ABSTRACT
Tumor cells use preexisting prosurvival signaling pathways to evade the damaging and cytotoxic effects of anticancer agents. Radiation therapy is a primary form of cytotoxic anticancer treatment, but agents that successfully modify the radiation response in vivo are lacking. MicroRNAs (miRNA) are global gene regulators that play critical roles in oncogenesis and have been found to regulate prosurvival pathways. However, there is little understanding of how cellular miRNA expression affects the response of a cancer to cytotoxic therapy and ultimately outcome. The let-7 family of miRNAs regulates expression of oncogenes, such as RAS, and is specifically down-regulated in many cancer subtypes. In fact, low levels of let-7 predict a poor outcome in lung cancer. Here, we report that the let-7 family of miRNAs is overrepresented in a class of miRNAs exhibiting altered expression in response to radiation. More strikingly, we also can create a radiosensitive state when the select let-7 family of miRNAs is overexpressed in vitro in lung cancer cells and in vivo in a Caenorhabditis elegans model of radiation-induced cell death, whereas decreasing their levels causes radioresistance. In C. elegans, we show that this is partly through control of the proto-oncogene homologue let-60/RAS and genes in the DNA damage response pathway. These findings are the first direct evidence that miRNAs can suppress resistance to anticancer cytotoxic therapy, a common feature of cancer cells, and suggest that miRNAs may be a viable tool to augment current cancer therapies.
Subject(s)
Lung Neoplasms/radiotherapy , MicroRNAs/biosynthesis , RNA, Messenger/antagonists & inhibitors , Radiation Tolerance/physiology , Animals , Caenorhabditis elegans/genetics , Caenorhabditis elegans/growth & development , Caenorhabditis elegans Proteins/biosynthesis , Caenorhabditis elegans Proteins/genetics , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , MicroRNAs/genetics , Proto-Oncogene Mas , RNA, Neoplasm/biosynthesis , RNA, Neoplasm/genetics , Reverse Transcriptase Polymerase Chain Reaction , Transfection , Tumor Cells, Cultured , ras Proteins/biosynthesis , ras Proteins/geneticsABSTRACT
A family of small, noncoding RNAs, known as microRNAs, has recently emerged as sequence-specific regulators of gene expression. Hundreds of microRNAs have been identified in almost all metazoans genomes, but they are only beginning to be classified by functional roles. Here, we review microRNAs that have been shown to play roles in two closely related processes, lifespan and metabolic regulation. Understanding the metabolic and lifespan regulatory roles of these novel gene regulators will undoubtedly further our understanding of the complex genetic networks that control lifespan and metabolism, and will also provide us with novel targets for the therapeutic intervention of metabolic and age-related diseases.
Subject(s)
Longevity , MicroRNAs , Alleles , Animals , Caenorhabditis elegans , Humans , Metabolism , Microarray Analysis , Models, BiologicalABSTRACT
The microRNA lin-4 and its target, the putative transcription factor lin-14, control the timing of larval development in Caenorhabditis elegans. Here, we report that lin-4 and lin-14 also regulate life span in the adult. Reducing the activity of lin-4 shortened life span and accelerated tissue aging, whereas overexpressing lin-4 or reducing the activity of lin-14 extended life span. Lifespan extension conferred by a reduction in lin-14 was dependent on the DAF-16 and HSF-1 transcription factors, suggesting that the lin-4-lin-14 pair affects life span through the insulin/insulin-like growth factor-1 pathway. This work reveals a role for microRNAs and developmental timing genes in life-span regulation.
