Restoration of p53 Function in Malignant Pleural Mesothelioma by microRNA

Authors

• A Singh
• N Bhattacharyya
• A Srivastava
• L Zhang
• CD Hoang

Abstract

A distinct feature of mesothelioma (MPM) is non-mutated, p53wt transcription factor (TF) which is frequently inactivated by deletion of p14ARF. Mouse double minute 2 homolog (MDM2) downstream to p14ARF is the predominant negative regulator of p53. Recently, p53-responsive miRNAs are recognized to play an important role in regulating the p53 and MDM2 equilibrium. miRNA-TF signaling networks are recurring control mechanisms in the transcriptome. We posit that identification of miRNA-driven positive feedback loops, which are functional epigenetic switches, could overcome common bypass mechanisms in MPM and activate p53. Using a novel meta-analysis algorithm, we assessed public datasets to identify differentially expressed miRNAs in MPM. We observed downregulation of miR-215 in MPM. Interestingly, miR-215 directly targets MDM2 and could induce a MDM2-p53 positive feedback loop. However, miR-215 action in MPM is unknown. So, we analyzed transcript abundance of miR-215 and MDM2 in MPM tissues by qPCR. miR-215 was significantly downregulated in MPM tissues compared to normal pleura, while MDM2 was inversely overexpressed. Ectopic re-expression of miR-215 in p53wt MPM cell lines with low endogenous miR-215 inhibited MDM2 expression. Concurrently, p53 was activated (p53-luciferase reporter assay). miR-215 stunted tumorigenic properties of MPM cells, including decreased proliferation, clonogenicity, anchorage-independent cell growth and 3D sphere formation. Significantly, miR-215 overexpression induced apoptosis in MPM cell lines. Thus, our results demonstrate that miR-215 restoration can effectively activate p53 in MPM and suggest a potential therapeutic strategy for MPM.

Scientific Focus Area: Cancer Biology

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