AURKA Activates FOXO3a to Form a Positive Feedback Loop in the Proliferation and Migration of Keloid Fibroblasts.

Objective: Keloids are benign fibroproliferative disorders with invasive growth exceeding the wound boundary. Aurora kinase A (AURKA) is a serine/threonine kinase highly expressed in various tumors, facilitating tumor growth and invasion. Currently, the role of AURKA in keloid remains unclear. Approach: Fibroblasts were isolated from keloid and normal skin samples. AURKA was evaluated by qPCR, Western blot, and immunohistochemistry. Transcriptome sequencing and dual-luciferase reporter assays were applied to figure out targets of AURKA. Following expression alteration and MLN8237 (an AURKA kinase inhibitor, AKI) treatment, phenotypical experiments were conducted to clarify biological functions of AURKA along with its target, and to probe into the clinical potential of AURKA inhibition. Results: AURKA was upregulated in keloid tissues and fibroblasts. Forkhead box O 3a (FOXO3a) was verified as a downstream of AURKA. Further experiments demonstrated that AURKA transactivated FOXO3a by binding to FOXO3a, while FOXO3a directly transactivated AURKA. Functionally, AURKA and FOXO3a cooperated in enhancing the proliferation and migration of keloid fibroblasts via protein kinase B (AKT) phosphorylation. Although MLN8237 weakened the proliferation and migration in keloid fibroblasts, the transactivation of AURKA on FOXO3a was independent of kinase activity. Innovation: This study reveals that AURKA and FOXO3a compose a transactivation loop in enhancing the proliferative and migrative properties of keloid fibroblasts, and proposes AURKA as a promising target. Conclusion: AURKA/FOXO3a loop promotes the proliferation and migration of keloid fibroblasts via AKT signaling. Despite the anti-keloid effects of AKIs, AURKA acts as a transcription factor independently of kinase activity, deepening our understanding on AKI insensitivity.