IL-1β Promotes Vasculogenic Mimicry of Breast Cancer Cells Through p38/MAPK and PI3K/Akt Signaling Pathways.
IL-1β Promotes Vasculogenic Mimicry of Breast Cancer Cells Through p38/MAPK and PI3K/Akt Signaling Pathways.
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DOI：
10.3389/fonc.2021.618839
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发表时间：
2021
影响因子：
4.7
通讯作者：
Yan Q
中科院分区：
文献类型：
--
作者：
Nisar MA;Zheng Q;Saleem MZ;Ahmmed B;Ramzan MN;Ud Din SR;Tahir N;Liu S;Yan Q
血管生成拟态（Vasculogenic mimicry，VM）是肿瘤细胞形成的一种微血管样结构，在肿瘤的恶性发展中起着重要作用。白细胞介素-1 β（IL-1β）是一种活性促炎细胞因子，在许多肿瘤类型中升高，包括乳腺癌。然而，IL-1β对乳腺癌VM的影响尚未明确阐明。本研究以乳腺癌细胞（MCF-7和MDA-MB-231）为研究对象，探讨IL-1β对促进VM的变化的影响。通过免疫印迹、免疫荧光染色和免疫组织化学（IHC）分析VM相关生物标志物（VE-cadherin、VEGFR-1、MMP-9、MMP-2、c-Fos和c-Jun）的表达来获得IL-1β刺激VM的证据。此外，在常氧/低氧条件下通过基于基质胶的脐带形成测定和通过苏木精和伊红染色（H&E）的微血管检查收集形态学证据。此外，还利用STRING和Gene Ontology数据库分析了IL-β刺激下VM相关的相互作用分子。结果表明，IL-1β处理后，MCF-7和MDA-MB-231细胞VM生物标志物的表达均增加。在常氧和缺氧条件下，IL-1β处理的细胞VM反应均增加。IL-1β还可增加转录因子AP-1复合物（c-Fos/c-Jun）的活化。生物信息学数据表明p38/MAPK和PI 3 K/Akt信号通路参与了IL-1β的刺激作用。添加信号通路抑制剂后，VM生物标志物的表达下调并减少交叉点的形成进一步证实了这一点。该研究表明，IL-1β通过p38/MAPK和PI 3 K/Akt信号通路刺激乳腺癌细胞中的VM及其相关事件。针对IL-1β促进的VM相关分子靶点，可能为控制乳腺癌细胞的侵袭性提供一种新的抗血管生成治疗策略。
Vasculogenic mimicry (VM), a micro vessel-like structure formed by the cancer cells, plays a pivotal role in cancer malignancy and progression. Interleukin-1 beta (IL-1β) is an active pro-inflammatory cytokine and elevated in many tumor types, including breast cancer. However, the effect of IL-1β on the VM of breast cancer has not been clearly elucidated. In this study, breast cancer cells (MCF-7 and MDA-MB-231) were used to study the effect of IL-1β on the changes that can promote VM. The evidence for VM stimulated by IL-1β was acquired by analyzing the expression of VM-associated biomarkers (VE-cadherin, VEGFR-1, MMP-9, MMP-2, c-Fos, and c-Jun) via western blot, immunofluorescent staining, and Immunohistochemistry (IHC). Additionally, morphological evidence was collected via Matrigel-based cord formation assay under normoxic/hypoxic conditions and microvessel examination through Hematoxylin and Eosin staining (H&E). Furthermore, the STRING and Gene Ontology database was also used to analyze the VM-associated interacting molecules stimulated by IL-β. The results showed that the expression of VM biomarkers was increased in both MCF-7 and MDA-MB-231 cells after IL-1β treatment. The increase in VM response was observed in IL-1β treated cells under both normoxia and hypoxia. IL-1β also increased the activation of transcription factor AP-1 complex (c-Fos/c-Jun). The bioinformatics data indicated that p38/MAPK and PI3K/Akt signaling pathways were involved in the IL-1β stimulation. It was further confirmed by the downregulated expression of VM biomarkers and reduced formation of the intersections upon the addition of the signaling pathway inhibitors. The study suggests that IL-1β stimulates the VM and its associated events in breast cancer cells via p38/MAPK and PI3K/Akt signaling pathways. Aiming the VM-associated molecular targets promoted by IL-1β may offer a novel anti-angiogenic therapeutic strategy to control the aggressiveness of breast cancer cells.
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