CDK1 bridges NF-κB and β-catenin signaling in response to H. pylori infection in gastric tumorigenesis
Shoumin Zhu,
Marwah Al-Mathkour,
Longlong Cao,
Shayan Khalafi,
Zheng Chen,
Julio Poveda,
Dunfa Peng,
Heng Lu,
Mohammed Soutto,
Tianling Hu,
Oliver G. McDonald,
Alexander Zaika,
Wael El-Rifai
Affiliations
Shoumin Zhu
Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
Marwah Al-Mathkour
Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
Longlong Cao
Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA; Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
Shayan Khalafi
Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
Zheng Chen
Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA
Julio Poveda
Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL, USA
Dunfa Peng
Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
Heng Lu
Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
Mohammed Soutto
Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
Tianling Hu
Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
Oliver G. McDonald
Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL, USA
Alexander Zaika
Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA; Department of Veterans Affairs, Miami Healthcare System, Miami, FL, USA
Wael El-Rifai
Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA; Department of Veterans Affairs, Miami Healthcare System, Miami, FL, USA; Corresponding author
Summary: Infection with Helicobacter pylori (H. pylori) is the main risk factor for gastric cancer, a leading cause of cancer-related death worldwide. The oncogenic functions of cyclin-dependent kinase 1 (CDK1) are not fully understood in gastric tumorigenesis. Using public datasets, quantitative real-time PCR, western blot, and immunohistochemical (IHC) analyses, we detect high levels of CDK1 in human and mouse gastric tumors. H. pylori infection induces activation of nuclear factor κB (NF-κB) with a significant increase in CDK1 in in vitro and in vivo models (p < 0.01). We confirm active NF-κB binding sites on the CDK1 promoter sequence. CDK1 phosphorylates and inhibits GSK-3β activity through direct binding with subsequent accumulation and activation of β-catenin. CDK1 silencing or pharmacologic inhibition reverses these effects and impairs tumor organoids and spheroid formation. IHC analysis demonstrates a positive correlation between CDK1 and β-catenin. The results demonstrate a mechanistic link between infection, inflammation, and gastric tumorigenesis where CDK1 plays a critical role.
