S100A4 Is Involved in Stimulatory Effects Elicited by the FGF2/FGFR1 Signaling Pathway in Triple-Negative Breast Cancer (TNBC) Cells.
S100A4 Is Involved in Stimulatory Effects Elicited by the FGF2/FGFR1 Signaling Pathway in Triple-Negative Breast Cancer (TNBC) Cells.
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DOI：
10.3390/ijms22094720
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发表时间：
2021-04-29
影响因子：
5.6
通讯作者：
Maggiolini M
中科院分区：
文献类型：
--
作者：
Santolla MF;Talia M;Maggiolini M
三阴性乳腺癌是一种临床预后较差的侵袭性乳腺癌亚型。近年来，在更好地了解TNBC的生物学格局方面取得了许多进展，但适当的目标仍有待确定。在本研究中，我们在分析“癌症基因组图谱的浸润性乳腺癌队列”(TCGA)数据集时，确定了FGF2和S100A4在TNBC中的表达水平高于非TNBC患者。此外，我们还发现在TNBC样本中FGF2的基因表达与S100A4呈正相关。通过定量PCR、Western印迹、CRISPR/Cas9基因组编辑、启动子研究、免疫荧光分析、亚细胞分级研究和芯片分析，我们还证明了FGF2通过FGFR1诱导TNBC细胞S100A4的上调和分泌，以及ERK1/2-AKT-c-Rel信号转导。利用FGF2刺激的TNBC细胞的条件培养液，我们还证实了S100A4/RAGE通路的旁分泌激活触发了血管内皮细胞(HUVECs)的血管生成效应，并促进了肿瘤相关成纤维细胞(CAF)的迁移。总之，我们的数据为FGF2/FGFR1轴通过S100A4对在TNBC细胞中引发的刺激效应的作用提供了新的见解。
Triple-negative breast cancer (TNBC) is an aggressive breast tumor subtype characterized by poor clinical outcome. In recent years, numerous advancements have been made to better understand the biological landscape of TNBC, though appropriate targets still remain to be determined. In the present study, we have determined that the expression levels of FGF2 and S100A4 are higher in TNBC with respect to non-TNBC patients when analyzing “The Invasive Breast Cancer Cohort of The Cancer Genome Atlas” (TCGA) dataset. In addition, we have found that the gene expression of FGF2 is positively correlated with S100A4 in TNBC samples. Performing quantitative PCR, Western blot, CRISPR/Cas9 genome editing, promoter studies, immunofluorescence analysis, subcellular fractionation studies, and ChIP assays, we have also demonstrated that FGF2 induces in TNBC cells the upregulation and secretion of S100A4 via FGFR1, along with the ERK1/2–AKT–c-Rel transduction signaling. Using conditioned medium from TNBC cells stimulated with FGF2, we have also ascertained that the paracrine activation of the S100A4/RAGE pathway triggers angiogenic effects in vascular endothelial cells (HUVECs) and promotes the migration of cancer-associated fibroblasts (CAFs). Collectively, our data provide novel insights into the action of the FGF2/FGFR1 axis through S100A4 toward stimulatory effects elicited in TNBC cells.
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