MSI1

Gene Summary

Gene:MSI1; musashi RNA binding protein 1
Location:12q24.31
Summary:This gene encodes a protein containing two conserved tandem RNA recognition motifs. Similar proteins in other species function as RNA-binding proteins and play central roles in posttranscriptional gene regulation. Expression of this gene has been correlated with the grade of the malignancy and proliferative activity in gliomas and melanomas. A pseudogene for this gene is located on chromosome 11q13. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:RNA-binding protein Musashi homolog 1
Source:NCBIAccessed: 31 August, 2019

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MSI1 (cancer-related)

Minuesa G, Albanese SK, Xie W, et al.
Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia.
Nat Commun. 2019; 10(1):2691 [PubMed] Free Access to Full Article Related Publications
The MUSASHI (MSI) family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We find that the small molecule Ro 08-2750 (Ro) binds directly and selectively to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells results in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2. Ro demonstrates in vivo inhibition of c-MYC and reduces disease burden in a murine AML leukemia model. Thus, we identify a small molecule that targets MSI's oncogenic activity. Our study provides a framework for targeting RNA binding proteins in cancer.

Yi C, Li G, Ivanov DN, et al.
Luteolin inhibits Musashi1 binding to RNA and disrupts cancer phenotypes in glioblastoma cells.
RNA Biol. 2018; 15(11):1420-1432 [PubMed] Article available free on PMC after 18/11/2019 Related Publications
RNA binding proteins have emerged as critical oncogenic factors and potential targets in cancer therapy. In this study, we evaluated Musashi1 (Msi1) targeting as a strategy to treat glioblastoma (GBM); the most aggressive brain tumor type. Msi1 expression levels are often high in GBMs and other tumor types and correlate with poor clinical outcome. Moreover, Msi1 has been implicated in chemo- and radio-resistance. Msi1 modulates a range of cancer relevant processes and pathways and regulates the expression of stem cell markers and oncogenic factors via mRNA translation/stability. To identify Msi1 inhibitors capable of blocking its RNA binding function, we performed a ~ 25,000 compound fluorescence polarization screen. NMR and LSPR were used to confirm direct interaction between Msi1 and luteolin, the leading compound. Luteolin displayed strong interaction with Msi1 RNA binding domain 1 (RBD1). As a likely consequence of this interaction, we observed via western and luciferase assays that luteolin treatment diminished Msi1 positive impact on the expression of pro-oncogenic target genes. We tested the effect of luteolin treatment on GBM cells and showed that it reduced proliferation, cell viability, colony formation, migration and invasion of U251 and U343 GBM cells. Luteolin also decreased the proliferation of patient-derived glioma initiating cells (GICs) and tumor-organoids but did not affect normal astrocytes. Finally, we demonstrated the value of combined treatments with luteolin and olaparib (PARP inhibitor) or ionizing radiation (IR). Our results show that luteolin functions as an inhibitor of Msi1 and demonstrates its potential use in GBM therapy.

Abbaszadegan MR, Riahi A, Forghanifard MM, Moghbeli M
WNT and NOTCH signaling pathways as activators for epidermal growth factor receptor in esophageal squamous cell carcinoma.
Cell Mol Biol Lett. 2018; 23:42 [PubMed] Article available free on PMC after 18/11/2019 Related Publications
Background: Esophageal squamous cell carcinoma (ESCC) is the most common histological type of esophageal cancer, with a poor prognosis. Deregulation of WNT and NOTCH signaling pathways is important in ESCC progression, which can be due to either malfunction of their components or crosstalk with other pathways. Therefore, identification of new crosstalk between such pathways may be effective to introduce new strategies for targeted therapy of cancer. A correlation study was performed to assess the probable interaction between growth factor receptors and WNT/NOTCH pathways via the epidermal growth factor receptor (EGFR) and Musashi1 (MSI1), respectively.
Methods: Levels of MSI1/EGFR mRNA expression in tumor tissues from 48 ESCC patients were compared to their corresponding normal tissues using real-time polymerase chain reaction.
Results: There was a significant correlation between EGFR and MSI1 expression (
Conclusion: This study confirms a direct correlation between MSI1 and EGFR and may support the important role of MSI1 in activation of EGFR through NOTCH/WNT pathways in ESCC.

