miR-802 Suppresses Acinar-to-Ductal Reprogramming During Early Pancreatitis and Pancreatic Carcinogenesis

Gastroenterology. 2022 Jan;162(1):269-284. doi: 10.1053/j.gastro.2021.09.029. Epub 2021 Sep 20.


Background & aims: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor that is almost uniformly lethal in humans. Activating mutations of KRAS are found in >90% of human PDACs and are sufficient to promote acinar-to-ductal metaplasia (ADM) during tumor initiation. The roles of miRNAs in oncogenic Kras-induced ADM are incompletely understood.

Methods: The Ptf1aCre/+LSL-KrasG12D/+ and Ptf1aCre/+LSL-KrasG12D/+LSL-p53R172H/+ and caerulein-induced acute pancreatitis mice models were used. mir-802 was conditionally ablated in acinar cells to study the function of miR-802 in ADM.

Results: We show that miR-802 is a highly abundant and acinar-enriched pancreatic miRNA that is silenced during early stages of injury or oncogenic KrasG12D-induced transformation. Genetic ablation of mir-802 cooperates with KrasG12D by promoting ADM formation. miR-802 deficiency results in de-repression of the miR-802 targets Arhgef12, RhoA, and Sdc4, activation of RhoA, and induction of the downstream RhoA effectors ROCK1, LIMK1, COFILIN1, and EZRIN, thereby increasing F-actin rearrangement. mir-802 ablation also activates SOX9, resulting in augmented levels of ductal and attenuated expression of acinar identity genes. Consistently with these findings, we show that this miR-802-RhoA-F-actin network is activated in biopsies of pancreatic cancer patients and correlates with poor survival.

Conclusions: We show miR-802 suppresses pancreatic cancer initiation by repressing oncogenic Kras-induced ADM. The role of miR-802 in ADM fills the gap in our understanding of oncogenic Kras-induced F-actin reorganization, acinar reprogramming, and PDAC initiation. Modulation of the miR-802-RhoA-F-actin network may be a new strategy to interfere with pancreatic carcinogenesis.

Keywords: Micro-RNA; Pancreatic Cancer; Pancreatitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acinar Cells / metabolism*
  • Acinar Cells / pathology
  • Animals
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Cellular Reprogramming*
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Mice, Transgenic
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Mutation
  • Pancreas / metabolism*
  • Pancreas / pathology
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Pancreatitis / genetics
  • Pancreatitis / metabolism*
  • Pancreatitis / pathology
  • Proto-Oncogene Proteins p21(ras) / genetics
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism
  • Signal Transduction


  • MIRN802 microRNA, human
  • MIRN802 microRNA, mouse
  • MicroRNAs
  • SOX9 Transcription Factor
  • SOX9 protein, human
  • Sox9 protein, mouse
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)