PA28γ acts as a dual regulator of IL-6 and CCL2 and contributes to tumor angiogenesis in oral squamous cell carcinoma

PA28γ promotes tumor development and progression and is suggested to play a role in tumor angiogenesis, but the molecular mechanisms have not been investigated. Here, we found that PA28γ enhanced the ability of OSCC cells to promote the migration, invasion, and tube formation of HUVECs and promoted tumor-induced angiogenesis in xenograft mice models in vivo. Then, a mechanism study revealed that the expression and secretion of IL-6 and CCL2 were dependent on PA28γ expression. Furthermore, blocking IL-6 or CCL2 or the transcription factor NF-κB induced the inhibition of tube formation in HUVECs co-cultured with PA28γ-overexpression OSCC cell supernatants. Moreover, we revealed that p-STAT3 and p-AKT, which are downstream of the IL-6 and CCL2 signaling axis, were downregulated in HUVECs co-cultured with the PA28γ-silenced supernatant and were upregulated with the PA28γ-overexpressing supernatant. In addition, IL-6, CCL2 and PA28γ expressions were correlated in a clinical OSCC cohort. Collectively, our study indicates that PA28γ contributes to tumor angiogenesis by regulating IL-6 and CCL2. PA28γ may be a novel therapeutic target as a dual regulator of IL-6 and CCL2 for treating PA28γ-positive OSCC.