A novel role of ribonuclease inhibitor in regulation of epithelial-to-mesenchymal transition and ILK signaling pathway in bladder cancer cells
A novel role of ribonuclease inhibitor in regulation of epithelial-to-mesenchymal transition and ILK signaling pathway in bladder cancer cells
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核糖核酸酶抑制剂在膀胱癌细胞上皮间质转化和ILK信号通路调节中的新作用
DOI：
10.1007/s00441-013-1638-2
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发表时间：
2013-05
期刊：
影响因子：
--
通讯作者：
Jun-xia Chen
中科院分区：
文献类型：
--
作者：
Dong-mei Xiong;Lin Li;Rong Jiang;Jun-xia Chen
人核糖核酸酶抑制剂（RI）是一种细胞质酸性蛋白，除抑制rna酶a和血管生成素活性外，还可能参与其他生物学功能。我们之前已经证明，RI可以抑制某些癌细胞的生长和转移。上皮-间质转化（Epithelial-mesenchymal transition， EMT）被认为是膀胱癌侵袭和转移的开始，并与膀胱癌的转移有关。因此，我们假设RI调节膀胱癌细胞的EMT。我们发现，在体外和体内，RI的过表达诱导了E-cadherin的上调，同时N-cadherin、Snail、Slug、vimentin和Twist等EMT相关蛋白以及基质金属蛋白2 （MMP-2）、MMP-9和Cyclin-D1的表达降低。在体外实验中，RI的上调抑制细胞增殖、迁移和侵袭，改变细胞形态和粘附，导致细胞骨架的重排。我们还证明，RI的上调可以降低整合素连接激酶（ILK）的表达，ILK是控制一系列生物过程的信号级联反应的核心成分。在T24细胞中，RI的过表达降低了ILK下游信号靶点p-Akt和p-GSK3β的磷酸化。我们进一步发现，具有高转移能力的膀胱癌在人类临床标本中具有较高的vimentin、Snail、Slug和Twist表达，以及较低的E-cadherin和RI表达。最后，我们提供的证据表明，RI的上调抑制膀胱癌的肿瘤发生和转移。因此，RI可能通过调节EMT和ILK信号通路在膀胱癌的发生发展中发挥新的作用。
Human ribonuclease inhibitor (RI) is a cytoplasmic acidic protein possibly involved in biological functions other than the inhibition of RNase A and angiogenin activities. We have previously shown that RI can inhibit growth and metastasis in some cancer cells. Epithelial-mesenchymal transition (EMT) is regarded as the beginning of invasion and metastasis and has been implicated in the metastasis of bladder cancer. We therefore postulate that RI regulates EMT of bladder cancer cells. We find that the over-expression of RI induces the up-regulation of E-cadherin, accompanied with the decreased expression of proteins associated with EMT, such as N-cadherin, Snail, Slug, vimentin and Twist and of matrix metalloprotein-2 (MMP-2), MMP-9 and Cyclin-D1, both in vitro and in vivo. The up-regulation of RI inhibits cell proliferation, migration and invasion, alters cell morphology and adhesion and leads to the rearrangement of the cytoskeleton in vitro. We also demonstrate that the up-regulation of RI can decrease the expression of integrin-linked kinase (ILK), a central component of signaling cascades controlling an array of biological processes. The over-expression of RI reduces the phosphorylation of the ILK downstream signaling targets p-Akt and p-GSK3β in T24 cells. We further find that bladder cancer with a high-metastasis capability shows higher vimentin, Snail, Slug and Twist and lower E-cadherin and RI expression in human clinical specimens. Finally, we provide evidence that the up-regulation of RI inhibits tumorigenesis and metastasis of bladder cancer in vivo. Thus, RI might play a novel role in the development of bladder cancer through regulating EMT and the ILK signaling pathway.
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