Transformation of the intestinal epithelium by the MSI2 RNA-binding protein

Wang, Shan; Li, Ning; Yousefi, Maryam; Nakauka-Ddamba, Angela; Li, Fan; Parada, Kimberly; Rao, Shilpa; Minuesa, Gerard; Katz, Yarden; Gregory, Brian D.; Kharas, Michael G.; Yu, Zhengquan; Lengner, Christopher J.

doi:10.1038/ncomms7517

Cited by 121 publications

(199 citation statements)

References 51 publications

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“…S6 A, B, E, and F). However, the claudin mRNAs lack [(G/A)U(n)AGU (n = 1-3)] the consensus motifs for MSI2 binding described in Wang et al (28), suggesting direct regulation of translation is not involved.…”

Section: Resultsmentioning

confidence: 99%

“…Although a number of studies have previously identified a role for the MSI2 paralogue MSI1 as oncogenic in a number of cancer types (30)(31)(32), MSI2 has attracted much less scrutiny. However, MSI2 has been shown to be oncogenic in a mouse model of colon cancer (28); MSI2 expression is induced by loss of the adenomatous polyposis coli (APC) gene, and overexpression of MSI2 phenocopies APC loss (28). MSI2 is also overexpressed and oncogenic in human leukemias.…”

Section: Discussionmentioning

confidence: 99%

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Musashi-2 (MSI2) supports TGF-β signaling and inhibits claudins to promote non-small cell lung cancer (NSCLC) metastasis

Kudinov

Deneka

Nikonova

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

133

140

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Non-small cell lung cancer (NSCLC) has a 5-y survival rate of ∼16%, with most deaths associated with uncontrolled metastasis. We screened for stem cell identity-related genes preferentially expressed in a panel of cell lines with high versus low metastatic potential, derived from NSCLC tumors of Kras LA1/+ ;P53 R172HΔG/+ (KP) mice. The Musashi-2 (MSI2) protein, a regulator of mRNA translation, was consistently elevated in metastasis-competent cell lines. MSI2 was overexpressed in 123 human NSCLC tumor specimens versus normal lung, whereas higher expression was associated with disease progression in an independent set of matched normal/primary tumor/lymph node specimens. Depletion of MSI2 in multiple independent metastatic murine and human NSCLC cell lines reduced invasion and metastatic potential, independent of an effect on proliferation. MSI2 depletion significantly induced expression of proteins associated with epithelial identity, including tight junction proteins [claudin 3 (CLDN3), claudin 5 (CLDN5), and claudin 7 (CLDN7)] and down-regulated direct translational targets associated with epithelial-mesenchymal transition, including the TGF-β receptor 1 (TGFβR1), the small mothers against decapentaplegic homolog 3 (SMAD3), and the zinc finger proteins SNAI1 (SNAIL) and SNAI2 (SLUG). Overexpression of TGFβRI reversed the loss of invasion associated with MSI2 depletion, whereas overexpression of CLDN7 inhibited MSI2-dependent invasion. Unexpectedly, MSI2 depletion reduced E-cadherin expression, reflecting a mixed epithelialmesenchymal phenotype. Based on this work, we propose that MSI2 provides essential support for TGFβR1/SMAD3 signaling and contributes to invasive adenocarcinoma of the lung and may serve as a predictive biomarker of NSCLC aggressiveness.on-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths in the world (1). Approximately 7% of individuals born in the United States in 2013 will ultimately be diagnosed with lung cancer, and 160,000 die from this disease each year (1). The 5-y survival rate for lung cancer is around 16% of diagnosed cases (2). Much of the lethality of lung cancer is due to frequent diagnosis of the malignancy at the metastatic stage, when fundamental changes in tumor biology cause the disease to be refractory to many treatments. A better understanding of the biological processes that promote NSCLC metastasis promises to further improve clinical care of the patients. Kras LA1/+ ;P53 R172HΔG/+ (KP) mice provide a useful and wellvalidated model for the study of NSCLC metastasis. These mice combine a mutant p53 allele (p53 R175HΔG) with an activating KrasG12D allele (Kras LA1 ) (3), leading to development of adenocarcinomas resembling human NSCLC, which are often characterized by mutation of KRAS (∼30%) (4) and loss of TP53 (∼60%) (5). Many of the KP tumors metastasize to sites commonly seen in NSCLC patients (3). These features make the KP murine model a useful tool with which to evaluate factors that underlie NSCLC metastasis. Among the pathways activated...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Musashi-2 (MSI2) supports TGF-β signaling and inhibits claudins to promote non-small cell lung cancer (NSCLC) metastasis

Kudinov

Deneka

Nikonova

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

133

140

View full text Add to dashboard Cite

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“…For example, APC can bind RNA and regulate the microtubule scaffold (50). Furthermore, the loss of Apc leads to the upregulation of Musashi proteins, which are pleiotropic translational regulators that affect numerous important signaling cascades, including the mTorc1 pathway (51,52). Second, characteristic for the deletion of Cnsk1a1 (but not Apc) induction of the DNA damage response, activation of the p53-driven genes, and cell senescence are likely augmented by IFN signaling activated by CK1␣ deletion.…”

Section: Discussionmentioning

confidence: 99%

Type I Interferons Control Proliferation and Function of the Intestinal Epithelium

Katlinskaya

Katlinski

Lasri

et al. 2016

Molecular and Cellular Biology

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“…The studies summarized above tie expression of MSI1 and MSI2, at least indirectly, to factors linked to maintenance of stem cell characteristics or induction of cancer. These include loss of APC and induction of TCF/LEF binding in colon cancer (37,38), and repression by KLF4 in pancreatic cancer (24). MSI1 expression, along with other stem cell markers, was negatively regulated in GBM xenografts and in depleted stem-like GBM cells treated with the c-MET inhibitor crizotinib (39).…”

Section: Control Of Musashi Protein Expressionmentioning

confidence: 99%

Musashi RNA-Binding Proteins as Cancer Drivers and Novel Therapeutic Targets

Kudinov

Karanicolas

Golemis

et al. 2017

Clinical Cancer Research

221

240

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Aberrant gene expression that drives human cancer can arise from epigenetic dysregulation. While much attention has focused on altered activity of transcription factors and chromatin-modulating proteins, proteins that act post-transcriptionally can potently affect expression of oncogenic signaling proteins. The RNA-binding proteins (RBPs) 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 regulators 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, TGF-β/SMAD3, MYC, cMET, and others. Based on these activities, MSI proteins maintain cancer stem cell populations and regulate cancer invasion, metastasis and development of more aggressive cancer phenotypes, including drug resistance. While 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.

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Transformation of the intestinal epithelium by the MSI2 RNA-binding protein

Cited by 121 publications

References 51 publications

Musashi-2 (MSI2) supports TGF-β signaling and inhibits claudins to promote non-small cell lung cancer (NSCLC) metastasis

Musashi-2 (MSI2) supports TGF-β signaling and inhibits claudins to promote non-small cell lung cancer (NSCLC) metastasis

Type I Interferons Control Proliferation and Function of the Intestinal Epithelium

Musashi RNA-Binding Proteins as Cancer Drivers and Novel Therapeutic Targets

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