Anti-miR-17 therapy delays tumorigenesis in MYC-driven hepatocellular carcinoma (HCC).
Anti-miR-17 therapy delays tumorigenesis in MYC-driven hepatocellular carcinoma (HCC).
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DOI：
10.18632/oncotarget.22342
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发表时间：
2018-01-19
期刊：
影响因子：
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通讯作者：
Felsher DW
中科院分区：
文献类型：
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作者：
Dhanasekaran R;Gabay-Ryan M;Baylot V;Lai I;Mosley A;Huang X;Zabludoff S;Li J;Kaimal V;Karmali P;Felsher DW
肝细胞癌（HCC）仍然是一个重大的临床挑战，治疗选择很少。MYC癌基因的基因组扩增和/或过表达是HCC中常见的分子事件，因此使其成为药物治疗的一个有吸引力的靶点。不幸的是，目前还没有针对MYC的直接药物治疗方法。作为一种替代策略，MYC调控的microrna可能是治疗阻断的下游靶点。MiR-17家族是一个受MYC转录调控的microRNA家族，在人类hcc中普遍过表达。在这项研究中，我们在MYC驱动的HCC条件转基因小鼠模型中系统递送了一种包裹抗mir -17寡核苷酸的新型脂质纳米颗粒（LNP）。在体内使用anti-miR-17治疗，而不使用对照抗mirna治疗，导致miR-17的直接靶点明显去抑制，细胞凋亡旺盛，增殖减少，并导致myc驱动的hcc的肿瘤发生延迟。全球基因表达谱揭示了miR-17靶基因的参与和MYC关键转录程序的抑制，包括细胞周期进展和增殖。因此，anti-miR-17是myc驱动的HCC的有效治疗方法。
Hepatocellular carcinoma (HCC) remains a significant clinical challenge with few therapeutic options. Genomic amplification and/or overexpression of the MYC oncogene is a common molecular event in HCC, thus making it an attractive target for drug therapy. Unfortunately, currently there are no direct drug therapies against MYC. As an alternative strategy, microRNAs regulated by MYC may be downstream targets for therapeutic blockade. MiR-17 family is a microRNA family transcriptionally regulated by MYC and it is commonly overexpressed in human HCCs. In this study, we performed systemic delivery of a novel lipid nanoparticle (LNP) encapsulating an anti-miR-17 oligonucleotide in a conditional transgenic mouse model of MYC driven HCC. Treatment with anti-miR-17 in vivo, but not with a control anti-miRNA, resulted in significant de-repression of direct targets of miR-17, robust apoptosis, decreased proliferation and led to delayed tumorigenesis in MYC-driven HCCs. Global gene expression profiling revealed engagement of miR-17 target genes and inhibition of key transcriptional programs of MYC, including cell cycle progression and proliferation. Hence, anti-miR-17 is an effective therapy for MYC-driven HCC.