非编码 RNA(lncRNA)已被涉及到子宫内膜癌的代谢途径、侵袭能力和转移过程。然而,二硫键程序性细胞死亡相关 lncRNA(DLLs)在子宫内膜癌中的预后意义仍不清楚。与子宫内膜癌相关的转录组和临床数据集来源于癌症基因组图谱(TCGA),而与二硫键程序性细胞死亡相关的基因则来源于现有文献。通过最小绝对收缩和选择算子(LASSO)与 Cox 回归方法相结合,确定了一组十个 DLLs,用于构建和验证风险预后模型。我们为子宫内膜癌患者预后预测设计了一个列线图,并通过基因集富集分析(GSEA)、主成分分析(PCA)、基因集分析(GSA)、免疫分析和对抗肿瘤药物的敏感性进一步检验了该模型。该模型采用一组十个 DLLs(包括 AC005034.2、AC020765.2、AL158071.4、AL161663.2、AP000787.1、CR392039.3、EMSLR、SEC24B-AS1、Z69733.1、Z94721.3)来建立预后模型。根据中位数风险值,将患者样本分为高风险和低风险队列,在训练和验证数据集均显示出显著的生存差异。风险评分与临床变量相结合,可作为预后的独立预测因子。GSEA 结果表明,高风险组主要与细胞外基质相互作用和细胞黏附分子等途径相关,提示与转移潜能可能相关。同时,我们还研究了风险组之间免疫功能和肿瘤突变负荷的差异,并确定了可能有效的抗肿瘤药物。总之,一组十个 DLL 可用于预测患者的预后,为子宫内膜癌的靶向治疗提供了潜在的依据。

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