Abbaszadegan MR, Taghehchian N, Li L, et al.
Contribution of KCTD12 to esophageal squamous cell carcinoma.
BMC Cancer. 2018; 18(1):853 [PubMed] Article available free on PMC after 18/11/2019 Related Publications
BACKGROUND: It has been shown that the expression of potassium channel tetramerization domain containing 12 (KCTD12) as a regulator of GABAB receptor signaling is reversely associated with gastrointestinal stromal tumors. In present study we examined the probable role of KCTD12 in regulation of several signaling pathways and chromatin remodelers in esophageal squamous cell carcinoma (ESCC).
METHODS: KCTD12 ectopic expression was done in KYSE30 cell line. Comparative quantitative real time PCR was used to assess the expression of stem cell factors and several factors belonging to the WNT/NOTCH and chromatin remodeling in transfected cells in comparison with non-transfected cells.
RESULTS: We observed that the KCTD12 significantly down regulated expression of NANOG, SOX2, SALL4, KLF4, MAML1, PYGO2, BMI1, BRG1, MSI1, MEIS1, EGFR, DIDO1, ABCC4, ABCG2, and CRIPTO1 in transfected cells in comparison with non-transfected cells. Migration assay showed a significant decrease in cell movement in ectopic expressed cells in comparison with non-transfected cells (p = 0.02). Moreover, KCTD12 significantly decreased the 5FU resistance in transfected cells (p = 0.01).
CONCLUSIONS: KCTD12 may exert its inhibitory role in ESCC through the suppression of WNT /NOTCH, stem cell factors, and chromatin remodelers and can be introduced as an efficient therapeutic marker.

Lan L, Liu H, Smith AR, et al.
Natural product derivative Gossypolone inhibits Musashi family of RNA-binding proteins.
BMC Cancer. 2018; 18(1):809 [PubMed] Article available free on PMC after 18/11/2019 Related Publications
BACKGROUND: The Musashi (MSI) family of RNA-binding proteins is best known for the role in post-transcriptional regulation of target mRNAs. Elevated MSI1 levels in a variety of human cancer are associated with up-regulation of Notch/Wnt signaling. MSI1 binds to and negatively regulates translation of Numb and APC (adenomatous polyposis coli), negative regulators of Notch and Wnt signaling respectively.
METHODS: Previously, we have shown that the natural product (-)-gossypol as the first known small molecule inhibitor of MSI1 that down-regulates Notch/Wnt signaling and inhibits tumor xenograft growth in vivo. Using a fluorescence polarization (FP) competition assay, we identified gossypolone (Gn) with a > 20-fold increase in Ki value compared to (-)-gossypol. We validated Gn binding to MSI1 using surface plasmon resonance, nuclear magnetic resonance, and cellular thermal shift assay, and tested the effects of Gn on colon cancer cells and colon cancer DLD-1 xenografts in nude mice.
RESULTS: In colon cancer cells, Gn reduced Notch/Wnt signaling and induced apoptosis. Compared to (-)-gossypol, the same concentration of Gn is less active in all the cell assays tested. To increase Gn bioavailability, we used PEGylated liposomes in our in vivo studies. Gn-lip via tail vein injection inhibited the growth of human colon cancer DLD-1 xenografts in nude mice, as compared to the untreated control (P < 0.01, n = 10).
CONCLUSION: Our data suggest that PEGylation improved the bioavailability of Gn as well as achieved tumor-targeted delivery and controlled release of Gn, which enhanced its overall biocompatibility and drug efficacy in vivo. This provides proof of concept for the development of Gn-lip as a molecular therapy for colon cancer with MSI1/MSI2 overexpression.

Chen HY, Lin LT, Wang ML, et al.
Musashi-1 promotes chemoresistant granule formation by PKR/eIF2α signalling cascade in refractory glioblastoma.
Biochim Biophys Acta Mol Basis Dis. 2018; 1864(5 Pt A):1850-1861 [PubMed] Related Publications
Musashi-1 (MSI1), one of the RNA-binding proteins, is abundantly found not only in neural stem cells but also in several cancer tissues and has been reported to act as a positive regulator of cancer progression. Growing evidence indicates that PKR and eIF2α play pivotal roles in the stimulation of stress granule formation as well as in the subsequent translation modulation in response to stressful conditions; however, little is known about whether MSI1 is involved in this PKR/eIF2α cancer stem cell-enhancing machinery. In this study, we demonstrated that MSI1 promotes human glioblastoma multiforme (GBM) stem cells and enhances chemoresistance when exposed to sublethal stress. The overexpression of MSI1 leads to a protective effect in mitigating drug-induced cell death, thus facilitating the formation of chemoresistant stress granules (SGs) in response to arsenic trioxide (ATO) treatment. SG components, such as PKR and eIF2α, were dominantly activated and assembled, while ATO was engaged. The activated PKR and eIF2α contribute to the downstream enhancement of stem cell genes, thereby promoting the progression of GBM. The silencing of MSI1 or PKR both obviously withdrew the phenomena. Taken together, our findings indicate that MSI1 plays a leading role in stress granule formation that grants cancer stem cell properties and chemoresistant stress granules in GBM, in response to stressful conditions via the PKR/eIF2α signalling cascade.

