Yu Xiaolan, Cao Yong, Tang Li, Yang Yingcheng, Chen Feng, Xia Jiyi
Department of Obstetrics and Gynecology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, China.
Experimental Medicine Center, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
J Cell Biochem. 2018 Aug;119(8):6842-6856. doi: 10.1002/jcb.26881. Epub 2018 Apr 25.
Baicalein, a natural flavonoid, has fascinating anti-cancer properties in breast cancer. Long noncoding RNAs (lncRNAs), a class of transcripts with no protein-coding potential, also exhibit critical roles in breast cancer. However, the molecular mechanisms mediating the anti-cancer properties of baicalein and whether lncRNAs are involved in the anti-cancer effects are still unclear. In this study, we identified a novel isoform of lncRNA PAX8-AS1 (PAX8-AS1-N), which is activated by baicalein in a dose- and time-dependent manner. Functional assays showed that PAX8-AS1-N reduced cell viability, inhibited cell-cycle progression, and induced apoptosis of breast cancer cells in vitro. Depletion of PAX8-AS1-N promoted breast xenograft tumor growth in vivo. Furthermore, depletion of PAX8-AS1-N attenuated the suppressive roles of baicalein on cell viability, the apoptosis induced by baicalein, and also the suppressive roles of baicalein on tumor growth in vivo. Mechanistically, PAX8-AS1-N bound to miR-17-5p, and up-regulated miR-17-5p targets, such as PTEN, CDKN1A, and ZBTB4. In addition, PAX8-AS1-N was down-regulated in breast cancer and reduced expression of PAX8-AS1-N indicated poor survival of breast cancer patients. In conclusion, our results demonstrated that PAX8-AS1-N activation mediated the anti-cancer effects of baicalein via regulating miR-17-5p, and suggested that baicalein and enhancing PAX8-AS1-N would be potential therapeutic strategies against breast cancer.
黄芩素是一种天然黄酮类化合物，在乳腺癌中具有迷人的抗癌特性。长链非编码RNA（lncRNAs）是一类没有蛋白质编码潜力的转录本，在乳腺癌中也发挥着关键作用。然而，介导黄芩素抗癌特性的分子机制以及lncRNAs是否参与抗癌作用仍不清楚。在本研究中，我们鉴定了一种lncRNA PAX8-AS1的新型异构体（PAX8-AS1-N），它被黄芩素以剂量和时间依赖性方式激活。功能测定表明，PAX8-AS1-N降低了细胞活力，抑制了细胞周期进程，并在体外诱导了乳腺癌细胞凋亡。PAX8-AS1-N的缺失促进了体内乳腺异种移植肿瘤的生长。此外，PAX8-AS1-N的缺失减弱了黄芩素对细胞活力的抑制作用、黄芩素诱导的凋亡以及黄芩素对体内肿瘤生长的抑制作用。机制上，PAX8-AS1-N与miR-17-5p结合，并上调了miR-17-5p的靶标，如PTEN、CDKN1A和ZBTB4。此外，PAX8-AS1-N在乳腺癌中下调，PAX8-AS1-N表达降低表明乳腺癌患者生存率低。总之，我们的结果表明，PAX8-AS1-N的激活通过调节miR-17-5p介导了黄芩素的抗癌作用，并表明黄芩素和增强PAX8-AS1-N将是对抗乳腺癌的潜在治疗策略。
