Keratinocyte chemoattractant (KC)/human growth-regulated oncogene (GRO) chemokines and pro-inflammatory chemokine networks in mouse and human ovarian epithelial cancer cells

Abstract

Chronic inflammation is an important underlying condition for ovarian tumor development, growth and progression. Since chemokine networks are activated by inflammation, patterns of chemokine gene expression were investigated in ovarian cancer cells. Chemokine specific microarrays were performed after mouse (ID8) and human (SKOV-3) ovarian surface epithelial cancer cells were exposed to the inflammatory agent bacterial endotoxin lipopolysaccharide (LPS, 10 microg/ml) and pro-inflammatory cytokines interleukin-1beta (IL-1, 10 ng/ml) and tumor necrosis factor-alpha (TNF, 10 ng/ml). In the mouse ID8 cells, LPS, IL-1 and TNF led to robust upregulation of keratinocyte chemoattractant (KC) chemokines CXCL1/2, mouse homologues of human growth-regulated oncogenes (GRO). Other chemokines, interferong inducible protein (IP)-10 (CXCL10), CCL7 and CCL20 were moderately upregulated. ID8 cells constitutively expressed CXCL16 and CCL2, but only CCL2 expression was enhanced by LPS, IL-1 and TNF. In the human SKOV-3 cells, LPS had no effect on chemokines expression due to the absence of the LPS receptor, toll-like receptor 4 (TLR4). However, IL-1 and TNF induced GROalpha/beta (CXCL1/2) in human SKOV-3 cells in a similar manner as observed with mouse ID8 cells. In SKOV-3 cells, IL-8 (CXCL8) was highly expressed and other chemokines GROgamma (CXCL3) and CCL20 were moderately expressed in response to IL-1 and TNF. The nuclear factor-kappaB (NF-kappaB) is a known mediator of cytokine and chemokines signaling. The NFkappaB inhibitor BAY 11-7082 attenuated expression of inflammatory-induced chemokines in the mouse and human ovarian cancer cells. Taken together, the results indicate that KC/GRO chemokines are the principal chemokines induced by LPS and pro-inflammatory cytokines IL-1 and TNF via NFkappaB signaling in ovarian surface epithelial cancer cells.

Phospholipase Cɛ has a crucial role in ultraviolet B-induced neutrophil-associated skin inflammation by regulating the expression of CXCL1/KC

“…36 Also, TNF-a is known to induce CXCL1/KC production in some cell types. 37 These reports raise the possibility that UVB upregulates CXCL1/KC production through enhancing TNF-a production in skin cells. Thus, we examined the possible involvement of TNF-a in UVB-induced CXCL1/KC production.…”

The emerging role of CXC chemokines in epithelial ovarian cancer

“…The nuclear factor-kB (NF-kB) pathway is also important in modulating autocrine and paracrine signalling between inflammatory markers in the cancer microenvironment (Son et al 2007). Notably, NF-kB regulates the CXCL12/CXCR4 autocrine signalling in ovarian cancer cell lines (Miyanishi et al 2010).…”

“…CXC chemokines in epithelial ovarian cancer Ness et al 2000, Fleming et al 2006, Son et al 2007, Coffelt & Scandurro 2008, Maccio & Madeddu 2012. As key mediators of inflammation, chemokines play two major roles: i) they are responsible for the recruitment and activation of immune cells into sites of malignancy (and possibly areas of pre-neoplastic growth) and ii) they mediate pro-and anti-angiogenic effects, processes required for the vascularisation and progression of tumours.…”

Norepinephrine Promotes the β1-Integrin–Mediated Adhesion of MDA-MB-231 Cells to Vascular Endothelium by the Induction of a GROα Release

“…We have also shown an upregulation of the gene expression level of IL-8 and GROa in response to norepinephrine incubation. The expression of the chemokines GROa, IL-8, and other inflammatory chemokines is under the control of NF-kB (46), which also holds true for the herein used HMVECs. NF-kB mediates the PPAR-induced upregulation of IL-8 in HUVECs (47).…”