Research Papers:

Hypoxia-inducible factor-1α activates transforming growth factor-β1/Smad signaling and increases collagen deposition in dermal fibroblasts

Xu Mingyuan, Pang Qianqian, Xu Shengquan, Ye Chenyi, Lei Rui, Shen Yichen and Xu Jinghong _

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Oncotarget. 2018; 9:3188-3197. https://doi.org/10.18632/oncotarget.23225

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Xu Mingyuan1, Pang Qianqian1, Xu Shengquan2, Ye Chenyi3, Lei Rui1, Shen Yichen1 and Xu Jinghong1

1Department of Plastic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China

2Department of Hand Surgery and Microsurgery Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China

3Department of Orthopedic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China

Correspondence to:

Xu Jinghong, email: [email protected]

Keywords: keloid; hypoxia; hypoxia-Inducible factor-1α; transforming growth factor-β1/Smad; collagen

Received: August 08, 2017     Accepted: November 16, 2017     Published: December 14, 2017


Hypoxia of local tissue occurs during the scar formation; however, the degree of ischemia and hypoxia in the central areas of keloids is more serious than those in normal scars. Hypoxia-induced factor (HIF), is one of the main cellular responses to hypoxia, allowing cells to adapt to low-oxygen conditions. We investigated the correlation among hypoxia, transforming growth factor-β1/Smad signaling and collagen deposition. Hypoxia up-regulated TGF-β1, Smad2/3, p-Smad2/3, Smad4, and total collagen in both normal and keloid fibroblasts via HIF-1α, which was attenuated by HIF-1α inhibition, but TβRII levels were not significantly altered. Silencing Smad4 under hypoxia decreased the mRNA and protein levels of HIF-1α, suggesting up-regulated Smad4 may also plays a role in promoting HIF-1α. Finally, we examined the role of the TGF-β1/Smad pathway in collagen deposition. When TβRII was inhibited by ITD-1 under hypoxic conditions, p-Smad2/3 levels and collagen deposition decreased. When inhibited TβRII by siRNA under normoxia, the levels of p-Smad2/3, Smad4 and collagen deposition also decreased. This result demonstrated that hypoxia promoted TGF-β1/Smad signaling via HIF-1α and that both HIF-1α and the TGF-β1/Smad signaling promotes collagen deposition in hypoxia, which is an important mechanism of keloid formation.

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