Abstract
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.
Highlights
LIV-1, a cell surface protein and a candidate mediator of the growth factor-elicited signaling molecule, has been associated with several important biologic processes by serving as a transporter for zinc and other ions [1,2,3,4,5]
We investigated the role of LIV-1 in regulating epithelial to mesenchymal transition (EMT) in ARCaP cells to assess the possible mechanism of LIV-1 action in the promotion of prostate cancer bone and soft tissue metastases
We previously reported that ARCaPE cells underwent EMT when treated with soluble factors including Insulin-like growth factor-1 (IGF-1), Epidermal growth factor (EGF), transforming growth factor-b1 (TGF-b1)
Summary
LIV-1, a cell surface protein and a candidate mediator of the growth factor-elicited signaling molecule, has been associated with several important biologic processes by serving as a transporter for zinc and other ions [1,2,3,4,5]. In the ER-positive ZR-75-1 breast cancer cell line, LIV-1 transcription is induced by estrogens [9]. LIV-1 expression is associated with ER status [10,11], and is positively correlated with the spread of cancer to regional lymph nodes [12]. Expression of LIV-1 was shown to be higher in tumor than normal tissues; RNAimediated suppression of LIV-1 significantly inhibited cell proliferation, colony formation, and reduced the migratory and invasive ability of the HeLa cells [13]. LIV-1 is essential for the nuclear localization of Snail, a master transcription factor promoting epithelial to mesenchymal transition (EMT), causing migration of gastrula organizing cells [15]. LIV-1 is an obligatory co-factor regulating EMT-associated genes [14,15,16]
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