PubMed | National Cancer Institute, Mayo Medical School, Mayo Clinic and Mayo Clinic Cancer Center, GI Research Unit and 2 more.
Type: | Journal: Cancer research | Year: 2016
Existing anti-angiogenic approaches to treat metastatic hepatocellular carcinoma (HCC) are weakly effectual, prompting further study of tumor angiogenesis in this disease setting. Here we report a novel role for the sulfatase 2 (SULF2) in driving HCC angiogenesis. Sulf2-deficient mice (Sulf2 KO) exhibited resistance to diethylnitrosamine-induced HCC and did not develop metastases like wild-type mice (Sulf2 WT). The smaller and less numerous tumors formed in Sulf2 KO mice exhibited a markedly lower microvascular density. In human HCC cells, SULF2 overexpression increased proliferation, adhesion, chemotaxis and endothelial tube formation in a paracrine fashion. Mechanistic analyses identified the extracellular matrix protein periostin (POSTN), a ligand of v3/5 integrins, as an effector function in SULF2-induced angiogenesis. POSTN silencing in HCC cells attenuated SULF2-induced angiogenesis and tumor growth in vivo. The TGF1-SMAD pathway was identified as a critical signaling axis between SULF2 and upregulation of POSTN transcription. In clinical specimens of HCC, elevated levels of SULF2 correlated with increased microvascular density, POSTN levels and relatively poorer patient survival. Together, our findings define an important axis controlling angiogenesis in HCC and a mechanistic foundation for rational drug development.
Nakamura I.,Mayo Clinic and Mayo Clinic Cancer Center |
Fernandez-Barrena M.G.,Mayo Clinic and Mayo Clinic Cancer Center |
Ortiz-Ruiz M.C.,University of Murcia |
Almada L.L.,Schulze Center for Novel Therapeutics |
And 17 more authors.
Journal of Biological Chemistry | Year: 2013
Background: Tissue regeneration is a complex process involving a network of ligand-activated pathways. Results: The sulfatase SULF2 modulates cell proliferation and organ growth through a WNT-dependent activation of the transcription factor GLI1. Conclusion: Together, these data define a novel cascade regulating tissue regeneration. Significance: The knowledge derived from this study will contribute to the understanding of the molecular mechanisms modulating regeneration and organogenesis. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.
PubMed | Mayo Clinic and Mayo Clinic Cancer Center
Type: Journal Article | Journal: PloS one | Year: 2014
Beclin 1 interacts with UV-irradiation-resistance-associated gene (UVRAG) to form core complexes that induce autophagy. While cells with defective autophagy are prone to genomic instability that contributes to tumorigenesis, it is unknown whether Beclin1 or UVRAG can regulate the DNA damage/repair response to cancer treatment in established tumor cells. We found that siRNA knockdown of Beclin 1 or UVRAG can increase radiation-induced DNA double strand breaks (DSBs), shown by pATM and H2Ax, and promote colorectal cancer cell death. Furthermore, knockdown of Beclin 1, UVRAG or ATG5 increased the percentage of irradiated cells with nuclear foci expressing 53BP1, a marker of nonhomologous end joining but not RAD51 (homologous recombination), compared to control siRNA. Beclin 1 siRNA was shown to attenuate UVRAG expression. Cells with a UVRAG deletion mutant defective in Beclin 1 binding showed increased radiation-induced DSBs and cell death compared to cells with ectopic wild-type UVRAG. Knockdown of Beclin 1 or UVRAG, but not ATG5, resulted in a significant increase in centrosome number (-tubulin staining) in irradiated cells compared to control siRNA. Taken together, these data indicate that Beclin 1 and UVRAG confer protection against radiation-induced DNA DSBs and may maintain centrosome stability in established tumor cells.
PubMed | Mayo Clinic and Mayo Clinic Cancer Center
Type: Journal Article | Journal: The Journal of biological chemistry | Year: 2013
Tissue regeneration requires the activation of a set of specific growth signaling pathways. The identity of these cascades and their biological roles are known; however, the molecular mechanisms regulating the interplay between these pathways remain poorly understood. Here, we define a new role for SULFATASE 2 (SULF2) in regulating tissue regeneration and define the WNT-GLI1 axis as a novel downstream effector for this sulfatase in a liver model of tissue regeneration. SULF2 is a heparan sulfate 6-O-endosulfatase, which releases growth factors from extracellular storage sites turning active multiple signaling pathways. We demonstrate that SULF2-KO mice display delayed regeneration after partial hepatectomy (PH). Mechanistic analysis of the SULF2-KO phenotype showed a decrease in WNT signaling pathway activity in vivo. In isolated hepatocytes, SULF2 deficiency blocked WNT-induced -CATENIN nuclear translocation, TCF activation, and proliferation. Furthermore, we identified the transcription factor GLI1 as a novel target of the SULF2-WNT cascade. WNT induces GLI1 expression in a SULF2- and -CATENIN-dependent manner. GLI1-KO mice phenocopied the SULF2-KO, showing delayed regeneration and decreased hepatocyte proliferation. Moreover, we identified CYCLIN D1, a key mediator of cell growth during tissue regeneration, as a GLI1 transcriptional target. GLI1 binds to the cyclin d1 promoter and regulates its activity and expression. Finally, restoring GLI1 expression in the liver of SULF2-KO mice after PH rescues CYCLIN D1 expression and hepatocyte proliferation to wild-type levels. Thus, together these findings define a novel pathway in which SULF2 regulates tissue regeneration in part via the activation of a novel WNT-GLI1-CYCLIN D1 pathway.