Transcriptional Induction of Periostin by a Sulfatase 2-TGFb1-SMAD Signaling Axis Mediates Tumor Angiogenesis in Hepatocellular Carcinoma

Gang Chen, Ikuo Nakamura, Renumathy Dhanasekaran, Eriko Iguchi, Ezequiel J. Tolosa, Paola A. Romecin, Renzo E. Vera, Luciana L. Almada, Alexander G. Miamen, Roongruedee Chaiteerakij, Mengtao Zhou, Michael K. Asiedu, Catherine D. Moser, Shaoshan Han, Chunling Hu, Bubu A. Banini, Abdul M. Oseini, Yichun Chen, Yong Fang, Dongye YangHassan M. Shaleh, Shaoqing Wang, Dehai Wu, Tao Song, Ju Seog Lee, Snorri S. Thorgeirsson, Eric Chevet, Vijay H. Shah, Martin E. Fernandez-Zapico, Lewis R. Roberts

Research output: Contribution to journalArticle

23 Scopus citations

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 avb3/5 integrins, as an effector protein in SULF2-induced angiogenesis. POSTN silencing in HCC cells attenuated SULF2-induced angiogenesis and tumor growth in vivo. The TGFb1/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.

Original languageEnglish (US)
Pages (from-to)632-645
Number of pages14
JournalCancer research
Volume77
Issue number3
DOIs
StatePublished - Feb 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Chen, G., Nakamura, I., Dhanasekaran, R., Iguchi, E., Tolosa, E. J., Romecin, P. A., Vera, R. E., Almada, L. L., Miamen, A. G., Chaiteerakij, R., Zhou, M., Asiedu, M. K., Moser, C. D., Han, S., Hu, C., Banini, B. A., Oseini, A. M., Chen, Y., Fang, Y., ... Roberts, L. R. (2017). Transcriptional Induction of Periostin by a Sulfatase 2-TGFb1-SMAD Signaling Axis Mediates Tumor Angiogenesis in Hepatocellular Carcinoma. Cancer research, 77(3), 632-645. https://doi.org/10.1158/0008-5472.CAN-15-2556