Programmed death ligand 1 promotes lymph node metastasis and glucose metabolism in cervical cancer by activating integrin beta 4/SNAI1/SIRT3 signaling pathway
Programmed death ligand 1 promotes lymph node metastasis and glucose metabolism in cervical cancer by activating integrin beta 4/SNAI1/SIRT3 signaling pathway
复制标题
程序性死亡配体1通过激活整合素β4/SNAI1/SIRT3信号通路促进宫颈癌淋巴结转移和糖代谢
DOI：
10.1038/s41388-018-0252-x
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发表时间：
2018
期刊：
影响因子：
8
通讯作者：
Wu Xiaohua
中科院分区：
文献类型：
--
作者：
Wang Shaojia;Li Jiajia;Xie Jie;Liu Fei;Duan Yachen;Wu Yong;Huang Shenglin;He Xianghuo;Wang Ziliang;Wu Xiaohua
尽管PD-L1已被证明通过其受体PD-1在T淋巴细胞中的结合在抑制抗肿瘤免疫中发挥了充分表征的作用，但对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，我们调查这个问题，并剖析PD-L1在人宫颈癌细胞中葡萄糖代谢，增殖，迁移和侵袭中的作用的分子机制。因此，我们发现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行为。在机制上，PD-L1直接与整合素β4（ITGB 4）结合，激活AKT/GSK 3 β信号通路，从而诱导转录抑制因子SNAI 1的表达。反过来，SNAIL通过抑制SIRT 3启动子活性影响参与上皮细胞向间质细胞转化的基因的表达，并调节葡萄糖代谢。PD-L1和ITGB 4在宫颈癌组织中的高表达与淋巴结转移和预后不良密切相关。最后，小鼠宫颈异种移植肿瘤的18 F-氟脱氧葡萄糖microPET/CT和生物发光成像分析显示，PD-L1过表达显著增加肿瘤葡萄糖摄取并促进淋巴结转移。总之，这些结果表明PD-L1可以通过激活ITGB 4/SNAI 1/SIRT 3信号通路促进宫颈癌的生长和转移，并且还表明靶向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。
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,18F-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.