1. Academic Validation
  2. E3 ubiquitin ligase FBXW11 as a novel inflammatory biomarker is associated with immune infiltration and NF-κB pathway activation in pancreatitis and pancreatic cancer

E3 ubiquitin ligase FBXW11 as a novel inflammatory biomarker is associated with immune infiltration and NF-κB pathway activation in pancreatitis and pancreatic cancer

  • Cell Signal. 2024 Jan 3:111033. doi: 10.1016/j.cellsig.2024.111033.
Peng Tan 1 Shuang Cai 2 Zhiwei Huang 3 Mo Li 3 Shenglu Liu 3 Jiatong Chen 3 Wenguang Fu 4 Lingyu Zhao 5
Affiliations

Affiliations

  • 1 Department of Cell Biology and Genetics, Institute of Genetics and Developmental Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710000, China; Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, Academician (Expert) Workstation of Sichuan Province, Department of General Surgery (Hepatopancreatobiliary surgery), The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China.
  • 2 Department of Cell Biology and Genetics, Institute of Genetics and Developmental Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710000, China.
  • 3 Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China.
  • 4 Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, Academician (Expert) Workstation of Sichuan Province, Department of General Surgery (Hepatopancreatobiliary surgery), The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China.; Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China.
  • 5 Department of Cell Biology and Genetics, Institute of Genetics and Developmental Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710000, China. Electronic address: zhaolingyu@xjtu.edu.cn.
Abstract

Background: Pancreatic Cancer (pancreatic ductal adenocarcinoma, PDAC) is an aggressive disease with an overall poor prognosis. Pancreatitis is a major risk factor for the development of PDAC. Due to the lack of reliable and accurate biomarkers, the diagnosis, treatment, and prognosis of PDAC face great challenges. It is of great significance to elucidate the pathogenesis of PDAC and explore novel inflammatory biomarkers.

Methods: We identified E3 ubiquitin ligases associated with pancreatic inflammation by combining multiple GEO datasets and UbiNet 2.0, and integrating the WGCNA algorithm and Limma R package. A risk score model for PDAC patients was established by using LASSO regression. We investigated the correlation between FBXW11 and immune cell infiltration using CIBERSORT, mMCP-counter, ImmuCellAI-mouse, QUANTISEQ, and TIMER algorithms, based on GEO, ArrayExpress, and TCGA datasets. We used Ubibrowser 2.0 to predict potential substrates for FBXW11. WikiPathway, MSigDB Hallmark, and Elsevier pathway analysis of FBXW11 key substrates were also performed using the EnrichR database. We detected protein expression through IHC, immunofluorescence, and western blot in the cerulein-induced acute pancreatitis mouse model.

Results: We first identified that FBXW11 exhibited a clear tendency to gradually increase in normal, pancreatitis, and PDAC patients. The validation analysis revealed that the FBXW11 protein exhibited significantly high expression in cerulein-induced acute pancreatitis mice, with its distribution primarily observed in the cytoplasm. Simultaneously, we developed a risk model utilizing the genes associated with FBXW11 to forecast the outcome of patients with PDAC and the likelihood of pancreatitis advancing to pancreatic Cancer. Functional analysis showed that FBXW11, as a novel inflammatory biomarker, had a significant positive correlation with macrophage infiltration and the NF-κB signaling pathway. Finally, the western blot assay of the NF-κB signaling pathway in pancreatic tissues demonstrated that high activation of NF-κB was correlated with high expression of FBXW11.

Conclusions: Our research not only provides evidence for FBXW11 as a novel inflammatory biomarker but also provides new insights into the research and clinical treatment of pancreatic Cancer.

Keywords

FBXW11; Immune infiltration; NF-κB pathway; Pancreatic cancer; Pancreatitis.

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