National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, China; Shenzhen Key Laboratory of Orthopaedic Diseases and Biomaterials Research, Shenzhen 518036, China; Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, China.
Department of Thoracic Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China.
Int Immunopharmacol. 2024 Dec 25;143(Pt 1):113282. doi: 10.1016/j.intimp.2024.113282. Epub 2024 Oct 8.
Anoikis, a form of programmed cell death induced by loss of cell contact, is closely associated with tumor invasion and metastasis, making it highly significant in lung cancer research. We examined the expression patterns and prognostic relevance of Anoikis-related genes (ARGs) in lung adenocarcinoma (LUAD) using the TCGA-LUAD database. This study identified molecular subtypes associated with Anoikis in LUAD and conducted functional enrichment analyses. We constructed an ARG risk score using univariate least absolute shrinkage and selection operator (LASSO) Cox regression, validated externally with GEO datasets and clinical samples. The clinical applicability of the prognostic model was evaluated using nomograms, calibration curves, decision curve analysis (DCA), and time-dependent AUC assessments. We identified four prognostically significant genes (PLK1, SLC2A1, CDKN3, PHLDA2) and two ARG-related molecular subtypes. ARGs were generally upregulated in LUAD and correlated with multiple pathways including the cell cycle and DNA replication. The prognostic model indicated that the low-risk group had better outcomes and significant correlations with clinicopathological features, tumor microenvironment, immune therapy responses, drug sensitivity, and pan-RNA epigenetic modification-related genes. Patients with low-risk LUAD were potential beneficiaries of immune checkpoint inhibitor (ICI) therapy. Prognostic ARGs' distribution and expression across various immune cell types were further analyzed using single-cell RNA sequencing. The pivotal role of CDKN3 in LUAD was confirmed through qRT-PCR and gene knockout experiments, demonstrating that CDKN3 knockdown inhibits tumor cell proliferation, migration, and invasion. Additionally, we constructed a ceRNA network involving CDKN3/hsa-miR-26a-5p/SNHG6, LINC00665, DUXAP8, and SLC2A1/hsa-miR-218-5p/RNASEH1-AS1, providing new insights for personalized and immune therapy decisions in LUAD patients.
失巢凋亡，一种由细胞接触丧失诱导的程序性细胞死亡形式，与肿瘤的侵袭和转移密切相关，因此在肺癌研究中具有重要意义。我们使用 TCGA-LUAD 数据库检查了肺癌中的失巢凋亡相关基因 (ARGs) 的表达模式和预后相关性。本研究确定了与 LUAD 中失巢凋亡相关的分子亚型，并进行了功能富集分析。我们使用单变量最小绝对收缩和选择算子 (LASSO) Cox 回归构建了一个 ARG 风险评分，并用 GEO 数据集和临床样本进行了外部验证。使用列线图、校准曲线、决策曲线分析 (DCA) 和时间依赖 AUC 评估评估了预后模型的临床适用性。我们确定了四个具有预后意义的基因 (PLK1、SLC2A1、CDKN3、PHLDA2) 和两个 ARG 相关的分子亚型。ARGs 在 LUAD 中普遍上调，并与包括细胞周期和 DNA 复制在内的多个途径相关。预后模型表明，低风险组的预后更好，与临床病理特征、肿瘤微环境、免疫治疗反应、药物敏感性和泛 RNA 表观遗传修饰相关基因有显著相关性。低风险 LUAD 患者可能受益于免疫检查点抑制剂 (ICI) 治疗。进一步使用单细胞 RNA 测序分析了不同免疫细胞类型中预后 ARGs 的分布和表达。通过 qRT-PCR 和基因敲除实验证实了 CDKN3 在 LUAD 中的关键作用，表明 CDKN3 敲低抑制肿瘤细胞增殖、迁移和侵袭。此外，我们构建了一个涉及 CDKN3/hsa-miR-26a-5p/SNHG6、LINC00665、DUXAP8 和 SLC2A1/hsa-miR-218-5p/RNASEH1-AS1 的 ceRNA 网络，为 LUAD 患者的个性化和免疫治疗决策提供了新的见解。
