Essential Role of Adhesion GPCR, GPR123, for Human Pluripotent Stem Cells and Reprogramming towards Pluripotency.

G-protein-coupled receptors (GPCRs) are the largest family of cell surface receptors. They modulate key physiological functions and are required in diverse developmental processes including embryogenesis, but their role in pluripotency maintenance and acquisition during the reprogramming towards hiPSCs draws little attention. Meanwhile, it is known that more than 106 GPCRs are overexpressed in human pluripotent stem cells (hPSCs). Previously, to identify novel effectors of reprogramming, we performed a high-throughput RNA interference (RNAi) screening assay and identified adhesion GPCR, GPR123, as a potential reprogramming effector. Its role has not been explored before. Herein, by employing GPR123 RNAi we addressed the role of GPR123 for hPSCs. The suppression of GPR123 in hPSCs leads to the loss of pluripotency and differentiation, impacted colony morphology, accumulation of cells at the G2 phase of the cell cycle, and absence of the scratch closure. Application of the GPR123 RNAi at the initiation stage of reprogramming leads to a decrease in the percentage of the "true" hiPSC colonies, a drop in E-cadherin expression, a decrease in the percentage of NANOG+ nuclei, and the absence of actin cytoskeleton remodeling. Together this leads to the absence of the alkaline-phosphatase-positive hiPSCs colonies on the 18th day of the reprogramming process. Overall, these data indicate for the first time the essential role of GPR123 in the maintenance and acquisition of pluripotency.

Adhesion GPR123 is an indicator for recurrence and prognosis in bladder cancer.

BACKGROUND: Bladder cancer is a common urinary cancer, and most patients suffer tumor recurrence after surgery. Identifying more prognostic biomarkers is an essential task for precious treatment. OBJECTIVE: To evaluate the expression and clinical significance of GPR123, Angiotensin-I a type of adhesion G protein-coupled receptors (aGPCRs), in bladder cancer. METHODS: The expressions of GPR123 in two retrospective cohorts comprised of 150 and 56 patients with bladder cancer respectively, were detected with and immunohistochemistry (IHC). Moreover, GPR123 mRNAs in 11 non-muscle-invasive bladder cancers (NMIBCs) and 11 muscle-invasive bladder cancers (MIBCs) were detected with qRT-PCR. The correlation between GPR123 and the clinicopathological characters was estimated by Chi-square test. The significance of GPR123 and other clinicopathological characters in recurrence and prognosis of bladder cancer was evaluated by univariate and multivariate analyses. RESULTS: GPR123 was mainly expressed in the cell membrane of bladder cancer. The percentages of high GPR123 expression in NMIBC and MIBC were 38.32 and 55.81 % in cohort 1, and 16.00 and 43.90 % in cohort 2. With qRT-PCR and IHC, we showed that GPR123 expression in MIBC was significantly higher than that in NMIBC. GPR123 was significantly associated with T and M stage of bladder cancer. GPR123 expression was all correlated with recurrence (disease-free survival rate), and prognosis (overall survival rate). High GPR123 expression was identified as independent biomarker indicating easier recurrence and poorer prognosis. CONCLUSIONS: GPR123 was an independent biomarker of bladder cancer for recurrence and prognosis, indicating that GPR123 detection with IHC after operation could help find the high-risk patients and direct the post-operational surveillance.