Despite the therapeutic potential of nucleic acid drugs, their clinical application has been limited in part by a lack of appropriate delivery systems. Exosomes or microvesicles are small endosomally derived vesicles that are secreted by a variety of cell types and tissues. Here, we show that exosomes can efficiently deliver microRNA (miRNA) to epidermal growth factor receptor (EGFR)-expressing breast cancer cells. Targeting was achieved by engineering the donor cells to express the transmembrane domain of platelet-derived growth factor receptor fused to the GE11 peptide. Intravenously injected exosomes delivered let-7a miRNA to EGFR-expressing xenograft breast cancer tissue in RAG2(-/-) mice. Our results suggest that exosomes can be used therapeutically to target EGFR-expressing cancerous tissues with nucleic acid drugs.

MicroRNAs (miRNAs) belong to a class of endogenously expressed non-coding small RNAs that function primarily as gene regulators. Growing evidence suggests that miRNAs play a significant role in tumor development, making them potential biomarkers for cancer diagnosis and prognosis. The miR-17-92 cluster has emerged as an important locus, being highly overexpressed in several cancers in association with cancer development and progression. The miR-17-92 miRNA cluster generates a single polycistronic primary transcript that yields six mature miRNAs: miR-17, miR-18a, miR-19a, miR-20a, miR-19b, and miR-92a. In colon cancer development, the pathophysiologic roles of these transcripts and their targets are largely unknown. In the present study, we performed copy number analyses of the six miRNAs transcribed from the miR-17-92 cluster in colon tumor tissues. We determined that miR-92a was transcribed at higher levels than the other five miRNAs in both adenomas and carcinoma. In addition, miR-92a directly targeted the anti-apoptotic molecule BCL-2-interacting mediator of cell death (BIM) in colon cancer tissues. An anti-miR-92a antagomir induced apoptosis of colon cancer-derived cell lines. These data indicate that miR-92a plays a pivotal role in the development of colorectal carcinoma. (Cancer Sci 2011; 102: 2264-2271 M icroRNAs (miRNAs) belong to a class of endogenously expressed non-coding small RNAs of approximately 22 nucleotides. These small RNAs influence gene regulation by pairing with mRNAs of protein-encoding genes to repress their expression via decreased translational efficiency and ⁄ or mRNA levels.(1) A growing body of evidence suggests that dysregulation of miRNA expression contributes to a wide variety of human diseases, including cancer. Almost 50% of known miRNAs are located within chromosomal regions frequently amplified or deleted in human cancers. (2) Colorectal cancer (CRC) is the second most common cause of cancer deaths in the Western world.(3) A heterogeneous disease, CRC develops from an accumulation of multiple genetic and epigenetic alterations that change global gene expression profiles; it is this genetic progression that contributes to the diverse phenotypes of CRC. A key step in the progression to cancer is genomic instability, which occurs in approximately 5% of adenomas through either microsatellite instability (MSI) or chromosomal instability (CIN). In CRC, CIN induces the development of aneuploid tumors, which exhibit a non-random pattern of chromosomal alterations that frequently include gains at 8q, 13q, and 20q and losses of 8p, 15q, 17p, and 18q.(4) The miR-17-92 cluster, located at 13q, encodes six miRNAs processed from a common precursor transcript. A role for miR-17-92 in the pathogenesis of human cancers has been implicated by the high incidence of amplification in multiple neoplasms, including diffuse large B cell lymphoma (5) and small cell lung cancer.(6,7)Furthermore, miR-92a derived from this cluster is highly expressed in leukemia (8) and hepatocellular carcinoma tissues....

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Runx family proteins play indispensable roles in the development of various hematopoietic lineage cells. However, their function in NK cells is still uncertain. We found that NK cells and CD8 T cells dominantly express Runx3 protein, whereas NKT cells and CD4 T cells express Runx1. Reverse transcription-PCR analysis revealed that Runx3 expression is initiated at the NK precursor stage and is maintained along the course of NK cell differentiation. In order to examine their role in the earlier stage of NK cell development, we introduced Runx dominant-negative (Runx dn) form into Lin(-)c-kit(+)Sca-1(+) hematopoietic stem cells, which were applied to NK cell-inducing culture. Post-cultured cells showed a decreased expression of IL-2/IL-15 common receptor beta subunit (CD122), consistent with another finding that Runx binds to promoter region of CD122 gene. To examine the Runx function in the later developmental stage, we used transgenic mouse, in which Runx dn form is expressed in immature and mature NK cells. This mouse showed decreased expressions of NK maturation markers, such as Ly49 family, Mac-1 and CD43, whereas IFN-gamma production was greatly enhanced. These findings suggest that Runx proteins, especially Runx3, play multiple roles in NK cell differentiation.

Many types of cells release phospholipid membrane vesicles thought to play key roles in cell-cell communication, antigen presentation, and the spread of infectious agents. Extracellular vesicles (EVs) carry various proteins, messenger RNAs (mRNAs), and microRNAs (miRNAs), like a “message in a bottle” to cells in remote locations. The encapsulated molecules are protected from multiple types of degradative enzymes in body fluids, making EVs ideal for delivering drugs. This review presents an overview of the potential roles of EVs as natural drugs and novel drug-delivery systems.