Free-Fatty Acid Receptor-4 (FFA4/GPR120) differentially regulates migration, invasion, proliferation and tumor growth of papillary renal cell carcinoma cells

Kidney cancer is among the 10 most common cancers, and renal cell carcinoma (RCC), which represent 90% of all kidney cancers, has the highest mortality rate of all genitourinary cancers. Papillary RCC (pRCC) is the second most frequent subtype of RCC and demonstrates distinct characteristics compared to other subtypes, including a high degree of metastasis and resistance to treatments against the more common clear cell RCC (ccRCC) subtype. Here, we demonstrate that the Free-Fatty Acid Receptor-4 (FFA4), a G protein-coupled receptor that is endogenously activated by medium-to-long chain free-fatty acids, is upregulated in pRCC compared to patient-matched normal kidney tissue, and that the expression of FFA4 increases with the degree of pathological grading of pRCC. Our data also show that FFA4 transcript is not expressed in ccRCC cell lines, but is expressed in the wellcharacterized metastatic pRCC cell line ACHN. Furthermore, we show that agonism of FFA4 with the selective agonist cpdA positively regulates ACHN cell migration and invasion in a manner dependent on PI3K/AKT/NF-?B signaling to COX-2 and MMP-9, with partial-dependence on EGFR transactivation. Our results also demonstrate that FFA4 agonism induces STAT-3-driven epithelial-mesenchymal transition, suggesting a significant role for FFA4 in pRCC metastasis. On the contrary, FFA4 agonism significantly reduces cell proliferation and tumor growth, suggesting that the receptor may have opposing effects on pRCC cell growth and migration. Together, our data demonstrate that FFA4 has significant functional roles in pRCC cells and may be an attractive target for study of pRCC and development of RCC pharmacotherapeutics.