Deguelin suppresses angiogenesis in human hepatocellular carcinoma by targeting HGF-c-Met pathway.

Ming Li,Xinfang Yu,Ting Liu,Haidan Liu,Feng Gao,Gang Deng,Wenbin Liu,Wei Li

doi:10.18632/oncotarget.22077

Abstract

Angiogenesis plays a crucial role in the development of human hepatocellular carcinoma (HCC). In the present study, we found a natural compound, deguelin, has a profound anti-angiogenesis effect on HCC. Deguelin suppressed vascular endothelial growth factor (VEGF)-induced human umbilical vascular endothelial cells (HUVECs) proliferation, migration, invasion, and capillary-like tube formation in vitro and reduced tumor angiogenesis in vivo. We discovered that VEGF receptor-mediated signal transduction cascades in HUVECs were inhibited by deguelin. Deguelin decreased the autocrine of VEGF in HCC cells in a time- and dose-dependent manner. Additionally, deguelin suppressed HGF-induced activation of the c-Met signaling pathway. Knocking down c-Met or inhibition of c-Met activation impaired HGF-mediated VEGF production. Importantly, we produced patient-derived hepatocellular carcinoma xenografts to evaluate the therapeutic effect of deguelin in vivo. Taken together, these results indicate that deguelin could inhibit HCC through suppression of angiogenesis on vascular endothelial cells and reduction of proangiogenic factors in cancer cells.

Highlights

Tumor angiogenesis, the development of new blood vessels from the existing vasculature, is considered to play an essential role in malignant neoplasia development [1]
Deguelin inhibits hepatocellular carcinoma cells growth in vitro and in vivo First, we investigated the activity of deguelin (Figure 1A) against hepatocellular carcinoma cells proliferation in Hep3B, HepG2 and MHCC97-H cells
We demonstrated that deguelin exerted a substantial anti-angiogenesis activity against human hepatocellular carcinoma

Summary

Introduction

The development of new blood vessels from the existing vasculature, is considered to play an essential role in malignant neoplasia development [1]. It is estimated that over 90% cancer deaths that occur are due to angiogenesis, invasion, and distant metastasis of cancer to vital organs [2]. The proliferation and migration of endothelial cells in response to chemotactic agents, such as vascular endothelial growth factor (VEGF), are considered a key step in the initiation of angiogenesis [3]. VEGFR2 plays an important role in mediating www.impactjournals.com/oncotarget the mitogenesis and permeability of endothelial cells [4]. VEGFR2 targeting therapies or angiogenesis blockade has been shown to be an effective strategy in inhibiting tumor growth and metastasis [6,7,8]

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Conclusion