Targeted Regression of Hepatocellular Carcinoma by Cancer-Specific RNA Replacement through MicroRNA Regulation.
Targeted Regression of Hepatocellular Carcinoma by Cancer-Specific RNA Replacement through MicroRNA Regulation.
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DOI：
10.1038/srep12315
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发表时间：
2015-07-20
影响因子：
4.6
通讯作者：
Lee SW
中科院分区：
文献类型：
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作者：
Kim J;Won R;Ban G;Ju MH;Cho KS;Young Han S;Jeong JS;Lee SW
肝细胞癌（HCC）具有高病死率和有限的治疗选择，副作用和低疗效。在这里，我们提出了一种基于癌症特异性转录后靶向的新的抗HCC方法。为此，开发了来自四膜虫I组内含子的反式剪接核酶，其可以通过HCC特异性替换端粒酶逆转录酶（TERT）RNA来特异性诱导治疗基因活性。为了避免由于再生肝组织中的TERT表达而引起的副作用，通过并入肝细胞选择性microRNA-122 a（miR-122 a）的互补结合位点来构建肝脏特异性microRNA调节的核酶，所述microRNA-122 a在HCC中下调。在原位植入HCC的小鼠模型中评估体内核酶活性。在多灶性HCC的异种移植和同基因原位小鼠模型中，全身施用编码所开发的核酶的腺病毒引起有效的抗癌作用和最小的肝毒性，其中miR-122 a调节核酶表达。值得注意的是，核酶诱导局部和全身抗肿瘤免疫，从而完全抑制同基因小鼠中的继发性肿瘤攻击。癌症特异性反式剪接核酶系统介导组织特异性microRNA调节的RNA替换，为HCC治疗提供了临床相关的，安全的和有效的策略。
Hepatocellular carcinoma (HCC) has a high fatality rate and limited therapeutic options with side effects and low efficacy. Here, we proposed a new anti-HCC approach based on cancer-specific post-transcriptional targeting. To this end, trans-splicing ribozymes from Tetrahymena group I intron were developed, which can specifically induce therapeutic gene activity through HCC-specific replacement of telomerase reverse transcriptase (TERT) RNA. To circumvent side effects due to TERT expression in regenerating liver tissue, liver-specific microRNA-regulated ribozymes were constructed by incorporating complementary binding sites for the hepatocyte-selective microRNA-122a (miR-122a), which is down-regulated in HCC. The ribozyme activity in vivo was assessed in mouse models orthotopically implanted with HCC. Systemic administration of adenovirus encoding the developed ribozymes caused efficient anti-cancer effect and the least hepatotoxicity with regulation of ribozyme expression by miR-122a in both xenografted and syngeneic orthotopic murine model of multifocal HCC. Of note, the ribozyme induced local and systemic antitumor immunity, thereby completely suppressing secondary tumor challenge in the syngeneic mouse. The cancer specific trans-splicing ribozyme system, which mediates tissue-specific microRNA-regulated RNA replacement, provides a clinically relevant, safe, and efficient strategy for HCC treatment.