Zhu Chenfang, Qi Xiaoliang, Zhou Xin, Nie Xin, Gu Yan
Department of General Surgery, Shanghai Ninth People's Hospital, Affiliated with Shanghai Jiaotong University, School of Medicine, Shanghai 200011, P.R. China.
Department of Surgery, George Washington University, Washington, DC 20052, USA.
Oncol Rep. 2016 Dec;36(6):3161-3171. doi: 10.3892/or.2016.5143. Epub 2016 Oct 4.
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.
在我们之前的研究中，发现硫酸酯酶2（Sulf2）可上调乳腺癌中血管内皮生长因子-D（VEGF-D）的表达。由于VEGF-D在淋巴管生成中起重要作用，我们推测Sulf2通过调节VEGF-D促进乳腺癌中的淋巴管生成。为了评估Sulf2在乳腺癌淋巴管生成中的功能，在体外测量了淋巴管内皮细胞（LEC）的增殖、凋亡、细胞周期、细胞迁移和管形成。在体内检查了裸鼠耳部和乳腺癌异种移植物中的淋巴管生成。此外，在LEC中筛选并验证了相关信号通路基因的表达水平。我们发现Sulf2显著增加了LEC的迁移和管形成，抑制了顺铂诱导的LEC凋亡，但对细胞增殖和细胞周期没有影响。此外，重组Sulf2（rSulf2）与VEGF-D联合进一步促进了LEC的增殖、细胞周期、迁移和管状结构形成，同时尤其在后期抑制了顺铂诱导的凋亡。Sulf2还显著增加了体内小鼠耳部和乳腺癌异种移植物中淋巴管的密度。AKT1也显示被Sulf2上调并激活。我们的结果证实，Sulf2通过调节VEGF-D促进乳腺癌细胞中的淋巴管生成，并且涉及AKT1相关信号通路。
