Many Aurora-A inhibitors have been developed for cancer therapy; however, the specificity and safety of Aurora-A inhibitors remain uncertain. The Aurora-A mRNA yields nine different 5'-UTR isoforms, which result from mRNA alternative splicing. Interestingly, we found that the exon 2-containing Aurora-A mRNA isoforms are predominantly expressed in cancer cell lines as well as human colorectal cancer tissues, making the Aurora-A mRNA exon 2 a promising treatment target in Aurora-A-overexpressing cancers. In this study, a selective siRNA, siRNA-2, which targets Aurora-A mRNA exon 2, was designed to translationally inhibit the expression of Aurora-A in cancer cells but not normal cells; locked nucleic acid (LNA)-modified siRNA-2 showed improved efficacy in inhibiting Aurora-A mRNA translation and tumor growth. Xenograft animal models combined with noninvasion in vivo imaging system (IVIS) analysis further confirmed the anticancer effect of LNA-siRNA-2 with improved efficiency and safety and reduced side effects. Mice orthotopically injected with colorectal cancer cells, LNA-siRNA-2 treatment not only inhibited the tumor growth but also blocked liver and lung metastasis. The results of our study suggest that LNA-siRNA-2 has the potential to be a novel therapeutic agent for cancer treatment.

中文翻译：

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选择性Aurora-A 5'-UTR siRNA抑制肿瘤的生长和转移。

已经开发出许多用于癌症治疗的Aurora-A抑制剂。但是，Aurora-A抑制剂的特异性和安全性仍不确定。Aurora-A mRNA可产生9种不同的5'-UTR亚型，这是由mRNA选择性剪接产生的。有趣的是，我们发现含外显子2的Aurora-A mRNA外显子主要在癌细胞系和人结肠直肠癌组织中表达，使Aurora-A mRNA外显子2成为Aurora-A过表达癌症中有希望的治疗靶标。在这项研究中，针对Aurora-A mRNA外显子2的选择性siRNA siRNA-2被设计为在癌细胞而非正常细胞中翻译抑制Aurora-A的表达。锁定核酸（LNA）修饰的siRNA-2在抑制Aurora-A mRNA的翻译和肿瘤生长方面显示出更高的功效。异种移植动物模型与非侵入性体内成像系统（IVIS）分析相结合，进一步证实了LNA-siRNA-2的抗癌作用，具有更高的效率和安全性，并减少了副作用。LNA-siRNA-2治疗通过原位注射大肠癌细胞的小鼠，不仅抑制了肿瘤的生长，而且还阻断了肝和肺的转移。我们的研究结果表明，LNA-siRNA-2具有成为癌症治疗新药的潜力。