Downregulation of PLK4 expression induces apoptosis and G0/G1‐phase cell cycle arrest in keloid fibroblasts

Abstract

Objectives: Keloids are benign fibroproliferative tumors that display many cancer-like characteristics, such as progressive uncontrolled growth, lack of spontaneous regression, and extremely high rates of recurrence. Polo-like kinase 4 (PLK4) was recently identified as a master regulator of centriole replication, and its aberrant expression is closely associated with tumorigenesis. This study aimed to investigate the expression and biological role of PLK4 in the pathogenesis of keloids. Materials and Methods:We evaluated the expression of PLK4 in keloids and adjacent normal skin tissue samples. Then, we established PLK4 knockdown and overexpression cell lines in keloid fibroblasts (KFs) and normal skin fibroblasts (NFs), respectively, to investigate the roles of PLK4 in the regulation of proliferation, migration, invasion, apoptosis, and cell cycle in KFs. Centrinone B (Cen-B), a highly selective PLK4 inhibitor, was used to inhibit PLK4 activity in KFs to evaluate the therapeutic effect on KFs.Results: We discovered that PLK4 was overexpressed in keloid dermal samples and KFs compared with adjacent normal skin samples and NFs derived from the same patients. High PLK4 expression was positively associated with the proliferation, migration, and invasion of KFs. Furthermore, knockdown of PLK4 expression or inhibition of PLK4 activity by Cen-B suppressed KF growth, induced KF apoptosis via the caspase-9/3 pathway, and induced cell cycle arrest at the G0/G1 phase in vitro.Conclusions: These findings demonstrate that PLK4 is a critical regulator of KF proliferation, migration, and invasion, and thus, Cen-B is a promising candidate drug for keloid treatment. | INTRODUCTIONKeloids are benign fibroproliferative reticular dermal tumors of unknown etiopathogenesis that can occur following any dermal injury, leading to an exophytic protuberant outgrowth that invades the adjacent normal skin beyond the original wound boundary. [1][2][3] Keloids are uniquely characterized by their aggressiveness, persistence, and progressive perilesional expansile behaviors. Due to their continued growth and lack of spontaneous regression, patients usually experience intense pain and pruritus, especially for keloid contractures located near the joints, which may lead to serious dysfunction and thus affect patients' physiological and psychological health.

Polo-like Kinase 4: A Multifaceted Marker Linking Tumor Aggressiveness and Unfavorable Prognosis, and Insights into Therapeutic Strategies

“…However, investigations into the correlation between PLK4 expression and tumor growth and prognosis in LUAD are limited [ 16 ]. In particular, studies have been conducted on the biological function of PLK4 in cancer apoptosis and its association with cancer prognosis [ 23 , 24 , 25 ], but still limited in LUAD. Although there have been previous studies on the expression of PLK4 in LUAD [ 15 , 16 ], additional evidence was needed as to whether PLK4 is suitable as a therapeutic target for LUAD.…”