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

PA28 gamma 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 PA28 gamma 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 PA28 gamma expression. Furthermore, blocking 1L-6 or CCL2 or the transcription factor NF-kappa B induced the inhibition of tube formation in HUVECs co-cultured with PA28 gamma-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 PA28 gamma-silenced supernatant and were upregulated with the PA28 gamma-over-expressing supernatant. In addition, IL-6, CCL2 and PA28 gamma expressions were correlated in a clinical OSCC cohort. Collectively, our study indicates that PA28 gamma contributes to tumor angiogenesis by regulating IL-6 and CCL2. PA28 gamma may be a novel therapeutic target as a dual regulator of IL-6 and CCL2 for treating PA28 gamma-positive OSCC. (C) 2018 Published by Elsevier B.V.