LIV-1 Promotes Prostate Cancer Epithelial-to-Mesenchymal Transition and Metastasis through HB-EGF Shedding and EGFR-Mediated ERK SignalingReportar como inadecuado




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LIV-1, a zinc transporter, is an effector molecule downstream from soluble growth factors. This protein has been shown to promote epithelial-to-mesenchymal transition EMT in human pancreatic, breast, and prostate cancer cells. Despite the implication of LIV-1 in cancer growth and metastasis, there has been no study to determine the role of LIV-1 in prostate cancer progression. Moreover, there was no clear delineation of the molecular mechanism underlying LIV-1 function in cancer cells. In the present communication, we found increased LIV-1 expression in benign, PIN, primary and bone metastatic human prostate cancer. We characterized the mechanism by which LIV-1 drives human prostate cancer EMT in an androgen-refractory prostate cancer cells ARCaP prostate cancer bone metastasis model. LIV-1, when overexpressed in ARCaPE derivative cells of ARCaP with epithelial phenotype cells, promoted EMT irreversibly. LIV-1 overexpressed ARCaPE cells had elevated levels of HB-EGF and matrix metalloproteinase MMP 2 and MMP 9 proteolytic enzyme activities, without affecting intracellular zinc concentration. The activation of MMPs resulted in the shedding of heparin binding-epidermal growth factor HB-EGF from ARCaPE cells that elicited constitutive epidermal growth factor receptor EGFR phosphorylation and its downstream extracellular signal regulated kinase ERK signaling. These results suggest that LIV-1 is involved in prostate cancer progression as an intracellular target of growth factor receptor signaling which promoted EMT and cancer metastasis. LIV-1 could be an attractive therapeutic target for the eradication of pre-existing human prostate cancer and bone and soft tissue metastases.



Autor: Hui-Wen Lue, Xiaojian Yang, Ruoxiang Wang, Weiping Qian, Roy Z. H. Xu, Robert Lyles, Adeboye O. Osunkoya, Binhua P. Zhou, Robert

Fuente: http://plos.srce.hr/



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