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Lipopolysaccharide facilitates immune escape of hepatocellular carcinoma cells via m6A modification of lncRNA MIR155HG to upregulate PD-L1 expression

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Abstract

Recent studies have suggested that the initiation and progression of hepatocellular carcinoma (HCC) are closely associated with lipopolysaccharide (LPS) of intestinal bacteria. However, the role of LPS in immune regulation of HCC remains largely unknown. An orthotopic Hepa1-6 tumor model of HCC was constructed to analyze the effect of LPS on the expression of immune checkpoint molecules PD-1 and PD-L1. Then we verified the regulation of PD-L1 by LPS in HCC cells. Based on the previous finding that lncRNA MIR155HG regulates PD-L1 expression in HCC cells, we analyzed the relationship of LPS signaling pathway molecules with PD-L1 and MIR155HG by bioinformatics. The molecular mechanism of MIR155HG regulating PD-L1 expression induced by LPS was investigated by RNA pull-down followed by mass spectrometry, RNA immunoprecipitation, fluorescence in situ hybridization, and luciferase reporter assay. Finally, the HepG2 xenograft model was established to determine the role of MIR155HG on PD-L1 expression in vivo. We showed that LPS induced PD-1 and PD-L1 expression in mouse tumor tissues and induced PD-L1 expression in HCC cells. Mechanistically, upregulation of METTL14 by LPS promotes the m6A methylation of MIR155HG, which stabilizes MIR155HG relying on the “reader” protein ELAVL1 (also known as HuR)-dependent pathway. Moreover, MIR155HG functions as a competing endogenous RNA (ceRNA) to modulate the expression of PD-L1 by miR-223/STAT1 axis. Our results suggested that LPS plays a critical role in immune escape of HCC through METTL14/MIR155HG/PD-L1 axis. This study provides a new insight for understanding the complex immune microenvironment of HCC.

Graphical abstract

1. LPS plays a critical role in immune escape of HCC, especially HCC with cirrhosis.

2. Our study reveals that LPS regulates PD-L1 by m6A modification of lncRNA in HCC.

3. MIR155HG plays an important role in LPS induced PD-L1 expression.

4. LPS-MIR155HG-PD-L1 regulatory axis provides a new target for the treatment of HCC.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

Not applicable.

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Funding

This work was supported by the National Natural Science Foundation of China (82173167); the Startup Fund for Scientific Research of Fujian Medical University (2019XQ2020); the Joint Funds for the Innovation of Science and Technology, Fujian province (2017Y9100); and the Natural Science Foundation of Fujian Province (2018J01296).

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  1. Lirong Peng and Banglun Pan contributed equally to this work.

Authors and Affiliations

  1. Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Cancer Center of Fujian Medical University, Fujian Medical University Union Hospital, Fuzhou, 350001, China

    Lirong Peng, Banglun Pan, Xiaoxia Zhang, Zengbin Wang, Jiacheng Qiu, Xiaoqian Wang & Nanhong Tang

  2. Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Research Center for Molecular Medicine, Fujian Medical University, Fuzhou, 350122, China

    Nanhong Tang

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  1. Lirong Peng
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Contributions

Conception and design: LP, BP, and NT. Development of methodology: BP and XZ. Data curation: ZW, JQ, and XW. Writing, review and/or revision of the manuscript: LP, BP, ZW, and NT. Study supervision: NT. All authors read and approved the final manuscript.

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Correspondence to Nanhong Tang.

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Ethical consent was granted from the ethics committee of Fujian Medical University Union Hospital. The animal experiments were approved by the Animal Ethics Committee of Fujian Medical University.

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Peng, L., Pan, B., Zhang, X. et al. Lipopolysaccharide facilitates immune escape of hepatocellular carcinoma cells via m6A modification of lncRNA MIR155HG to upregulate PD-L1 expression. Cell Biol Toxicol 38, 1159–1173 (2022). https://doi.org/10.1007/s10565-022-09718-0

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