Cathepsin L in Lung Adenocarcinoma: Prognostic Significance and Immunotherapy Response Through a Multi Omics Perspective

Jianming Lu; Jiaqi Liang; Gang Xiao; Zitao He; Guifang Yu; Le Zhang; Chao Cai; Gao Yi; Jianjiang Xie

doi:10.1177/11769351241307492

Cathepsin L in Lung Adenocarcinoma: Prognostic Significance and Immunotherapy Response Through a Multi Omics Perspective

Cancer Inform. 2024 Dec 16:23:11769351241307492. doi: 10.1177/11769351241307492. eCollection 2024.

Authors

Jianming Lu¹, Jiaqi Liang², Gang Xiao^{1

3}, Zitao He¹, Guifang Yu⁴, Le Zhang⁵, Chao Cai⁶, Gao Yi², Jianjiang Xie^{1

3}

Affiliations

¹ 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.
² 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.
³ Department of Thoracic Surgery, Guangzhou First People's Hospital, The Second Affiliated Hospital of South China University of Technology, Guangzhou, Guangdong, China.
⁴ Oncology 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.
⁵ Institute for Integrative Genome Biology, University of California, Riverside, Riverside, CA, USA.
⁶ Department of Urology, Guangdong Key Laboratory of Urology, Guangzhou Institute of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.

Abstract

Objectives: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Cathepsin L; Lung adenocarcinoma; immunotherapy; multi-center study; omics analysis; prognostic biomarker.