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

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

  • Cell Death Dis. 2024 Oct 18;15(10):756. doi: 10.1038/s41419-024-07153-z.
Zhixin Huang # 1 2 3,  Ying Li # 4,  Yan Qian # 1 2,  Ertao Zhai 1 2,  Zeyu Zhao 1 2 3,  Tianhao Zhang 1 2 3,  Yinan Liu 1 2 3,  Linying Ye 1 2 3,  Ran Wei 1 2 3,  Risheng Zhao 1 2,  Zikang Li 1 2 3,  Zhi Liang 1 2 3,  Shirong Cai 5 6,  Jianhui Chen 7 8
Affiliations

Affiliations

  • 1 Division of Gastrointestinal Surgery Center, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China.
  • 2 Gastric Cancer Center, Sun Yat-sen University, Guangzhou, 510080, Guangdong, China.
  • 3 Laboratory of Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China.
  • 4 Guangdong Provincial Key Laboratory of Microbial Safety and Health, National Health Commission Science and Technology Innovation Platform for Nutrition and Safety of Microbial Food, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, 510070, China.
  • 5 Division of Gastrointestinal Surgery Center, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China. caishr@mail.sysu.edu.cn.
  • 6 Gastric Cancer Center, Sun Yat-sen University, Guangzhou, 510080, Guangdong, China. caishr@mail.sysu.edu.cn.
  • 7 Division of Gastrointestinal Surgery Center, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, Guangdong, China. chenjh45@mail.sysu.edu.cn.
  • 8 Department of General Surgery, Guangxi Hospital Division of The First Affiliated Hospital, Sun Yat-sen University, Nanning, 530000, Guangxi, China. chenjh45@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 39424639 DOI: 10.1038/s41419-024-07153-z
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.

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