Inhibition of miR-10b treats metastatic breast cancer by targeting stem cell-like properties

Despite advances in breast cancer screening and treatment, prognosis for metastatic disease remains dismal at 30% five-year survival. This is due, in large, to the failure of current therapeutics to target properties unique to metastatic cells. One of the drivers of metastasis is miR-10b, a small noncoding RNA implicated in cancer cell invasion, migration, viability, and proliferation. We have developed a nanodrug termed MN-anti-miR10b that delivers anti-miR10b antisense oligomers to cancer cells. In mouse models of metastatic triple-negative breast cancer, MN-anti-miR10b has been shown to prevent onset of metastasis and eliminate existing metastasis in combination with chemotherapy even after treatment has been stopped. Recent studies have implicated miR-10b in conferring stem cell-like properties onto cancer cells, such as chemoresistance. In this study, we show transcriptional evidence that inhibition of miR-10b with MN-anti-miR10b activates developmental processes in cancer cells and that stem-like cancer cells have increased miR-10b expression. We then demonstrate that treatment of breast cancer cells with MN-anti-miR10b reduces their stemness confirming that these properties make metastatic cells susceptible to the nanodrug actions. Collectively, these findings indicate that inhibition of miR-10b functions to impair breast cancer cell stemness, positioning MN-anti-miR10b as an effective treatment option for stem-like breast cancer subtypes. To identify therapeutic mechanisms of mir-10b inhibition, MDA-MB-231 and 4T1 breast cancer cells were treated with MN-anti-miR10b (anti-miR-10b nanodrug), magnetic nanoparticle (MN; vehicle), or left them untreated for 48 hours. We then performed differential gene expression analysis of data from RNA-seq analysis and functional enrichment analyses on significantly upregulated and downregulated genes.

尽管乳腺癌筛查与治疗技术已取得长足进展，但转移性乳腺癌患者的五年生存率仍仅为30%，预后极差。这在很大程度上缘于当前疗法难以靶向转移性癌细胞所特有的生物学特性。转移过程的关键驱动因素之一是miR-10b，这是一种小型非编码RNA（small noncoding RNA），已被证实与癌细胞侵袭、迁移、存活及增殖密切相关。我们研发了一款名为MN-anti-miR10b的纳米药物，可将抗miR-10b反义寡核苷酸递送至癌细胞内。在转移性三阴性乳腺癌小鼠模型中，研究证实MN-anti-miR10b联合化疗不仅可预防转移发生，甚至可在停药后清除已形成的转移灶。近期研究表明，miR-10b可赋予癌细胞干细胞样特性，例如化疗耐药性。本研究通过转录层面的证据证实，利用MN-anti-miR10b抑制miR-10b可激活癌细胞内的发育相关进程，且干细胞样癌细胞的miR-10b表达水平更高。随后我们证实，采用MN-anti-miR10b处理乳腺癌细胞可降低其干细胞干性，由此确认这类特性正是转移性癌细胞对该纳米药物作用敏感的原因。综上，上述研究结果表明，抑制miR-10b可削弱乳腺癌细胞的干细胞干性，这使得MN-anti-miR10b成为干细胞样乳腺癌亚型的有效治疗选择。为明确miR-10b抑制的治疗机制，我们将MDA-MB-231与4T1乳腺癌细胞分别用MN-anti-miR10b（抗miR-10b纳米药物）、磁性纳米颗粒（magnetic nanoparticle，MN；载体）处理，同时设置未处理对照组，处理时长均为48小时。随后我们对RNA测序所得数据进行差异基因表达分析，并对显著上调及下调的基因开展功能富集分析。