Ikuo Nakamura, Shaoshan Han, Mengtao Zhou, Yong Fang, Dongye Yang, Hassan M. Shaleh, Martin E. Fernandez-Zapico, Tao Song, Ezequiel J. Tolosa, Ju Seog Lee, Yichun Chen, Alexander G. Miamen, Luciana L. Almada, Gang Chen, Chunling Hu, Roongruedee Chaiteerakij, Abdul M. Oseini, Eriko Iguchi, Eric Chevet, Dehai Wu, Catherine D. Moser, Michael K. Asiedu, Paola A. Romecin, Lewis R. Roberts, Vijay H. Shah, Renumathy Dhanasekaran, Bubu A. Banini, Renzo E. Vera, Snorri S. Thorgeirsson, Shaoqing Wang, CRLCC Eugène Marquis (CRLCC), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Schulze Center for Novel Therapeutics, Division of Oncology Research [Rochester], Mayo Clinic [Rochester], CA165076, National Institutes of Health, P30DK084567, National Institute of Diabetes and Digestive and Kidney Diseases, 81201953, National Natural Science Foundation of China, CA15083, Mayo Clinic Cancer Center, and Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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. Fil: Chen, Gang. Mayo Clinic; Estados Unidos. Wenzhou Medical University; China Fil: Nakamura, Ikuo. Mayo Clinic; Estados Unidos Fil: Dhanasekaran, Renumathy. Mayo Clinic; Estados Unidos. University of Stanford; Estados Unidos Fil: Iguchi, Eriko. Schulze Center For Novel Therapeutics, Mayo Clinic; Estados Unidos Fil: Tolosa, Ezequiel Julian. Schulze Center For Novel Therapeutics, Mayo Clinic; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina Fil: Romecin, Paola A.. Schulze Center For Novel Therapeutics, Mayo Clinic; Estados Unidos Fil: Vera, Renzo Emanuel. Schulze Center For Novel Therapeutics, Mayo Clinic; Estados Unidos. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina Fil: Almada, Luciana Victoria. Schulze Center For Novel Therapeutics, Mayo Clinic; Estados Unidos Fil: Miamen, Alexander G.. Mayo Clinic; Estados Unidos Fil: Chaiteerakij, Roongruedee. Mayo Clinic; Estados Unidos Fil: Zhou, Mengtao. Wenzhou Medical University; China Fil: Asiedu, Michael K.. Mayo Clinic; Estados Unidos Fil: Moser, Catherine D.. Mayo Clinic; Estados Unidos Fil: Han, Shaoshan. Mayo Clinic; Estados Unidos Fil: Hu, Chunling. Mayo Clinic; Estados Unidos Fil: Banini, Bubu A.. Mayo Clinic; Estados Unidos Fil: Oseini, Abdul M.. Mayo Clinic; Estados Unidos Fil: Chen, Yichun. Mayo Clinic; Estados Unidos Fil: Fang, Yong. Mayo Clinic; Estados Unidos Fil: Yang, Dongye. Mayo Clinic; Estados Unidos Fil: Shaleh, Hassan M.. Mayo Clinic; Estados Unidos Fil: Wang, Shaoqing. Mayo Clinic; Estados Unidos Fil: Wu, Dehai. Mayo Clinic; Estados Unidos Fil: Song, Tao. Mayo Clinic; Estados Unidos Fil: Lee, Ju-Seog. Anderson Cancer Center; Estados Unidos Fil: Thorgeirsson, Snorri S.. National Cancer Institute; Estados Unidos Fil: Chevet, Eric. Université Rennes; Francia Fil: Shah, Vijay H.. Mayo Clinic; Estados Unidos Fil: Fernandez-Zapico, Martin E.. Schulze Center For Novel Therapeutics, Mayo Clinic; Estados Unidos Fil: Roberts, Lewis R.. Mayo Clinic; Estados Unidos