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Dickkopf-1 promotes angiogenesis by upregulating VEGF receptor 2-mediated mTOR/p70S6K signaling in hepatocellular carcinoma

 Sang Hyun Seo  ;  Kyung Joo Cho  ;  Hye Jung Park  ;  Hyemi Kim  ;  Hye Won Lee  ;  Beom Kyung Kim  ;  Jun Yong Park  ;  Do Young Kim  ;  Sang Hoon Ahn  ;  Seung Up Kim 
 AMERICAN JOURNAL OF CANCER RESEARCH, Vol.11(10) : 4788-4806, 2021-10 
Journal Title
Issue Date
Dickkopf-1 ; angiogenesis ; epithelial-mesenchymal transition ; hepatocellular carcinoma ; vascular endothelial growth factor receptor 2
The expression of Dickkopf-1 (DKK1), a negative regulator of the Wnt/β-catenin signaling pathway, is upregulated in hepatocellular carcinoma (HCC). Here, we investigated the tumorigenic and angiogenic potential of DKK1 in HCC. Stable cell lines were established using the clustered regularly interspaced short palindromic repeats (CRISPR)-associated nuclease 9 (CRISPR/Cas9)-based DKK1 knock-out system in Hep3B cells and the tetracycline-based DKK1 inducible system in Huh7 cells. Multicellular tumor spheroids (MCTSs) were cultured using Hep3B stable cells. We also employed xenografts generated using Hep3B stable cells and transgenic mouse models established using hydrodynamic tail vein injection. The angiogenic potential increased in HUVECs treated with CM from Huh7 stable cells with high DKK1 expression and Hep3B wild-type cells. DKK1 accelerated the downstream molecules of vascular endothelial growth factor receptor 2 (VEGFR2)-mediated mTOR/p70 S6 kinase (p70S6K) signaling. MCTSs generated using Hep3B wild-type cells promoted compact spheroid formation and increased the expression of CD31 and epithelial-mesenchymal transition (EMT) markers, and increased the VEGFR2-mediated mTOR/p70S6K signaling, compared to the controls (all P<0.01). Xenograft tumors generated using Hep3B cells with DKK1 knock-out (n=10) exhibited slower growth than, the controls (n=10) and the expression of Ki-67, VEGFR2, CD31 and EMT markers decreased (all P<0.05). In addition, forced DKK1 expression with HRAS in transgenic mouse livers (n=5) resulted in the formation of more tumors and increased expression of downstream molecules of VEGFR2-mediated mTOR/p70S6K signaling pathway as well as Ki67, CD31 and EMT markers (P<0.05), compared to that of the controls (n=5). Our findings indicate that DKK1 facilitates angiogenesis and tumorigenesis by upregulating VEGFR2-mediated mTOR/p70S6K signaling in HCC.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Do Young(김도영)
Kim, Beom Kyung(김범경) ORCID logo https://orcid.org/0000-0002-5363-2496
Kim, Seung Up(김승업) ORCID logo https://orcid.org/0000-0002-9658-8050
Kim, Hye Mi(김혜미)
Park, Jun Yong(박준용) ORCID logo https://orcid.org/0000-0001-6324-2224
Park, Hye Jung(박혜정) ORCID logo https://orcid.org/0000-0002-1862-1003
Ahn, Sang Hoon(안상훈) ORCID logo https://orcid.org/0000-0002-3629-4624
Lee, Hye Won(이혜원) ORCID logo https://orcid.org/0000-0002-3552-3560
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