Through 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, we have 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. First, we have previously performed studies which show that knock-down of specific anti-apoptosis molecules can successfully render a previously apoptosis-resistant lung cancer cell more susceptible to apoptosis induction and result in cancer cell death. Our goal to elucidate the mechanisms responsible for the differences in apoptosis expression in lung cancer sub-types have previously led us to identify a specific microRNA which is involved in the regulation of the translational expression of the most potent IAP (inhibitor of apoptosis). Furthermore, we have identified the putative binding site on the messenger RNA for this microRNA and have also determined the critical nucleic acid base(s) necessary for the microRNA-messenger RNA interaction. The actions of this particular microRNA can down-regulate the expression of IAP, therefore rendering the cancer cell more susceptible to cell-death induction by other pro-apoptosis agents. In pursuing this work, we have now identified a cytogenetic abnormality which is responsible for the decreased expression of the microRNA. In the next steps, we will continue this work by attempting to validate this new potential biomarker clinically. As well, we will try to determine a method for creating an assay for this new biomarker. Also, we have plans to determine in vivo, using small animal models, the activity of exogenous supplied microRNA to lung cancer tumors. Second, we will investigate other microRNAs which may be involved in lung cancer carcinogenesis and progression.
| 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 |
