title: LIV-1 promotes prostate cancer epithelial-to-mesenchymal transition and metastasis through HB-EGF shedding and EGFR-mediated ERK signaling.
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 ARCaP(E) (derivative cells of ARCaP with epithelial phenotype) cells, promoted EMT irreversibly. LIV-1 overexpressed ARCaP(E) 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 ARCaP(E) 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.
authors: Department of Biology, Georgia State University, Atlanta, Georgia, United States of America.
authors: Hui-Wen
authors: HW
authors: Lue
authors: Xiaojian
authors: X
authors: Yang
authors: Ruoxiang
authors: R
authors: Wang
authors: Weiping
authors: W
authors: Qian
authors: Roy Z H
authors: RZ
authors: Xu
authors: Robert
authors: R
authors: Lyles
authors: Adeboye O
authors: AO
authors: Osunkoya
authors: Binhua P
authors: BP
authors: Zhou
authors: Robert L
authors: RL
authors: Vessella
authors: Majd
authors: M
authors: Zayzafoon
authors: Zhi-Ren
authors: ZR
authors: Liu
authors: Haiyen E
authors: HE
authors: Zhau
authors: Leland W K
authors: LW
authors: Chung
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D001859:Bone Neoplasms / Q000556:secondary; D027682:Cation Transport Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D015398:Signal Transduction; D012983:Soft Tissue Neoplasms / Q000556:secondary
chemical_list: D000906:Antibodies; D027682:Cation Transport Proteins; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; C418627:SLC39A6 protein, human; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9