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

// Ming Li 4, 5, * , Xinfang Yu 6, * , Wei Li 7, * , Ting Liu 1 , Gang Deng 8 , Wenbin Liu 9 , Haidan Liu 3 and Feng Gao 1, 2 1 Department of Ultrasonography, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China 2 State Key Laboratory of Powder Metallurgy, Central South University, Changsha, Hunan 410006, P.R. China 3 Clinical Center for Gene Diagnosis and Therapy, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China 4 School of Stomatology, Hunan University of Chinese Medicine, Changsha, Hunan 410208, P.R. China 5 Changsha Stomatological Hospital, Changsha, Hunan 410004, P.R. China 6 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA 7 Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China 8 Department of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China 9 Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China * These authors contributed equally to this work Correspondence to: Haidan Liu, email: lhd1129@126.com Feng Gao, email: gfeng0731@gmail.com Keywords: hepatocellular carcinoma; deguelin; angiogenesis; VEGF; c-Met Received: July 20, 2016 Accepted: October 11, 2017 Published: October 26, 2017 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.