TGFbeta-regulated epithelial-mesenchymal transition (EMT)

摘要 侵袭性肿瘤是转移性的，并且对常规疗法具有内在抗性，这代表了一种关键的 问题介导的发病率和死亡率，如果不是所有的肿瘤，包括乳腺癌。据推测 针对上皮-间质转化（EMT）和随后的癌症干细胞形成， （CSCs）可能是降低原发性乳腺癌产生转移性乳腺癌的一种手段。 衍生物.在癌症的背景下，经历EMT的细胞具有增强的肿瘤引发能力， 能够产生乳腺球，表现出细胞表面标志物和基因表达谱， 正常乳腺（MaSC）和乳腺癌（BCSC）干细胞，并变得更耐 化疗药物我们最近证实了TGFβ诱导的EMT在肿瘤形成中的作用 起始细胞（TIC），通过涉及RNA结合蛋白hnRNP E1（E1）的信号通路。在此， 我们的数据表明，TGFβ/E1/信号通路导致胚胎lncRNA的诱导， Platr 18（pluripotent associated transcript 18）。我们发现，这种lncRNA在正常人中不表达， 上皮或其他成人体组织，但高度诱导的TGFβ/E1轴和细胞具有 经历EMT或癌症进展期间。该提案的科学前提是，TGFβ- 介导的EMT程序通过TGFβ/E1信号传导诱导TIC的产生和肿瘤进展， 重新激活静音平台18。其目标是描述Platr 18功能的分子机制， 确定其在通过VSIG-3调节T细胞介导的免疫中的作用，以及通过VSIG-3调节肿瘤神经支配， Sema4F

Abstract Aggressive tumors that are metastatic and intrinsically resistant to conventional therapies represent a critical issue mediating the morbidity and mortality of most, if not all tumors, including breast cancer. It is postulated that targeting the epithelial-mesenchymal transition (EMT) and the ensuing formation of cancer stem cells (CSCs) is likely to represent a means of reducing the rate at which primary breast cancers spawn metastatic derivatives. In the context of cancer, cells having undergone an EMT have enhanced tumor-initiating ability, are capable of generating mammospheres, exhibit cell-surface markers and gene expression profiles similar to both normal mammary (MaSC) and breast cancer (BCSC) stem cells and become more resistant to chemotherapeutics. We have recently demonstrated a role for TGFβ-induced EMT in the formation of tumor initiating cells (TICs), through a signaling pathway involving the RNA binding protein hnRNP E1 (E1). Herein, our data demonstrates that this TGFβ/E1/ signaling pathway leads to the induction of an embryonic lncRNA known as Platr18 (pluripotent associated transcript 18). We show that this lncRNA is not expressed in normal epithelium or other adult somatic tissues but is highly induced by the TGFβ/E1 axis and in cells having undergone an EMT or during cancer progression. The scientific premise of the proposal is that the TGFβ- mediated EMT program induces the generation of TICs and tumor progression through TGFβ/E1 signaling and reactivation of silenced Platr18. Its goals are to delineate the molecular mechanism(s) of Platr18 function and determine its role in modulating T-cell mediated immunity through VSIG-3 & tumor innervation through Sema4F.