2. Academic Validation
  3. Transcriptional deregulation by FOXM1-JUP signaling confers dual oncogenic drivers for pancreatic tumorigenesis and therapeutic resistance

Transcriptional deregulation by FOXM1-JUP signaling confers dual oncogenic drivers for pancreatic tumorigenesis and therapeutic resistance

  • Cell Commun Signal. 2025 Nov 27;23(1):513. doi: 10.1186/s12964-025-02512-5.
Kailing Yang # 1 2,  Zhihong He # 1 2,  Tingting Jiang 1 2,  Tian Cai 1 2 3,  Xiaojia Li 4,  Keping Xie 5
Affiliations

Affiliations

  • 1 Center for Pancreatic Cancer Research, The South China University of Technology School of Medicine, Guangzhou, 510006, China.
  • 2 The South China University of Technology Comprehensive Cancer Center, Guangdong, China.
  • 3 Department of Laboratory Medicine, The First People's Hospital of Foshan, Foshan, China.
  • 4 Center for Pancreatic Cancer Research, The South China University of Technology School of Medicine, Guangzhou, 510006, China. [email protected].
  • 5 Center for Pancreatic Cancer Research, The South China University of Technology School of Medicine, Guangzhou, 510006, China. [email protected].
  • # Contributed equally.
PMID: 41310714 DOI: 10.1186/s12964-025-02512-5
Abstract

Purpose: Junction plakoglobin (JUP/γ-catenin) is a dual-component cell adhesion molecule of adherens junctions and desmosomes, maintaining epithelial homeostasis while paradoxically involving oncogenic transformation. In pancreatic ductal adenocarcinoma (PDAC), the mechanistic role and clinical implications of JUP signaling in oncogenic reprogramming remains undefined.

Experimental design: Gene expression and its association with clinicopathologic characteristics and therapeutic resistance of patients with PDAC were analyzed using IHC and bioinformatics and functionally validated by using mouse models. Protein expression and their regulation were measured by using gain- and loss-of-function assays and Molecular Biology methods.

Results: Our immunostaining results and bioinformatics reveals JUP overexpression in pancreatic intraepithelial neoplasia (PanIN) and primary tumors, correlating with advanced TNM staging and diminished survival. Enforced JUP expression promoted PDAC proliferation, migration and invasion in vitro and PDAC growth and metastasis in vivo, whereas decreased expression of JUP exerted opposing effects. JUP expression was positively correlated with FOXM1 expression in PDAC tissues. Mechanistically, FOXM1 transcriptionally activated JUP expression by directly binding to the promoter region of JUP. Moreover, treatment of gemcitabine and oxaliplatin induced JUP expression and subsequently rendered PDAC cells therapeutic resistance, which was reversed by deletion of JUP, whereas knockdown of JUP also attenuated FOXM1-driven therapeutic resistance.

Conclusions: Therefore, our findings suggest that JUP promotes PDAC tumorigenesis and progression through FOXM1-JUP transcriptional axis and the combination of FOXM1 and JUP be a more precise biomarker for targeted therapy and prognostic prediction, nominating this dyad as an actionable vulnerability for molecularly targeted interventions in PDAC.

Keywords

Cell junction; FOXM1; Pancreatic cancer; Plakoglobin; Tumorigenesis.

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