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The Pluripotency Factor Musashi-2 Is a Novel Target for Lung Cancer Therapy

ABSTRACT: Previously we reported that mithramycin represses multiple pathways critical for stem cell signaling and pluripotency in lung cancer cells. This phenomenon coincided with decreased side population fraction and dramatic dose-dependent growth arrest of lung cancer cells in vitro and in vivo. In the present study, microarray, quantitative reverse transcriptase polymerase chain reaction and immunoblot experiments were performed to further examine the effects of mithramycin on stem cell gene expression in lung cancer cells. This analysis revealed that mithramycin significantly inhibited expression of musashi-2 (MSI2), which encodes a RNA binding protein that mediates self-renewal and pluripotency in normal stem cells and has been implicated in mediating aggressive phenotype of a variety of human malignancies. MSI2 expression levels were significantly increased in non–small cell lung cancer lines and were even more dramatically elevated in small-cell lung cancer lines relative to cultured normal human respiratory epithelial cells (small airway epithelial cells / normal human bronchial epithelia / human bronchial epithelial cells; P?

SUBMITTER: Zhang M

PROVIDER: S-EPMC5946505 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Project description:Aberrant gene expression that drives human cancer can arise from epigenetic dysregulation. Although much attention has focused on altered activity of transcription factors and chromatin-modulating proteins, proteins that act posttranscriptionally can potently affect expression of oncogenic signaling proteins. The RNA-binding proteins (RBP) Musashi-1 (MSI1) and Musashi-2 (MSI2) are emerging as regulators of multiple critical biological processes relevant to cancer initiation, progression, and drug resistance. Following identification of Musashi as a regulator of progenitor cell identity in Drosophila, the human Musashi proteins were initially linked to control of maintenance of hematopoietic stem cells, then stem cell compartments for additional cell types. More recently, the Musashi proteins were found to be overexpressed and prognostic of outcome in numerous cancer types, including colorectal, lung, and pancreatic cancers; glioblastoma; and several leukemias. MSI1 and MSI2 bind and regulate the mRNA stability and translation of proteins operating in essential oncogenic signaling pathways, including NUMB/Notch, PTEN/mTOR, TGFβ/SMAD3, MYC, cMET, and others. On the basis of these activities, MSI proteins maintain cancer stem cell populations and regulate cancer invasion, metastasis, and development of more aggressive cancer phenotypes, including drug resistance. Although RBPs are viewed as difficult therapeutic targets, initial efforts to develop MSI-specific inhibitors are promising, and RNA interference-based approaches to inhibiting these proteins have had promising outcomes in preclinical studies. In the interim, understanding the function of these translational regulators may yield insight into the relationship between mRNA expression and protein expression in tumors, guiding tumor-profiling analysis. This review provides a current overview of Musashi as a cancer driver and novel therapeutic target. Clin Cancer Res; 23(9); 2143-53. ©2017 AACR.

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The Pluripotency Factor Musashi-2 Is a Novel Target for Lung Cancer Therapy

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