IL11 signaling mediates piR-2158 suppression of cell stemness and angiogenesis in breast cancer.
IL11 signaling mediates piR-2158 suppression of cell stemness and angiogenesis in breast cancer.
复制标题
IL11信号传导介导PIR-2158抑制乳腺癌细胞干和血管生成的抑制。
作者：
Zhao Q;Qian L;Guo Y;Lü J;Li D;Xie H;Wang Q;Ma W;Liu P;Liu Y;Wang T;Wu X;Han J;Yu Z
越来越多的证据表明，piwi相互作用rna （piRNAs）在人类癌细胞中的异常表达通过控制癌细胞的干细胞性来调节肿瘤的发生和进展。本文中，我们发现piR-2158在人乳腺癌肿瘤中下调，特别是在来自患者和细胞系的ALDH+乳腺癌干细胞（BCSCs）中，这在两种乳腺癌基因工程小鼠模型（MMTV-Wnt和MMTV-PyMT）中得到进一步验证。piR-2158在基底样或腔型乳腺癌细胞中过度表达可抑制细胞增殖、迁移、上皮-间质转化（EMT）和体外干性。在小鼠体内使用双乳腺肿瘤靶向piRNA递送系统可减少肿瘤生长。RNA-seq、ChIP-seq和荧光素酶报告基因分析表明，piR-2158通过与AP-1转录因子亚基FOSL1竞争，结合il - 11启动子，从而成为il - 11的转录抑制因子。STAT3信号介导pir -2158- il - 11对癌细胞干细胞和肿瘤生长的调控。此外，通过体外MDA-MB-231和HUVECs共培养和体内肿瘤内皮细胞CD31染色，我们证实了pir -2158- il - 11对乳腺癌血管生成的抑制作用。综上所述，本研究不仅揭示了piR-2158通过调控肿瘤干细胞和肿瘤血管生成抑制乳腺肿瘤发生的新机制，而且为乳腺癌的治疗提供了新的治疗策略。
Emerging evidence has indicated the aberrant expression of PIWI-interacting RNAs (piRNAs) in human cancer cells to regulate tumor development and progression by governing cancer cell stemness. Herein, we identified downregulation of piR-2158 in human breast cancer tumors, especially in ALDH+ breast cancer stem cells (BCSCs) from patients and cell lines, which was further validated in two types of genetically engineered mouse models of breast cancer (MMTV-Wnt and MMTV-PyMT). Enforced overexpression of piR-2158 in basal-like or luminal subtypes of breast cancer cells suppressed cell proliferation, migration, epithelial-mesenchymal transition (EMT) and stemness in vitro. Administration of a dual mammary tumor-targeting piRNA delivery system in mice reduced tumor growth in vivo. RNA-seq, ChIP-seq and luciferase reporter assays demonstrated piR-2158 as a transcriptional repressor of IL11 by competing with AP-1 transcription factor subunit FOSL1 to bind the promoter of IL11. STAT3 signaling mediated piR-2158-IL11 regulation of cancer cell stemness and tumor growth. Moreover, by co-culturing of MDA-MB-231 and HUVECs in vitro and CD31 staining of tumor endothelial cells in vivo, we demonstrated inhibition of angiogenesis by piR-2158-IL11 in breast cancer. In conclusion, the current study not only reveals a novel mechanism through which piR-2158 inhibits mammary gland tumorigenesis via regulating cancer stem cells and tumor angiogenesis, but also provides a novel therapeutic strategy in treatment of breast cancer.
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