Oncotarget

Research Papers:

Simultaneous silencing of TGF-β1 and COX-2 reduces human skin hypertrophic scar through activation of fibroblast apoptosis

Jia Zhou, Yixuan Zhao, Vera Simonenko, John J. Xu, Kai Liu, Deling Wang, Jingli Shi, Tianyi Zhong, Lixia Zhang, Lun Zeng, Bin Huang, Shenggao Tang, Alan Y. Lu, A. James Mixson, Yangbai Sun, Patrick Y. Lu and Qingfeng Li _

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Oncotarget. 2017; 8:80651-80665. https://doi.org/10.18632/oncotarget.20869

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Abstract

Jia Zhou1,*, Yixuan Zhao1,*, Vera Simonenko2,*, John J. Xu3, Kai Liu1, Deling Wang3, Jingli Shi3, Tianyi Zhong3, Lixia Zhang3, Lun Zeng4, Bin Huang4, Shenggao Tang5, Alan Y. Lu5, A. James Mixson6, Yangbai Sun1, Patrick Y. Lu2 and Qingfeng Li1

1Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2Sirnaomics, Inc., Gaithersburg, MD, USA

3Suzhou Sirnaomics Pharmaceuticals, Ltd., Biobay, Suzhou, China

4Guangzhou Xiangxue Pharmaceuticals, Co. Ltd., Guangzhou, China

5Guangzhou Nanotides Pharmaceuticals, Co. Ltd., Guangzhou, China

6Department of Pathology, School of Medicine, University of Maryland, Baltimore, MD, USA

*These authors contributed equally to this work and share co-first authorship

Correspondence to:

Qingfeng Li, email: dr.liqingfeng@shsmu.edu.cn

Patrick Y. Lu, email: plu@sirnaomics.com

Yangbai Sun, email: drsunyb@foxmail.com

Keywords: siRNA therapeutics, hypertrophic scar, TGF-β1, COX-2, synergistic effect

Received: November 16, 2016     Accepted: August 26, 2017     Published: September 14, 2017

ABSTRACT

Excessive skin scars due to elective operations or trauma represent a challenging clinical problem. Pathophysiology of hypertrophic scars entails a prolonged inflammatory and proliferative phase of wound healing. Over expression of TGF-β1 and COX-2 play key regulatory roles of the aberrant fibrogenic responses and proinflammatory mediators. When we silenced TGF-β1 and COX-2 expression simultaneously in primary human fibroblasts, a marked increase in the apoptotic cell population occurred in contrast to those only treated with either TGF-β1 or COX-2 siRNA alone. Furthermore, using human hypertrophic scar and skin graft implant models in mice, we observed significant size reductions of the implanted tissues following intra-scar administration of TGF-β1/COX-2 specific siRNA combination packaged with Histidine Lysine Polymer (HKP). Gene expression analyses of those treated tissues revealed silencing of the target gene along with down regulations of pro-fibrotic factors such as α-SMA, hydroxyproline acid, Collagen 1 and Collagen 3. Using TUNEL assay detection, we found that the human fibroblasts in the implanted tissues treated with the TGF-β1/COX-2siRNAs combination exhibited significant apoptotic activity. Therefore we conclude that a synergistic effect of the TGF-β1/COX-2siRNAs combination contributed to the size reductions of the hypertrophic scar implants, through activation of fibroblast apoptosis and re-balancing between scar tissue deposition and degradation.


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