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

Abstract

Hepatocellular carcinoma (HCC) is a common and deadly cancer. Most cases of HCC arise in a cirrhotic/fibrotic liver, indicating that environment may play 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 and cancer cells. Moreover, extracellular vesicles (EVs), or exosomes, have been identified as an important arm of this intercellular communication platform. Finally, these studies have shown that EVs can carry microRNA (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 demonstrated that stellate cell-derived EVs 1) can be loaded with an miR species of choice (miR-335-5p); 2) are taken up by HCC cells in vitro and more importantly in vivo; 3) can supply the miR-335-5p cargo to recipient HCC cells in vitro as well as in vivo; and 4) inhibit HCC cell proliferation and invasion in vitro as well as induce HCC tumor shrinkage in vivo. Finally, we identified messenger RNA targets for miR-335 that are down-regulated after treatment with EV-miR-335-5p. This study informs potential therapeutic strategies in HCC, whereby stellate cell-derived EVs are loaded with therapeutic nucleic acids and delivered in vivo. (Hepatology 2018;67:940-954).

The significance of exosomes in the development and treatment of hepatocellular carcinoma

“…The function of the substance in HCC exosomes Long noncoding ribonucleic acid expression and promoting sensitivity of cancer cells to chemotherapy[117].Fang Wang and other researchers have found that stellate cell-derived EVs could load miR-335-5p. What makes us exhilarated is that miR-335-5 could be introduced into HCC cells to inhibit tumor growth and metastasis, which thereby provides a new treatment strategy for liver cancer[118]. Another research by Kenji Takahashiet al have found that during the process of mediating chemotherapeutic stress response, RNAi-mediated knockdown of EVs (exosomes) lncRNAs could reduce the function and progression of tumor cells in HCC, which promotes the treatment of HCC[119].…”

Exosome-based liquid biopsy in the management of hepatocellular carcinoma

“…Furthermore, exosomes isolated from human hepatic stellate (LX2) cells were loaded with miR-335-5p and these exosomes were taken up by HCC cells in vitro and in vivo. This preclinical study showed an inhibition of HCC cell proliferation and invasion in vitro and also demonstrated HCC tumour shrinkage in vivo upon uptake of these engineered exosomes [50] . There are several advantages of using exosome-based therapy, as exosomes show low immunogenicity, toxicity and are stable in tissue and in circulation.…”

The Crosstalk between Tumor Cells and the Microenvironment in Hepatocellular Carcinoma: The Role of Exosomal microRNAs and Their Clinical Implications

“…In addition, the overexpression of miR-320a in CAFs has been reported as an effective method to produce miR-320a-enriched exosomes that can transfer this miRNA to HCC cells, thus suppressing proliferation, migration, and metastasis when binding to its direct target, PBX3 [66]. The same approach was used to down-regulate the expression of several key genes that induce proliferation and invasion of HCC cells by taking advantage of HSC-derived exosomes loaded with tumor suppressor miR-335-5p [106]. Another study provided a novel approach to pack miR-26a into exosomes to selectively target HCC cells through the scavenger receptor, resulting in the inhibition of cell migration and proliferation [107].…”