Abstract LB210: MicroRNA function is malleable and can be governed by target gene expression levels

Abstract

Abstract MicroRNAs are short, noncoding RNA molecules that reduce the expression of target genes by inhibiting messenger RNA translation and promoting messenger RNA degradation. They are highly dysregulated in cancer, with many microRNAs appearing to have potent oncogenic or tumor suppressive effects. As a result, there exists substantial interest in targeting microRNAs for cancer therapy. However, the literature is filled with conflicting accounts as to whether specific microRNAs are oncogenic or tumor suppressive, with many microRNAs appearing to exhibit entirely opposite functions when placed in different contexts. One explanation for this duality is that individual microRNAs can target tens to hundreds of different genes, many of which may possess opposing functions. Hence, it is likely that the expression levels of the target genes influence whether an individual microRNA will have a net oncogenic or net tumor suppressive effect. To examine this hypothesis, we developed a computational model of miR-125b's effect on the apoptosis pathway. This is an ideal system for examining the expression level hypothesis, as miR-125b is a microRNA that targets several closely interacting pro- and anti-apoptotic members of the pathway, which can be easily modeled as a system of differential equations. From the model, we elucidate a general trend that miR-125b is more pro-apoptotic when its anti-apoptotic targets are overexpressed and/or its pro-apoptotic targets are underexpressed, while it is more anti-apoptotic when its pro-apoptotic targets are overexpressed and/or its anti-apoptotic targets are underexpressed. To examine this experimentally, we switched miR-125b from being tumor suppressive to being oncogenic in cells by modifying the expression levels of one of miR-125b's anti-apoptotic targets. In addition, we observed that treating cells with anticancer drugs can also reverse miR-125b's status as a tumor suppressor. These results have important implications for the use of microRNAs as therapeutic targets in cancer. Citation Format: Alexander A. Svoronos, Stuart G. Campbell, Donald M. Engelman. MicroRNA function is malleable and can be governed by target gene expression levels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB210.