Our laboratory is interested in mechanisms of regulation of gene expression in cancer, with a focus on the biology of transcription factors and microRNAs (miRs). Currently, our efforts are primarily directed as follows:
1) Regulation of expression of miR-21 in colon cancer
MiR-21 is an established “oncomiR" in a variety of adult malignancies. In colon cancer, miR-21 levels show progressive increase with disease stage and predict poorer prognosis. However, little is currently known about mechanisms behind the upregulation of miR-21 levels in more advanced / aggressive colon cancers. Like most microRNAs, miR-21 is transcribed as an RNA precursor (pri-miR-21) by RNA Polymerase II, and subsequently processed by the microprocessor complex and Dicer, to yield, respectively, pre-miR-21 and the mature miR-21. Using cell culture models, we are currently working to determine the relevant mechanisms that regulate miR-21 levels in colon cancer, with a focus on the role of growth factor signaling pathways and transcription factors.
2) Role of microRNAs in Ewing Sarcoma oncogenesis
Ewing Sarcoma is the second most common bone and soft tissue malignancy of adolescents and young adults, with relatively poor outcome. Ewing Sarcoma is driven by a unique class of oncogenic fusions, composed of the transcriptional activation domain of the EWS protein and the DNA-binding domain of an Ets transcription factor, most commonly Fli1. We have identified a number of microRNAs that fit a profile of mediators of EWS / Ets-driven oncogenesis in Ewing Sarcoma. Using cell culture and animal tumor models, we are currently working to determine: 1) which of these microRNAs modulate Ewing Sarcoma oncogenesis; 2) what are the relevant molecular pathways involved; 3) how is the expression of these microRNAs regulated; 4) what is the therapeutic potential of these microRNAs in Ewing Sarcoma.