LPAR2-mediated action promotes human renal cell carcinoma via MAPK/NF-κB signaling to regulate cytokine network

Abstract

Purpose: Lysophosphatidic acid (LPA) exerts various physiological and pathological effects by activating its distinct G-protein-coupled LPA receptors. We demonstrated that LPA can increase the migration and proliferation of renal carcinoma cells. Meanwhile, LPAR1 and LPAR2 were preferentially expressed in renal cancer (RC) cell lines. So, the study aimed to determine the LPA receptor subtypes involved in LPA-induced actions and whether they could be used as a precision therapeutic target for renal cancer.

Methods: Biological approaches combined with big data analysis were used to demonstrate the role of LPAR2 in the progression of renal cancer.

Results: We found that the proliferation, clone formation, and migration in response to LPA were enhanced in LPAR2-overexpressing renal cancer cells, whereas, the actions were suppressed by LPAR2 antagonist in the cells. LPAR2 has also shown clinical diagnostic and prognostic value in renal carcinoma based on bioinformatics analysis and clinical tissue microarray analysis. In vivo study shown that tumor growth and metastasis were significantly increased in the LPAR2-overexpressing cells-derived solid tumors. LPA stimulated MAPK and NF-κB activation, and LPA-induced actions were inhibited by MAPKs and NF-κB inhibitors, respectively. Subsequently, the transcriptomic results revealed that LPAR2 strongly affected the cytokines production, and the increased IL6, CXCL8, and TNF were confirmed again using Kit assay.

Conclusions: We have identified that LPAR2 is critical for LPA-promoted renal cancer progression, and the actions mainly dependent the MAPK and NF-κB activation mechanism. Then, the expression of inflammatory factors activated by NF-κB is also suspected to be involved in LPAR2-mediated carcinogenesis. Thus, LPAR2 may be a promising therapeutic target for renal cancer.

Keywords: Bioinformatics; Cytokine network; In vivo tumorigenicity; Lysophosphatidic acid receptor 2; Renal cell carcinoma.