Keloid-derived keratinocytes acquire a fibroblast-like appearance and an enhanced invasive capacity in a hypoxic microenvironment in vitro

Ma,Xiaoyang; Chen,Jia; Xu,Bei; Long,Xiao; Qin,Han; Zhao,Robert  Chunhua; Wang,Xiaojun

doi:10.3892/ijmm.2015.2135

Keloid-derived keratinocytes acquire a fibroblast-like appearance and an enhanced invasive capacity in a hypoxic microenvironment in vitro

Authors:
- Xiaoyang Ma
- Jia Chen
- Bei Xu
- Xiao Long
- Han Qin
- Robert Chunhua Zhao
- Xiaojun Wang
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Affiliations: Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China, Institute of Basic Medical Sciences and School of Basic Medicine, Center of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, P.R. China
Published online on: March 13, 2015 https://doi.org/10.3892/ijmm.2015.2135
Pages: 1246-1256
Copyright: © Ma et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

A keloid scar is an overgrowth of dense fibrous tissue that develops around a wound. These scars are raised scars that spread beyong the margins of the orinigal wound to normal skin by invasion. Keloid tissue consists of both an epithelium and dermal fibroblasts. Recent studies have primarily focused on keloid fibroblasts; however, the precise role of keratinocytes in the invasion process of keloids remains to be identified. Hypoxia is a typical characteristic of keloid scars, as well as other solid tumors. The expression of the transcription factor, hypoxia‑inducible factor‑1α (HIF‑1α), is mainly induced by hypoxia and is known for its ability to induce proliferative and transformative changes in cells; its expression has been shown to correlate with tumor invasion and metastasis. In the present study, we used immunohistochemistry, fluorescence staining and western blot analysis and demonstrated that HIF‑1α was highly expressed in both the epithelial layer of keloid tissue specimens and in hypoxia‑exposed keratinocytes, which suggested that the keloid keratinocytes underwent epithelial‑to‑mesenchymal transition (EMT) in vitro. The high expression of mesenchymal markers, such as as vimentin and fibronectin was confirmed, as well as the reduced expression of E‑cadherin and zonula occludens-1 (ZO‑1) during this process by detection at the protein and mRNA level. Moreover, siRNA targeting HIF‑1α reversed the changes which had occurred in the morphology of the keratinocytes (cells had acquired a fibroblast‑like appearance) and suppressed the invasive ability of the keratinocytes. In conclusion, the present findings demonstrate that the hypoxia/HIF‑1α microenvironment provides a favorable environment for keloid‑derived keratinocytes to adopt a fibroblast‑like appearance through EMT. This transition may be responsible for the enhanced capacity of keloid keratinocytes to invade, allowing the keloids to extend beyond the wound margin.

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