Lang Y, Kong X, He C, et al.
Musashi1 Promotes Non-Small Cell Lung Carcinoma Malignancy and Chemoresistance via Activating the Akt Signaling Pathway.
Cell Physiol Biochem. 2017; 44(2):455-466 [PubMed] Related Publications
BACKGROUND/AIMS: Lung cancer is one of the leading causes for cancer mortality. The poor therapeutic outcome of non-small cell lung carcinoma (NSCLC) is mainly due to late diagnosis and chemoresistance. In this study, we investigated the role of Musashi1 (MSI1) in NSCLC malignancy and chemoresistance.
METHODS: Colony formation, MTT, glucose uptake and lactate production assays were employed to study lung cancer cell malignancy and chemoresistance. RT-PCR and Western blotting were performed to detect mRNA and protein expressions of genes. We used immunohistochemistry and Pearson correlation analysis to study the relationship of gene expression.
RESULTS: We demonstrated that MSI1 was able to promote the proliferation and glucose metabolism of NSCLC cells, and to mediate the sensitivity to chemotherapy drugs in NSCLC cells. Importantly, we found that MSI1 could regulate the activity of Akt signaling. The regulation of NSCLC proliferation, glucose metabolism and chemoresistance by MSI1 was dependent on the modulation of the activity of the Akt signaling pathway. We also found that MSI1 was a target of miR-181a-5p, a microRNA involved in the regulation of cancer development. The expression levels of MSI1 and miR-181a-5p were negatively correlated in NSCLC.
CONCLUSION: MSI1 promotes non-small cell lung carcinoma malignancy and chemoresistance via activating the Akt signaling pathway, which provides a new strategy for the therapy of NSCLC.

Chen HY, Lin LT, Wang ML, et al.
Musashi-1 Enhances Glioblastoma Cell Migration and Cytoskeletal Dynamics through Translational Inhibition of Tensin3.
Sci Rep. 2017; 7(1):8710 [PubMed] Article available free on PMC after 18/11/2019 Related Publications
The RNA-binding protein Musashi-1 (MSI1) exerts essential roles in multiple cellular functions, such as maintenance of self-renewal and pluripotency of stem cells. MSI1 overexpression has been observed in several tumor tissues, including glioblastoma (GBM), and is considered as a well-established marker for tumor metastasis and recurrence. However, the molecular mechanisms by which MSI1 regulates cell migration are still undetermined. Here we reported that MSI1 alters cell morphology, promotes cell migration, and increases viscoelasticity of GBM cells. We also found that MSI1 directly binds to the 3'UTR of Tensin 3 (TNS3) mRNA, a negative regulator of cell migration, to inhibit its translation. Additionally, we identified that RhoA-GTP could be a potential regulator in MSI1/TNS3-mediated cell migration and morphological changes. In a xenograft animal model, high expression ratio of MSI1 to TNS3 enhanced GBM tumor migration. We also confirmed that MSI1 and TNS3 expressions are mutually exclusive in migratory tumor lesions, and GBM patients with MSI1

Kharas MG, Lengner CJ
Stem Cells, Cancer, and MUSASHI in Blood and Guts.
Trends Cancer. 2017; 3(5):347-356 [PubMed] Article available free on PMC after 18/11/2019 Related Publications
The mammalian MSI family of RNA-binding proteins (RBPs) have important roles as oncoproteins in an array of tumor types, including leukemias, glioblastomas, and pancreatic, breast, lung, and colorectal cancers. The mammalian Msi genes, Msi1 and Msi2, have been most thoroughly investigated in two highly proliferative tissues prone to oncogenic transformation: the hematopoietic lineage and the intestinal epithelium. Despite their vast phenotypic differences, MSI proteins appear to have an analogous role in governing the stem cell compartment in both of these tissues, potentially providing a paradigm for a broader understanding of MSI function and oncogenic activities. In this review, we focus on the function of MSI in the blood and the intestine, and discuss therapeutic strategies for targeting this pathway.

