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

Huairong Zhang1,2,3, Andrea Liliam Gomez Corredor2, Julia Messina-Pacheco2

  • 1Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Communications Biology
|June 8, 2021
PubMed

Insights

Regenerating protein 3A (REG3A) and its homolog REG3B promote pancreatic acinar-ductal metaplasia (ADM), a precursor to pancreatic cancer. Targeting REG3A/REG3B or its receptor EXTL3 may prevent pancreatic ductal adenocarcinoma (PDAC) development.

Area of Science:

  • Oncology
  • Gastroenterology
  • Cell Biology

Background:

  • Persistent acinar-to-ductal metaplasia (ADM) is a recognized precursor to pancreatic ductal adenocarcinoma (PDAC).
  • The molecular mechanisms driving persistent ADM remain incompletely understood.

Purpose of the Study:

  • To investigate the role of regenerating protein 3A (REG3A) in promoting ADM.
  • To elucidate the signaling pathways and molecular targets involved in REG3A-mediated ADM.

Main Methods:

  • Analysis of human pancreatic tissue adjacent to PDAC.
  • 3D cell culture of human and murine acinar cells treated with REG3A or REG3B.
  • In vivo studies using REG3B transgenic mice and caerulein-induced pancreatitis models.
  • Investigation of the RAS-RAF-MEK-ERK signaling pathway and EXTL3 receptor function.

Main Results:

  • ADM areas in human pancreas tissue adjacent to PDAC show elevated REG3A levels.
  • Exogenous REG3A and REG3B induce ADM in vitro and in vivo.
  • REG3B promotes ADM progression, with some cases advancing to PanIN in vivo.
  • REG3B signals through EXTL3 to activate the RAS-RAF-MEK-ERK pathway.

Conclusions:

  • REG3A/REG3B drives persistent ADM by binding to EXTL3 and activating the RAS-RAF-MEK-ERK pathway.
  • Targeting REG3A/REG3B, EXTL3, or downstream effectors offers a potential strategy to prevent PDAC initiation.

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