Lipocalin2 suppresses metastasis of colorectal cancer by attenuating NF-κB-dependent activation of snail and epithelial mesenchymal transition

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.

MicroRNA-1224-5p Inhibits Metastasis and Epithelial-Mesenchymal Transition in Colorectal Cancer by Targeting SP1-Mediated NF-κB Signaling Pathways

“…The activation of the NF-κB signaling pathway is related to the malignant transformation and progression of CRC and the regulation of malignant characteristics of cancer cells (40,41). In addition, NF-κB plays a critical role in CRC EMT (42). Here, we demonstrated that NF-κB inhibitors terminate the stimulation of miR-1224-5p knockdown during CRC cell migration, invasion, and EMT.…”

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

“…In breast and thyroid cancers high LCN2 expression strongly correlated with advanced tumor grade and poor prognosis, but in ovarian, pancreatic and CRC it was associated well-differentiated tumors and a good prognosis (93). Overexpression of LCN2 in CRC cells suppressed proliferation, migration and invasion in vitro and tumor growth and metastasis in vivo (46). Similar tumor suppressive functions have been observed in liver cancer (47).…”

“…Lipocalin 2 (LCN2), also known as neutrophil gelatinaseassociated lipocalin (NGAL), is a secreted glycoprotein involved in iron trafficking. Increased LCN2 expression has been observed in ovarian (43), thyroid (44), breast (45,93), lung (94), colon (46), and pancreatic (95,96) cancers. In breast and thyroid cancers high LCN2 expression strongly correlated with advanced tumor grade and poor prognosis, but in ovarian, pancreatic and CRC it was associated well-differentiated tumors and a good prognosis (93).…”

SATB2-AS1 Suppresses Colorectal Carcinoma Aggressiveness by Inhibiting SATB2-Dependent Snail Transcription and Epithelial–Mesenchymal Transition

“…EMT can be triggered by a set of pleiotropically acting transcription factors (TF), including Snail1/2, Twist1/2, and Zeb1/2 (37). Snail (Snail1), as one of the most important EMT-TFs, is frequently overexpressed in different types of metastatic cancers, including colorectal carcinoma (38). Epigenetic modification, transcriptional, and posttranscriptional regulatory mechanisms are involved tightly in Snail expression (39).…”