Baculovirus-Mediated miRNA Regulation to Suppress Hepatocellular Carcinoma Tumorigenicity and Metastasis
Baculovirus-Mediated miRNA Regulation to Suppress Hepatocellular Carcinoma Tumorigenicity and Metastasis
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DOI：
10.1038/mt.2014.126
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发表时间：
2015-01-01
影响因子：
12.4
通讯作者：
Hu, Yu-Chen
中科院分区：
文献类型：
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作者：
Chen, Chiu-Ling;Wu, Jaw-Ching;Hu, Yu-Chen
MicroRNA 122 （miR-122）是肝细胞癌（HCC）的肿瘤抑制因子，但在HCC细胞中表达较低。MiR-151在HCC细胞中异常过表达并促进HCC转移，但其在HCC致瘤性中的作用尚不清楚。为了对抗HCC的致瘤性/转移，我们开发了基于睡美人（SB）的混合杆状病毒（BV）载体，表达(i) miR-122前体（pre-miR-122）， （ii） miR-151海绵，或（iii） pre-miR-122和miR-151海绵。用表达miR-122前体的BV转导侵袭性HCC细胞（Mahlavu），在6周内显著提高miR-122水平，抑制下游效应物（如ADAM10和Bcl-w）的水平，体外增殖、不依赖锚定生长、运动和迁移/侵袭。瘤内注射pre- mir -122表达的BV可减弱HCC的生长/转移。表达BV的miR-151海绵在6周内降低miR-151水平，增强RhoGDIA表达，抑制rhogtpase，以及Mahlavu细胞的运动和迁移/侵袭。瘤内注射表达miR-151海绵的BV不仅能抑制HCC转移，还能抑制体内细胞增殖、MMP表达和肿瘤生长。BV共表达pre-miR-122和miR-151海绵也同时增强了miR-122的表达并抑制了miR-151，尽管缺乏协同作用，但仍具有抗肿瘤/抗转移作用。这些数据暗示了SB-based杂交BV在持续调节miRNA和抑制HCC致瘤性/转移方面的潜力。
MicroRNA 122 (miR-122) is a tumor suppressor for hepatocellular carcinoma (HCC) but is lowly expressed in HCC cells. MiR-151 is aberrantly overexpressed in HCC cells and promotes HCC metastasis yet its roles on HCC tumorigenicity are unknown. To combat HCC tumorigenicity/ metastasis, we developed Sleeping Beauty (SB)-based hybrid baculovirus (BV) vectors that expressed (i) miR-122 precursors (pre-miR-122), (ii) miR-151 sponges, or (iii) pre-miR-122 and miR-151 sponges. Transduction of aggressive HCC cells (Mahlavu) with the pre-miR-122-expressing BV tremendously enhanced miR-122 levels for >6 weeks, suppressed the levels of downstream effectors (e.g., ADAM10 and Bcl-w), proliferation, anchorage-independent growth, motility and migration/invasion in vitro. Intratumoral injection of the pre-miR-122-expressing BV attenuated the HCC growth/metastasis. The miR-151 sponges-expressing BV diminished the miR-151 levels for 6 weeks, enhanced RhoGDIA expression, suppressed RhoGTPases, as well as motility and migration/invasion of Mahlavu cells. Intratumoral injection of the miR-151 sponge-expressing BV impeded not only HCC metastasis but also cell proliferation, MMP expression and tumor growth in vivo. The BV co-expressing pre-miR-122 and miR-151 sponges also simultaneously enhanced miR-122 expression and inhibited miR-151, and conferred antitumor/ anti-metastasis effects albeit lack of synergism. These data implicate the potentials of the SB-based hybrid BV for persistently modulating miRNA and suppressing HCC tumorigenicity/metastasis.