A selective Aurora-A 5′-UTR siRNA inhibits tumor growth and metastasis. (1st March 2020)

• Record Type: Journal Article
• Authors: Lai, Chien-Hsien; Chen, Ruo-Yu; Hsieh, Hsing-Pang; Tsai, Shaw-Jenq; Chang, Kung-Chao; Yen, Chia-Jui; Huang, Yu-Chuan; Liu, Yao-Wen; Lee, Jenq-Chang; Lai, Yi-Chien; Hung, Liang-Yi; Lin, Bo-Wen
• Is Part Of: Cancer letters. Volume 472(2020)
• Page Start: 97
• Page End: 107
• Publication Date: 2020-03-01
• Subjects: RNAi -- Locked nucleic acid -- Colorectal cancer -- Untranslated region; CRC colorectal cancer -- DMEM Dulbecco's Modified Eagle Medium -- IVIS in vivo imaging system -- LNA locked nucleic acid -- MEM Minimum Essential Medium -- NOD/SCID nonobese diabetic/severe combined immunodeficiency -- RISC RNA-induced silencing complex -- PARP1 poly (ADP-ribose) polymerase -- siRNA small interfering RNA -- UTR untranslated region; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.12.031
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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. Highlights: Aurora-A exon 2 is a promising treatment target for cancer therapy. A selective siRNA, siRNA-2, can translationally inhibit Aurora-A in cancer. SiRNA-2 only inhibits Aurora-A expression in cancer cells but not normal cells. Locked nucleic acid (LNA)-modified siRNA-2 shows an improved anti-cancer efficacy. LNA-siRNA-2 can inhibit the tumor growth and block liver and lung metastasis.