LIV-1 enhances the aggressive phenotype through the induction of epithelial to mesenchymal transition in human pancreatic carcinoma cells

Abstract

Abstract. 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. IntroductionLIV-1 is a member of new subfamily of zinc transporters, termed LZT (LIV-1 subfamily of ZIP zinc transporters) and is suggested to be located to the plasma membrane. It has been shown to act as a zinc transporter, leading to an increase in intracellular zinc levels (1). Zinc plays various roles in cell metabolism and is involved in cellular processes such as cell growth, differentiation and gene transcription (2,3), suggesting that its altered distribution might promote tumorigenesis. LIV-1 was originally identified as an estrogen-induced gene in the breast cancer cell line ZR-75-1 (4) and its expression was also shown to be correlated with lymph node involvement of the breast carcinoma, indicating a role for LIV-1 in metastasis (5).Epithelial to mesenchymal transition (EMT) is a general phenomenon that is an essential event in embryonic development, tissue remodelling and wound repair. During EMT, a loss of intracellular adhesion is observed along with extensive remodelling of the cytoskeleton and expression of components specific to a mesenchymal phenotype. Epithelial cells undergoing the transition to a mesenchymal phenotype also display an increased propensity for migration (6-8). Therefore, this transition is considered to be an important event during malignant tumor progression an...

Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial–Mesenchymal Transition

“…For instance, once activated, STAT3, in combination with estrogen receptor (ER), binds to the LIV-1 promoter leading to the induction of LIV-1 expression, followed by proteolytic N-terminal cleavage of the LIV-1 protein and its subsequent translocation to the plasma membrane. Subsequently, LIV-1 stabilizes Snail through inactivation of GSK3β [24][25][26]. In addition, RANKL is known to enhance EMT in prostate cancer through the STAT3/LIV-1 axis [27].…”

Oestrogen-regulated protein SLC39A6: a biomarker of good prognosis in luminal breast cancer

“…Data for ER, PgR, HER2, Ki67, GATA3, FOXA1 and TFF1 were available as previously published [ 13 , 15 , 18 , 21 ] [ 31 ]. ER and PgR positivity were defined as positive nuclear staining in ≥ 1% of the invasive tumour cells [ 13 , 21 , 23 ]; 75% of the patients had ER + tumours. HER2 positivity was defined as strong positive membranous staining in ≥ 10% of the invasive tumour cells (score + 3).…”

“…Overexpression of SLC39A6 has been related to the progression of several types of cancer, including breast [ 13 , 18 ], prostate [ 21 ], pancreatic [ 23 ], cervical [ 24 ] and liver cancer [ 25 ]. An in vitro study suggested that SLC39A6 is involved in metastasis in BC, as overexpression of SLC39A6 promoted the epithelial-mesenchymal transition (EMT) [ 15 ].…”