Theranostics 2022; 12(8):3776-3793. doi:10.7150/thno.69494 This issue

Research Paper

Crosstalk between macrophage-derived PGE2 and tumor UHRF1 drives hepatocellular carcinoma progression

Jian Zhang1,2#, Hongyan Zhang1,2#, Xiuli Ding1,2#, Jia Hu2, Yongkui Li2, Jinxiang Zhang3, Hui Wang4, Shanshan Qi1,2, Aqing Xie1,2, Jie Shi2, Mengxi Xiang1,2, Yawen Bin2, Guobin Wang5✉, Lin Wang1,2✉, Zheng Wang2,5✉

1. Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China 430022.
2. Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China 430022.
3. Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China 430022.
4. Department of Human Genetics, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China 430030.
5. Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China 430022.
#These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Zhang J, Zhang H, Ding X, Hu J, Li Y, Zhang J, Wang H, Qi S, Xie A, Shi J, Xiang M, Bin Y, Wang G, Wang L, Wang Z. Crosstalk between macrophage-derived PGE2 and tumor UHRF1 drives hepatocellular carcinoma progression. Theranostics 2022; 12(8):3776-3793. doi:10.7150/thno.69494. Available from https://www.thno.org/v12p3776.htm

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Abstract

Graphic abstract

Background: Tumor-associated macrophages (TAMs) and dysregulated tumor epigenetics contribute to hepatocellular carcinoma (HCC) progression. However, the mechanistic interactions between TAMs and tumor epigenetics remain poorly understood.

Methods: Immunohistochemistry and multiplexed fluorescence staining were performed to evaluate the correlation between TAMs numbers and UHRF1 expression in human HCC tissues. PGE2 neutralizing antibody and COX-2 inhibitor were used to analyze the regulation of TAMs isolated from HCC tissues on UHRF1 expression. Multiple microRNA prediction programs were employed to identify microRNAs that target UHRF1 3'UTR. Luciferase reporter assay was applied to evaluate the regulation of miR-520d on UHRF1 expression. Chromatin immunoprecipitation (ChIP) assays were performed to assess the abundance of H3K9me2 in the KLF6 promoter and DNMT1 in the CSF1 promoter regulated by UHRF1. The functional roles of TAM-mediated oncogenic network in HCC progression were verified by in vitro colony formation assays, in vivo xenograft experiments and analysis of clinical samples.

Results: Here, we find that TAMs induce and maintain high levels of HCC UHRF1, an oncogenic epigenetic regulator. Mechanistically, TAM-derived PGE2 stimulates UHRF1 expression by repressing miR-520d that targets the 3'-UTR of UHRF1 mRNA. In consequence, upregulated UHRF1 methylates H3K9 to diminish tumor KLF6 expression, a tumor inhibitory transcriptional factor that directly transcribes miR-520d. PGE2 reduces KLF6 occupancy in the promoter of miR-520d, dampens miR-520d expression, and sustains robust UHRF1 expression. Moreover, UHRF1 promotes CSF1 expression by inducing DNA hypomethylation of the CSF1 promoter and supports TAM accumulation.

Conclusions: Capitalizing on studies on HCC cells and tissues, animal models, and clinical information, we reveal a previously unappreciated TAM-mediated oncogenic network via multiple reciprocal enforcing molecular nodes. Targeting this network may be an approach to treat HCC patients.

Keywords: hepatocellular carcinoma, TAMs, UHRF1, epigenetic regulator, crosstalk, miRNA