PA28γ acts as a dual regulator of IL-6 and CCL2 and contributes to tumor angiogenesis in oral squamous cell carcinoma
PA28γ acts as a dual regulator of IL-6 and CCL2 and contributes to tumor angiogenesis in oral squamous cell carcinoma
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PA28γ 作为 IL-6 和 CCL2 的双重调节剂，有助于口腔鳞状细胞癌中的肿瘤血管生成。
DOI：
10.1016/j.canlet.2018.04.024
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发表时间：
2018-01-01
期刊：
影响因子：
9.7
通讯作者：
Chen, Qianming
中科院分区：
文献类型：
--
作者：
Liu, Sai;Liu, Dongjuan;Chen, Qianming
PA 28 γ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，但尚未研究其分子机制。在这里，我们发现PA 28 γ增强了OSCC细胞促进HUVECs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肿瘤诱导的血管生成。随后，机制研究揭示了IL-6和CCL 2的表达和分泌依赖于PA 28 γ表达。此外，阻断IL-6或CCL 2或转录因子NF-κ B诱导与PA 28 γ-过表达的OSCC细胞上清液共培养的HUVEC中管形成的抑制。此外，我们发现，p-STAT 3和p-AKT，这是下游的IL-6和CCL 2信号转导轴，下调与PA 28 γ沉默的上清液共培养的HUVEC和上调与PA 28 γ过表达的上清液。此外，IL-6、CCL 2和PA 28 γ表达在临床OSCC队列中相关。总的来说，我们的研究表明，PA 28 γ通过调节IL-6和CCL 2促进肿瘤血管生成。PA 28 γ可能作为IL-6和CCL 2的双重调节剂治疗PA 28 γ阳性的OSCC的新的治疗靶点。(C)2018爱思唯尔出版社
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.