Exploring the role of microRNA 21 and 210 in tumorigenesis after local tumor ablation in a mouse model with metastatic colorectal carcinoma

探索 microRNA 21 和 210 在转移性结直肠癌小鼠模型局部肿瘤消融后肿瘤发生中的作用

基本信息

项目摘要

Minimally invasive image-guided local thermal ablation of the liver, using techniques such as radiofrequency ablation (RFA), is at present in widespread clinical use. Recently, the initial understanding that this therapy results in only beneficial effects, which are limited to the treatment site has been challenged. Previous work showed that ablation therapy causes unwanted systemic side effects, which have a radical impact on distant tumor formation. This poorly characterized process includes an altered tumor microenvironment, which bases on the production of cytokines and growth factors and the modulation of downstream gene expression pathways of remnant tumor cells. Previous studies showed that microRNAs (miRs) - short, non-coding RNA-sequences - are involved in many pathways of cancer initiation and development. An overexpression of pro-tumorigenic miRs (i.e., 21 and 210) in tumor cells is associated with high cell proliferation and tumor growth as well as poor prognosis.The initial proposal focused on the interactions between miRs and proteins, which are locally and systemically elevated after hepatic RFA. These proteins were previously identified by the host institution and may contribute to tumor growth. Secondly, the experiments aimed to specifically target miR21 and 210 therapeutically, which may offer a direct method to regulate and mitigate cancer progression.In this extension, I am interested to translate these observations to an experimental set-up using a clinically relevant drug. Curcumin, which is already used to treat a variety of medical conditions, has been previously identified to act as a tumor suppressing agent. The host institution has already investigated the use of curcumin as an adjuvant drug after hepatic RFA showing a drug-induced decrease of post-RFA tumor growth by reduction of pro-tumorigenic miR21 and 210. Now, I would like to investigate these observations in an established colorectal metastases mouse model, which is reflecting the clinical situation in the context of hepatic RFA more realistically. I am eager to obtain a better understanding of the relationship between the post-ablation elevation and inhibition of miRs, and proteins previously linked to post-ablational tumorigenesis. The proposed experiments aim to advance the findings of the previous study by determining key proteins including STAT3, IL-6, c-MET, and Hsp70, evaluating their role in the regulation network, and allowing to develop therapies that specifically modulate these factors.In summary, the proposed investigations aim to decrease post-RFA tumor growth by inhibition of miR21 and 210 using curcumin as a clinically relevant drug and to eventually improve the therapeutic outcome of affected patients.
使用诸如射频消融(RFA)的技术的肝脏的微创图像引导的局部热消融目前在临床上广泛使用。最近,这种疗法仅产生有益效果的初步认识受到了挑战,这种有益效果仅限于治疗部位。先前的研究表明,消融治疗会引起不必要的全身副作用,对远处肿瘤形成产生根本性影响。这种表征不佳的过程包括改变的肿瘤微环境,其基于细胞因子和生长因子的产生以及残余肿瘤细胞的下游基因表达途径的调节。先前的研究表明,microRNA(miRs)-短的非编码RNA序列-参与癌症发生和发展的许多途径。促肿瘤发生miR的过表达(即,21和210)与高细胞增殖和肿瘤生长以及不良预后相关。最初的建议集中在miR和蛋白质之间的相互作用,这些蛋白质在肝脏RFA后局部和全身升高。这些蛋白质先前已由宿主机构鉴定,可能有助于肿瘤生长。其次,这些实验旨在特异性靶向miR 21和210治疗,这可能提供一种直接的方法来调节和减轻癌症进展。在此扩展中,我有兴趣将这些观察转化为使用临床相关药物的实验设置。姜黄素,这是已经用于治疗各种医疗条件,已被确定为以前作为一种肿瘤抑制剂。主办机构已经研究了在肝RFA后使用姜黄素作为辅助药物,显示通过减少促肿瘤发生miR 21和210,药物诱导的RFA后肿瘤生长减少。现在,我想在已建立的结直肠转移小鼠模型中研究这些观察结果,该模型更真实地反映了肝RFA背景下的临床情况。我渴望更好地了解消融后miR升高和抑制之间的关系,以及先前与消融后肿瘤发生相关的蛋白质。所提出的实验旨在通过确定包括STAT 3、IL-6、c-MET和Hsp 70在内的关键蛋白质,评估它们在调节网络中的作用,并允许开发特异性调节这些因子的疗法,来推进先前研究的发现。拟议的调查旨在减少员额-使用姜黄素作为临床相关药物,通过抑制miR 21和210来抑制RFA肿瘤生长,并最终改善受影响患者的治疗结果。

项目成果

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Dr. Lukas Salvermoser其他文献

Dr. Lukas Salvermoser的其他文献

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