期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：28
页码：8650-8655
DOI：10.1073/pnas.1500886112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceNonsmall cell lung cancer (NSCLC) is one of the deadliest cancers in the world. Although a very small subset of NSCLC patients respond to TNF-related apoptosis-inducing ligand (TRAIL), resistance remains a major hindrance to successful treatment. miRNAs are small noncoding RNAs of [~]24 nt that negatively regulate gene expression. Here, we show that miR-148a is significantly down-regulated in cells with acquired TRAIL resistance. Furthermore, we have determined that miR-148a can sensitize cells to TRAIL and inhibit tumorigenesis by targeting matrix metalloproteinase 15 and Rho-associated kinase 1 protein expression. Thus, miR-148a could be a promising prognostic and therapeutic tool in NSCLC treatment. Nonsmall cell lung cancer (NSCLC) is one of the leading causes of death worldwide. TNF-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in malignant cells without inducing significant toxicity in normal cells. However, several carcinomas, including lung cancer, remain resistant to TRAIL. MicroRNAs (miRNAs) are small noncoding RNAs of [~]24 nt that block mRNA translation and/or negatively regulate its stability. They are often aberrantly expressed in cancer and have been implicated in increasing susceptibility or resistance to TRAIL-induced apoptosis by inhibiting key functional proteins. Here we show that miR-148a is down-regulated in cells with acquired TRAIL-resistance compared with TRAIL-sensitive cells. Enforced expression of miR-148a sensitized cells to TRAIL and reduced lung tumorigenesis in vitro and in vivo through the down-modulation of matrix metalloproteinase 15 (MMP15) and Rho-associated kinase 1 (ROCK1). These findings suggest that miR-148a acts as a tumor suppressor and might have therapeutic application in the treatment of NSCLC.
