Lcn2 was also reported to be a biomarker in cholangiocarcinoma;[35] these findings suggest that the role of Lcn2 is dependent on the liver tumor with an epithelial phenotype. Our results are in good agreement with previous observations in cancer of the ovary, where Lcn2 expression is almost completely absent in tissue samples from normal ovaries, but strongly expressed in both borderline and grade

1 tumors, and weakly to moderately expressed in grade 2 and 3 tumors.[4] Furthermore, moderate to strong expression of Lcn2 was observed in the epithelial ovarian cancer cell lines SKOV3 and OVCA433, while no expression was detected in mesenchymal-like OVHS1, PEO36, or HEY cell lines. Taken together, Lcn2 expression appears to be linked find more to the epithelial phenotype of tumors and is lost as the tumor progresses and becomes undifferentiated. Lcn2 has been implicated in the induction of cellular proliferation because its expression is associated with a variety of proliferative cells.[36, 37] Lcn2 expression is required for Bcr-Abl-induced http://www.selleckchem.com/PARP.html tumorigenesis in leukemia

cells.[38] Lcn2 expression promotes breast tumor growth and progression,[39-41] and also increases colon cancer migration and invasion.[42] Furthermore, down-regulation of Lcn2 by antisense RNA suppresses human esophageal MCE carcinoma SHEEC cell invasion in vivo by reducing matrix metalloproteinase (MMP)−9 activity.[43] In the present study, Lcn2 suppressed the proliferation, migration, and invasion of EMT phenotypic HCC cells in vitro and tumor growth and metastasis in vivo. This is consistent with results

from a previous study that reported that Lcn2 suppressed Ras-transformed 4T1 mouse mammary tumor cell invasiveness in vitro and tumor growth and lung metastases in vivo.[9] Furthermore, Lcn2 blocked human colon cancer KM12SM cell invasion and liver metastasis.[10] A recent study also proposed that Lcn2 may act as a suppressor of invasion and angiogenesis in advanced pancreatic cancer cells.[11] These apparently conflicting observations could be due to distinct functions of Lcn2 in different cell types. Our focus in this study was to determine the mechanisms by which Lcn2 inhibits growth factor-mediated EMT in association with invasion and metastasis in HCC. Loss of E-cadherin expression has been associated with activation of the EGF/EGFR cascade in several cancer types, including pancreatic cancer and cervical cancer.[25, 27] EGF-induced EMT phenotypes were inhibited in the presence of AG1478, an inhibitor of EGF receptor tyrosine kinase activity. Lim et al.[4] reported that EGF down-regulated both E-cadherin and Lcn2 expression in ovarian cancer cells.