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Inflammatory-miR-301a circuitry drives mTOR and Stat3-dependent PSC activation in chronic pancreatitis and PanIN

Fugui Li1, Miaomiao Wang2, Xun Li2

  • 1Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, 528403 Zhongshan, China.

Molecular Therapy. Nucleic Acids
|February 25, 2022
PubMed

Insights

MicroRNA-301a (miR-301a) drives pancreatic fibrosis and precancerous lesion development by activating pancreatic stellate cells. Inhibiting miR-301a shows promise for treating pancreatic cancer and chronic pancreatitis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Oncology

Background:

  • Activated pancreatic stellate cells (PSCs) are key players in chronic pancreatitis and pancreatic intraepithelial neoplasia (PanIN).
  • Targeting PSC activation is crucial for developing therapies against pancreatic cancer-related fibrosis.
  • MicroRNA-301a (miR-301a) is a pro-inflammatory microRNA implicated in tumor stroma activation.

Purpose of the Study:

  • To investigate the role of miR-301a in PSC activation, pancreatic fibrosis, and PanIN development.
  • To explore miR-301a as a potential therapeutic target for pancreatic diseases.

Main Methods:

  • Studied miR-301a expression in mouse models of chronic pancreatitis and PanIN.
  • Utilized genetic ablation of miR-301a in mouse models.
  • Analyzed the impact of miR-301a downregulation on PSC proliferation and activation, and its targets Tsc1 and Gadd45g.
  • Investigated the interaction between PSCs, miR-301a, Gadd45g, and pancreatic cancer cells.

Main Results:

  • miR-301a was highly expressed in activated PSCs, correlating with fibrosis and PanIN formation in mice.
  • Genetic deletion of miR-301a reduced pancreatic fibrosis and PanIN.
  • Downregulating miR-301a inhibited PSC proliferation and activation by targeting Tsc1 and Gadd45g.
  • Aberrant miR-301a and Gadd45g expression in PSCs affected cancer cell interactions.

Conclusions:

  • miR-301a promotes PanIN development and maintains PSC activation and desmoplasia in pancreatic cancer.
  • miR-301a activates Tsc1/mTOR and Gadd45g/Stat3 pathways, facilitating fibrosis and PanIN.
  • Targeting miR-301a offers a potential therapeutic strategy for pancreatic fibrosis and cancer.
Keywords:
Gadd45gTsc1chronic pancreatitismiR-301apancreatic intraepithelial neoplasia

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