Induction of miR-21 by stereotactic body radiotherapy contributes to the pulmonary fibrotic response

Ok Seon Kwon, Keun Tae Kim, Eunioo Lee, Myoungjae Kim, Seo Hyun Choi, Henghong Li, Albert J. Fornace, Jaeho Cho, Yun Sil Lee, Ji Seon Lee, Yoon Jin Lee, Hyuk Jin Cha

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Abstract

Radiation-induced lung fibrosis, the most serious effect of lung cancer radiotherapy on normal tissue, remains a major technical obstacle to the broader application of radiotherapy to patients with lung cancer. This study describes the use of an image-guided irradiation system in mice mimicking stereotactic body radiotherapy (SBRT) to examine the molecular features of chronic fibrotic response after radiation injury. MicroRNA (miR) array analysis of injured pulmonary tissue identified a set of miRs whose expression was significantly increased in damaged lung tissue. In particular, miR-21 expression was increased at the radiation injury site, concurrent with collagen deposition. Although the inhibition of miR-21 by its specific inhibitor anti-miR-21 only marginally affected endothelial-mesenchymal transition (EndMT) in lung endothelial cells, this inhibition significantly reduced collagen synthesis in lung fibroblasts. Furthermore, ectopic expression of miR-21 was sufficient to promote a fibrotic response in lung fibroblasts, enhancing Smad2 phosphorylation concurrent with Smad7 downregulation. These findings indicate that the induction of miR-21 expression is responsible for fibrotic responses observed in mesenchymal cells at the injury site through the potentiation of TGF-β signaling. Local targeting of miR-21 at the injured area could have potential therapeutic utility in mitigating radiation-induced lung fibrosis.

Original languageEnglish
Article numbere0154942
JournalPloS one
Volume11
Issue number5
DOIs
Publication statusPublished - 2016 May 1

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Radiosurgery
Radiotherapy
radiotherapy
MicroRNAs
microRNA
lungs
Lung
radiation injury
Radiation
Radiation Injuries
Fibroblasts
lung neoplasms
Tissue
fibrosis
fibroblasts
collagen
Lung Neoplasms
Fibrosis
Collagen
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Kwon, O. S., Kim, K. T., Lee, E., Kim, M., Choi, S. H., Li, H., ... Cha, H. J. (2016). Induction of miR-21 by stereotactic body radiotherapy contributes to the pulmonary fibrotic response. PloS one, 11(5), [e0154942]. https://doi.org/10.1371/journal.pone.0154942
Kwon, Ok Seon ; Kim, Keun Tae ; Lee, Eunioo ; Kim, Myoungjae ; Choi, Seo Hyun ; Li, Henghong ; Fornace, Albert J. ; Cho, Jaeho ; Lee, Yun Sil ; Lee, Ji Seon ; Lee, Yoon Jin ; Cha, Hyuk Jin. / Induction of miR-21 by stereotactic body radiotherapy contributes to the pulmonary fibrotic response. In: PloS one. 2016 ; Vol. 11, No. 5.
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abstract = "Radiation-induced lung fibrosis, the most serious effect of lung cancer radiotherapy on normal tissue, remains a major technical obstacle to the broader application of radiotherapy to patients with lung cancer. This study describes the use of an image-guided irradiation system in mice mimicking stereotactic body radiotherapy (SBRT) to examine the molecular features of chronic fibrotic response after radiation injury. MicroRNA (miR) array analysis of injured pulmonary tissue identified a set of miRs whose expression was significantly increased in damaged lung tissue. In particular, miR-21 expression was increased at the radiation injury site, concurrent with collagen deposition. Although the inhibition of miR-21 by its specific inhibitor anti-miR-21 only marginally affected endothelial-mesenchymal transition (EndMT) in lung endothelial cells, this inhibition significantly reduced collagen synthesis in lung fibroblasts. Furthermore, ectopic expression of miR-21 was sufficient to promote a fibrotic response in lung fibroblasts, enhancing Smad2 phosphorylation concurrent with Smad7 downregulation. These findings indicate that the induction of miR-21 expression is responsible for fibrotic responses observed in mesenchymal cells at the injury site through the potentiation of TGF-β signaling. Local targeting of miR-21 at the injured area could have potential therapeutic utility in mitigating radiation-induced lung fibrosis.",
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Kwon, OS, Kim, KT, Lee, E, Kim, M, Choi, SH, Li, H, Fornace, AJ, Cho, J, Lee, YS, Lee, JS, Lee, YJ & Cha, HJ 2016, 'Induction of miR-21 by stereotactic body radiotherapy contributes to the pulmonary fibrotic response', PloS one, vol. 11, no. 5, e0154942. https://doi.org/10.1371/journal.pone.0154942

