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

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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.