HIF-2-dependent expression of stem cell factor promotes metastasis in hepatocellular carcinoma

Xiuchao Wang, Jie Dong, Li Jia, Tiansuo Zhao, Mingxiao Lang, Zengxun Li, Chungen Lan, Xin Li, Jihui Hao, Hongwei Wang, Tai Qin, Chongbiao Huang, Shengyu Yang, Ming Yu, He Ren

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)113-124
Number of pages12
JournalCancer Letters
Volume393
DOIs
StatePublished - May 1 2017

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Stem Cell Factor
Hepatocellular Carcinoma
Neoplasm Metastasis
Chromatin Immunoprecipitation
Response Elements
Vimentin
Cadherins
RNA Interference
Luciferases
Cell Movement
Carcinogenesis
Up-Regulation
Cytokines

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Wang, Xiuchao ; Dong, Jie ; Jia, Li ; Zhao, Tiansuo ; Lang, Mingxiao ; Li, Zengxun ; Lan, Chungen ; Li, Xin ; Hao, Jihui ; Wang, Hongwei ; Qin, Tai ; Huang, Chongbiao ; Yang, Shengyu ; Yu, Ming ; Ren, He. / HIF-2-dependent expression of stem cell factor promotes metastasis in hepatocellular carcinoma. In: Cancer Letters. 2017 ; Vol. 393. pp. 113-124.
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title = "HIF-2-dependent expression of stem cell factor promotes metastasis in hepatocellular carcinoma",
abstract = "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.",
author = "Xiuchao Wang and Jie Dong and Li Jia and Tiansuo Zhao and Mingxiao Lang and Zengxun Li and Chungen Lan and Xin Li and Jihui Hao and Hongwei Wang and Tai Qin and Chongbiao Huang and Shengyu Yang and Ming Yu and He Ren",
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Wang, X, Dong, J, Jia, L, Zhao, T, Lang, M, Li, Z, Lan, C, Li, X, Hao, J, Wang, H, Qin, T, Huang, C, Yang, S, Yu, M & Ren, H 2017, 'HIF-2-dependent expression of stem cell factor promotes metastasis in hepatocellular carcinoma', Cancer Letters, vol. 393, pp. 113-124. https://doi.org/10.1016/j.canlet.2017.01.032

HIF-2-dependent expression of stem cell factor promotes metastasis in hepatocellular carcinoma. / Wang, Xiuchao; Dong, Jie; Jia, Li; Zhao, Tiansuo; Lang, Mingxiao; Li, Zengxun; Lan, Chungen; Li, Xin; Hao, Jihui; Wang, Hongwei; Qin, Tai; Huang, Chongbiao; Yang, Shengyu; Yu, Ming; Ren, He.

In: Cancer Letters, Vol. 393, 01.05.2017, p. 113-124.

Research output: Contribution to journalArticle

TY - JOUR

T1 - HIF-2-dependent expression of stem cell factor promotes metastasis in hepatocellular carcinoma

AU - Wang, Xiuchao

AU - Dong, Jie

AU - Jia, Li

AU - Zhao, Tiansuo

AU - Lang, Mingxiao

AU - Li, Zengxun

AU - Lan, Chungen

AU - Li, Xin

AU - Hao, Jihui

AU - Wang, Hongwei

AU - Qin, Tai

AU - Huang, Chongbiao

AU - Yang, Shengyu

AU - Yu, Ming

AU - Ren, He

PY - 2017/5/1

Y1 - 2017/5/1

N2 - 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.

AB - 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.

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