title: Sulfatase 2 facilitates lymphangiogenesis in breast cancer by regulating VEGF-D.
abstract: In our previous studies, sulfatase 2 (Sulf2) was found to upregulate vascular endothelial growth factor-D (VEGF-D) expression in breast cancer. As VEGF-D plays an important role in lymphangiogenesis, we hypothesized that Sulf2 facilitates lymphangiogenesis in breast cancer by regulating VEGF-D. To evaluate the functions of Sulf2 on lymphangiogenesis in breast cancer, proliferation, apoptosis, cell cycle, cell mobility and tube-formation of lymphatic endothelial cells (LECs) were measured in vitro. Lymphangiogenesis in nude mouse ears and breast cancer xenografts were examined in vivo. Furthermore, the expression levels of related signaling pathway genes were screened and verified in LECs. We found that Sulf2 significantly increased the mobility and tube formation of the LECs, inhibited cisplatin-induced LEC apoptosis, but had no effect on cell proliferation and the cell cycle. Moreover, recombinant Sulf2 (rSulf2) combined with VEGF-D further promoted the proliferation, cell cycle, mobility and tube-like structure formation in the LECs, and at the same time inhibited cisplatin-induced apoptosis especially in the late stage. Sulf2 also significantly increased the density of lymphatic vessels in mouse ears and breast cancer xenografts in vivo. AKT1 was also shown to be upregulated and activated by Sulf2. Our results confirmed that Sulf2 facilitated lymphangiogenesis in breast cancer cells by regulating VEGF-D and that the AKT1‑related signaling pathway was involved.
authors.affiliation: Department of General Surgery, Shanghai Ninth People's Hospital, Affiliated with Shanghai Jiaotong University, School of Medicine, Shanghai 200011, P.R. China.
authors.forename: Chenfang
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Department of General Surgery, Shanghai Ninth People's Hospital, Affiliated with Shanghai Jiaotong University, School of Medicine, Shanghai 200011, P.R. China.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Qi
authors.affiliation: Department of Surgery, George Washington University, Washington, DC 20052, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of General Surgery, Shanghai Ninth People's Hospital, Affiliated with Shanghai Jiaotong University, School of Medicine, Shanghai 200011, P.R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Nie
authors.affiliation: Department of General Surgery, Shanghai Ninth People's Hospital, Affiliated with Shanghai Jiaotong University, School of Medicine, Shanghai 200011, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gu
mesh_terms: D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000201:enzymology*; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D042583:Lymphangiogenesis; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D015398:Signal Transduction; D013429:Sulfatases; D015238:Sulfotransferases / Q000502:physiology*; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism*
chemical_list: C579459:VEGFD protein, human; D042643:Vascular Endothelial Growth Factor D; D015238:Sulfotransferases; C470792:SULF2 protein, human; D013429:Sulfatases