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Programmed death ligand 1 promotes lymph node metastasis and glucose metabolism in cervical cancer by activating integrin β4/SNAI1/SIRT3 signaling pathway

Oncogene volume 37, pages 4164–4180 (2018)Cite this article

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Abstract

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.

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Acknowledgements

We thank RuiBi for the samples for the TMA study, Guangqi Qin for manufacturing the TMAs, and Jun Chen and Jianping Zhang for help with animal imaging. This work was supported in part by grants from the National Nature Science Foundation of China (81672569 to X.W.) and the National Nature Science Young Foundation of China (81502235 to Z.W.).

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    1. Department of Gynecological Oncology and Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

      Shaojia Wang, Jiajia Li, Fei Liu, Yachen Duan, Yong Wu, Shenglin Huang, Xianghuo He, Ziliang Wang & Xiaohua Wu

    2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China

      Shaojia Wang, Jiajia Li, Jie Xie, Fei Liu, Yachen Duan, Yong Wu, Ziliang Wang & Xiaohua Wu

    3. Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

      Jie Xie

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    Wang, S., Li, J., Xie, J. et al. Programmed death ligand 1 promotes lymph node metastasis and glucose metabolism in cervical cancer by activating integrin β4/SNAI1/SIRT3 signaling pathway. Oncogene 37, 4164–4180 (2018). https://doi.org/10.1038/s41388-018-0252-x

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