2. Academic Validation
  3. Hypomethylation-mediated upregulation of PHOX1 promotes gastric cancer progression via transactivation of NGFR

Hypomethylation-mediated upregulation of PHOX1 promotes gastric cancer progression via transactivation of NGFR

  • Cell Death Discov. 2025 Nov 28;11(1):548. doi: 10.1038/s41420-025-02811-3.
Yanyan Li # 1 2 3,  Weiwei Liu # 2 3,  Lisheng Zheng # 2 3,  Guifang Zhu # 4,  Xuexia Qian 2 3 5,  Rui Zeng 1 2 3,  Yangwei Xu 2 3,  Weiye Huang 2 3,  Yongjun Huang 2 3,  Qingling Zhang 6 7 8
Affiliations

Affiliations

  • 1 Department of Pathology, School of Medicine, South China University of Technology, Guangzhou, China.
  • 2 Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China.
  • 3 Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application, Guangzhou, China.
  • 4 Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
  • 5 State Key Laboratory of Cancer Biology, Department of Pathology, School of Basic Medicine, Xijing Hospitaland, Fourth Military Medical University, Xi'an, Shaanxi Province, China.
  • 6 Department of Pathology, School of Medicine, South China University of Technology, Guangzhou, China. [email protected].
  • 7 Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China. [email protected].
  • 8 Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41315175 DOI: 10.1038/s41420-025-02811-3
Abstract

Gastric Cancer (GC) remains a leading cause of global cancer-related mortality with limited therapeutic options, and its molecular mechanisms are incompletely understood. Through integrative analysis of TCGA and GEO datasets, coupled with clinical cohort validation, we identified frequent overexpression of the transcription factor PHOX1 in GC tissues, which correlated significantly with advanced T/M stages and poor patient survival. We demonstrated that PHOX1 promoter hypomethylation, particularly at the CpG site cg04123776, drives its overexpression in GC. Functional assays revealed that overexpression of PHOX1 enhanced GC cell proliferation, migration, and invasion in vitro, while knockdown of PHOX1 inhibited these malignant behaviors. Additionally, orthotopic xenograft models confirmed its pro-metastatic role in promoting liver metastasis of GC cells. Mechanistically, RNA Sequencing, chromatin immunoprecipitation assays, and luciferase reporter assays demonstrated that PHOX1 directly activated Nerve Growth Factor Receptor (NGFR) transcription. Rescue experiments with siRNA against NGFR and an ERK1/2 inhibitor further established that PHOX1 drove malignant phenotypes via NGFR and downstream ERK1/2 signaling. In conclusion, our study defines PHOX1 as a methylation-sensitive oncogene in GC, orchestrating tumor progression through transcriptional activation of NGFR, and the PHOX1-NGFR-ERK1/2 axis may serve as a therapeutic target for metastatic GC.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-50846
    99.83%, ERK1/2 Inhibitor
    ERK