Lu Jianming, Liang Jiaqi, Xiao Gang, He Zitao, Yu Guifang, Zhang Le, Cai Chao, Yi Gao, Xie Jianjiang
Center for Medical Research on Innovation and Translation, Institute of Clinical Medicine, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China.
Pneumology Department, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.
Cancer Inform. 2024 Dec 16;23:11769351241307492. doi: 10.1177/11769351241307492. eCollection 2024.
Lung adenocarcinoma (LUAD), a predominant form of lung cancer, is characterized by a high rate of metastasis and recurrence, leading to a poor prognosis for LUAD patients. This study aimed to identify and rigorously validate a highly precise biomarker, Cathepsin L (CTSL), for the prognostic prediction of lung adenocarcinoma.
We employed a multicenter and omics-based approach, analyzing RNA sequencing data and mutation information from public databases such as The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The DepMap portal with Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR/Cas9) technology was used to assess the functional impact of CTSL. Immunohistochemistry (IHC) was conducted on a local cohort to validate the prognostic significance of CTSL at the protein expression level.
Our findings revealed a significant correlation between elevated CTSL expression and advanced disease stage in LUAD patients. Kaplan-Meier survival analysis and Cox regression modeling revealed that high CTSL expression is associated with poor overall survival. The in vitro studies corroborated these findings, revealing notable suppression of tumor proliferation following CTSL knockout in cell lines, particularly in LUAD. Functional enrichment revealed that CTSL activated pathways associated with tumor progression, such as angiogenesis and Transforming growth factor beta (TGF-beta) signaling, and inhibited pathways such as apoptosis and DNA repair. Mutation analysis revealed distinct variations in the CTSL expression groups.
This study highlights the crucial role of CTSL as a prognostic biomarker in LUAD. This combined multicenter and omics-based analysis provides comprehensive insights into the biological role of CTSL, supporting its potential as a target for therapeutic intervention and a marker for prognosis in patients with LUAD.
肺腺癌（LUAD）是肺癌的主要形式，其特点是转移和复发率高，导致LUAD患者预后不良。本研究旨在识别并严格验证一种用于肺腺癌预后预测的高精度生物标志物——组织蛋白酶L（CTSL）。
我们采用了基于多中心和组学的方法，分析了来自公共数据库如癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）的RNA测序数据和突变信息。利用带有成簇规律间隔短回文重复序列（CRISPR/Cas9）技术的DepMap门户来评估CTSL的功能影响。对一个本地队列进行免疫组织化学（IHC），以在蛋白质表达水平上验证CTSL的预后意义。
我们的研究结果显示，LUAD患者中CTSL表达升高与疾病晚期显著相关。Kaplan-Meier生存分析和Cox回归模型显示，高CTSL表达与总体生存不良相关。体外研究证实了这些发现，显示在细胞系中，特别是在LUAD细胞系中，CTSL基因敲除后肿瘤增殖受到显著抑制。功能富集分析显示，CTSL激活了与肿瘤进展相关的通路，如血管生成和转化生长因子β（TGF-β）信号通路，并抑制了如细胞凋亡和DNA修复等通路。突变分析揭示了CTSL表达组中的明显差异。
本研究强调了CTSL作为LUAD预后生物标志物的关键作用。这种基于多中心和组学的综合分析为CTSL的生物学作用提供了全面的见解，支持其作为治疗干预靶点和LUAD患者预后标志物的潜力。
