Faculty Information |
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Article types | Original article |
Language | English |
Refereed paper | Not refereed |
Title | Transcriptional Induction of Periostin by a Sulfatase 2-TGFβ1-SMAD Signaling Axis Mediates Tumor Angiogenesis in Hepatocellular Carcinoma |
Journal | Formal name:Cancer research Abbreviation:Cancer Res ISSN code:1538-7445(Electronic)0008-5472(Linking) |
Domestic / Foregin | Foregin |
Volume, Number, Page | 77(3),pp.632-45 |
Papers・Author | Chen Gang, Nakamura Ikuo, Dhanasekaran Renumathy, Iguchi Eriko, Tolosa Ezequiel J, Romecin Paola A, Vera Renzo E, Almada Luciana L, Miamen Alexander G, Chaiteerakij Roongruedee, Zhou Mengtao, Asiedu Michael K, Moser Catherine D, Han Shaoshan, Hu Chunling, Banini Bubu A, Oseini Abdul M, Chen Yichun, Fang Yong, Yang Dongye, Shaleh Hassan M, Wang Shaoqing, Wu Dehai, Song Tao, Lee Ju-Seog, Thorgeirsson Snorri S, Chevet Eric, Shah Vijay H, Fernandez-Zapico Martin E, Roberts Lewis R |
Publication date | 2017/02 |
Papers・Description | 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. |
DOI | 10.1158/0008-5472.CAN-15-2556 |
PMID | 27872089 |