Lipocalin-2-induced cytokine production enhances endometrial carcinoma cell survival and migration

Abstract

Lipocalin-2 (Lcn-2) is an acute-phase protein that has been implicated in diverse physiological processes in mice, including: apoptosis, ion transport, inflammation, cell survival, and tumorigenesis. This study characterized the biological activity of Lcn-2 in human endometrial carcinoma cells (RL95-2). Exposure of RL95-2 cells to Lcn-2 for >24 h reduced Lcn-2-induced cell apoptosis, changed the cell proliferation and up-regulated cytokine secretions, including: interleukin-8 (IL-8), inteleukin-6 (IL-6), monocyte chemotatic protein-1 (MCP-1) and growth-related oncogene (GRO). However, IL-8 mRNA and protein levels were dramatically increased in Lcn-2-treated RL95-2 cells. To determine the IL-8 effect on Lcn-2-treated RL95-2 cells was our major focus. Adding recombinant IL-8 (rIL-8) resulted in decreased caspase-3 activity in Lcn-2-treated cells, whereas the addition of IL-8 antibodies resulted in significantly increased caspase-3 activity and decreased cell migration. Data indicate that IL-8 plays a crucial role in the induction of cell migration. Interestingly, Lcn-2-induced cytokines, secretion from RL95-2 cells, could not show the potent cell migration ability with the exception of IL-8. We conclude that Lcn-2 triggered cytokine secretions to prevent RL95-2 cells from undergoing apoptosis and subsequently increased cell migration. We hypothesize that Lcn-2 increased cytokine secretion by RL95-2 cells, which in turn activated a cellular defense system. This study suggests that Lcn-2 may play a role in the human female reproductive system or in endometrial cancer.

Lipocalin 2 induces the epithelial–mesenchymal transition in stressed endometrial epithelial cells: possible correlation with endometriosis development in a mouse model

“…The finding supports a relationship between LCN2 and angiogenesis during the growth of endometrial tissue within the peritoneum. We have previously shown that LCN2 stimulates the secretion of angiogenesis-related cytokines from an endometrial cell line (RL95-2; Lin et al 2011). Our current study showed time-dependent production of LCN2, which supports the idea that LCN2 stimulates the expansion of ectopic endometrial tissue in the peritoneum.…”

“…As mentioned earlier, LCN2 is upregulated in the endometriotic lesions (Konno et al 2007, Becker et al 2010. We previously found that LCN2 is upregulated in the endometrial carcinoma cells (RL95-2 cells derived from endometrial epithelia) under oxidative stress and that LCN2-induced secreted cytokines trigger cell proliferation and migration (Lin et al 2011). These findings indicate that LCN2 is a stress factor that responds to environmental stress by triggering changes in cellular physiology.…”

“…Cellular stress may initiate endometriosis by affecting the immune system, thereby allowing tissue from the uterine lining to grow in an abnormal location (Augoulea et al 2009). We have previously shown that LCN2 increases intracellular oxidative stress and triggers the secretion of cytokines from nutrient-deprived cells (Lin et al 2011). Cytokines likely prevent endometrial cell apoptosis, thereby facilitating cell migration.…”

Immunohistochemical detection of a specific receptor for lipocalin2 (solute carrier family 22 member 17, SLC22A17) and its prognostic significance in endometrial carcinoma

“…Lin and colleagues reported that LCN2 treatment induced cell apoptosis up to 48 hours in endometrial carcinoma RL95-2 cells. However, LCN2 simultaneously induced IL-8 expression which enhanced cell survival and migration after 48 hours (Lin et al, 2011).…”

Characterization of Acute-Phase Proteins (Apps)

“…IL-8 thereby offers the potential to promote the formation of tumor (48). Based on the result of Lin et al (41), LCN2 could induce IL-8 expression and secretion and enhance cell migration and invasion. This suggests IL-8 as an LCN2-induced tumor factor.…”