Lysophosphatidic Acid Upregulates Recepteur D’origine Nantais Expression and Cell Invasion via Egr-1, AP-1, and NF-κB Signaling in Bladder Carcinoma Cells

Abstract

Muscle invasive bladder carcinoma is a highly malignant cancer with a high mortality rate, due to its tendency to metastasize. The tyrosine kinase recepteur d’origine nantais (RON) promotes bladder carcinoma metastasis. Lysophosphatidic acid (LPA) is a phospholipid derivative, which acts as a signaling molecule to activate three high affinity G-protein coupled receptors, LPA1, LPA2, and LPA3. This in turn leads to cell proliferation and contributes to oncogenesis. However, little is known about the effects of LPA on invasive bladder cancer (IBC). In this study, we discovered that LPA upregulated RON expression, which in turn promoted cell invasion in bladder cancer T24 cells. As expected, we found that the LPA receptor was essential for the LPA induced increase in RON expression. More interestingly, we discovered that LPA induced RON expression via the MAPK (ERK1/2, JNK1/2), Egr-1, AP-1, and NF-κB signaling axes. These results provide experimental evidence and novel insights regarding bladder malignancy metastasis, which could be helpful for developing new therapeutic strategies for IBC treatment.