REG3A accelerates pancreatic cancer cell growth under IL-6-associated inflammatory condition: Involvement of a REG3A-JAK2/STAT3 positive feedback loop
REG3A accelerates pancreatic cancer cell growth under IL-6-associated inflammatory condition: Involvement of a REG3A-JAK2/STAT3 positive feedback loop
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DOI：
10.1016/j.canlet.2015.03.014
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发表时间：
2015-06-28
期刊：
影响因子：
9.7
通讯作者：
Xiang, Ming
中科院分区：
文献类型：
--
作者：
Liu, Xiulan;Wang, Jun;Xiang, Ming
再生基因蛋白（Regenerating Gene Protein，REG）3A是一种分子量为19 kD的胰腺分泌蛋白，具有促生长功能。以前我们证明REG 3A的过表达，作为JAK 2/STAT 3通路上调的关键分子，有助于炎症相关胰腺癌（PaC）的发展。然而，与REG 3A信令相关的确切网络仍然不清楚。在这里，我们确定，暴露于细胞因子IL-6的人PaC细胞激活致癌JAK 2/STAT 3途径，直接上调REG 3A的表达，加速细胞周期的进程，通过促进CyclinD 1的表达，并提高抗凋亡Bcl家族的表达。重要的是，REG 3A的激活反而会增强JAK 2/STAT 3途径以构成REG 3A-JAK 2/STAT 3正反馈环，这导致IL-6/JAK 2/STAT 3的致癌作用的放大，这是一种与炎症相关的肿瘤发生相关的经典途径，最终导致PaC细胞过度增殖和体外和体内肿瘤形成。此外，发现EGFR介导用于PaC细胞生长和JAK 2/STAT 3活化的REG 3A信号，因此作为REG 3A受体起作用。总的来说，我们的结果提供了REG 3A和IL-6通过REG 3A-JAK 2/STAT 3正反馈回路对PaC发展的协同作用的存在的第一个证据。(C)2015爱思唯尔爱尔兰有限公司版权所有。
Regenerating gene protein (REG) 3A is a 19 kD secretory pancreas protein with pro-growth function. Previously we demonstrated that overexpression of REG3A, acting as a key molecule for up-regulation of the JAK2/STAT3 pathway, contributed to inflammation-related pancreatic cancer (PaC) development. However the exact network associated with REG3A signaling still remains unclear. Here we determined that exposure of human PaC cells to cytokine IL-6 activated the oncogenic JAK2/STAT3 pathway, which directly upregulated REG3A expression, accelerated cell cycle progression by promoting CyclinD1 expression, and enhancing the expression of the anti-apoptosis Bcl family. Importantly, the activation of REG3A would instead enhance the JAK2/STAT3 pathway to constitute a REG3A-JAK2/STAT3 positive feedback loop, which leads to the amplification of the oncogenic effects of IL-6/JAK2/STAT3, a classic pathway linking to inflammation-related tumorigenesis, ultimately resulting in PaC cell over-proliferation and tumor formation both in vitro and in vivo. Moreover, EGFR was found to mediate the REG3A signal for PaC cell growth and JAK2/STAT3 activation, thus functioning as a REG3A receptor. Collectively, our results provide the first evidence for the presence of the synergistic effect of REG3A and IL-6 on PaC development via a REG3A-JAK2/STAT3 positive feedback loop. (C) 2015 Elsevier Ireland Ltd. All rights reserved.