Chang Wuguang, Gao Wuyou, Wu Yawei, Luo Bin, Zhong Lekai, Zhong Leqi, Lin Wenqian, Wen Zhesheng, Chen Youfang
Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.
Department of Thoracic Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
Front Med (Lausanne). 2025 Jan 7;11:1497312. doi: 10.3389/fmed.2024.1497312. eCollection 2024.
The lysosome plays a vitally crucial role in tumor development and is a major participant in the cell death process, involving aberrant functional and structural changes. However, there are few studies on lysosome-associated genes (LAGs) in lung adenocarcinoma (LUAD).
Bulk RNA-seq of LUAD was downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The lysosome risk signature was constructed after univariate and least absolute shrinkage and selection operator (Lasso) cox regression analysis of the TCGA training set, and its capability was validated by additional validation sets from GEO. Single cell sequencing (scRNA) was obtained from GEO to analyze the differences of lysosome risk signature at the single-cell level and the differences in the function and pathway. In vitro experiments have validated the function of CTSH in LUAD.
The risk signature contained seven key LAGs, and patients were categorized into high- and low-risk groups based on a specific calculation formula. The LAG risk signature, which accurately predicted the prognostic status of LUAD patients, was still regarded as an independent prognostic indicator in multifactorial cox regression analysis. Subsequently, the combination of the signature and key clinical information was used to construct a column-line diagram for clinical assessment, which had a high discriminatory power. Immune infiltration analysis from bulk RNA-seq and scRNA-seq indicated that the low-risk group was immune-activated and had a better benefit in the prediction of immunotherapy. Finally, we validated its role in inhibiting tumor proliferation and metastasis in LUAD cells by knockdown of CTSH.
We defined a new biomarker that provided unique insights for individualized survival prediction and immunotherapy recommendations for LUAD patients.
溶酶体在肿瘤发展中起着至关重要的作用，是细胞死亡过程的主要参与者，涉及功能和结构的异常变化。然而，关于肺腺癌（LUAD）中溶酶体相关基因（LAGs）的研究较少。
从癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）下载LUAD的批量RNA测序数据。对TCGA训练集进行单变量和最小绝对收缩和选择算子（Lasso）cox回归分析后构建溶酶体风险特征，并通过来自GEO的额外验证集验证其能力。从GEO获得单细胞测序（scRNA）数据，以分析溶酶体风险特征在单细胞水平上的差异以及功能和通路的差异。体外实验验证了CTSH在LUAD中的功能。
风险特征包含七个关键LAGs，并根据特定计算公式将患者分为高风险和低风险组。LAG风险特征准确预测了LUAD患者的预后状态，在多因素cox回归分析中仍被视为独立的预后指标。随后，将该特征与关键临床信息相结合，构建了用于临床评估的列线图，具有较高的鉴别力。来自批量RNA测序和scRNA测序的免疫浸润分析表明，低风险组具有免疫激活作用，在免疫治疗预测中具有更好的获益。最后，我们通过敲低CTSH验证了其在抑制LUAD细胞肿瘤增殖和转移中的作用。
我们定义了一种新的生物标志物，为LUAD患者的个体化生存预测和免疫治疗推荐提供了独特的见解。
