NPFFR2 Contributes to the Malignancy of Hepatocellular Carcinoma Development by Activating RhoA/YAP Signaling

SIMPLE SUMMARY: G protein–coupled receptors (GPCRs) are the most critical protein group for drug development, targeting about 35% of approved drugs. As their abnormal activation causes many diseases, including cancer, it is beneficial to discover novel GPCRs that are aberrantly expressed in cancer and function in cancer progression. We discovered that neuropeptide FF receptor 2 (NPFFR2) is aberrantly expressed in liver cancer and promotes malignancy by enhancing the activity of RhoA/YAP, and inhibiting NPFFR2 dramatically reduced the malignant phenotypes. We expect that these findings provide a novel potential target for cancer treatment. ABSTRACT: G protein–coupled receptors (GPCRs) are a diverse family of cell surface receptors implicated in various physiological functions, making them common targets for approved drugs. Many GPCRs are abnormally activated in cancers and have emerged as therapeutic targets for cancer. Neuropeptide FF receptor 2 (NPFFR2) is a GPCR that helps regulate pain and modulates the opioid system; however, its function remains unknown in cancers. Here, we found that NPFFR2 is significantly up-regulated in liver cancer and its expression is related to poor prognosis. Silencing of NPFFR2 reduced the malignancy of liver cancer cells by decreasing cell survival, invasion, and migration, while its overexpression increased invasion, migration, and anchorage-independent cell growth. Moreover, we found that the malignant function of NPFFR2 depends on RhoA and YAP signaling. Inhibition of Rho kinase activity completely restored the phenotypes induced by NPFFR2, and RhoA/F-Actin/YAP signaling was controlled by NPFFR2. These findings demonstrate that NPFFR2 may be a potential target for the treatment of hepatocellular carcinoma.