Onyeisi Jessica Oyie Sousa, El-Shorafa Heba M, Greve Burkhard, Götte Martin
Department of Gynecology and Obstetrics, Münster University Hospital 48149, Münster, Germany.
Department of Gynecology and Obstetrics, Münster University Hospital 48149, Münster, Germany; Department of Laboratory Medical Sciences, Faculty of Medical Sciences, Alaqsa University, Gaza, Palestine.
Matrix Biol. 2025 Apr;136:127-133. doi: 10.1016/j.matbio.2025.02.002. Epub 2025 Feb 10.
Syndecan-4 (SDC4), a heparan sulfate proteoglycan, is aberrantly expressed in breast cancer and plays a significant role in tumor progression by influencing cell proliferation and promoting invasive growth. This study aimed to characterize its role in the tumor microenvironment by analyzing the contribution of SDC4 to vasculogenic mimicry (VM) and angiogenesis in human breast cancer cells. We silenced SDC4 in the triple-negative breast cancer (TNBC) cell lines MDA-MB-231, MDA-MB-468, and SUM-149 and analyzed its functions in vitro. SDC4 knockdown inhibited the VM of MDA-MB-231 cells as analyzed by fluorescence microscopy. Moreover, RT-qPCR revealed decreased expression of KLF4, EGR1, and HPSE, factors involved in VM, proangiogenic and pro-invasive processes in all TNBC cell lines. Western blotting revealed a partially cell-line-dependent regulation of these proteins by SDC4. At the functional level, SDC4 knockdown also impaired angiogenesis, decreasing the number of nodes and meshes in a 3D co-culture model comprising endothelial cells and TNBC cells. Using a Proteome Profile Human Angiogenesis Array, we observed that SDC4 knockdown decreased the secretion of VEGF and IGFBP-1, while it increased the secretion of IL-8, uPA, and amphiregulin in the conditioned media of the MDA-MB-231 and MDA-MB-468 co-cultures. Independent RT-qPCR analyses of gene expression were consistent with those of the angiogenesis array. Overall, these findings highlighted the crucial role of SDC4 in regulating both vasculogenic mimicry and angiogenesis in TNBC cells. The data indicate that SDC4 acts as a crucial regulatory molecule and represents a promising target for therapeutic strategies in breast cancer.
Syndecan-4（SDC4）是一种硫酸乙酰肝素蛋白聚糖，在乳腺癌中异常表达，并通过影响细胞增殖和促进侵袭性生长在肿瘤进展中发挥重要作用。本研究旨在通过分析SDC4对人乳腺癌细胞中血管生成拟态（VM）和血管生成的贡献，来表征其在肿瘤微环境中的作用。我们在三阴性乳腺癌（TNBC）细胞系MDA-MB-231、MDA-MB-468和SUM-149中沉默SDC4，并在体外分析其功能。通过荧光显微镜分析，SDC4敲低抑制了MDA-MB-231细胞的VM。此外，RT-qPCR显示，在所有TNBC细胞系中，参与VM、促血管生成和促侵袭过程的KLF4、EGR1和HPSE的表达均降低。蛋白质印迹显示，SDC4对这些蛋白质的调节部分依赖于细胞系。在功能水平上，SDC4敲低也损害了血管生成，减少了包含内皮细胞和TNBC细胞的三维共培养模型中的节点和网孔数量。使用蛋白质组学人类血管生成阵列，我们观察到SDC4敲低减少了VEGF和IGFBP-1的分泌，而增加了MDA-MB-231和MDA-MB-468共培养条件培养基中IL-8、uPA和双调蛋白的分泌。基因表达的独立RT-qPCR分析与血管生成阵列的分析结果一致。总体而言，这些发现突出了SDC4在调节TNBC细胞中血管生成拟态和血管生成方面的关键作用。数据表明，SDC4作为一种关键的调节分子，是乳腺癌治疗策略中一个有前景的靶点。