Qin G, Lian J, Yue D, et al.
Musashi1, a potential prognostic marker in esophageal squamous cell carcinoma.
Oncol Rep. 2017; 38(3):1724-1732 [PubMed] Article available free on PMC after 18/11/2019 Related Publications
Esophageal cancer ranks as the sixth leading cause of cancer-related deaths worldwide. Cancer stemness is mainly considered to be the key factor for cancer recurrence particularly in esophageal cancer. It is important to identify cancer stem cell markers as targets in future therapies. The present study aimed to investigate the expression of putative cancer stem cell-related marker musashi1 (Msi1) and assess the correlation with clinicopathologcal status of esophageal squamous cell carcinoma (ESCC) cases. We then clarified the role of Msi1 in esophageal cancer cells during proliferation, apoptosis, sphere formation and migration. Finally, we investigated the relationship of Msi1 with the prognosis of ESCC patients. ESCC tissue samples from 93 patients and 20 paired histologically normal tissues were procured for immunohistochemical analysis. We analyzed the characteristics of Msi1, using sphere formation and anchorage independent growth. Moreover, using flow cytometry and Cell Counting Kit-8 (CCK-8) assay, we investigated the role of Msi1 in cancer cell proliferation and apoptosis. Furthermore, we clarified the role of Msi1 in the process of sphere formation and migration of ESCC cells through knockdown of Msi1 expression by siRNA in ESCC cell lines. The results revealed that there was a higher expression of Msi1 in ESCC specimens compared with normal tissues. In addition, Msi1 expression was significantly associated with clinical stage and lymph node metastasis. Most importantly, the increased immunocytochemical staining of Msi1 in spheroid cells revealed the stemness characteristics of Msi1 in ESCC. In addition, we found that silencing of Msi1 decreased cell proliferation, migration and induced apoptosis in TE-7 and KYSE70 cells. Furthermore, downregulation of Msi1 attenuated the sphere formation ability of ESCC cells. Patients with higher expression of Msi1 had a shorter survival. In conclusion, Msi1 acts as a stemness-associated gene in esophageal cancer cell lines and could serve as a prognostic marker in patients with ESCC.

Wang X, Shojaie A, Zhang Y, et al.
Exploratory plasma proteomic analysis in a randomized crossover trial of aspirin among healthy men and women.
PLoS One. 2017; 12(5):e0178444 [PubMed] Article available free on PMC after 18/11/2019 Related Publications
Long-term use of aspirin is associated with lower risk of colorectal cancer and other cancers; however, the mechanism of chemopreventive effect of aspirin is not fully understood. Animal studies suggest that COX-2, NFκB signaling and Wnt/β-catenin pathways may play a role, but no clinical trials have systematically evaluated the biological response to aspirin in healthy humans. Using a high-density antibody array, we assessed the difference in plasma protein levels after 60 days of regular dose aspirin (325 mg/day) compared to placebo in a randomized double-blinded crossover trial of 44 healthy non-smoking men and women, aged 21-45 years. The plasma proteome was analyzed on an antibody microarray with ~3,300 full-length antibodies, printed in triplicate. Moderated paired t-tests were performed on individual antibodies, and gene-set analyses were performed based on KEGG and GO pathways. Among the 3,000 antibodies analyzed, statistically significant differences in plasma protein levels were observed for nine antibodies after adjusting for false discoveries (FDR adjusted p-value<0.1). The most significant protein was succinate dehydrogenase subunit C (SDHC), a key enzyme complex of the mitochondrial tricarboxylic acid (TCA) cycle. The other statistically significant proteins (NR2F1, MSI1, MYH1, FOXO1, KHDRBS3, NFKBIE, LYZ and IKZF1) are involved in multiple pathways, including DNA base-pair repair, inflammation and oncogenic pathways. None of the 258 KEGG and 1,139 GO pathways was found to be statistically significant after FDR adjustment. This study suggests several chemopreventive mechanisms of aspirin in humans, which have previously been reported to play a role in anti- or pro-carcinogenesis in cell systems; however, larger, confirmatory studies are needed.

