Department of Gynecological Oncology and Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Oncogene. 2018 Jul;37(30):4164-4180. doi: 10.1038/s41388-018-0252-x. Epub 2018 Apr 30.
Although PD-L1 has been shown to play a well-characterized role in inhibiting antitumor immunity via engagement of its receptor PD-1 in T lymphocytes, little is known about the tumor cell-intrinsic function of PD-L1 and its association with prognosis. Here, we investigate this issue and dissect the molecular mechanisms underlying the role of PD-L1 in glucose metabolism, proliferation, migration, and invasion in human cervical cancer cells. As a result, we found that PD-L1 overexpression in cervical cancer cells increases glucose metabolism and metastasis-related behaviors. Mechanistically, PD-L1 bound directly to integrin β4 (ITGB4), activating the AKT/GSK3β signaling pathway and consequently inducing the expression of the transcriptional repressor SNAI1. SNAIL in turn influenced the expression of genes involved in the epithelial-to-mesenchymal transition and regulated glucose metabolism by inhibiting SIRT3 promoter activity. High expression of PD-L1 and ITGB4 in human cervical carcinomas was significantly associated with lymph node metastasis and poor prognosis. Finally, F-fluorodeoxyglucose microPET/CT and bioluminescence imaging analyses of cervical xenograft tumors in mice revealed that PD-L1 overexpression markedly increases tumor glucose uptake and promotes lymph node metastasis. Together, these results demonstrate that PD-L1 can promote the growth and metastasis of cervical cancer by activating the ITGB4/SNAI1/SIRT3 signaling pathway, and also suggest the possibility of targeting PD-L1 and its downstream effectors as a potential approach for interfering with cervical cancer growth and metastasis.
虽然 PD-L1 通过与其受体 PD-1 在 T 淋巴细胞中的结合，已被证明在抑制抗肿瘤免疫方面发挥了很好的作用，但人们对 PD-L1 的肿瘤细胞内在功能及其与预后的关系知之甚少。在这里，我们研究了这个问题，并剖析了 PD-L1 在人宫颈癌细胞葡萄糖代谢、增殖、迁移和侵袭中的作用的分子机制。结果发现，PD-L1 在宫颈癌细胞中的过表达增加了葡萄糖代谢和转移相关的行为。从机制上讲，PD-L1 直接与整合素 β4（ITGB4）结合，激活 AKT/GSK3β 信号通路，从而诱导转录抑制因子 SNAI1 的表达。SNAIL 反过来通过抑制 SIRT3 启动子活性影响参与上皮间质转化的基因的表达，并调节葡萄糖代谢。人宫颈癌中 PD-L1 和 ITGB4 的高表达与淋巴结转移和预后不良显著相关。最后，对小鼠宫颈癌异种移植瘤的 F-氟脱氧葡萄糖 microPET/CT 和生物发光成像分析表明，PD-L1 过表达显著增加了肿瘤的葡萄糖摄取并促进了淋巴结转移。总之，这些结果表明，PD-L1 通过激活 ITGB4/SNAI1/SIRT3 信号通路促进宫颈癌的生长和转移，并提示靶向 PD-L1 及其下游效应物作为干扰宫颈癌生长和转移的潜在方法的可能性。
