p65/miR-23a/CCL22 axis regulated regulatory T cells recruitment in hepatitis B virus positive hepatocellular carcinoma.

CCL22 played critical roles in Tregs recruitment. The upstream regulators modulating CCL22 in hepatocellular carcinoma (HCC) were not clearly understood. MiR-23a, p-p65, p65, CCL22, and Foxp3 levels were monitored by RT-qPCR and western blotting. Immunofluorescence assay was used to perform the costaining of Foxp3 and CD4 on liver tissues. Transwell assay was applied to evaluate the migration ability of Tregs. Dual-luciferase assay was performed to determine relationship of miR-23a/CCL22 and p65/miR-23a. Chromatin immunoprecipitation (ChIP) was applied to detect the direct binding of p65 to miR-23a promoter. Xenograft tumor models were developed to investigate the functions of p65 and miR-23a in vivo. HBV infection was associated with reduced survival and increased Tregs recruitment in HCC patients. MiR-23a was decreased, whereas p65, CCL22, and Foxp3 were increased in HBV+ tumors. MiR-23a was inversely correlated with CCL22 and Foxp3 expression in HCC. MiR-23a directly targeted CCL22 3'UTR, leading to CCL22 reduction and attenuated Tregs recruitment. Meanwhile, p65 functioned as a transcription repressor of miR-23a by directly binding to its promoter. Inhibition of p65 induced miR-23 expression, leading to less CCL22 expression and Tregs recruitment in vitro. CCL22 was the indispensable effector underlying p65/miR-23a axis and Tregs recruitment. MiR-23a inhibitor promoted xenografted tumor growth accompanying with upregulation of CCL22, whereas p65 inhibition exerted opposite effects. Blockage of p65 disinhibited miR-23a expression, leading to CCL22 reduction and repress Tregs recruitment. Targeting p65/miR-23a/CCL22 axis was a novel approach for HBV+ HCC treatment. © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Citation

Zhi-Qin Li, Hong-Yan Wang, Qing-Lei Zeng, Jing-Ya Yan, Yu-Shu Hu, Hua Li, Zu-Jiang Yu. p65/miR-23a/CCL22 axis regulated regulatory T cells recruitment in hepatitis B virus positive hepatocellular carcinoma. Cancer medicine. 2020 Jan;9(2):711-723

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PMID: 31769216

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