REG3A/REG3B promotes acinar to ductal metaplasia through binding to EXTL3 and activating the RAS-RAF-MEK-ERK signaling pathway

Commun Biol. 2021 Jun 7;4(1):688. doi: 10.1038/s42003-021-02193-z.

Abstract

Persistent acinar to ductal metaplasia (ADM) is a recently recognized precursor of pancreatic ductal adenocarcinoma (PDAC). Here we show that the ADM area of human pancreas tissue adjacent to PDAC expresses significantly higher levels of regenerating protein 3A (REG3A). Exogenous REG3A and its mouse homolog REG3B induce ADM in the 3D culture of primary human and murine acinar cells, respectively. Both Reg3b transgenic mice and REG3B-treated mice with caerulein-induced pancreatitis develop and sustain ADM. Two out of five Reg3b transgenic mice with caerulein-induced pancreatitis show progression from ADM to pancreatic intraepithelial neoplasia (PanIN). Both in vitro and in vivo ADM models demonstrate activation of the RAS-RAF-MEK-ERK signaling pathway. Exostosin-like glycosyltransferase 3 (EXTL3) functions as the receptor for REG3B and mediates the activation of downstream signaling proteins. Our data indicates that REG3A/REG3B promotes persistent ADM through binding to EXTL3 and activating the RAS-RAF-MEK-ERK signaling pathway. Targeting REG3A/REG3B, its receptor EXTL3, or other downstream molecules could interrupt the ADM process and prevent early PDAC carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Humans
  • MAP Kinase Signaling System
  • Male
  • Metaplasia / metabolism
  • Metaplasia / pathology
  • Mice, Inbred C57BL
  • N-Acetylglucosaminyltransferases / analysis
  • N-Acetylglucosaminyltransferases / metabolism*
  • Pancreatic Ducts / metabolism
  • Pancreatic Ducts / pathology
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Pancreatitis-Associated Proteins / analysis
  • Pancreatitis-Associated Proteins / metabolism*
  • Signal Transduction
  • Tumor Cells, Cultured
  • raf Kinases / metabolism
  • ras Proteins / metabolism

Substances

  • EXTL3 protein, human
  • Extl3 protein, mouse
  • Pancreatitis-Associated Proteins
  • REG3A protein, human
  • Reg3b protein, mouse
  • N-Acetylglucosaminyltransferases
  • raf Kinases
  • ras Proteins

Supplementary concepts

  • Pancreatic Carcinoma