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Environmental monobutyl phthalate exposure promotes liver cancer via reprogrammed cholesterol metabolism and activation of the IRE1α-XBP1s pathway

Oncogene volume 43, pages 2355–2370 (2024)Cite this article

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Abstract

Humans are widely exposed to phthalates, a major chemical plasticizer that accumulates in the liver. However, little is known about the impact of chronic phthalate exposure on liver cancer development. In this study, we applied a long-term cell culture model by treating the liver cancer cell HepG2 and normal hepatocyte L02 to environmental dosage of monobutyl phthalate (MBP), the main metabolite of phthalates. Interestingly, we found that long-term MBP exposure significantly accelerated the growth of HepG2 cells in vitro and in vivo, but barely altered the function of L02 cells. MBP exposure triggered reprogramming of lipid metabolism in HepG2 cells, where cholesterol accumulation subsequently activated the IRE1α-XBP1s axis of the unfolded protein response. As a result, the XBP1s-regulated gene sets and pathways contributed to the increased aggressiveness of HepG2 cells. In addition, we also showed that MBP-induced cholesterol accumulation fostered an immunosuppressive microenvironment by promoting tumor-associated macrophage polarization toward the M2 type. Together, these results suggest that environmental phthalates exposure may facilitate liver cancer progression, and alerts phthalates exposure to patients who already harbor liver tumors.

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Fig. 1: Chronic MBP exposure accelerates the growth of HepG2 cells in vitro and in vivo.
Fig. 2: RNA-seq and ATAC-seq analysis of liver cells chronically exposed to MBP.
Fig. 3: MBP exposure reprograms lipid metabolism in HepG2 cells.
Fig. 4: MBP exposure activates the IRE1α-XBP1s pathway in HepG2 cells.
Fig. 5: MBP-induced cholesterol accumulation is causal to the activation of IRE1α-XBP1s pathway.
Fig. 6: The molecular landscape regulated by XBP1s in HepG2 cells exposed to MBP.
Fig. 7: MBP-induced tumor cell cholesterol accumulation promotes macrophage infiltration and M2-polarization.
Fig. 8: Schematic summary of the study.

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Data availability

The RNA-seq, ATAC-seq and CUT & Tag seq data are archived in the GEO database (GSE248562) and available to all. Other data that support the findings of this study are available from the corresponding author upon request.

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Funding

This study was supported by National Key R&D Program of China (2022YFA0807000) to XS, National Natural Science Foundation of China (81972752) to YJ, and Fundamental Research Funds for the Central Universities (YCJJ202201011) to TZ.

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Author notes

  1. These authors contributed equally: Tingting Zhang, Faming Zhao.

Authors and Affiliations

  1. School of Life and Health Sciences, Hainan University, Haikou, 570228, China

    Tingting Zhang, Faming Zhao, Yanxia Hu & Xia Sheng

  2. School of Environmental Science and Engineering, Hainan University, Haikou, 570228, China

    Tingting Zhang, Faming Zhao, Yanxia Hu & Xia Sheng

  3. School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Tingting Zhang, Faming Zhao, Jinlan Wei, Fengzhen Cui & Xia Sheng

  4. School of Public Health, Guangdong Medical University, Dongguan, 523808, China

    Fengzhen Cui

  5. Department of Neurology, Wuhan Fourth Hospital, Wuhan, 430033, China

    Yahang Lin

  6. Department of Biosciences, University of Oslo, 0371, Oslo, Norway

    Yang Jin

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  1. Tingting Zhang
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Contributions

TZ performed most of the experiments and wrote the manuscript. FZ performed bioinformatics analyses and wrote the manuscript. YH, JW, FC and YL contributed to experiments. YJ revised the manuscript. XS conceived the project, supervised the work, and wrote the manuscript.

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Correspondence to Xia Sheng.

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Zhang, T., Zhao, F., Hu, Y. et al. Environmental monobutyl phthalate exposure promotes liver cancer via reprogrammed cholesterol metabolism and activation of the IRE1α-XBP1s pathway. Oncogene 43, 2355–2370 (2024). https://doi.org/10.1038/s41388-024-03086-1

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