Pathophysiological role of microRNA-29 in pancreatic cancer stroma

Jason J. Kwon, Sarah C. Nabinger, Zachary Vega, Smiti Snigdha Sahu, Ravi K. Alluri, Zahi Abdul-Sater, Zhangsheng Yu, Jesse Gore, Grzegorz Nalepa, Romil Saxena, Murray Korc, Janaiah Kota

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Dense fibrotic stroma associated with pancreatic ductal adenocarcinoma (PDAC) is a major obstacle for drug delivery to the tumor bed and plays a crucial role in pancreatic cancer progression. Current, anti-stromal therapies have failed to improve tumor response to chemotherapy and patient survival. Furthermore, recent studies show that stroma impedes tumor progression, and its complete ablation accelerates PDAC progression. In an effort to understand the molecular mechanisms associated with tumor-stromal interactions, using in vitro and in vivo models and PDAC patient biopsies, we show that the loss of miR-29 is a common phenomenon of activated pancreatic stellate cells (PSCs)/fibroblasts, the major stromal cells responsible for fibrotic stromal reaction. Loss of miR-29 is correlated with a significant increase in extracellular matrix (ECM) deposition, a major component in PDAC stroma. Our in vitro miR-29 gain/loss-of-function studies document the role of miR-29 in PSC-mediated ECM stromal protein accumulation. Overexpression of miR-29 in activated stellate cells reduced stromal deposition, cancer cell viability, and cancer growth in co-culture. Furthermore, the loss of miR-29 in TGF-β1 activated PSCs is SMAD3 dependent. These results provide insights into the mechanistic role of miR-29 in PDAC stroma and its potential use as a therapeutic agent to target PDAC.

Original languageEnglish
Article number11450
JournalScientific Reports
Volume5
DOIs
StatePublished - Jun 22 2015

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MicroRNAs
Pancreatic Neoplasms
Adenocarcinoma
Pancreatic Stellate Cells
Neoplasms
Stromal Cells
Extracellular Matrix Proteins
Coculture Techniques
Extracellular Matrix
Cell Survival
Fibroblasts
Biopsy
Drug Therapy
Survival
Therapeutics
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

  • General

Cite this

Kwon, J. J., Nabinger, S. C., Vega, Z., Sahu, S. S., Alluri, R. K., Abdul-Sater, Z., ... Kota, J. (2015). Pathophysiological role of microRNA-29 in pancreatic cancer stroma. Scientific Reports, 5, [11450]. https://doi.org/10.1038/srep11450

Pathophysiological role of microRNA-29 in pancreatic cancer stroma. / Kwon, Jason J.; Nabinger, Sarah C.; Vega, Zachary; Sahu, Smiti Snigdha; Alluri, Ravi K.; Abdul-Sater, Zahi; Yu, Zhangsheng; Gore, Jesse; Nalepa, Grzegorz; Saxena, Romil; Korc, Murray; Kota, Janaiah.

In: Scientific Reports, Vol. 5, 11450, 22.06.2015.

Research output: Contribution to journalArticle

Kwon, JJ, Nabinger, SC, Vega, Z, Sahu, SS, Alluri, RK, Abdul-Sater, Z, Yu, Z, Gore, J, Nalepa, G, Saxena, R, Korc, M & Kota, J 2015, 'Pathophysiological role of microRNA-29 in pancreatic cancer stroma', Scientific Reports, vol. 5, 11450. https://doi.org/10.1038/srep11450
Kwon JJ, Nabinger SC, Vega Z, Sahu SS, Alluri RK, Abdul-Sater Z et al. Pathophysiological role of microRNA-29 in pancreatic cancer stroma. Scientific Reports. 2015 Jun 22;5. 11450. https://doi.org/10.1038/srep11450
Kwon, Jason J. ; Nabinger, Sarah C. ; Vega, Zachary ; Sahu, Smiti Snigdha ; Alluri, Ravi K. ; Abdul-Sater, Zahi ; Yu, Zhangsheng ; Gore, Jesse ; Nalepa, Grzegorz ; Saxena, Romil ; Korc, Murray ; Kota, Janaiah. / Pathophysiological role of microRNA-29 in pancreatic cancer stroma. In: Scientific Reports. 2015 ; Vol. 5.
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