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The miR-92a-2-5p in exosomes from macrophages increases liver cancer cells invasion via altering the AR/PHLPP/p-AKT/β-catenin signaling

Abstract

Early studies indicated that the androgen receptor (AR) might play important roles in the regulating of the initiation and progression of hepatocellular carcinoma (HCC), but its linkage to the surrounding macrophages and their impacts on the HCC progression remain unclear. Here we found that macrophages in liver cancer might function via altering the microRNA, miR-92a-2-5p, in exosomes to decrease liver cancer cells AR expression, which might then lead to increase the liver cancer cells invasion. Mechanism dissection revealed that miR-92a-2-5p from the exosomes could target the 3′UTR of AR mRNA to suppress AR translation, altering the PHLPP/p-AKT/β-catenin signaling to increase liver cancer cells invasion. Preclinical studies demonstrated that targeting this newly identified signaling with miR-92a-2-5p inhibitors led to suppress liver cancer progression. Together, these findings suggest that macrophages in the liver cancer tumor microenvironment may function via exosomes to regulate liver cancer progression, and targeting this newly identified macrophages/exosomes-miR-92a-2-5p/AR/PHLPP/p-AKT/β-catenin signaling may help in the development of novel treatment strategies to better suppress liver cancer progression.

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Fig. 1: The invasion capacity of liver cancer cells increases after co-culture with macrophages.
Fig. 2: Mechanism dissection of how macrophages increase liver cancer cells invasion: via altering the AR expression.
Fig. 3: Mechanism dissection of how macrophages decrease AR expression in liver cancer cells: via altering the miRNAs.
Fig. 4: Mechanism dissection of how macrophages increase miRNAs level in liver cancer: via exosomes secretion from macrophages to liver cancer cells.
Fig. 5: Mechanism dissection of how miR-92a-2-5p alters the AR expression under the co-culture condition: via direct targeting of the 3′UTR of AR mRNA.
Fig. 6: Mechanism dissection of how the macrophage/miR-92a-2-5p/AR axis alters the invasion capacity of liver cancer cells: through the PHLPP/p-AKT/β-catenin pathway.
Fig. 7: Preclinical studies targeting this newly identified signaling with miR-92a-2-5p inhibitor with suppression of liver cancer progression.

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Acknowledgements

This work was supported by NIH grant (CA155477) and George Whipple Professorship and National Natural Science Foundation of China (81903004). We thank Karen Wolf for editing the manuscript.

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Correspondence to Yixiong Li or Chawnshang Chang.

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Liu, G., Ouyang, X., Sun, Y. et al. The miR-92a-2-5p in exosomes from macrophages increases liver cancer cells invasion via altering the AR/PHLPP/p-AKT/β-catenin signaling. Cell Death Differ 27, 3258–3272 (2020). https://doi.org/10.1038/s41418-020-0575-3

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