Non-coding RNAs in tumorigenesis

We are investigating the role of microRNAs (miRNAs) in cancer as well as other aspects of tumor development. MiRNAs are a class of small noncoding RNAs that post-transcriptionally regulate the expression of target mRNA transcripts. Many miRNAs target mRNAs involved in processes aberrant in tumorigenesis, such as proliferation, survival, and differentiation. While previous work has shown a global decrease of mature miRNA expression in human cancers, it is unclear whether this global repression of miRNAs reflects the undifferentiated state of tumors or causally contributes to the transformed phenotype. In mammals, miRNA processing-impaired cells formed tumors with accelerated kinetics. We are studying the let-7 miRNA family, proposed to function in tumor suppression, by targeting oncogenes, such as K-Ras. We found that let-7 functionally inhibits non-small cell tumor development (Kumar et al., 2008). In the absence of miRNA activity, embryonic stem cells have been shown to be impaired in their ability to differentiate properly. Since miRNA-mediated repression is dependent on the presence of Argonaute proteins, we are currently investigating the role of Argonaute in promoting tumor progression and metastasis. To explore microRNAs as potential therapeutic agents, we are testing conditional microRNA expression and nanoparticle-mediated microRNA mimic delivery in mouse models of lung cancer. Also, accumulating evidence indicates that long intergenic non-coding RNAs (lincRNAs) play key roles in diverse biological processes, including dosage compensation, imprinting, cell cycle control, apoptosis, and others. We are interested in examining the function and mechanism of action of lincRNAs that are transcriptionally regulated by the p53 tumor suppressor. Using genetic models, we are investigating the effects of lincRNA deficiency on the control of expression of p53 target genes and on the p53-dependent cellular response.

Non-coding RNAs in tumorigenesis

Single molecule RNA FISH detection of the p53-regulated, long intergenic non-coding RNA, lincRNA-p21 [red], DAPI [blue].