Specific delivery of microRNA93 into HBV-replicating hepatocytes downregulates protein expression of liver cancer susceptible gene MICA
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Motoko Ohno1,*, Motoyuki Otsuka1,2,*, Takahiro Kishikawa1, Chikako Shibata1, Takeshi Yoshikawa1, Akemi Takata1, Ryosuke Muroyama3, Norie Kowatari3, Masaya Sato1, Naoya Kato3, Shun’ichi Kuroda4 and Kazuhiko Koike1
1 Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
2 Japan Science and Technology Agency, PRESTO, Kawaguchi, Saitama, Japan
3 Unit of Disease Control Genome Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
4 Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan
* These authors contributed equally to this work
Motoyuki Otsuka , email:
Keywords: Hepatitis; Bionanocapsules; Drug delivery; Primary hepatocyte
Received: June 13, 2014 Accepted: June 24, 2014 Published: June 26, 2014
Chronic hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC). To date, the lack of efficient in vitro systems supporting HBV infection and replication has been a major limitation of HBV research. Although primary human hepatocytes support the complete HBV life cycle, their limited availability and difficulties with gene transduction remain problematic. Here, we used human primary hepatocytes isolated from humanized chimeric uPA/SCID mice as efficient sources. These hepatocytes supported HBV replication in vitro. Based on analyses of mRNA and microRNA (miRNA) expression levels in HBV-infected hepatocytes, miRNA93 was significantly downregulated during HBV infection. MiRNA93 is critical for regulating the expression levels of MICA protein, which is a determinant for HBV-induced HCC susceptibility. Exogenous addition of miRNA93 in HBV-infected hepatocytes using bionanocapsules consisted of HBV envelope L proteins restored MICA protein expression levels in the supernatant. These results suggest that the rescued suppression of soluble MICA protein levels by miRNA93 targeted to HBV-infected hepatocytes using bionanocapsules may be useful for the prevention of HBV-induced HCC by altering deregulated miRNA93 expression.
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