1. Transcriptional Induction of Periostin by a Sulfatase 2-TGFβ1-SMAD Signaling Axis Mediates Tumor Angiogenesis in Hepatocellular Carcinoma.
- Author
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Chen G, Nakamura I, Dhanasekaran R, Iguchi E, Tolosa EJ, Romecin PA, Vera RE, Almada LL, Miamen AG, Chaiteerakij R, Zhou M, Asiedu MK, Moser CD, Han S, Hu C, Banini BA, Oseini AM, Chen Y, Fang Y, Yang D, Shaleh HM, Wang S, Wu D, Song T, Lee JS, Thorgeirsson SS, Chevet E, Shah VH, Fernandez-Zapico ME, and Roberts LR
- Subjects
- Animals, Biomarkers, Tumor analysis, Blotting, Western, Carcinoma, Hepatocellular metabolism, Carcinoma, Hepatocellular mortality, Chromatin Immunoprecipitation, Enzyme-Linked Immunosorbent Assay, Gene Knockdown Techniques, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Liver Neoplasms metabolism, Liver Neoplasms mortality, Mice, Mice, Knockout, Neovascularization, Pathologic metabolism, Oligonucleotide Array Sequence Analysis, Real-Time Polymerase Chain Reaction, Signal Transduction physiology, Smad Proteins metabolism, Sulfatases, Sulfotransferases metabolism, Transforming Growth Factor beta1 metabolism, Carcinoma, Hepatocellular pathology, Cell Adhesion Molecules biosynthesis, Gene Expression Regulation, Neoplastic physiology, Liver Neoplasms pathology, Neovascularization, Pathologic pathology
- Abstract
Existing antiangiogenic 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 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 endothelial proliferation, adhesion, chemotaxis, and tube formation in a paracrine fashion. Mechanistic analyses identified the extracellular matrix protein periostin (POSTN), a ligand of αvβ3/5 integrins, as an effector protein in SULF2-induced angiogenesis. POSTN silencing in HCC cells attenuated SULF2-induced angiogenesis and tumor growth in vivo The TGFβ1/SMAD pathway was identified as a critical signaling axis between SULF2 and upregulation of POSTN transcription. In clinical HCC specimens, 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. Cancer Res; 77(3); 632-45. ©2016 AACR., (©2016 American Association for Cancer Research.)
- Published
- 2017
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