TGFbeta-regulated epithelial-mesenchymal transition (EMT)

摘要 侵袭性肿瘤是转移性的，对传统治疗具有内在的抵抗力，这是一种关键的 调解大多数肿瘤(如果不是所有肿瘤)的发病率和死亡率的问题，包括乳腺癌。这是假定的 靶向上皮-间充质转化(EMT)和随后形成的肿瘤干细胞 (CSCs)很可能是一种降低原发乳腺癌转移率的方法 衍生品。在癌症的背景下，经历了EMT的细胞具有增强的启动肿瘤的能力， 能够产生乳房，展示类似的细胞表面标记和基因表达谱 对正常乳腺(MASC)和乳腺癌(BCSC)干细胞具有更强的抵抗力 化疗药物。我们最近证实了转化生长因子β诱导的EMT在肿瘤形成中的作用。 启动细胞(TICs)，通过涉及RNA结合蛋白hnRNP E1(E1)的信号通路。在这里， 我们的数据表明，这种转化生长因子β/e1/信号通路导致了胚胎lncrna的诱导。 被称为Platr18(多能相关转录本18)。我们发现这种lncRNA在正常组织中不表达。 上皮或其他成年体细胞组织，但由转化生长因子β/E_1轴高度诱导，并在具有 经历过EMT或在癌症进展期间。该建议的科学前提是转化生长因子β- 介导的EMT程序通过转化生长因子β/E1信号通路诱导抽动的产生和肿瘤进展 重新激活沉默的Platr18。其目标是阐明Platr18功能的分子机制(S)和 确定其在VSIG-3调节T细胞免疫中的作用及肿瘤神经传导途径 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.