title: The transcription factor PAX2 regulates ADAM10 expression in renal cell carcinoma.
abstract: 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.
authors: Pharmazentrum Frankfurt/ZAFES, Klinikum der Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
authors: Kai
authors: K
authors: Doberstein
authors: Josef
authors: J
authors: Pfeilschifter
authors: Paul
authors: P
authors: Gutwein
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002295:Carcinoma, Transitional Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D015536:Down-Regulation; D053492:Elafin / Q000235:genetics / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D007124:Immunoenzyme Techniques; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000378:metabolism; D051762:PAX2 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D015820:Cadherins; D053492:Elafin; D008565:Membrane Proteins; D039842:Neural Cell Adhesion Molecule L1; D051762:PAX2 Transcription Factor; C497318:PAX2 protein, human; C506806:PI3 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051057:Proto-Oncogene Proteins c-akt; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human