Chiou GY, Yang TW, Huang CC, et al.
Musashi-1 promotes a cancer stem cell lineage and chemoresistance in colorectal cancer cells.
Sci Rep. 2017; 7(1):2172 [PubMed] Article available free on PMC after 18/11/2019 Related Publications
Colorectal cancers (CRCs) are a critical health issue worldwide. Cancer stem cell (CSC) lineages are associated with tumour transformation, progression, and malignant transformation. However, how lineages are transformed and how chemoresistance is acquired by CRCs remain largely unknown. In this report, we demonstrated that the RNA-binding protein Musashi-1 enhanced the development of CD44

Freitag D, McLean AL, Simon M, et al.
NANOG overexpression and its correlation with stem cell and differentiation markers in meningiomas of different WHO grades.
Mol Carcinog. 2017; 56(8):1953-1964 [PubMed] Related Publications
NANOG, as a key regulator of pluripotency and acting synergistically with other factors, has been described as a crucial transcription factor in various types of cancer. In meningiomas the expression of this marker has not yet been described. With our study, we aimed to identify and localize NANOG and other possible markers of pluripotency, stem cell properties and differentiation in meningioma tissue, to elucidate a possible effect on tumorigenesis. The gene expression levels of NANOG (NANOG1 and NANOGP8), SOX2, OCT4, KLF4, ABCG2, CMYC, MSI1, CD44, NOTCH1, NES, SALL4B, TP53, and EPAS1 were quantitatively examined using RT-qPCR in 33 surgical specimens of low- (WHO grade I) as well as in high-grade (WHO grade II/III) meningiomas with dural tissue as reference. Immunofluorescence co-localization analysis following confocal fluorescence microscopy for NANOG, OCT4, SOX2, Nestin, KI-67, and CD44 was also performed. There was a significant overexpression of NANOG, MSI1, and EPAS1 and a downregulation of NES in all examined tumors. Subgroup analysis (WHO grade I versus grade II/III) revealed differences in the expression of NANOG, CD44, and MSI1. We found 1% NANOG-positive (NANOG+) cells in low-grade and 2% in grade II/III meningiomas co-expressing the other mentioned markers in various compositions. In particular, NANOG+ cells expressing SOX2 and OCT4 were successfully identified (26% low-grade versus 20% high-grade). Our data reveal an overexpression of NANOG and other markers of pluripotency and stemness in meningiomas. Such potentially pluripotent "stem cell-like" cells may have an impact on tumorigenesis and progression in human meningiomas.

Kudinov AE, Karanicolas J, Golemis EA, Boumber Y
Musashi RNA-Binding Proteins as Cancer Drivers and Novel Therapeutic Targets.
Clin Cancer Res. 2017; 23(9):2143-2153 [PubMed] Article available free on PMC after 18/11/2019 Related Publications
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

Gong P, Wang Y, Gao Y, et al.
Msi1 promotes tumor progression by epithelial-to-mesenchymal transition in cervical cancer.
Hum Pathol. 2017; 65:53-61 [PubMed] Related Publications
Musashi1 (Msi1) is an RNA-binding protein that has been reported to be a pivotal regulator in tumorigenesis and progression in several cancers. However, its function and mechanism in cervical cancer is still unknown. In this study, Msi1 expression was found elevated in cervical cancers by immunohistochemistry and correlated with poor outcomes. Then, endogenous Msi1 was silenced in cervical cancer cell lines by short hairpin RNA, and its function and mechanism were determined. The results showed that the silencing of Msi1 in SiHa and HeLa cells inhibited the cells' migratory and invasive abilities in vitro and tumor progression in vivo. Epithelial-to-mesenchymal transition (EMT) markers were down-regulated, and Wnt activity was inhibited by the silencing of Msi1. In clinical tissues, positive correlations between Msi1 and EMT markers were found. In conclusion, Msi1, a diagnostic marker and potential therapeutic target, promoted the EMT progression through activation of the Wnt signaling pathway in cervical cancers, thereby contributing to poor prognosis.

