Previously, we conducted systematic profiling expression of apoptosis pathway proteins with respect to histological sub-types of non-small cell lung cancer in human lung cancer cell lines and identified specific patterns of defects in the expression and regulation of apoptosis pathways in lung cancer cells. Also, these apoptosis pathway differences between lung cancer cell types may correlate with specific intra-cellular road-blocks that are critical to overcome in order to cause cell death in the lung cancer cell. In past studies we observed that attenuated expression of specific anti-apoptosis molecules can successfully render an apoptosis-resistant lung cancer cell more susceptible to apoptosis induction, resulting in re-activated cancer cell death. Our goal to elucidate the mechanisms responsible for the differences in apoptosis expression in lung cancer sub-types has led us to identify specific microRNAs which are involved in the regulation of the translational expression of key apoptosis members. This work has led to our laboratory's novel discovery that human microRNA-24 directly regulates the expression of XIAP (the most potent member of the human inhibitors of apoptosis proteins) in cancer and normal cells. In the publication describing this work (Xie et al. Oncogene 2012), we characterized the binding site on the messenger RNA critical for the microRNA-messenger RNA interaction. The actions of microRNA-24 can down-regulate the expression of XIAP, therefore rendering the cancer cell more susceptible to cell-death induction by other pro-apoptosis agents. In pursuing this work, we identified a cytogenetic abnormality, corresponding to the loss of the miR-24 locus on human chromosome 19, which is responsible for the decreased expression of the microRNA in the affected cancer cells. Furthermore, we found that miR-24 overexpression in cancer cells of multiple types lead to restored sensitivity to apoptosis induction and consequent reactivated apoptotic cell death. From this related work, we have identified another microRNA which significantly inhibits cancer cell proliferation. How this specific microRNA exerts its effects against the cancer cell is the focus of continuing work in the lab. Along with this work, we are actively working to identify other microRNA regulators of the apoptosis pathway in order to understand the detailed and global roles that microRNAs participate in the normal and aberrant functioning of cell death pathways. The knowledge gained from this project is directly integrated into the novel therapeutics project in the laboratory.
|Xie, Y; Tobin, L A; Camps, J et al. (2013) MicroRNA-24 regulates XIAP to reduce the apoptosis threshold in cancer cells. Oncogene 32:2442-51|