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Tumor-secreted LCN2 impairs gastric cancer progression via autocrine inhibition of the 24p3R/JNK/c-Jun/SPARC axis

Authors :
Zhixin Huang
Ying Li
Yan Qian
Ertao Zhai
Zeyu Zhao
Tianhao Zhang
Yinan Liu
Linying Ye
Ran Wei
Risheng Zhao
Zikang Li
Zhi Liang
Shirong Cai
Jianhui Chen
Source :
Cell Death and Disease, Vol 15, Iss 10, Pp 1-15 (2024)
Publication Year :
2024
Publisher :
Nature Publishing Group, 2024.

Abstract

Abstract Gastric cancer (GC) is one of the most lethal malignancies worldwide. Despite extensive efforts to develop novel therapeutic targets, effective drugs for GC remain limited. Recent studies have indicated that Lipocalin (LCN)2 abnormalities significantly impact GC progression; however, its regulatory network remains unclear. Our study investigates the functional role and regulatory mechanism of action of LCN2 in GC progression. We observed a positive correlation between LCN2 expression, lower GC grade, and better prognosis in patients with GC. LCN2 overexpression suppressed GC proliferation and metastasis both in vitro and in vivo. Transcriptome sequencing identified secreted protein acidic and rich in cysteine (SPARC) as a pivotal downstream target of LCN2. Mechanistically, c-Jun acted as a transcription factor inducing SPARC expression, and LCN2 downregulated SPARC by inhibiting the JNK/c-Jun pathway. Moreover, LCN2 bound to its receptor, 24p3R, via autocrine signaling, which directly inhibited JNK phosphorylation and then inhibited the JNK/c-Jun pathway. Finally, analysis of clinical data demonstrated that SPARC expression correlated negatively with lower GC grade and better prognosis, and that LCN2 expression correlated negatively with p-JNK, c-Jun, and SPARC expression in GC. These findings suggest that the LCN2/24p3R/JNK/c-Jun/SPARC axis is crucial in the malignant progression of GC, offering novel prognostic markers and therapeutic targets.

Subjects

Subjects :
Cytology
QH573-671

Details

Language :
English
ISSN :
20414889
Volume :
15
Issue :
10
Database :
Directory of Open Access Journals
Journal :
Cell Death and Disease
Publication Type :
Academic Journal
Accession number :
edsdoj.b4dc1ba1348b4c83a755c036af676fe4
Document Type :
article
Full Text :
https://doi.org/10.1038/s41419-024-07153-z