Yamashita Ryo, Sato Mitsuo, Kakumu Tomohiko, Hase Tetsunari, Yogo Naoyuki, Maruyama Eiichi, Sekido Yoshitaka, Kondo Masashi, Hasegawa Yoshinori
Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
Cancer Med. 2015 Apr;4(4):551-64. doi: 10.1002/cam4.412. Epub 2015 Jan 30.
Both pro- and anti-oncogenic roles of miR-221 and miR-222 microRNAs are reported in several types of human cancers. A previous study suggested their oncogenic role in invasiveness in lung cancer, albeit only one cell line (H460) was used. To further evaluate involvement of miR-221 and miR-222 in lung cancer, we investigated the effects of miR-221 and miR-222 overexpression on six lung cancer cell lines, including H460, as well as one immortalized normal human bronchial epithelial cell line, HBEC4. miR-221 and miR-222 induced epithelial-to-mesenchymal transition (EMT)-like changes in a minority of HBEC4 cells but, unexpectedly, both the microRNAs rather suppressed their invasiveness. Consistent with the prior report, miR-221 and miR-222 promoted growth in H460; however, miR-221 suppressed growth in four other cell lines with no effects in one, and miR-222 suppressed growth in three cell lines but promoted growth in two. These are the first results to show tumor-suppressive effects of miR-221 and miR-222 in lung cancer cells, and we focused on clarifying the mechanisms. Cell cycle and apoptosis analyses revealed that growth suppression by miR-221 and miR-222 occurred through intra-S-phase arrest and/or apoptosis. Finally, lung cancer cell lines transfected with miR-221 or miR-222 became more sensitive to the S-phase targeting drugs, possibly due to an increased S-phase population. In conclusion, our data are the first to show tumor-suppressive effects of miR-221 and miR-222 on lung cancer, warranting testing their potential as therapeutics for the disease.
在多种人类癌症中，均有关于微小RNA miR - 221和miR - 222促癌和抑癌作用的报道。先前的一项研究表明它们在肺癌侵袭中发挥致癌作用，尽管该研究仅使用了一种细胞系（H460）。为了进一步评估miR - 221和miR - 222在肺癌中的作用，我们研究了miR - 221和miR - 222过表达对包括H460在内的六种肺癌细胞系以及一种永生化正常人支气管上皮细胞系HBEC4的影响。miR - 221和miR - 222在少数HBEC4细胞中诱导了上皮 - 间质转化（EMT）样变化，但出乎意料的是，这两种微小RNA均抑制了它们的侵袭性。与先前的报道一致，miR - 221和miR - 222促进了H460细胞的生长；然而，miR - 221抑制了其他四种细胞系的生长，对一种细胞系无影响，miR - 222抑制了三种细胞系的生长，但促进了两种细胞系的生长。这些是首次表明miR - 221和miR - 222在肺癌细胞中具有肿瘤抑制作用的结果，我们致力于阐明其机制。细胞周期和凋亡分析表明，miR - 221和miR - 222通过S期内停滞和/或凋亡来抑制生长。最后，转染了miR - 221或miR - 222的肺癌细胞系对S期靶向药物变得更加敏感，这可能是由于S期细胞群体增加所致。总之，我们的数据首次表明miR - 221和miR - 222对肺癌具有肿瘤抑制作用，这使得有必要测试它们作为该疾病治疗药物的潜力。
