RhoGDIβ promotes Sp1/MMP-2 expression and bladder cancer invasion through perturbing miR-200c-targeted JNK2 protein translation.
RhoGDIβ promotes Sp1/MMP-2 expression and bladder cancer invasion through perturbing miR-200c-targeted JNK2 protein translation.
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RhoGDI beta 通过干扰 miR-200c 靶向的 JNK2 蛋白翻译促进 Sp1/MMP-2 表达和膀胱癌侵袭
DOI：
10.1002/1878-0261.12132
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发表时间：
2017-11
影响因子：
6.6
通讯作者：
Huang C
中科院分区：
文献类型：
--
作者：
Huang H;Jin H;Zhao H;Wang J;Li X;Yan H;Wang S;Guo X;Xue L;Li J;Peng M;Wang A;Zhu J;Wu XR;Chen C;Huang C
我们最近的研究表明，RhoGDIβ 能够以 X-link 凋亡抑制剂蛋白依赖性方式促进人膀胱癌 (BC) 侵袭和转移，同时增加基质金属蛋白酶 (MMP)-2 蛋白表达水平。我们还发现 RhoGDIβ 和 MMP-2 蛋白表达在侵袭性 BC 组织和细胞系中持续上调。在本研究中，我们发现 RhoGDIβ 的敲低抑制了 MMP-2 蛋白的表达，并减少了人 BC 细胞的侵袭，而 RhoGDIβ 的异位表达则上调了 MMP-2 蛋白的表达并促进了侵袭。机制研究表明，RhoGDIβ 通过增加转录因子 Sp1 与 mmp-2 启动子区域的特异性结合，在转录水平上调 MMP-2。进一步研究发现，RhoGDIβ过表达导致miR-200c下调，而miR-200c能够直接靶向jnk2 mRNA的3'-UTR并减弱JNK2蛋白翻译，进而导致Sp1 mRNA和蛋白表达减弱，抑制Sp1依赖性mmp-2转录。总的来说，我们的研究表明，RhoGDIβ 过表达会抑制 miR-200c 丰度，从而导致 JNK2 蛋白翻译、Sp1 表达、mmp-2 转录和 BC 侵袭增加。这些发现与我们之前显示的凋亡蛋白 X-link 抑制剂介导 RhoGDIβ 和 mmp-2 mRNA 稳定的结果一起，揭示了 MMP-2 调节网络的性质，该网络导致 MMP-2 过度表达和 BC 侵袭。
Our most recent studies demonstrate that RhoGDIβ is able to promote human bladder cancer (BC) invasion and metastasis in an X‐link inhibitor of apoptosis protein‐dependent fashion accompanied by increased levels of matrix metalloproteinase (MMP)‐2 protein expression. We also found that RhoGDIβ and MMP‐2 protein expressions are consistently upregulated in both invasive BC tissues and cell lines. In the present study, we show that knockdown of RhoGDIβ inhibited MMP‐2 protein expression accompanied by a reduction of invasion in human BC cells, whereas ectopic expression of RhoGDIβ upregulated MMP‐2 protein expression and promoted invasion as well. The mechanistic studies indicated that MMP‐2 was upregulated by RhoGDIβ at the transcriptional level by increased specific binding of the transcription factor Sp1 to the mmp‐2 promoter region. Further investigation revealed that RhoGDIβ overexpression led to downregulation of miR‐200c, whereas miR‐200c was able directly to target 3′‐UTR of jnk2 mRNA and attenuated JNK2 protein translation, which resulted in attenuation of Sp1 mRNA and protein expression in turn, inhibiting Sp1‐dependent mmp‐2 transcription. Collectively, our studies demonstrate that RhoGDIβ overexpression inhibits miR‐200c abundance, which consequently results in increases of JNK2 protein translation, Sp1 expression, mmp‐2 transcription, and BC invasion. These findings, together with our previous results showing X‐link inhibitor of apoptosis protein mediating mRNA stabilization of both RhoGDIβ and mmp‐2, reveal the nature of the MMP‐2 regulatory network, which leads to MMP‐2 overexpression and BC invasion.
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影响因子：
--
作者：
Jin H;Yu Y;Hu Y;Lu C;Li J;Gu J;Zhang L;Huang H;Zhang D;Wu XR;Gao J;Huang C
通讯作者：
Huang C
影响因子：
24.5
作者：
Hur K;Toiyama Y;Takahashi M;Balaguer F;Nagasaka T;Koike J;Hemmi H;Koi M;Boland CR;Goel A
通讯作者：
Goel A
影响因子：
20.3
作者：
Benasciutti, E;Pagès, G;Crippa, MP
通讯作者：
Crippa, MP
影响因子：
3.4
作者：
Jiao, Aihong;Sui, Minghua;Li, Junxia
通讯作者：
Li, Junxia
影响因子：
5.5
作者：
Jacob A;Prekeris R
通讯作者：
Prekeris R