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Hepatic stellate cells promote intrahepatic cholangiocarcinoma progression via NR4A2/osteopontin/Wnt signaling axis

Oncogene volume 40, pages 2910–2922 (2021)Cite this article

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Abstract

Intrahepatic cholangiocarcinoma (ICC) is a highly fatal malignancy characterized by a vast amount of intra-tumoral fibroblasts. These fibroblasts are potentially implicated in maintaining the high aggressiveness of ICC, whereas its pro-cancer mechanisms remain scarcely reported. Here, by establishing co-culture models of ICC cells and hepatic stellate cells (HSCs), we identified that HSCs triggered the expression of nuclear receptor family 4 subgroup A member 2 (NR4A2), a transcription factor previously reported as a molecular switch between inflammation and cancer, in ICC cells. Functionally, NR4A2 promotes tumor proliferation, metastatic potentiality and represents an independent prognostic indicator for overall survival in ICC patients. Mechanistically, NR4A2 upregulates osteopontin (OPN) expression through transcriptional activation and thereby augments the activity of Wnt/β-catenin signaling. Intriguingly, in the context of co-culture, vascular endothelial growth factor (VEGF), a previously proved NR4A2 stimulus, not only enhances NR4A2 expression, but also can be blunted by the interference of the NR4A2-OPN axis. Altogether, this study suggests the NR4A2/OPN/Wnt signaling axis to be a pivotal executor of HSC-instigated cancer-promoting roles in ICC, and the NR4A2/OPN/VEGF positive feedback loop may help to reinforce the effect.

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Fig. 1: Establishment of direct co-culture models and altered signaling pathways exhibited by HSCs-primed ICCs.
Fig. 2: NR4A2 is the most sensitive responder towards stimulation of HSCs among the NR4A family members.
Fig. 3: NR4A2 promotes tumor proliferation, migration, and invasion.
Fig. 4: HSCs-induced epithelial-mesenchymal transition (EMT) is partially attributed to NR4A2-medicated osteopontin (OPN) upregulation.
Fig. 5: NR4A2-OPN axis activates Wnt/β-catenin signaling pathway.
Fig. 6: PGE2 and VEGF are responsible for HSC-instigated NR4A2 upregulation.
Fig. 7: Proposed model of HSCs promote ICC progression via NR4A2/OPN/Wnt signaling axis.

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Acknowledgements

This project is supported by the National Natural Science Foundation of China (NO.81772510; NO.81902419; NO.81902993; NO. 82072677, NO. 82072672); National Key Research and Development Program of China (NO.2017YFC0908101 and NO.2017YFC0908102); Research Programs of Science and Technology Commission Foundation of Shanghai (NO.18XD1401100); Medical and Health Key Programs of Science and Technology Plan of Xiamen (NO.3502Z20191105); 2020 Youth Talent Program of Obstetrics & Gynecology Hospital of Fudan University obtained by Dr. Yi-Peng Fu and Research and Development Program of Zhongshan Hospital, Fudan University (NO. 2020ZSFZ13, NO. 2019ZSFZ13, NO. 2018ZSFZ055, NO. ZSLC62, NO. ZHZS17, NO. 2019-275, NO. 2020-312, NO. 2021-353).

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Author notes

  1. These authors contributed equally: Chu-Yu Jing, Yi-Peng Fu, Cheng Zhou, Mei-Xia Zhang

Authors and Affiliations

  1. The Liver Cancer Institute, Zhongshan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, 180 Fenglin Road, Shanghai, 200032, China

    Chu-Yu Jing, Cheng Zhou, Yong Yi, Jin-Long Huang, Wei Gan, Juan Zhang, Su-Su Zheng, Bo-Heng Zhang & Shuang-Jian Qiu

  2. Department of Breast Surgery, The Obstetrics & Gynecology Hospital of Fudan University, 419 Fangxie Road, Shanghai, 200090, China

    Yi-Peng Fu

  3. Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China

    Cheng Zhou, Yong Yi, Jin-Long Huang, Wei Gan & Shuang-Jian Qiu

  4. Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, 17 Yongwaizheng Street, Nanchang, 330006, Jiangxi, China

    Mei-Xia Zhang

  5. Center for Evidence-Based Medicine, Shanghai Medical School, Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China

    Bo-Heng Zhang

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Contributions

Study design, drafting of the manuscript, study supervision, and obtaining funding: SJ-Q, BH-Z, CY-J, and YP-F; Provision of study material or patients: SJ-Q, BH-Z, and YP-F; Experimental data acquirement, analysis, and interpretation: CY-J, YP-F, CZ, MX-Z, YY, JZ, JL-H, SS-Z, and WG.

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Correspondence to Yi-Peng Fu, Bo-Heng Zhang or Shuang-Jian Qiu.

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Jing, CY., Fu, YP., Zhou, C. et al. Hepatic stellate cells promote intrahepatic cholangiocarcinoma progression via NR4A2/osteopontin/Wnt signaling axis. Oncogene 40, 2910–2922 (2021). https://doi.org/10.1038/s41388-021-01705-9

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