IL-1β-stimulated urokinase plasminogen activator expression through NF-κB in gastric cancer after HGF treatment

Abstract

Abstract. The potential of hepatocyte growth factor (HGF) to regulate the expression of urokinase plasminogen activator (uPA) in a gastric cancer cell is not widely acknowledged. To identify the genes associated with the plasminogen activator proteolytic axis by HGF, we used cDNA microarray technology and selected genes upregulated or downregulated in two gastric cell lines (NUGC-3 and MKN-28). First, IL-1β RNA and protein were confirmed to be upregulated. Then, we investigated the effect of IL-1β induced by HGF on the uPA system, facilitating the migration and invasion of cancer cells in the metastatic process. The role for IL-1β in HGF-induced upregulation of uPA was determined by knockdown of IL-1β with IL-1β shRNA and a chromatin immune precipitation assay. The levels of IL-1β and uPA were upregulated in cells treated with HGF in a dose-dependent manner. HGF-induced upregulation of uPA was suppressed by IL-1β knockdown. HGF enhanced the binding activity of NF-κB to the uPA promoter in control cells, but not in the IL-1β shRNA cells. We confirmed the functional role of HGF inactivation of the uPA promoter by a reporter gene assay. Downregulation of IL-1β using IL-1β shRNA also decreased cell proliferation and in vitro cell invasion. IL-1β stimulated uPA expression through ERK and NF-κB in gastric cancer, which may therefore be promising targets for gastric cancer therapy.

Experimental and Clinical Evidence Supports the Use of Urokinase Plasminogen Activation System Components as Clinically Relevant Biomarkers in Gastroesophageal Adenocarcinoma

“…Lee, K., et al, [70] HGF signal transduction via PKC/PKD pathway can release HDAC5; HDAC5 increased uPA and MMP-9 activity. Blockade of HDAC5 (even in presence of exogenous HGF) resulted in reduced uPA protein levels.…”

“…Key cancer signalling pathways also alter uPAS mRNA and protein expression in GOC cell lines and xenografts. uPAS expression can be modulated by targeting key pathways with drug blockade [66,67], transfection of interfering or promoting RNA [68][69][70][71] and exposure to exogenous stimulating proteins [72][73][74][75][76][77]. Table 1 summarises the molecules and pathways linked to the regulation of uPAS in GOC cell lines.…”

“…Exposure to exogenous growth factors such as epidermal growth factor increases uPAR mRNA expression, and this appears to occur through the mitogen-activated protein kinase (MAPK)/extracellular signal-related kinases (ERK) signalling pathway [72]. uPA and uPAR are both also upregulated upon HGF exposure, again, uPAS expression is reportedly linked to the MAPK/ERK pathway rather than phosphoinositide 3-kinase (PI3K) pathway [70]. Increased prostaglandin E2 levels (including as a result of nicotine exposure) resulted in increased uPA and uPAR levels via the cyclooxygenase-prostaglandin pathway [74,75].…”

Extracellular Collagen Promotes Interleukin-1β–Induced Urokinase-Type Plasminogen Activator Production by Human Corneal Fibroblasts

“…11 Furthermore, NFjB is a key mediator of IL-1b effects and the uPA gene promoter contains binding sites for this transcription factor. 19,[32][33][34] Interleukin-1b also activates MAPK signaling pathways including those mediated by ERK, JNK, and p38 MAPK. 35,36 We confirmed that IL-1b activates these MAPKs and NF-jB in corneal fibroblasts cultured in a collagen gel.…”

Positive feedback loop of IL-1β/Akt/RARα/Akt signaling mediates oncogenic property of RARα in gastric carcinoma

“…Interlenkin-1β (IL-1β) is a member of proinflammatory cytokine family which are produced by both tumor cells and stromal cells [12]. It has been reported to govern the proliferation and invasion related proteins of GC [13, 14]. Nevertheless, whether IL-1β regulates RARα expression in development and progression of GC is unclear.…”