Prostaglandin E2 Induces the Expression of IL-1α in Colon Cancer Cells

Abstract

PGE2 has been shown to exert pro-oncogenic effects in colorectal neoplasia through producing autocrine or paracrine growth factors. In the present study, we demonstrate that PGE2 induced the expression of IL-1α in colon cancer cells, which plays critical roles in tumor metastasis and neoangiogenesis in a variety of cancers. PGE2 increased the levels of both IL-1α mRNA and protein, suggesting a positive feedback loop between the IL-1 pathway and PGE2 signaling. Mechanistically, PGE2 induced the expression of IL-1α at both transcriptional and posttranscriptional levels. PGE2 stimulated the transcriptional activity of the IL-1α promoter and significantly stabilized IL-1α mRNA. Moreover, we show that IL-1α enhanced colorectal neoplasia, stimulating cell migration and neoangiogenesis. Knockdown of the expression of IL-1α by small-interfering RNA resulted in a reduction of vascular endothelial growth factor secretion in colon cancer cells and an inhibition of tube formation by HUVECs. Thus, our results suggest that PGE2 induces the expression of proinflammatory cytokine IL-1α, which may potentially enhance the proneoplastic actions of the cyclooxygenase-2/PGE2 signaling pathway.

Seminal plasma induces the expression of IL-1α in normal and neoplastic cervical cells via EP2/EGFR/ PI3K/AKT pathway

“…The role of the EP2 receptor in mediating these effects was further confirmed using the selective EP2 agonist butaprost. This is consistent with similar study by Shao et al (2007) where it was shown that PGE 2 , acting via EP2 receptor activate cAMP/PKA pathway to mediate the expression of IL-1α in colon cancer cells in an autocrine/paracrine mechanism [18]. EP2 and its signaling have been found to be up-regulated in cervical cancer [9] and its role in the induction of IL-1α in cervical cancer could explain the greater expression of IL-1α in cervical cancer tissue explant relative to normal cervical tissue.…”

“…Once released, IL-1α can act in an autocrine/paracrine manner within the site of production to regulate inflammation and tumorigenesis. Indeed, Shao and colleagues showed in their study that IL-1α stimulates the migration of colon cancer cells [18]. It is therefore plausible that in sexually active women with underlying pre-invasive or invasive cervical condition, repeated exposure of the elevated EP2 receptor expressed on the neoplastic cervical epithelial cells [9] to PGE 2 present in seminal plasma could enhance tumorigenesis following ligand-receptor binding and activation of similar intracellular signaling pathway to induce IL-1α expression.…”

“…IL-1α possesses a wide range of inflammatory, immunologic and tumorigenic properties [15-17]. IL-1α is secreted by a variety of cells including monocytes, tissue macrophages, neutrophils, fibroblasts, smooth muscle cells, dendritic cells, and cervical epithelium [15,18,19]. Accumulative evidence suggests that IL-1α plays a crucial role in tumorigenesis.…”

Lack of association between an insertion/deletion polymorphism in IL1A and risk of colorectal cancer

“…The IL1A gene encoding IL-1a is targeted by miR-122 and miR-378 , and IL-1a mRNA and protein have been detected in highly metastatic colon cancer cells (Matsuo et al, 2009). In addition, knocking down the expression of IL-1a leads to a reduction of vascular endothelial growth factor secretion in colon cancer cells (Shao and Sheng, 2007). Taken together, these findings indicate that miR-122/miR-378 and their target gene IL1A potentially play a role in CRC tumorigenesis.…”

IL‐1α secreted by colon cancer cells enhances angiogenesis: The relationship between IL‐1α release and tumor cells' potential for liver metastasis

“…IL-1b is present in the circulation of patients undergoing infectious or inflammatory responses, whereas IL-1a is rarely found in the circulation [6]. Voronov et al [7] demonstrated the critical roles of IL-1 in tumor invasiveness and angiogenesis in vivo, and many reports demonstrated the importance of IL-1 in colon cancer progression [8][9][10][11][12]. We have previously reported that IL-1a acts through its type I receptor (IL-1RI) to play an important role in invasive and angiogenic behaviors in pancreatic cancer cell lines, and confirmed that only those cancer cell lines highly metastatic to the liver express IL-1a mRNA [13][14][15].…”