Abstract
BackgroundLipocalin2 (LCN2) is a secretory protein that is aberrantly expressed in several types of cancer and has been involved in metastatic progression. However, neither mechanisms nor the role that LCN2 plays in the metastasis of colorectal cancer are clear.MethodsLCN2 expression in colorectal cancer was detected by immunohistochemistry in 400 tissue specimens and Kaplan-Meier survival analysis was performed. In vitro, real-time PCR, western blot, colony formation assay, immunofluorescence assay, wound healing assay, migration and invasion experiment were performed to investigate the effects of LCN2 in epithelial mesenchymal transition (EMT), migration and invasion, respectively. In vivo mouse xenograft and metastasis models were utilized to determine tumorigenicity and metastasis ability, and immunohistochemistry, real-time PCR, western blot were used to evaluate the related protein expression. Luciferase reporter assay was used to explore the role of LCN2 on NF-ĸB promoter.ResultsLCN2 was highly expressed in 66.5% of the specimens, and significantly correlated with positive E-cadherin in the membrane and negative nuclear β-catenin. Higher expression of LCN2 together with negative NF-κB expression was negatively related to nuclear accumulation of snail and predicted favorable prognosis. LCN2 blocked cell proliferation, migration and invasion in vitro and in vivo, and inhibited translocation of NF-κB into nucleus. NF-κB could reverse the effect of LCN2 on EMT and promote snail expression. Rescued snail expression had similar effect without influencing NF-κB activity.ConclusionLCN2 may be an important negative regulator in EMT, invasion and metastasis of CRC via acting as upstream of NF-κB/snail signaling pathway. Thereby combinative manipulation of LCN2 and NF-κB/snail pathway may represent a novel and promising therapeutic approach for the patients with CRC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0564-9) contains supplementary material, which is available to authorized users.
Highlights
Lipocalin2 (LCN2) is a secretory protein that is aberrantly expressed in several types of cancer and has been involved in metastatic progression
Aberrant expression of LCN2 in Colorectal cancer (CRC) tissues and cell lines We previously reported that the LCN2 level was markedly higher in the primary colon cell line SW480 than in the paired metastatic colon cell line SW620 by analyzing the differential secretome based on the LC-MS/MS-based label-free quantitative proteomics approach
These results suggested that LCN2 maybe involved in the progression of CRC
Summary
Lipocalin (LCN2) is a secretory protein that is aberrantly expressed in several types of cancer and has been involved in metastatic progression. Lipocalin (LCN2, known as neutrophil gelatinaseassociated lipocalin), is dysregulated in a variety of cancers such as pancreatic cancer [3], prostate cancer [4], and hepatocellular carcinoma [5]. It was initially considered as a defender of innate immunity for its capacity to sequester iron, which blocked bacteria growth [6]. LCN2 prevented metastasis and epithelial mesenchymal transition (EMT) in hepatocellular carcinoma [7] and was a novel suppressor of invasion and angiogenesis in pancreatic cancer [8]. LCN2 has been correlated with disease advancement [9] and appears to modulate several pathways such as the ERK/slug pathway in prostate cancer [10] and the Met/FAK pathway in liver cancer [11] to contribute to EMT progression
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