Chen HY, Lin LT, Wang ML, et al.
Musashi-1 regulates AKT-derived IL-6 autocrinal/paracrinal malignancy and chemoresistance in glioblastoma.
Oncotarget. 2016; 7(27):42485-42501 [PubMed] Article available free on PMC after 18/11/2019 Related Publications
Glioblastoma multiform (GBM) is one of the most lethal human malignant brain tumors with high risks of recurrence and poor treatment outcomes. The RNA-binding protein Musashi-1 (MSI1) is a marker of neural stem/progenitor cells. Recent study showed that high expression level of MSI1 positively correlates with advanced grade of GBM, where MSI1 increases the growth of GBM. Herein, we explore the roles of MSI1 as well as the underlying mechanisms in the regulation of drug resistance and tumorigenesis of GBM cells. Our results demonstrated that overexpression of MSI1 effectively protected GBM cells from drug-induced apoptosis through down-regulating pro-apoptotic genes; whereas inhibition of AKT withdrew the MSI1-induced anti-apoptosis and cell survival. We further showed that MSI1 robustly promoted the secretion of the pro-inflammatory cytokine IL-6, which was governed by AKT activity. Autonomously, the secreted IL-6 enhanced AKT activity in an autocrine/paracrine manner, forming a positive feedback regulatory loop with the MSI1-AKT pathway. Our results conclusively demonstrated a novel drug resistance mechanism in GBM cells that MSI1 inhibits drug-induced apoptosis through AKT/IL6 regulatory circuit. MSI1 regulates both cellular signaling and tumor-microenvironmental cytokine secretion to create an intra- and intercellular niche for GBM to survive from chemo-drug attack.

Fox RG, Lytle NK, Jaquish DV, et al.
Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma.
Nature. 2016; 534(7607):407-411 [PubMed] Article available free on PMC after 18/11/2019 Related Publications
Pancreatic intraepithelial neoplasia is a pre-malignant lesion that can progress to pancreatic ductal adenocarcinoma, a highly lethal malignancy marked by its late stage at clinical presentation and profound drug resistance. The genomic alterations that commonly occur in pancreatic cancer include activation of KRAS2 and inactivation of p53 and SMAD4 (refs 2-4). So far, however, it has been challenging to target these pathways therapeutically; thus the search for other key mediators of pancreatic cancer growth remains an important endeavour. Here we show that the stem cell determinant Musashi (Msi) is a critical element of pancreatic cancer progression both in genetic models and in patient-derived xenografts. Specifically, we developed Msi reporter mice that allowed image-based tracking of stem cell signals within cancers, revealing that Msi expression rises as pancreatic intraepithelial neoplasia progresses to adenocarcinoma, and that Msi-expressing cells are key drivers of pancreatic cancer: they preferentially harbour the capacity to propagate adenocarcinoma, are enriched in circulating tumour cells, and are markedly drug resistant. This population could be effectively targeted by deletion of either Msi1 or Msi2, which led to a striking defect in the progression of pancreatic intraepithelial neoplasia to adenocarcinoma and an improvement in overall survival. Msi inhibition also blocked the growth of primary patient-derived tumours, suggesting that this signal is required for human disease. To define the translational potential of this work we developed antisense oligonucleotides against Msi; these showed reliable tumour penetration, uptake and target inhibition, and effectively blocked pancreatic cancer growth. Collectively, these studies highlight Msi reporters as a unique tool to identify therapy resistance, and define Msi signalling as a central regulator of pancreatic cancer.

Onzi GR, Ledur PF, Hainzenreder LD, et al.
Analysis of the safety of mesenchymal stromal cells secretome for glioblastoma treatment.
Cytotherapy. 2016; 18(7):828-37 [PubMed] Related Publications
BACKGROUND AIMS: The purpose of this study was to investigate whether the secretome of human adipose-derived stem cells (hADSC) affects human glioblastoma (GBM) cancer stem cell (CSC) subpopulation or has any influence on drug resistance and cell migration, evaluating the safety of hADSCs for novel cancer therapies.
METHODS: hADSCs were maintained in contact with fresh culture medium to produce hADSCs conditioned medium (CM). GBM U87 cells were cultured with CM and sphere formation, expression of genes related to resistance and CSCs-MGMT, OCT4, SOX2, NOTCH1, MSI1-and protein expression of OCT4 and Nanog were analyzed. The influence of hADSC CM on GBM resistance to temozolomide (TMZ) was evaluated by measuring cumulative population doubling and hADSC CM influence on tumor cell migration was analyzed using transwell assay.
RESULTS: hADSC CM did not alter CSC-related features such as sphere-forming capacity and expression of genes related to CSC. hADSC CM treatment alone did not change proliferation rate of U87 cells and, most important, did not alter the response of tumor cells to TMZ. However, hADSC CM secretome increased the migration capacity of glioblastoma cells.
DISCUSSION: hADSC CM neither induced an enrichment of CSCs in U87 cells population nor interfered in the response to TMZ in culture. Nevertheless, paracrine factors released by hADSCs were able to modulate glioblastoma cells migration. These findings provide novel information regarding the safety of using hADSCs against cancer and highlight the importance of considering hADSC-tumor cells interactions in tumor microenvironment in the design of novel cell therapies.

