M2 macrophage-induced lncRNA PCAT6 facilitates tumorigenesis and angiogenesis of triple-negative breast cancer through modulation of VEGFR2
M2 macrophage-induced lncRNA PCAT6 facilitates tumorigenesis and angiogenesis of triple-negative breast cancer through modulation of VEGFR2
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M2巨噬细胞诱导的lncRNA PCAT6通过调节VEGFR2促进三阴性乳腺癌的肿瘤发生和血管生成
DOI：
10.1038/s41419-020-02926-8
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发表时间：
2020-09-09
影响因子：
9
通讯作者：
Wang, Qiong
中科院分区：
文献类型：
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作者：
Dong, Fang;Ruan, Shengnan;Wang, Qiong
作为一种常见的女性恶性肿瘤，三阴性乳腺癌（TNBC）是乳腺癌（BC）中恶性程度最高的亚型。本研究进一步研究了长非编码RNA（lncRNA）前列腺癌相关转录本6（PCAT 6）在TNBC中的作用。功能测定，包括EdU、伤口愈合、transwell和免疫荧光染色，揭示了PCAT 6对细胞增殖、迁移和EMT过程的影响。管形成试验揭示了PCAT 6在血管生成中的功能。还建立了体内测定以探索PCAT 6对肿瘤生长和微血管生成的影响。结果显示，PCAT 6在体外和体内均促进TNBC细胞增殖、迁移和血管生成。随后，本研究揭示了M2巨噬细胞分泌VEGF刺激PCAT 6上调，从而促进TNBC中的血管生成。接下来，通过生物信息学分析和机制分析，我们确定PCAT 6通过ceRNA模式正调控VEGFR 2表达，进而参与VEGFR/AKT/mTOR信号通路，促进血管生成。此外，PCAT 6结合去泛素化酶USP 14，以诱导VEGFR 2的去泛素化。总的来说，M2巨噬细胞诱导的PCAT 6上调通过ceRNA和去泛素化模式调节VEGFR 2表达促进TNBC肿瘤发生。
As a common female malignancy, triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancers (BC). This study further studied the role of long noncoding RNA (lncRNA) prostate cancer-associated transcript 6 (PCAT6) in TNBC. Functional assays, including EdU, wound healing, transwell, and immunofluorescence staining, revealed the effect of PCAT6 on cell proliferation, migration, and EMT process. The tube-formation assay disclosed the function of PCAT6 on angiogenesis. In vivo assays were also established to explore the impact of PCAT6 on tumor growth and microangiogenesis. The results revealed that PCAT6 boosted TNBC cell proliferation, migration, and angiogenesis both in vitro and in vivo. Then, this study unveiled that M2 macrophage secreted VEGF to stimulate the upregulation of PCAT6, thus promoting angiogenesis in TNBC. Next, through bioinformatics analysis and mechanism assays, we identified that PCAT6 positively regulated VEGFR2 expression via ceRNA pattern and then participated in VEGFR/AKT/mTOR signaling pathway to accelerate angiogenesis. Moreover, PCAT6 bound USP14, a deubiquitinase, to induce the deubiquitination of VEGFR2. On the whole, M2 macrophage-induced upregulation of PCAT6 facilitates TNBC tumorigenesis through modulation of VEGFR2 expression via ceRNA and deubiquitination patterns.