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.

癌症干细胞是耐药性和肿瘤复发的主要原因，而筛选癌症干细胞的靶标对于肿瘤治疗至关重要。在这里，我们研究了称为G蛋白偶联受体87（GPR87）的G蛋白偶联受体在胰腺导管腺癌（PDA）干细胞扩增中的作用和调节机制。我们发现GPR87是PDA患者的独立预后因素：GPR87高的患者预后较差。GPR87显着促进了球的形成能力，增加了侧群（SP）细胞的数量，增加了PDA干细胞标志物的表达，并增强了肿瘤的起始能力，表明GPR87促进了PDA干细胞的扩增。机理分析表明，信号转导子和转录激活子3（STAT3）直接与GPR87的启动子结合，从而增加GPR87的表达。相反，GPR87也激活了STAT3。进一步的分析表明，GPR87激活了Janus激酶2（JAK2），后者可以激活STAT3，抑制过表达GPR87的PDA细胞中的JAK2激活，从而显着抑制PDA干细胞的扩增。这些发现表明，GPR87，JAK2和STAT3形成了一个正反馈环，从而增加了PDA干细胞的数量。在PDA标本中，GPR87的表达与STAT3和JAK2的磷酸化水平呈正相关，证实GPR87通过激活JAK2 / STAT3促进了PDA干细胞的扩增。总而言之，我们发现GPR87以及JAK2和STAT3