Shi Yang, Liu Can, Liu Xin, Tang Dean G, Wang Junchen
Department of Pathology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; Department of Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Science Park, Smithville, Texas, United States of America; Cancer Stem Cell Institute, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Science Park, Smithville, Texas, United States of America.
PLoS One. 2014 Mar 4;9(3):e90022. doi: 10.1371/journal.pone.0090022. eCollection 2014.
Lung cancer is among the most lethal malignancies with a high metastasis and recurrence rate, which is probably due to the existence of lung cancer stem cells (CSCs). CSCs in many tumors including non-small cell lung cancer (NSCLC) have been identified using adhesion molecular CD44, either individually or in combination with other marker(s). MicroRNAs (miRNAs) regulate both normal stem cells and CSCs and dysregulation of miRNAs has been implicated in tumorigenesis. Recently, miR-34a was found to be downregulated in NSCLC cells but the biological functions of miR-34a in regulating NSCLC cell behavior have not been extensively studied. Here we show that transfection of synthetic miR-34a, but not the negative control (NC) miRNA oligonucleotides (oligos) in three NSCLC cell lines, i.e., A549, H460, and H1299, inhibited their holoclone formation, clonogenic expansion, and tumor regeneration in vivo. Furthermore, the lentiviral vector-mediated overexpression of miR-34a in purified CD44hi H460 cells also inhibited tumor outgrowth. In contrast, expression of miR-34a antagomirs (i.e., antisense oligos) in the CD44lo H460 cells promoted tumor development. Our study shows that miR-34a is a negative regulator of the tumorigenic properties of NSCLC cells and CD44hi lung CSCs, and establishes a strong rationale for developing miR-34a as a novel therapeutic agent against NSCLC.
肺癌是最致命的恶性肿瘤之一，具有高转移和复发率，这可能归因于肺癌干细胞（CSCs）的存在。包括非小细胞肺癌（NSCLC）在内的许多肿瘤中的CSCs已通过黏附分子CD44单独或与其他标志物联合鉴定出来。微小RNA（miRNAs）调节正常干细胞和CSCs，miRNAs失调与肿瘤发生有关。最近，发现miR-34a在NSCLC细胞中表达下调，但miR-34a在调节NSCLC细胞行为中的生物学功能尚未得到广泛研究。在这里，我们表明，在三种NSCLC细胞系即A549、H460和H1299中转染合成的miR-34a，而不是阴性对照（NC）微小RNA寡核苷酸（oligos），可抑制它们的全克隆形成、克隆性扩增和体内肿瘤再生。此外，慢病毒载体介导的miR-34a在纯化的CD44hi H460细胞中的过表达也抑制了肿瘤生长。相反，在CD44lo H460细胞中表达miR-34a拮抗剂（即反义oligos）促进了肿瘤发展。我们的研究表明，miR-34a是NSCLC细胞和CD44hi肺CSCs致瘤特性的负调节因子，并为将miR-34a开发为一种新型抗NSCLC治疗药物奠定了坚实的理论基础。
