The transcription factor PAX2 regulates ADAM10 expression in renal cell carcinoma
The transcription factor PAX2 regulates ADAM10 expression in renal cell carcinoma
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DOI：
10.1093/carcin/bgr195
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发表时间：
2011-11-01
期刊：
影响因子：
4.7
通讯作者：
Gutwein, Paul
中科院分区：
文献类型：
--
作者：
Doberstein, Kai;Pfeilschifter, Josef;Gutwein, Paul
ADAM 10是一种金属蛋白酶，在各种癌症的进展和转移中起重要作用。在本研究中，我们提出了令人信服的证据，PAX 2可以结合到ADAM 10的启动子和调节ADAM 10蛋白在肾癌细胞中的表达。我们进一步表明，ADAM 10是L1-CAM和c-Met的组成性切割的主要脱落酶，这两种重要的蛋白质参与肾癌的进展。ADAM 10的下调导致更分散的细胞表型，这伴随着Slug的诱导和E-cadherin的丢失，这在上皮向间充质转化（EMT）期间观察到。另外，ADAM 10的下调降低了肾癌细胞的增殖，但诱导了肾癌细胞的迁移。值得注意的是，PAX 2的下调导致L1-CAM表达增加，这伴随着大量金属蛋白酶介导的可溶性L1-CAM的释放。重要的是，可溶性L1-CAM诱导内皮细胞的增殖和肾癌细胞的迁移。最后，我们可以证明PAX 2的沉默导致PI 3 K/Akt通路的L1-CAM依赖性激活，PI 3 K/Akt通路是介导癌细胞存活的一个重要通路。总之，我们确定PAX 2作为L1-CAM和ADAM 10的调节剂，其在包括肾细胞癌在内的各种癌症的进展中起关键作用，并且ADAM 10的下调可能是肾癌发展的早期步骤，因为它似乎参与EMT过程。
ADAM10 is a metalloprotease that plays an important role in the progression and metastasis of various cancers. In the present study, we present compelling evidence that PAX2 can bind to the promotor of ADAM10 and regulate ADAM10 protein expression in renal cancer cells. We further show that ADAM10 is the major sheddase for the constitutive cleavage of L1-CAM and c-Met, two important proteins involved in the progression of renal cancer. The downregulation of ADAM10 led to a more scattered cell phenotype, which was accompanied by the induction of Slug and the loss of E-cadherin, which is observed during epithelial-to-mesenchymal transition (EMT). In addition, the downregulation of ADAM10 reduced the proliferation but induced the migration of renal cancer cells. Notably, the downregulation of PAX2 led to an increased L1-CAM expression, which was accompanied by a massive metalloprotease-mediated release of soluble L1-CAM. Importantly, soluble L1-CAM induced the proliferation of endothelial cells and the migration of renal cancer cells. Finally, we can demonstrate that the silencing of PAX2 led to an L1-CAM-dependent activation of the PI3K/Akt pathway, one important pathway mediating cancer cell survival. In summary, we identified PAX2 as a regulator of L1-CAM and ADAM10, which play crucial roles in the progression of various cancers including renal cell carcinoma and the downregulation of ADAM10 maybe an earlier step in renal cancer development as it seems to be involved in processes of EMT.