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.
Highlights
Bladder cancer is one of the most common cancers in the world and has a much higher incidence in males and aged individuals [1]
We revealed that Lysophosphatidic acid (LPA) induced recepteur d’origine nantais (RON) expression through the MAPK (ERK1/2, JNK1/2) Egr-1, AP-1, and NF-κB signaling axes
We found that stimulation of RON by macrophage stimulating protein (MSP) upregulated uPAR expression, which enhanced gastric cancer cell invasiveness [9]
Summary
Bladder cancer is one of the most common cancers in the world and has a much higher incidence in males and aged individuals [1]. Bladder cancer has been classified into non-invasive bladder cancer (NIBC) and invasive bladder cancer (IBC) by urologists [2]. It is important to know the mechanism of bladder cancer cells invasion and to develop therapeutic treatments for IBC. Several molecules promoting cancer cell invasion and metastasis have been identified, of which recepteur d’origine nantais (RON), encoded by the macrophage stimulating protein receptor (MST1R) gene, is very important [6]. MST1R is related to the c-MET receptor tyrosine kinase [7,8]. Upon stimulation by ligands such as macrophage-stimulating protein, RON activates the downstream signaling axis comprising Src, Ras, and MAPKs, which in turn upregulate a number of cell invasion related molecules such as uPAR and enhance cancer cell invasiveness [9]
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