Linc00514 通过 Jagged1 介导的 Notch 信号通路促进乳腺癌转移和肿瘤相关巨噬细胞的 M2 极化。
Linc00514 promotes breast cancer metastasis and M2 polarization of tumor-associated macrophages via Jagged1-mediated notch signaling pathway.
机构信息
Department of Breast Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, 88 Jiefang Rd, Hangzhou, 310009, People's Republic of China.
Department of Urology, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, 310009, China.
出版信息
J Exp Clin Cancer Res. 2020 Sep 17;39(1):191. doi: 10.1186/s13046-020-01676-x.
BACKGROUND
Tumor-associated macrophages (TAMs) and tumor cells are important components of the tumor microenvironment. M2 polarization of TAMs, which is a major actor in breast cancer malignancy and metastasis, can be induced by breast cancer cells. However, the potential mechanisms of the interaction between breast cancer cells and TAMs remain unclear.
METHODS
The candidate breast cancer-associated long non-coding RNAs (lncRNAs) were analyzed using the GEO database. Functional assays, including MTT assay, Transwell assay, and EdU labeling detection, were performed to investigate the oncogenic role of linc00514 in breast cancer progression. The co-culture and ELISA assays were used to assess the role of linc00514 in macrophage recruitment and M2 polarization. RNA immunoprecipitation, RNA pull-down, and luciferase reporter assays were applied to determine the mechanism of linc00514 in breast cancer metastasis. Mouse xenograft models, mouse pulmonary metastatic models, and mouse primary tumor models were used to assess the role of linc00514 in M2 macrophage polarization and breast cancer tumorigenicity.
RESULTS
Linc00514 was highly expressed in clinical breast cancer tissues and breast cancer cell lines. Overexpression of linc00514 promoted the proliferation and invasion of breast cancer cells and increased xenograft tumor volumes and pulmonary metastatic nodules. Overexpression of linc00514 also increased the percentage of macrophages expressing M2 markers CD206 and CD163. Mechanistically, linc00514 promoted Jagged1 expression in a transcriptional manner by increasing the phosphorylation of a transcription factor STAT3. Subsequently, Jagged1-mediated Notch signaling pathway promoted IL-4 and IL-6 secretions in breast cancer cells and ultimately inducing M2 polarization of macrophages.
CONCLUSION
Linc00514 plays an important role in regulating breast cancer tumorigenicity and M2 macrophage polarization via Jagged1-mediated Notch signaling pathway.
背景
肿瘤相关巨噬细胞（TAMs）和肿瘤细胞是肿瘤微环境的重要组成部分。TAMs 的 M2 极化是乳腺癌恶性和转移的主要因素，可被乳腺癌细胞诱导。然而，乳腺癌细胞与 TAMs 之间相互作用的潜在机制尚不清楚。
方法
使用 GEO 数据库分析候选乳腺癌相关长非编码 RNA（lncRNA）。进行 MTT 测定、Transwell 测定和 EdU 标记检测等功能测定，以研究 linc00514 在乳腺癌进展中的致癌作用。共培养和 ELISA 测定用于评估 linc00514 在巨噬细胞募集和 M2 极化中的作用。RNA 免疫沉淀、RNA 下拉和荧光素酶报告基因测定用于确定 linc00514 在乳腺癌转移中的作用机制。小鼠异种移植模型、小鼠肺转移模型和小鼠原发性肿瘤模型用于评估 linc00514 在 M2 巨噬细胞极化和乳腺癌致瘤性中的作用。
结果
linc00514 在临床乳腺癌组织和乳腺癌细胞系中高表达。linc00514 的过表达促进了乳腺癌细胞的增殖和侵袭，并增加了异种移植肿瘤体积和肺转移结节。linc00514 的过表达还增加了表达 M2 标志物 CD206 和 CD163 的巨噬细胞的百分比。在机制上，linc00514 通过增加转录因子 STAT3 的磷酸化，以转录方式促进 Jagged1 的表达。随后，Jagged1 介导的 Notch 信号通路促进了乳腺癌细胞中 IL-4 和 IL-6 的分泌，最终诱导巨噬细胞的 M2 极化。
结论
linc00514 通过 Jagged1 介导的 Notch 信号通路在调节乳腺癌致瘤性和 M2 巨噬细胞极化中发挥重要作用。
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