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Cancers 2019, 11(3), 349; https://doi.org/10.3390/cancers11030349

A Feedback Loop Formed by ATG7/Autophagy, FOXO3a/miR-145 and PD-L1 Regulates Stem-Like Properties and Invasion in Human Bladder Cancer

Nelson Institute of Environmental Medicine, New York University School of Medicine, New York, NY 10010, USA
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Received: 14 January 2019 / Revised: 8 March 2019 / Accepted: 8 March 2019 / Published: 12 March 2019
(This article belongs to the Special Issue Fox Proteins and Cancers: Old Proteins with Emerging New Tales)
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Abstract

Programmed cell death protein 1 (PD-1) and its ligand PD-L1 blockade have been identified to target immune checkpoints to treat human cancers with durable clinical benefit. Several studies reveal that the response to PD-1-PD-L1 blockade might correlate with PD-L1 expression levels in tumor cells. However, the mechanistic pathways that regulate PD-L1 protein expression are not understood. Here, we reported that PD-L1 protein is regulated by ATG7-autophagy with an ATG7-initiated positive feedback loop in bladder cancer (BC). Mechanistic studies revealed that ATG7 overexpression elevates PD-L1 protein level mainly through promoting autophagy-mediated degradation of FOXO3a, thereby inhibiting its initiated miR-145 transcription. The lower expression of miR-145 increases pd-l1 mRNA stability due to the reduction of its direct binding to 3′-UTR of pd-l1 mRNA, in turn leading to increasing in pd-l1 mRNA stability and expression, and finally enhancing stem-like property and invasion of BC cells. Notably, overexpression of PD-L1 in ATG7 knockdown cells can reverse the defect of autophagy activation, FOXO3A degradation, and miR-145 transcription attenuation. Collectively, our results revealed a positive feedback loop to promoting PD-L1 expression in human BC cells. Our study uncovers a novel molecular mechanism for regulating pd-l1 mRNA stability and expression via ATG7/autophagy/FOXO3A/miR-145 axis and reveals the potential for using combination treatment with autophagy inhibitors and PD-1/PD-L1 immune checkpoint blockade to enhance therapeutic efficacy for human BCs. View Full-Text
Keywords: ATG7; PD-L1; stem-like property; invasion; human bladder cancer ATG7; PD-L1; stem-like property; invasion; human bladder cancer
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Zhu, J.; Li, Y.; Luo, Y.; Xu, J.; Liufu, H.; Tian, Z.; Huang, C.; Li, J.; Huang, C. A Feedback Loop Formed by ATG7/Autophagy, FOXO3a/miR-145 and PD-L1 Regulates Stem-Like Properties and Invasion in Human Bladder Cancer. Cancers 2019, 11, 349.

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