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Theranostics 2024; 14(1):436-450. doi:10.7150/thno.90322 This issue Cite

Research Paper

Vitamin D binding protein (VDBP) hijacks twist1 to inhibit vasculogenic mimicry in hepatocellular carcinoma

Lu-ning Qin¹, Heng Zhang^1,2,✉, Qing-qing Li¹, Ting Wu¹, Shan-bin Cheng^1,2, Kai-wen Wang^1,2, Yue Shi¹, Hao-ran Ren¹, Xue-wu Xing^3,✉, Cheng Yang^1,✉, Tao Sun^1,✉

1. State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China.
2. Tianjin International Joint Academy of Biomedicine, Tianjin, China.
3. Department of Orthopedics, Tianjin First Central Hospital, Tianjin, China.

✉ Corresponding authors: Tao Sun, email: tao.sunedu.cn; Cheng Yang, email: cheng.yangedu.cn; Xue-wu Xing, email: xuewuxingedu.cn; Heng Zhang, email: zhangheng043nankai.edu.cn.

Abstract

Rationale: Vitamin D (VD) has been suggested to have antitumor effects, however, research on the role of its transporter vitamin D-binding protein (VDBP, gene name as GC) in tumors is limited. In this study, we demonstrated the mechanism underlying the inhibition of vasculogenic mimicry (VM) by VDBP in hepatocellular carcinoma (HCC) and proposed an anti-tumor strategy of combining anti-PD-1 therapy with VD.

Methods: Three-dimensional cell culture models and mice with hepatocyte-specific GC deletion were utilized to study the correlation between VDBP expression and VM. A patient-derived tumor xenograft (PDX) model was further applied to validate the therapeutic efficacy of VD in combination with an anti-PD-1 drug.

Results: The study revealed that VDBP expression is negatively correlated with VM in HCC patients and elevated VDBP expression is associated with a favorable prognosis. The mechanism studies suggested VDBP hindered the binding of Twist1 on the promoter of VE-cadherin by interacting with its helix-loop-helix DNA binding domain, ultimately leading to the inhibition of VM. Furthermore, VD facilitated the translocation of the vitamin D receptor (VDR) into the nucleus where VDR interacts with Yin Yang 1 (YY1), leading to the transcriptional activation of VDBP. We further demonstrated that the combination of VD and anti-PD-1 led to an improvement in the anti-tumor efficacy of an anti-PD-1 drug.

Conclusion: Collectively, we identified VDBP as an important prognostic biomarker in HCC patients and uncovered it as a therapeutic target for enhancing the efficacy of immune therapy.

Keywords: VDBP, HCC, VM, VDR, YY1

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