Abstract
The coxsackie and adenovirus receptor (CAR) is a cell adhesion molecule mostly localized to cell-cell contacts in epithelial and endothelial cells. CAR is known to regulate tumor progression, however, its physiological role in keratinocyte migration and proliferation, two essential steps in re-epithelialization during wound healing, has less been investigated. Here we showed that CAR was predominantly expressed in the epidermis of human skin, CAR knockdown by RNAi significantly accelerated HaCaT cell migration and proliferation. In addition, knockdown of CAR in vitro increased p-Src, p-p38, and p-JNK protein levels; however, Src inhibitor PP2 prevented the increase of p-Src and p-p38 induced by CAR RNAi, but not p-JNK, and decelerated cell migration and proliferation. More intriguingly, in vivo CAR RNAi on the skin area surrounding the wounds on rat back visually accelerated wound healing and re-epithelialization process, while treatment with PP2 or p38 inhibitor SB203580 obviously inhibited these effects. By contrast, overexpressing CAR in HaCaT cells significantly decelerated cell migration and proliferation. Above results demonstrate that suppression of CAR could accelerate HaCaT cell migration and proliferation, and promote wound healing in rat skin, probably via Src-p38 MAPK pathway. CAR thus might serve as a novel therapeutic target for facilitating wound healing.
Highlights
Pathways related to cell migration and proliferation, such as Akt, STAT3 phosphorylation[13] and Ras activation[14]
Our results showed that repression of CAR expression could stimulate keratinocyte migration, proliferation, and in vivo wound healing probably via Src-p38 MAPK pathway, CAR might serve as a potential molecular target to promote wound healing
CAR was for the first time shown to negatively regulate HaCaT cell migration, proliferation, and in vivo wound healing, the underlying mechanism was at least partially clarified
Summary
Pathways related to cell migration and proliferation, such as Akt, STAT3 phosphorylation[13] and Ras activation[14]. We hypothesize that CAR could regulate epidermal cell migration, proliferation, and wound healing, at least in part, through Src-MAPK pathway. To test this hypothesis, we utilized HaCaT cells, an immortalized human keratinocyte line, and wounded rats on the back skin as in vitro and in vivo models in this study, respectively. We exploited RNAi technique alone or combination with drug treatment, such as PP2, a putative Src inhibitor[17], and SB203580, a p38 inhibitor, to investigate the mechanisms underlying CAR’s regulation on cell migration, proliferation, and in vivo wound healing. Our results showed that repression of CAR expression could stimulate keratinocyte migration, proliferation, and in vivo wound healing probably via Src-p38 MAPK pathway, CAR might serve as a potential molecular target to promote wound healing
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