Abstract
Although hypoxia has been shown to promote keratinocyte migration and reepithelialization, the underlying molecular mechanisms remain largely unknown. ADAM17, a member of the metalloproteinase superfamily, has been implicated in a variety of cellular behaviors such as proliferation, adhesion, and migration. ADAM17 is known to promote cancer cell migration under hypoxia, and whether or how ADAM17 plays a role in hypoxia-induced keratinocyte migration has not been identified. Here, we found that ADAM17 expression and activity were significantly promoted in keratinocytes under hypoxic condition, inhibition of ADAM17 by TAPI-2, or silencing of ADAM17 using small interfering RNA which suppressed the hypoxia-induced migration of keratinocytes significantly, indicating a pivotal role for ADAM17 in keratinocyte migration. Further, we showed that p38/MAPK was activated by hypoxia. SB203580, an inhibitor of p38/MAPK, significantly attenuated the upregulation of ADAM17 as well as the migration of keratinocytes induced by hypoxia. Activation of p38/MAPK by MKK6 (Glu) overexpression, however, had adverse effects. Taken together, our study demonstrated that hypoxia-induced keratinocyte migration requires the p38/MAPK-ADAM17 signal axis, which sheds new light on the regulatory mechanisms of keratinocyte migration. Our study might also help in developing therapeutic strategies to facilitate wound healing in vivo, where cells are migrated in a hypoxic microenvironment.
Highlights
Wound healing, an important physiological process that restores the integrity of skin after trauma, consists of a sequence of well-characterized stages governed by sequential and overlapping phases, in which reepithelialization is the key stage depending upon keratinocyte migration from the wound margins [1]
We demonstrated that p38/MAPK played a critical role in ADAM17 expression as well as keratinocyte migration under hypoxia
We further investigated the keratinocyte migration under hypoxia using cell motility assay
Summary
An important physiological process that restores the integrity of skin after trauma, consists of a sequence of well-characterized stages governed by sequential and overlapping phases, in which reepithelialization is the key stage depending upon keratinocyte migration from the wound margins [1]. A low oxygen concentration, is a microenvironmental hallmark of most solid cancers and wound healing. When the skin is injured, hypoxia occurs due to vascular disruption, vasoconstriction, and increased oxygen consumption [2]. Evidence has identified hypoxia as an inherent impediment to cancer therapy due to its contributions to chemoresistance, angiogenesis, and invasiveness [3,4,5]. Hypoxia was found to stimulate angiogenesis, granulated tissue formation, and wound repair in diabetic mice [6]. Relative hypoxia has been shown to promote keratinocyte migration and reepithelialization [7,8,9]. Considerable research has explored the mechanisms by which hypoxia controls keratinocyte migration during wound healing, the underlying molecular mechanism remains largely unknown
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