25800

SLC39A6

LIV-1 is a downstream target of STAT3 and is essential for the nuclear localization of Snail, a master regulator of epithelial to mesenchymal transition (EMT). Little is known about the association of LIV-1 with pancreatic carcinoma development, therefore, expression of LIV-1 mRNA was analyzed by real-time reverse transcriptase polymerase chain reaction (RT-PCR) in 9 cultured cell lines (8 carcinoma and 1 normal duct cell lines) and 24 pancreatic tissues (12 carcinoma and 12 normal tissues). Localization of this gene product was investigated by immunohistochemistry in 72 pancreatic carcinoma and the relation between its expression and clinicopathological findings was examined. To assess the function of LIV-1 in pancreatic carcinoma cells, stable siRNA expressing Panc-1 cells were generated. Higher expression of LIV-1 mRNA was found in both pancreatic carcinoma cell lines and pancreatic carcinoma tissues compared to normal duct cell line and histologically normal tissues, respectively. Immunohistochemical analysis revealed that LIV-1 expression was frequently found in 76.4% of pancreatic carcinoma tissues and its expression level was associated with tumor size and lymphatic infiltration. Down-regulated LIV-1 cells showed significant inhibition of anchorage-dependent or -independent proliferation and cell motility in vitro and reduction of tumor growth and metastasis in vivo. Furthermore, nuclear expression of Snail was decreased and E-cadherin expression was restored in LIV-1 siRNA expressing pancreatic carcinoma cells. These findings indicate that LIV-1 may be involved in acquisition of the aggressive phenotype of human pancreatic carcinoma cells through the induction of epithelial to mesenchymal transition.

Vertebrate gastrulation is a critical step in the establishment of body plan. During gastrulation, epithelial-mesenchymal transition (EMT) occurs. EMT is one of the central events of embryonic development, organ and tissue regeneration, and cancer metastasis. Signal transducers and activators of transcription (STATs) mediate biological actions such as cell proliferation, differentiation and survival in response to cytokines and growth factors, in a variety of biological processes. STATs are also important in EMT during gastrulation, organogenesis, wound healing and cancer progression. We previously showed that STAT3 is activated in the organizer during zebrafish gastrulation and its activity is essential for gastrulation movements. The requirement for STAT3 is cell-autonomous for the anterior migration of gastrula organizer cells, and non-cell-autonomous for the convergence of neighbouring cells. The molecular mechanisms of STAT's action in EMT, however, are unknown. Here we identify LIV1, a breast-cancer-associated zinc transporter protein, as a downstream target of STAT3 that is essential and sufficient for STAT3's cell-autonomous role in the EMT of zebrafish gastrula organizer cells. Furthermore, we demonstrate that LIV1 is essential for the nuclear localization of zinc-finger protein Snail, a master regulator of EMT. These results establish a molecular link between STAT3, LIV1 and Snail in EMT.