Biochemistry, Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece.
Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, SE 75123 Uppsala, Sweden.
Matrix Biol. 2018 Dec;74:35-51. doi: 10.1016/j.matbio.2018.05.011. Epub 2018 May 26.
Serglycin is an intracellular proteoglycan that is expressed and constitutively secreted by numerous malignant cells, especially prominent in the highly-invasive, triple-negative MDA-MB-231 breast carcinoma cells. Notably, de novo expression of serglycin in low aggressive estrogen receptor α (ERα)-positive MCF7 breast cancer cells promotes an aggressive phenotype. In this study, we discovered that serglycin promoted epithelial to mesenchymal transition (EMT) in MCF7 cells as shown by increased expression of mesenchymal markers vimentin, fibronectin and EMT-related transcription factor Snail2. These phenotypic traits were also associated with the development of drug resistance toward various chemotherapy agents and induction of their proteolytic potential as shown by the increased expression of matrix metalloproteinases, including MMP-1, MMP-2, MMP-9, MT1-MMP and up-regulation of urokinase-type plasminogen activator. Knockdown of serglycin markedly reduced the expression of these proteolytic enzymes in MDA-MB-231 cells. In addition, serglycin expression was closely linked to a pro-inflammatory gene signature including the chemokine IL-8 in ERα-negative breast cancer cells and tumors. Notably, serglycin regulated the secretion of IL-8 in breast cancer cells independently of their ERα status and promoted their proliferation, migration and invasion by triggering IL-8/CXCR2 downstream signaling cascades including PI3K, Src and Rac activation. Thus, serglycin promotes the establishment of a pro-inflammatory milieu in breast cancer cells that evokes an invasive mesenchymal phenotype via autocrine activation of IL-8/CXCR2 signaling axis.
硫酸乙酰肝素蛋白聚糖是一种细胞内蛋白聚糖，由许多恶性细胞表达并持续分泌，在高度侵袭性的三阴性 MDA-MB-231 乳腺癌细胞中尤为突出。值得注意的是，在低侵袭性雌激素受体 α (ERα)阳性 MCF7 乳腺癌细胞中从头表达硫酸乙酰肝素蛋白聚糖可促进侵袭表型。在这项研究中，我们发现硫酸乙酰肝素蛋白聚糖在 MCF7 细胞中促进上皮间质转化 (EMT)，表现为间充质标志物波形蛋白、纤维连接蛋白和 EMT 相关转录因子 Snail2 的表达增加。这些表型特征也与对各种化疗药物的耐药性发展以及其蛋白水解潜力的诱导有关，表现为基质金属蛋白酶（包括 MMP-1、MMP-2、MMP-9、MT1-MMP）的表达增加以及尿激酶型纤溶酶原激活物的上调。硫酸乙酰肝素蛋白聚糖的敲低显著降低了 MDA-MB-231 细胞中这些蛋白水解酶的表达。此外，硫酸乙酰肝素蛋白聚糖的表达与 ERα 阴性乳腺癌细胞和肿瘤中的炎症基因特征密切相关，包括趋化因子 IL-8。值得注意的是，硫酸乙酰肝素蛋白聚糖通过触发包括 PI3K、Src 和 Rac 激活在内的 IL-8/CXCR2 下游信号级联反应，独立于 ERα 状态调节乳腺癌细胞中 IL-8 的分泌，并通过自分泌激活 IL-8/CXCR2 信号轴促进其增殖、迁移和侵袭。因此，硫酸乙酰肝素蛋白聚糖促进了乳腺癌细胞中促炎微环境的建立，通过自分泌激活 IL-8/CXCR2 信号轴引发侵袭性间质表型。
