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HMGB1 correlates with angiogenesis and poor prognosis of perihilar cholangiocarcinoma via elevating VEGFR2 of vessel endothelium

Oncogene volume 38, pages 868–880 (2019)Cite this article

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Abstract

Perihilar cholangiocarcinoma (PHCCA) is the most common type of cholangiocarcinoma with low resection rate and high morbidity. The study of PHCCA biomarkers made progresses slowly compared with intrahepatic cholangiocarcinoma because of surgical complexity and low possibility of radical surgery, which resulted in the difficulty of specimen obtainment. To screen and identify new biomarkers in PHCCA, we constructed a retrospective cohort with 121 PHCCA patients and a prospective cohort consisting of 64 PHCCA patients, and screened the candidate biomarkers by immunohistochemistry and quantified PCR. In our study, expression of high mobility group box 1 (HMGB1) was demonstrated to be significantly associated with microvascular density (MVD) and unfavorable prognosis of PHCCA in both retrospective and prospective study. Moreover, HMGB1 concentrations in bile and serum of PHCCA patients and healthy controls were detected and compared. Postoperative serum HMGB1 and reflux cholangitis indicated recurrence and unfavorable prognosis of PHCCA. With experiments in vitro and in vivo, we demonstrated that intracellular HMGB1 could be released from PHCCA cells and induce invasion and angiogenesis with LPS stimulation. VEGFR2 expression in vessel endothelial cells was upregulated by the released HMGB1 from PHCCA, resulting in the ectopic angiogenesis. In conclusion, intracellular HMGB1 could be released from PHCCA cells and promote angiogenesis via elevating VEGFR2 in vessel endothelial cells. High expression of HMGB1 was associated with MVD and poor prognosis in clinical analyzation. Postoperative serum HMGB1 and cholangitis could predict high recurrence and unfavorable prognosis.

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Acknowledgements

We would like to thank Prof. Bo Han for his help for specimen collection and immunohistochemistry evaluation.

Funding

The study was supported by National Natural Science Foundation of China (Grant Nos. 81601668 and 31701013), Shandong Province Major Research and Design Program (Grant Nos. 2017GSF218059 and 2016GSF201132), Natural Science Foundation of Shandong (Grant No. ZR2017BC032), and China Postdoctoral Science Foundation (Grant Nos. 2017M610167 and 2017T100163).

Author contributions

Y-FX and Z-LL performed the IHC and clinical analysis. Y-FX, CP, and H-DL performed the experiments in vitro. S-LN, SG, and Z-LZ collected the specimens. Y-FX, Z-LZ, and J-MY designed the experiments. Z-LZ and J-MY collected the funding.

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Authors and Affiliations

  1. Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China

    Yun-Fei Xu, Zeng-Li Liu, Shang-Lei Ning, Sen Guo & Zong-Li Zhang

  2. Department of Emergency Medicine and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China

    Chang Pan

  3. Department of Pathology, Qianfoshan Hospital of Shandong University, Jinan, China

    Xiao-Qing Yang

  4. Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA

    Hong-Da Liu

  5. Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, China

    Jin-Ming Yu

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  1. Yun-Fei Xu
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Correspondence to Jin-Ming Yu or Zong-Li Zhang.

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Xu, YF., Liu, ZL., Pan, C. et al. HMGB1 correlates with angiogenesis and poor prognosis of perihilar cholangiocarcinoma via elevating VEGFR2 of vessel endothelium. Oncogene 38, 868–880 (2019). https://doi.org/10.1038/s41388-018-0485-8

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