Exosome - miR-335 as a novel therapeutic strategy in hepatocellular carcinoma

Abstract

Hepatocellular Cancer (HCC) is a common and deadly cancer. Most cases of HCC arise in a cirrhotic/fibrotic liver, raising the possibility that the environment plays a paramount role in cancer genesis. Previous studies from our group and others have shown that, in desmoplastic cancers, there is a rich intercellular communication between activated, cancer-associated fibroblasts (CAF) and cancer cells. Moreover, Extracellular Vesicles (EVs), or exosomes, were identified asan important arm of this intercellular communication platform. Last, these studies have shown that EVs can carry miR species in vivo and deliver them to desmoplastic cancers. The precise role played by activated liver fibroblasts/stellate cells in HCC development is insufficiently known. Based on previous studies, it appears plausible that activated fibroblasts produce signals carried by EVs that promote HCC genesis. In the current study, we first hypothesized and then showed that stellate cell-derived EVs 1) can be loaded with a miR species of choice (miR-335-5p); 2) are uptaken by HCC cells in vitro and more importantly in vivo; 3) can supplythe miR-335-5p cargo to recipient HCC cells in vitro as well as in vivo; and finally that they 4) inhibit HCC cell proliferation and invasion in vitroas well as induce HCC tumor shrinkage in vivo. Last, we identified mRNA targets for miR-335 that are down-regulated following treatments with EV-miR-335-5p. This study informs novel therapeutic strategies in HCC, whereby stellate cell-derived EVs are loaded with therapeutic nucleic acids and delivered in vivo. This article is protected by copyright. All rights reserved.

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