microRNAs

We have been investigating the role of microRNAs (miRNAs) in cancer as well as other aspects of tumor development. MicroRNAs (miRNAs) are a recently discovered 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. We have demonstrated that impaired microRNA processing enhances cellular transformation and tumorigenesis (Kumar et al., 2007). Cancer cells expressing short hairpin RNAs (shRNAs) targeting three different components of the miRNA processing machinery showed a substantial decrease in steady-state miRNA levels and a more pronounced transformed phenotype. In animals, miRNA processing-impaired cells formed tumors with accelerated kinetics. We went on to study the let-7 miRNA family, which has been proposed to function in tumor suppression (reduced expression of let-7 family members is common in non-small cell lung cancer). We found that let-7 functionally inhibits non-small cell tumor development (Kumar et al., 2008). We are also studying miR-17~92, miR-106b~25, and miR-106a~363, a family of highly conserved miRNA clusters. Amplification and overexpression of miR-17 92 is observed in human cancers, and its oncogenic properties have been confirmed in a mouse model of B cell lymphoma. We have knocked out the miR-17~92 clusters in the mouse, revealing essential and overlapping functions (Ventura et al., 2008). Mice deficient for miR-17 92 die shortly after birth with lung hypoplasia and a ventricular septal defect. Absence of miR-17 92 also leads to increased levels of the proapoptotic protein Bim and inhibits B cell development at the pro-B to pre-B transition. These results provide key insights into the physiologic functions of this family of microRNAs and suggest a link between the oncogenic properties of miR-17 92 and its functions during B lymphopoiesis and lung development.