Jones NM, Rowe MR, Shepherd PR, McConnell MJ
Targeted inhibition of dominant PI3-kinase catalytic isoforms increase expression of stem cell genes in glioblastoma cancer stem cell models.
Int J Oncol. 2016; 49(1):207-16 [PubMed] Related Publications
Cancer stem cells (CSC) exhibit therapy resistance and drive self-renewal of the tumour, making cancer stem cells an important target for therapy. The PI3K signalling pathway has been the focus of considerable research effort, including in glioblastoma (GBM), a cancer that is notoriously resistant to conventional therapy. Different isoforms of the catalytic sub-unit have been associated with proliferation, migration and differentiation in stem cells and cancer stem cells. Blocking these processes in CSC would improve patient outcome. We examined the effect of isoform specific PI3K inhibitors in two models of GBM CSC, an established GBM stem cell line 08/04 and a neurosphere formation model. We identified the dominant catalytic PI3K isoform for each model, and inhibition of the dominant isoform blocked AKT phosphorylation, as did pan-PI3K/mTOR inhibition. Analysis of SOX2, OCT4 and MSI1 expression revealed that inhibition of the dominant p110 subunit increased expression of cancer stem cell genes, while pan-PI3K/mTOR inhibition caused a similar, though not identical, increase in cancer stem cell gene expression. This suggested that PI3K inhibition enhanced, rather than blocked, CSC activity. Careful analysis of the response to specific isoform inhibition will be necessary before specific subunit inhibitors can be successfully deployed against GBM CSC.

Moghbeli M, Rad A, Farshchian M, et al.
Correlation Between Meis1 and Msi1 in Esophageal Squamous Cell Carcinoma.
J Gastrointest Cancer. 2016; 47(3):273-7 [PubMed] Related Publications
PURPOSE: Homeobox (HOX) transcription factors are critical regulators of cell fate, stem cell functions, and gastrointestinal development. They require three-amino acid loop extension (TALE) homeodomain proteins such as Meis1 to enhance their transcriptional efficiencies. There are complicated associations between different signaling pathways such as the Wnt and NOTCH and tumor progression. It has been investigated that GSK-3 as an important component of the Wnt pathway facilitates the expression of HOX target genes. Therefore, in the present study, we assessed the probable correlation between Wnt, NOTCH, and HOX genes in esophageal squamous cell carcinoma (ESCC) progression and metastasis through the correlational study between the Msi1 as an important activator for both of the NOTCH and Wnt pathways and Meis1.
METHODS: Levels of Meis1 and Msi1 messenger RNA (mRNA) expression in 51 ESCC patients were compared to the normal tissues using real-time polymerase chain reaction.
RESULTS: Only 3 out of 51 (5.9 %) cases had Meis1/Msi1 overexpression and also 3/51 (5.9 %) cases had Meis1/Msi1 underexpression. There was a significant correlation between the Msi1 and Mesi1 mRNA expression (p = 0.037). All of the Msi1/Meis1 underexpressed tumors were poorly differentiated (p = 0.003). Meis1 under/Msi1 overexpressed cases also were in T3 tumor depth of invasion (p = 0.019). And there was a significant correlation between the Msi1/Meis1 underexpression and gender (p = 0.045).
CONCLUSIONS: Our results show that Meis1 may have a positive feedback with Msi1 during the ESCC progression.

