Impact of Circulating Exosomal Mir-92b on Tumor Development and Immunoediting from Immune Surveillance to Immune Escape in Hepatocellular Carcinoma

One of potential mechanisms for HCC recurrence is the existence of cellular and non-cellular factors responsible for HCC development and recurrence in the peripheral blood. Recently, tumor-derived microvesicles are highlighted for diagnostic and therapeutic targets. One of tumor-derived microvesicles, exosomes are cell-derived small vesicles (40-100 nm diameter), which carry proteins, mRNAs and non-coding RNAs such as microRNAs. In our pilot study, we have confirmed the impact of circulating exosomes on HCC development in a rat model of HCC. Microarray revealed unique microRNA profile in HCC serum exosomes and miR-92b was selected as one of highly expressing microRNAs. There are several studies regarding the association between miR-92b and tumor development. To further explore its target mRNA and functions, we used three different prediction tools, miRDB, TargetScan and microRNA.org, to select potential target mRNA, and identified CD69 as one of potential candidates. To the best of our knowledge, there is no definitive study to demonstrate the impact of miR-92b on CD69. CD69 plays a crucial role in NK cell functions including cytotoxicity. In addition, activated macrophages also express CD69, suggesting the potential impacts of circulating exosomal miR-92b on NK cell and macrophage functions. We therefore speculate that HCC-derived circulating exosomal miR-92b may edit host immune system by suppression of CD69 expression, NK cell and macrophage functions, resulting in the creation of favorable tumor microenvironment for immune escape. In this project, we will explore the effect of exosomes and miR-92b on tumor cell biology and on immune surveillance of tumors. We will finally explore the therapeutic potential of miR-92b-targeted therapy in HCC. We expect to gather solid evidences to demonstrate the mechanisms of tumor development and immunoediting from immune surveillance to immune escape by circulating exosomal miR-92b in HCC.

Project ID:PC10608-1817
External Project ID:MOST106-2320-B182-033