The role of TGF-beta in tumorigenesis

这项建议的主要目的是阐明新的机制， 多功能细胞因子TGF-β影响肿瘤转移。TGF-β在 在发育和体内平衡的调节中控制多种类型的细胞功能。 在肿瘤发生过程中，已知TGF-β在早期阶段抑制肿瘤形成，但作为一种抑制剂， 该过程的后期阶段，包括转移的有效启动子。虽然框架 TGF-β是调节多种生物学行为的主要信号通路， 过程已经建立，TGF-β功能的机制，以确定 这些生物过程的具体结果仍有待充分探讨。许多microRNAs 发现在癌细胞中，miRNAs下调，导致其表达上调。 靶向基因影响肿瘤发生。我们打算检验特定的miRNAs是 TGF-β介导物调节肿瘤转移背景下的各种细胞功能。在 初步研究，我们发现乳腺和肝脏中一组miRNAs的表达水平， 在TGF-β治疗后癌症减少。其中，miR-34 a和miR-126是 选择用于进一步分析，因为它们假定的靶基因CCL 22和SDF 1是 参与调节性T细胞（Treg）和间充质干细胞（MSC）的募集， 分别基于这些结果，我们进一步假设TGF-β增强了肿瘤的生长， 通过两种新的机制改变肿瘤微环境来转移： 通过抑制miR-34 a以诱导CCL 22的产生来抑制免疫功能， 这反过来又刺激了Treg细胞在转移性肿瘤区域的积累， 发生定植，并募集MSC以支持转移细胞的生长。我们 我提出了两个目的来验证我们的假设，确定miR-34 a和miR-126的功能， TGF-β介导物影响体外和体内转移，并通过 TGF-β调节这些miRNA的表达/加工。最后， 这些TGF-β促进转移的新机制的特征将提供 转移性癌症治疗的潜在新靶点。

The primary objective of this proposal is to elucidate new mechanisms by which the multifunctional cytokine TGF-¿ affects tumor metastasis. TGF-¿ plays important roles in controlling many types of cellular functions in the regulation of development and homeostasis. During tumorigenesis, TGF-¿ is known to inhibit tumor formation in the early stage, but act as a potent promoter for late stages of the process, including metastasis. While the framework of the primary signaling pathway through which TGF-¿ acts to regulate a wide range of biological processes has been established, the mechanisms by which TGF-¿ functions to determine specific outcomes of those biological processes remain to be fully explored. Many microRNAs (miRNAs) are found to be down-regulated in cancer cells, leading to the up-regulation of their target genes to affect tumorigenesis. We intend to test the hypothesis that specific miRNAs are mediators of TGF-¿ to regulate various cellular functions in the context of tumor metastasis. In preliminary studies, we found that the expression level of a set of miRNAs in breast and liver cancers was decreased upon treatment of TGF-¿. Among them, miR-34a and miR-126 were chosen for further analyses because of their putative target genes, CCL22 and SDF1, are involved in the recruitment of regulatory T cells (Treg) and mesenchymal stem cells (MSCs), respectively. Based on those results, we further hypothesize that TGF-¿ enhances tumor metastasis by changing the tumor microenvironment through two new mechanisms: the inhibition of immune function via the repression of miR-34a to induce the production of CCL22, which in turn stimulates the accumulation of Treg cells in the areas where metastatic colonization occurs, and recruitment of MSCs to support the growth of metastatic cells. We propose two aims to test our hypothesis, determining the functions of miR-34a and miR-126 as mediators of TGF-¿ to affect metastasis in vitro and in vivo, and elucidating the mechanism by which TGF-¿ regulates the expression/processing of these miRNAs. Ultimately, characterization of these novel mechanisms by which TGF-¿ promotes metastasis will provide potential new targets for metastatic cancer therapy.