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

利用射频消融(RFA)等技术，在图像引导下对肝脏进行微创局部热消融，目前已广泛应用于临床。最近，最初的理解，即这种疗法只产生有益的效果，仅限于治疗部位，这一点受到了挑战。以前的工作表明，消融治疗会引起不必要的全身副作用，这些副作用对远处肿瘤的形成有根本性的影响。这一特征不佳的过程包括肿瘤微环境的改变，其基础是细胞因子和生长因子的产生以及残余肿瘤细胞下游基因表达途径的调节。以前的研究表明，microRNAs(MiRs)是一种短的、非编码的RNA序列，参与了许多癌症发生和发展的途径。促进肿瘤发生的miRs(即21和210)在肿瘤细胞中的过度表达与高细胞增殖和肿瘤生长以及预后不良有关。最初的研究集中在miRs和蛋白质之间的相互作用，这些蛋白质在肝脏RFA后局部和系统地升高。这些蛋白质先前已被宿主机构鉴定，可能与肿瘤生长有关。其次，这些实验的目的是在治疗上针对miR21和210，这可能提供一种直接的方法来调节和减缓癌症的进展。在这一扩展中，我有兴趣将这些观察转化为使用临床相关药物的实验装置。姜黄素已被用于治疗各种疾病，此前已被确定为肿瘤抑制剂。主办机构已经研究了姜黄素作为肝脏RFA后的辅助药物的使用，显示药物通过减少促肿瘤形成的miR21和210而导致RFA后肿瘤生长的减少。现在，我想在一个已建立的结直肠转移小鼠模型中调查这些观察结果，该模型更真实地反映了肝脏RFA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，以及以前与消融后肿瘤发生有关的蛋白质。建议的实验旨在通过确定包括STAT3、IL-6、c-MET和Hsp70在内的关键蛋白，评估它们在调节网络中的作用，并允许开发专门调节这些因子的疗法来推进先前研究的结果。综上所述，建议的研究旨在通过使用姜黄素作为临床相关药物通过抑制miR21和210来减少RFA后肿瘤的生长，并最终改善受影响患者的治疗结果。

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.