HIF-2-dependent expression of stem cell factor promotes metastasis in hepatocellular carcinoma.
Stem cell factor (SCF) is a multifunctional cytokine responsible for tumorigenesis and progression. In this study, we report that increased expression of SCF in hepatocellular carcinoma (HCC) patients is highly associated with metastasis and poor prognosis. SCF inhibition with RNAi inhibited HCC cell migration, invasion in vitro, and reduced intrahepatic metastases burden and significantly prolonged survival in a HCC xeograft mouse model. SCF depletion in HCC xeograft decreased the expression of vimentin and increase the expression of E-cadherin, implicating a role for SCF in epithelial-mesenchymal transition. Our data further demonstrated that HCC cells secreted soluble SCF to promote HUVECs angiogenesis. The overexpression of SCF in HCC is regulated by hypoxic conditions through a selective HIF-2α-dependent mechanism. Knocking-down HIF-2α significantly decreased expression of SCF. Chromatin immunoprecipitation and luciferase assay demonstrated that HIF-2α directly induce the transcription of SCF gene through the hypoxia response element in SCF promoter. In conclusion, we demonstrate that the hypoxia microenvironment in HCC up-regulates SCF expression, which in turn promotes angiogenesis and HCC metastasis.
Department of Nutrition and Food Hygiene, School of Public Health, Tianjin Medical University, Tianjin, 300070 China; Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, 300060 China.
Xiuchao
X
Wang
Department of Nutrition and Food Hygiene, School of Public Health, Tianjin Medical University, Tianjin, 300070 China.
Jie
J
Dong
Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, 300060 China; Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, United Kingdom.
Li
L
Jia
Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, 300060 China.
Tiansuo
T
Zhao
Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, 300060 China.
Mingxiao
M
Lang
Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, 300060 China.
Zengxun
Z
Li
Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, 300060 China.
Chungen
C
Lan
Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, 300060 China.
Xin
X
Li
Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, 300060 China.
Jihui
J
Hao
Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, 300060 China.
Hongwei
H
Wang
Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, 300060 China.
Tai
T
Qin
Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, 300060 China.
Chongbiao
C
Huang
Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, PA 17033, USA.
Shengyu
S
Yang
Department of Nutrition and Food Hygiene, School of Public Health, Tianjin Medical University, Tianjin, 300070 China. Electronic address: minnieyu@tmu.edu.cn.
Ming
M
Yu
Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Department of Pancreatic Cancer, Tianjin, 300060 China. Electronic address: renhe@tjmuch.com.
He
H
Ren
D000818:Animals; D015703:Antigens, CD; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000556:secondary*; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D019899:Paracrine Communication; D011379:Prognosis; D034622:RNA Interference; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D000072258:Tumor Hypoxia; D015854:Up-Regulation; D014746:Vimentin / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D015703:Antigens, CD; D051792:Basic Helix-Loop-Helix Proteins; D015820:Cadherins; D019089:Stem Cell Factor; D014746:Vimentin; D000099162:Endothelial PAS Domain-Containing Protein 1; C513384:CDH1 protein, human
Angiogenesis; Epithelial–mesenchymal transition (EMT); Hepatocellular carcinoma (HCC); Hypoxia-inducible factor-2α (HIF-2α); Stem cell factor (SCF)