由人类巨细胞病毒编码的G蛋白偶联受体（GPCR）US28与快速进展的胶质母细胞瘤（一种预后通常较差的侵袭性脑肿瘤）有关。在这里，我们展示了US28通过增强由神经酰胺-1-磷酸酯（S1P）介导的信号传导来增加U251胶质母细胞瘤细胞的恶性程度。US28的表达增加了S1P信号传导轴的关键组分的丰富程度，包括产生S1P的酶[sphingosine kinase 1 (SK1)]，一个S1P受体[S1P receptor 1 (S1P1)]以及S1P本身。增强的S1P信号传导通过激活激酶AKT和CHK1以及转录调节因子cMYC和STAT3，以及增加癌细胞PP2A抑制物（CIP2A）的丰富程度，促进了胶质母细胞瘤细胞的增殖和存活，从而驱动了多个前馈信号传导回路。抑制S1P信号传导消除了US28的促增殖和抗凋亡效应。US28还在被HCMV感染的细胞中激活了S1P信号传导轴。本研究揭示了S1P和CIP2A在前馈信号传导中的核心作用，从而促进了US28加剧胶质母细胞瘤的进展。

The G protein-coupled receptor (GPCR) US28 encoded by the human cytomegalovirus (HCMV) is associated with accelerated progression of glioblastomas, aggressive brain tumors with a generally poor prognosis. Here, we showed that US28 increased the malignancy of U251 glioblastoma cells by enhancing signaling mediated by sphingosine-1-phosphate (S1P), a bioactive lipid that stimulates oncogenic pathways in glioblastoma. US28 expression increased the abundance of the key components of the S1P signaling axis, including an enzyme that generates S1P [sphingosine kinase 1 (SK1)], an S1P receptor [S1P receptor 1 (S1P1)], and S1P itself. Enhanced S1P signaling promoted glioblastoma cell proliferation and survival by activating the kinases AKT and CHK1 and the transcriptional regulators cMYC and STAT3 and by increasing the abundance of cancerous inhibitor of PP2A (CIP2A), driving several feed-forward signaling loops. Inhibition of S1P signaling abrogated the proliferative and anti-apoptotic effects of US28. US28 also activated the S1P signaling axis in HCMV-infected cells. This study uncovers central roles for S1P and CIP2A in feed-forward signaling that contributes to the US28-mediated exacerbation of glioblastoma.