Journal of Biological Chemistry
Volume 287, Issue 17, 20 April 2012, Pages 13952-13958
Journal home page for Journal of Biological Chemistry

Molecular Bases of Disease
Multifunction Protein Staphylococcal Nuclease Domain Containing 1 (SND1) Promotes Tumor Angiogenesis in Human Hepatocellular Carcinoma through Novel Pathway That Involves Nuclear Factor κB and miR-221*

https://doi.org/10.1074/jbc.M111.321646Get rights and content
Under a Creative Commons license
open access

Staphylococcal nuclease domain-containing 1 (SND1) is a multifunctional protein that is overexpressed in multiple cancers, including hepatocellular carcinoma (HCC). Stable overexpression of SND1 in Hep3B cells expressing a low level of SND1 augments, whereas stable knockdown of SND1 in QGY-7703 cells expressing a high level of SND1 inhibits establishment of xenografts in nude mice, indicating that SND1 promotes an aggressive tumorigenic phenotype. In this study we analyzed the role of SND1 in regulating tumor angiogenesis, a hallmark of cancer. Conditioned medium from Hep3B-SND1 cells stably overexpressing SND1 augmented, whereas that from QGY-SND1si cells stably overexpressing SND1 siRNA significantly inhibited angiogenesis, as analyzed by a chicken chorioallantoic membrane assay and a human umbilical vein endothelial cell differentiation assay. We unraveled a linear pathway in which SND1-induced activation of NF-κB resulted in induction of miR-221 and subsequent induction of angiogenic factors Angiogenin and CXCL16. Inhibition of either of these components resulted in significant inhibition of SND1-induced angiogenesis, thus highlighting the importance of this molecular cascade in regulating SND1 function. Because SND1 regulates NF-κB and miR-221, two important determinants of HCC controlling the aggressive phenotype, SND1 inhibition might be an effective strategy to counteract this fatal malady.

Angiogenesis
Cancer Biology
Chemokines
Liver Cancer
NF-κB
CXCL16
SND1
Angiogenin
miR-221

Cited by (0)

*

This work was supported in part by grants from the Dana Foundation, the James S. McDonnell Foundation, a Massey Cancer Center pilot project grant, and National Cancer Institute Grants R01 CA138540 (to D. S.) and R01 CA134721 (to P. B. F.).

This article contains supplemental Figs. S1–S4.

1

Holder of the Thelma Newmeyer Corman Chair in Cancer Research, a Samuel Waxman Cancer Research Foundation (SWCRF) Investigator, and a National Foundation for Cancer Research (NFCR) Investigator.

3

Harrison Endowed Scholar in Cancer Research and a Blick scholar.