Induction of miR-21 by stereotactic body radiotherapy contributes to the pulmonary fibrotic response. / Kwon, Ok Seon; Kim, Keun Tae; Lee, Eunioo; Kim, Myoungjae; Choi, Seo Hyun; Li, Henghong; Fornace, Albert J.; Cho, Jaeho; Lee, Yun Sil; Lee, Ji Seon; Lee, Yoon Jin; Cha, Hyuk Jin.

In: PloS one, Vol. 11, No. 5, e0154942, 01.05.2016.

Research output: Contribution to journalArticle

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T1 - Induction of miR-21 by stereotactic body radiotherapy contributes to the pulmonary fibrotic response

AU - Kwon, Ok Seon

AU - Kim, Keun Tae

AU - Lee, Eunioo

AU - Kim, Myoungjae

AU - Choi, Seo Hyun

AU - Li, Henghong

AU - Fornace, Albert J.

AU - Cho, Jaeho

AU - Lee, Yun Sil

AU - Lee, Ji Seon

AU - Lee, Yoon Jin

AU - Cha, Hyuk Jin

PY - 2016/5/1

Y1 - 2016/5/1

N2 - Radiation-induced lung fibrosis, the most serious effect of lung cancer radiotherapy on normal tissue, remains a major technical obstacle to the broader application of radiotherapy to patients with lung cancer. This study describes the use of an image-guided irradiation system in mice mimicking stereotactic body radiotherapy (SBRT) to examine the molecular features of chronic fibrotic response after radiation injury. MicroRNA (miR) array analysis of injured pulmonary tissue identified a set of miRs whose expression was significantly increased in damaged lung tissue. In particular, miR-21 expression was increased at the radiation injury site, concurrent with collagen deposition. Although the inhibition of miR-21 by its specific inhibitor anti-miR-21 only marginally affected endothelial-mesenchymal transition (EndMT) in lung endothelial cells, this inhibition significantly reduced collagen synthesis in lung fibroblasts. Furthermore, ectopic expression of miR-21 was sufficient to promote a fibrotic response in lung fibroblasts, enhancing Smad2 phosphorylation concurrent with Smad7 downregulation. These findings indicate that the induction of miR-21 expression is responsible for fibrotic responses observed in mesenchymal cells at the injury site through the potentiation of TGF-β signaling. Local targeting of miR-21 at the injured area could have potential therapeutic utility in mitigating radiation-induced lung fibrosis.

AB - Radiation-induced lung fibrosis, the most serious effect of lung cancer radiotherapy on normal tissue, remains a major technical obstacle to the broader application of radiotherapy to patients with lung cancer. This study describes the use of an image-guided irradiation system in mice mimicking stereotactic body radiotherapy (SBRT) to examine the molecular features of chronic fibrotic response after radiation injury. MicroRNA (miR) array analysis of injured pulmonary tissue identified a set of miRs whose expression was significantly increased in damaged lung tissue. In particular, miR-21 expression was increased at the radiation injury site, concurrent with collagen deposition. Although the inhibition of miR-21 by its specific inhibitor anti-miR-21 only marginally affected endothelial-mesenchymal transition (EndMT) in lung endothelial cells, this inhibition significantly reduced collagen synthesis in lung fibroblasts. Furthermore, ectopic expression of miR-21 was sufficient to promote a fibrotic response in lung fibroblasts, enhancing Smad2 phosphorylation concurrent with Smad7 downregulation. These findings indicate that the induction of miR-21 expression is responsible for fibrotic responses observed in mesenchymal cells at the injury site through the potentiation of TGF-β signaling. Local targeting of miR-21 at the injured area could have potential therapeutic utility in mitigating radiation-induced lung fibrosis.

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