State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Department of Emergency and Oral Medicine, The School of Stomatology, China Medical University, Liaoning Institute of Dental Research, Liaoning Province Key Laboratory of Oral Diseases, Liaoning Province Translational Medicine Research Center of Oral Diseases, Shenyang, Liaoning, China.
Cancer Lett. 2018 Aug 1;428:192-200. doi: 10.1016/j.canlet.2018.04.024. Epub 2018 Apr 24.
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.
PA28γ 促进肿瘤的发生和发展，并被认为在肿瘤血管生成中发挥作用，但分子机制尚未被研究。在这里，我们发现 PA28γ 增强了 OSCC 细胞促进 HUVEC 迁移、侵袭和管形成的能力，并在体内异种移植小鼠模型中促进了肿瘤诱导的血管生成。然后，一项机制研究表明，IL-6 和 CCL2 的表达和分泌依赖于 PA28γ 的表达。此外，阻断 IL-6 或 CCL2 或转录因子 NF-κB 诱导与过表达 PA28γ 的 OSCC 细胞上清共培养的 HUVEC 管形成的抑制。此外，我们发现与过表达 PA28γ 的上清液相比，与沉默 PA28γ 的上清液共培养的 HUVECs 中 IL-6 和 CCL2 信号轴的下游 p-STAT3 和 p-AKT 下调，而与过表达 PA28γ 的上清液相比则上调。此外，在临床 OSCC 队列中，IL-6、CCL2 和 PA28γ 的表达呈正相关。总之，我们的研究表明，PA28γ 通过调节 IL-6 和 CCL2 促进肿瘤血管生成。PA28γ 可能是一种新的治疗靶点，可作为治疗 PA28γ 阳性 OSCC 的 IL-6 和 CCL2 的双重调节剂。
