MicroRNA-1291 in Regulation of Xenobiotic Disposition and Cell Differentiation

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DESCRIPTION (provided by applicant): Understanding the molecular mechanisms in the control of xenobiotic disposition is critical for rational drug development and therapy. Although some mechanisms are known, much remains undefined. MicroRNAs (miRNAs) are a large group of recently identified, short, noncoding RNAs that govern target gene expression in cells. The PI's laboratory has demonstrated that several miRNAs (e.g., miR-27b, -328 and -519c) control posttranscriptional regulation of cytochrome P450 enzymes (e.g., CYP3A4) and ABC transporters (e.g., ABCG2), and consequently affect drug disposition. Furthermore, there is increasing evidence that some miRNAs are differentially expressed in human tumor and non-tumor tissues. Indeed, several aberrantly expressed miRNAs (e.g., miR-34a) have been identified as master regulators of cancer cellular processes. Very recently, the PI's group has revealed that a previously uncharacterized miRNA miR-1291 modulates intracellular doxorubicin accumulation and chemosensitivity via direct targeting of ABCC1. In addition, miR-1291 is significantly downregulated in human pancreatic ductal adenocarcinoma (PDAC) as well as pancreatic and breast cancer cell lines. Restoration of miR-1291 function inhibits tumorigenesis in vivo, which is associated with an induction of cell cycle arrest in vitro. Therefore, studies ar proposed to test the hypothesis that miR-1291 controls multiple cellular processes through the regulation of target genes, and miR-1291 may be utilized to treat cancers or improve the efficacy of anticancer drugs (e.g., doxorubicin). Aim 1 is to delineate the mechanistic functions of miR-1291 in the regulation of drug disposition and endobiotics homeostasis. Aim 2 is to define the roles and molecular mechanisms of miR-1291 in the control of cancer cell proliferation, invasion, and tumor progression processes. Aim 3 is to establish the effectiveness and safety profiles of miR-1291 therapeutics in clinically relevant animal models. The feasibility of the proposed research is supported by exciting preliminary findings obtained from patient samples as well as animal and human cell line models. Results are anticipated to establish the mechanistic roles of miR-1291 in the regulation of drug disposition and cell differentiation processes, and lay the basic foundation for the development of miR-1291-based therapy.