Department of Thoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Oncology Department I, Huai'an 82 Hospital, Huai'an, Jiangsu, China.
Front Immunol. 2024 Oct 30;15:1481753. doi: 10.3389/fimmu.2024.1481753. eCollection 2024.
Lung cancer is a leading cause of cancer-related deaths, with its incidence continuing to rise. Chromatin remodeling, a crucial process in gene expression regulation, plays a significant role in the development and progression of malignant tumors. However, the role of chromatin regulators (CRs) in lung adenocarcinoma (LUAD) remains underexplored.
This study developed a chromatin regulator-related signature (CRRS) using a 429-combination machine learning approach to predict survival outcomes in LUAD patients. The CRRS model was validated across multiple independent datasets. We also investigated the impact of CRRS on the immune microenvironment, focusing on immune cell infiltration. To identify potential therapeutic targets, TFF1, a chromatin regulator, was knocked down using siRNA in LUAD cells. We assessed its impact through apoptosis analysis, proliferation assays, and in vivo tumor growth studies. Additional validation was performed using Ki67 expression and TUNEL assays.
The CRRS accurately predicted survival outcomes and was shown to modulate immune cell infiltration in the tumor microenvironment. High-risk patients demonstrated increased activity in cell cycle regulation and DNA repair pathways, along with distinct mutation profiles and immune responses compared to low-risk patients. TFF1 emerged as a key therapeutic target. Knockdown of TFF1 significantly inhibited LUAD cell proliferation, induced apoptosis, and suppressed in vivo tumor growth. Ki67 and TUNEL assays confirmed the role of TFF1 in regulating tumor growth and cell death.
These findings highlight the potential of chromatin regulators in prognostic modeling and immune modulation in LUAD. TFF1 was identified as a promising therapeutic target, suggesting that targeting TFF1 could provide new treatment strategies. Further research is warranted to explore its full potential and therapeutic applicability.
肺癌是癌症相关死亡的主要原因，其发病率持续上升。染色质重塑是基因表达调控的关键过程，在恶性肿瘤的发生和发展中起着重要作用。然而，染色质调节剂（CRs）在肺腺癌（LUAD）中的作用仍未得到充分探索。
本研究使用 429 种组合的机器学习方法开发了一种染色质调节剂相关特征（CRRS），以预测 LUAD 患者的生存结果。CRRS 模型在多个独立数据集上进行了验证。我们还研究了 CRRS 对免疫微环境的影响，重点关注免疫细胞浸润。为了确定潜在的治疗靶点，使用 siRNA 敲低 LUAD 细胞中的 TFF1（一种染色质调节剂）。我们通过凋亡分析、增殖测定和体内肿瘤生长研究评估了其影响。使用 Ki67 表达和 TUNEL 测定进行了额外的验证。
CRRS 准确预测了生存结果，并显示调节肿瘤微环境中的免疫细胞浸润。与低风险患者相比，高危患者在细胞周期调控和 DNA 修复途径中表现出更高的活性，并且具有独特的突变谱和免疫反应。TFF1 是一个关键的治疗靶点。TFF1 的敲低显著抑制了 LUAD 细胞的增殖，诱导了细胞凋亡，并抑制了体内肿瘤的生长。Ki67 和 TUNEL 测定证实了 TFF1 在调节肿瘤生长和细胞死亡中的作用。
这些发现强调了染色质调节剂在 LUAD 中的预后建模和免疫调节中的潜在作用。TFF1 被确定为一个有前途的治疗靶点，表明靶向 TFF1 可能提供新的治疗策略。需要进一步研究以探索其全部潜力和治疗适用性。
