G Protein-Coupled Receptor GPR87 Promotes the Expansion of PDA Stem Cells through Activating JAK2/STAT3.

Cancer stem cells are the main reason for drug resistance and tumor relapse, and screening the targets for cancer stem cells is essential for tumor therapy. Here, we studied the role and regulatory mechanism of a G protein-coupled receptor named as G protein-coupled receptor 87 (GPR87) in the expansion of pancreatic ductal adenocarcinoma (PDA) stem cells. We found that GPR87 was an independent prognostic factor for PDA patients: patients with high GPR87 had a poor outcome. GPR87 significantly promoted the sphere formation ability, increased side population (SP) cell number, increased the expression of PDA stem cell markers, and increased the tumor initiation ability, suggesting that GPR87 promotes the expansion of PDA stem cells. Mechanism analysis suggested that signal transducer and activator of transcription 3 (STAT3) directly bound to the promoter of GPR87 to increase GPR87 expression; inversely, GPR87 also activated STAT3. Further analysis suggested that GPR87 activated Janus kinase 2 (JAK2), which can activate STAT3, inhibiting JAK2 activation in GPR87-overexpressing PDA cells, which significantly inhibited the expansion of PDA stem cells; these findings suggested that GPR87, JAK2, and STAT3 formed a positive feedback loop increasing PDA stem cell population. In PDA specimens, GPR87 expression is positively correlated with the phosphorylation level of STAT3 and JAK2, confirming GPR87 promoted PDA stem cell expansion through activating JAK2/STAT3. In summary, we found that GPR87, together with JAK2 and STAT3, formed a positive feedback loop to promote the expansion of PDA stem cells.