miR-301a-mediated crosstalk between the Hedgehog and HIPPO/YAP signaling pathways promotes pancreatic cancer

Cancer Biol Ther. 2025 Dec;26(1):2457761. doi: 10.1080/15384047.2025.2457761. Epub 2025 Jan 23.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge in oncology due to its dismal prognosis and limited therapeutic options. In this study, we investigated the role of miR-301a in facilitating crosstalk between the Hedgehog (Hh) and HIPPO/YAP signaling pathways during the progression of PDAC. Our findings revealed that miR-301a served as a central regulatory node, targeting Gli1 within the Hh pathway and STK4 within the HIPPO/YAP pathway. Immunohistochemical and molecular analyses confirmed dysregulation of pathway components in pancreatic cancer, underscoring the pivotal role of miR-301a. Functional assays demonstrated the impact of miR-301a on cell proliferation and apoptosis, particularly in synergy with TNF-α. Overall, our study elucidated the intricate interplay between the Hh and HIPPO/YAP pathways mediated by miR-301a, providing valuable insights into potential therapeutic strategies for intervening in PDAC.

Keywords: Gli1; Hedgehog; Hippo/YAP; MST1(STK4); miR-301a.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Apoptosis
  • Carcinoma, Pancreatic Ductal* / genetics
  • Carcinoma, Pancreatic Ductal* / metabolism
  • Carcinoma, Pancreatic Ductal* / pathology
  • Cell Line, Tumor
  • Cell Proliferation*
  • Gene Expression Regulation, Neoplastic
  • Hedgehog Proteins* / genetics
  • Hedgehog Proteins* / metabolism
  • Hippo Signaling Pathway*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Pancreatic Neoplasms* / genetics
  • Pancreatic Neoplasms* / metabolism
  • Pancreatic Neoplasms* / pathology
  • Protein Serine-Threonine Kinases* / genetics
  • Protein Serine-Threonine Kinases* / metabolism
  • Signal Transduction*
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism
  • YAP-Signaling Proteins / metabolism
  • Zinc Finger Protein GLI1 / genetics
  • Zinc Finger Protein GLI1 / metabolism

Substances

  • MicroRNAs
  • Hedgehog Proteins
  • Transcription Factors
  • Protein Serine-Threonine Kinases
  • MIRN301A microRNA, human
  • YAP-Signaling Proteins
  • Adaptor Proteins, Signal Transducing
  • YAP1 protein, human
  • Zinc Finger Protein GLI1
  • STK4 protein, human
  • GLI1 protein, human
  • Intracellular Signaling Peptides and Proteins