Liu Y-S, Lin H-Y, Lai S-W, Huang C-Y, Huang B-R, Chen P-Y, Wei K-C, Lu D-Y
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan.
Oncogene. 2017 Aug 31;36(35):5006-5022. doi: 10.1038/onc.2017.129. Epub 2017 May 1.
Tumor-associated macrophages (TAMs) originate as circulating monocytes, and are recruited to gliomas, where they facilitate tumor growth and migration. Understanding the interaction between TAM and cancer cells may identify therapeutic targets for glioblastoma multiforme (GBM). Vascular cell adhesion molecule-1 (VCAM-1) is a cytokine-induced adhesion molecule expressed on the surface of cancer cells, which is involved in interactions with immune cells. Analysis of the glioma patient database and tissue immunohistochemistry showed that VCAM-1 expression correlated with the clinico-pathological grade of gliomas. Here, we found that VCAM-1 expression correlated positively with monocyte adhesion to GBM, and knockdown of VCAM-1 abolished the enhancement of monocyte adhesion. Importantly, upregulation of VCAM-1 is dependent on epidermal-growth-factor-receptor (EGFR) expression, and inhibition of EGFR effectively reduced VCAM-1 expression and monocyte adhesion activity. Moreover, GBM possessing higher EGFR levels (U251 cells) had higher VCAM-1 levels compared to GBMs with lower levels of EGFR (GL261 cells). Using two- and three-dimensional cultures, we found that monocyte adhesion to GBM occurs via integrin α4β1, which promotes tumor growth and invasion activity. Increased proliferation and tumor necrosis factor-α and IFN-γ levels were also observed in the adherent monocytes. Using a genetic modification approach, we demonstrated that VCAM-1 expression and monocyte adhesion were regulated by the miR-181 family, and lower levels of miR-181b correlated with high-grade glioma patients. Our results also demonstrated that miR-181b/protein phosphatase 2A-modulated SP-1 de-phosphorylation, which mediated the EGFR-dependent VCAM-1 expression and monocyte adhesion to GBM. We also found that the EGFR-dependent VCAM-1 expression is mediated by the p38/STAT3 signaling pathway. Our study suggested that VCAM-1 is a critical modulator of EGFR-dependent interaction of monocytes with GBM, which raises the possibility of developing effective and improved therapies for GBM.
肿瘤相关巨噬细胞（TAM）起源于循环单核细胞，被募集到胶质瘤中，在那里它们促进肿瘤生长和迁移。了解TAM与癌细胞之间的相互作用可能会为多形性胶质母细胞瘤（GBM）确定治疗靶点。血管细胞黏附分子-1（VCAM-1）是一种细胞因子诱导的黏附分子，表达于癌细胞表面，参与与免疫细胞的相互作用。对胶质瘤患者数据库和组织免疫组化分析表明，VCAM-1表达与胶质瘤的临床病理分级相关。在此，我们发现VCAM-1表达与单核细胞对GBM的黏附呈正相关，敲低VCAM-1可消除单核细胞黏附的增强。重要的是，VCAM-1的上调依赖于表皮生长因子受体（EGFR）的表达，抑制EGFR可有效降低VCAM-1表达和单核细胞黏附活性。此外，与EGFR水平较低的GBM（GL261细胞）相比，EGFR水平较高的GBM（U251细胞）具有更高的VCAM-1水平。使用二维和三维培养，我们发现单核细胞对GBM的黏附通过整合素α4β1发生，这促进了肿瘤生长和侵袭活性。在黏附的单核细胞中还观察到增殖增加以及肿瘤坏死因子-α和干扰素-γ水平升高。使用基因修饰方法，我们证明VCAM-1表达和单核细胞黏附受miR-181家族调节，且miR-181b水平较低与高级别胶质瘤患者相关。我们的结果还表明，miR-181b/蛋白磷酸酶2A调节SP-1的去磷酸化，这介导了EGFR依赖的VCAM-1表达和单核细胞对GBM的黏附。我们还发现EGFR依赖的VCAM-1表达由p38/STAT3信号通路介导。我们的研究表明，VCAM-1是EGFR依赖的单核细胞与GBM相互作用的关键调节因子，这增加了开发有效且改进的GBM治疗方法的可能性。
