Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, RJ, Brazil.
Program of Cellular Biology, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil.
Biochem Biophys Res Commun. 2018 Sep 26;504(1):270-276. doi: 10.1016/j.bbrc.2018.08.169. Epub 2018 Aug 30.
Protease-activated receptor 2 (PAR2) is a G-protein coupled receptor which is activated upon cleavage of its N-terminal region. PAR2 has been associated with many aspects regarding tumor progression, such as the production of pro-tumoral cytokines. Granulocyte colony-stimulating factor (G-CSF) is a cytokine essential to neutrophil production and maturation, and it is often overexpressed in tumors. In this study, we evaluated the ability of PAR2 to modulate G-CSF expression. PAR2 and G-CSF were significantly more expressed in metastatic (4T1 and MDA-MB-231) as compared to non-metastatic (67NR and MCF7) breast cancer cell lines. In addition, PAR2 stimulation by a synthetic agonist peptide significantly increased G-CSF gene expression in the metastatic cell lines. Knockdown of PAR2 in 4T1 cells decreased G-CSF expression and secretion. In addition, treatment of 4T1 with the commercial PAR2 antagonist, ENMD-1068, significantly decreased G-CSF expression. cBioPortal analyses of the TCGA database showed a significant co-occurrence of G-CSF and PAR2 gene overexpression in breast cancer samples. In conclusion, our data suggest that PAR2 contributes to G-CSF expression in breast cancer cells, possibly favoring tumor progression.
蛋白酶激活受体 2（PAR2）是一种 G 蛋白偶联受体，其 N 端区域被切割后被激活。PAR2 与肿瘤进展的许多方面有关，例如产生促肿瘤细胞因子。粒细胞集落刺激因子（G-CSF）是一种对中性粒细胞生成和成熟至关重要的细胞因子，并且经常在肿瘤中过度表达。在这项研究中，我们评估了 PAR2 调节 G-CSF 表达的能力。转移性（4T1 和 MDA-MB-231）与非转移性（67NR 和 MCF7）乳腺癌细胞系相比，PAR2 和 G-CSF 的表达明显更高。此外，合成激动肽刺激 PAR2 显著增加了转移性细胞系中 G-CSF 的基因表达。在 4T1 细胞中敲低 PAR2 会降低 G-CSF 的表达和分泌。此外，用商业 PAR2 拮抗剂 ENMD-1068 处理 4T1 细胞可显著降低 G-CSF 的表达。TCGA 数据库的 cBioPortal 分析显示，乳腺癌样本中 G-CSF 和 PAR2 基因过表达存在显著的共发生。总之，我们的数据表明 PAR2 有助于乳腺癌细胞中 G-CSF 的表达，可能有利于肿瘤进展。
