Cargando…

Pathophysiological role of microRNA-29 in pancreatic cancer stroma

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....

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476113/
https://www.ncbi.nlm.nih.gov/pubmed/26095125
http://dx.doi.org/10.1038/srep11450
_version_ 1782377550345928704
author 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
author_facet 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
author_sort Kwon, Jason J.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4476113
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-44761132015-06-24 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 Sci Rep Article 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. Nature Publishing Group 2015-06-22 /pmc/articles/PMC4476113/ /pubmed/26095125 http://dx.doi.org/10.1038/srep11450 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
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
title Pathophysiological role of microRNA-29 in pancreatic cancer stroma
title_full Pathophysiological role of microRNA-29 in pancreatic cancer stroma
title_fullStr Pathophysiological role of microRNA-29 in pancreatic cancer stroma
title_full_unstemmed Pathophysiological role of microRNA-29 in pancreatic cancer stroma
title_short Pathophysiological role of microRNA-29 in pancreatic cancer stroma
title_sort pathophysiological role of microrna-29 in pancreatic cancer stroma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476113/
https://www.ncbi.nlm.nih.gov/pubmed/26095125
http://dx.doi.org/10.1038/srep11450
work_keys_str_mv AT kwonjasonj pathophysiologicalroleofmicrorna29inpancreaticcancerstroma
AT nabingersarahc pathophysiologicalroleofmicrorna29inpancreaticcancerstroma
AT vegazachary pathophysiologicalroleofmicrorna29inpancreaticcancerstroma
AT sahusmitisnigdha pathophysiologicalroleofmicrorna29inpancreaticcancerstroma
AT alluriravik pathophysiologicalroleofmicrorna29inpancreaticcancerstroma
AT abdulsaterzahi pathophysiologicalroleofmicrorna29inpancreaticcancerstroma
AT yuzhangsheng pathophysiologicalroleofmicrorna29inpancreaticcancerstroma
AT gorejesse pathophysiologicalroleofmicrorna29inpancreaticcancerstroma
AT nalepagrzegorz pathophysiologicalroleofmicrorna29inpancreaticcancerstroma
AT saxenaromil pathophysiologicalroleofmicrorna29inpancreaticcancerstroma
AT korcmurray pathophysiologicalroleofmicrorna29inpancreaticcancerstroma
AT kotajanaiah pathophysiologicalroleofmicrorna29inpancreaticcancerstroma