Li N, Yousefi M, Nakauka-Ddamba A, et al.
The Msi Family of RNA-Binding Proteins Function Redundantly as Intestinal Oncoproteins.
Cell Rep. 2015; 13(11):2440-2455 [PubMed] Article available free on PMC after 18/11/2019 Related Publications
Members of the Msi family of RNA-binding proteins have recently emerged as potent oncoproteins in a range of malignancies. MSI2 is highly expressed in hematopoietic cancers, where it is required for disease maintenance. In contrast to the hematopoietic system, colorectal cancers can express both Msi family members, MSI1 and MSI2. Here, we demonstrate that, in the intestinal epithelium, Msi1 and Msi2 have analogous oncogenic effects. Further, comparison of Msi1/2-induced gene expression programs and transcriptome-wide analyses of Msi1/2-RNA-binding targets reveal significant functional overlap, including induction of the PDK-Akt-mTORC1 axis. Ultimately, we demonstrate that concomitant loss of function of both MSI family members is sufficient to abrogate the growth of human colorectal cancer cells, and Msi gene deletion inhibits tumorigenesis in several mouse models of intestinal cancer. Our findings demonstrate that MSI1 and MSI2 act as functionally redundant oncoproteins required for the ontogeny of intestinal cancers.

Baulch JE, Geidzinski E, Tran KK, et al.
Irradiation of primary human gliomas triggers dynamic and aggressive survival responses involving microvesicle signaling.
Environ Mol Mutagen. 2016; 57(5):405-15 [PubMed] Related Publications
Malignant gliomas are heterogeneous populations of dynamically interacting cells. Genomic and transcriptional changes define this cellular hierarchy and allow certain tumor cells to co-opt metabolic machinery and adopt gene expression profiles that promote cellular reprogramming. Resultant expansion of privileged subpopulations can then rapidly adapt to microenvironmental stress that ultimately influence tumor response to therapeutic intervention. In this study, primary gliomas were subjected to acute or chronic irradiation and analyzed for changes in survival parameters, oxidative stress, gene expression, and cell invasion before and after treatment with secreted microvesicles isolated from irradiated and nonirradiated glioma cells. We found that primary gliomas exposed to ionizing radiation undergo metabolic changes that increase oxidative stress, alter gene expression, and affect the contents of and response to cellular secreted microvesicles. Radiation-induced changes were exacerbated under chronic as compared to acute irradiation paradigms and promoted cellular reprogramming through enhanced expression of key transcription factors and regulators involved in differentiation and pluripotency (SOX2, POU3F2, SALL2, OLIG2, NANOG, POU5F1v1, MSI1). Irradiation also affected changes in paracrine signaling mediated by cellular secreted microvesicles that significantly altered target cell phenotype. Primary gliomas treated with microvesicles exhibited increased radioresistance and treatment with microvesicles from chronically irradiated gliomas promoted invasion via induction of increased matrix metalloproteinase II activity. Together, our data describe a complex radiation response of primary glioma cells involving metabolic and transcriptional changes that alter radiation sensitivity and induce invasive behavior. These important changes can contribute to tumor growth and recurrence, and confound interventions designed to forestall disease progression. Environ. Mol. Mutagen. 57:405-415, 2016. © 2015 Wiley Periodicals, Inc.

Shi C, Zhang Z
miR-761 inhibits tumor progression by targeting MSI1 in ovarian carcinoma.
Tumour Biol. 2016; 37(4):5437-43 [PubMed] Related Publications
Increasing evidences have revealed that microRNAs regulate various biological processes. However, the roles of miR-761 have not been investigated in ovarian cancer. Here, we found that miR-761 expression was significantly lower in ovarian cancer tissues than in their paired noncancerous tissues. Further study revealed that miR-761 overexpression inhibited the ovarian cancer cell proliferation and invasion. Mechanistically, we demonstrated that the oncogenic properties of miR-761 in ovarian cancer were mediated in part by regulating MSI1 expression. miR-761 and MSI1 are inversely expressed in ovarian cancer tissues. In conclusion, we demonstrated that miR-761 repressed ovarian cancer proliferation and invasion by targeting MSI1.

Rauscher GH, Kresovich JK, Poulin M, et al.
Exploring DNA methylation changes in promoter, intragenic, and intergenic regions as early and late events in breast cancer formation.
BMC Cancer. 2015; 15:816 [PubMed] Article available free on PMC after 18/11/2019 Related Publications
BACKGROUND: Breast cancer formation is associated with frequent changes in DNA methylation but the extent of very early alterations in DNA methylation and the biological significance of cancer-associated epigenetic changes need further elucidation.
METHODS: Pyrosequencing was done on bisulfite-treated DNA from formalin-fixed, paraffin-embedded sections containing invasive tumor and paired samples of histologically normal tissue adjacent to the cancers as well as control reduction mammoplasty samples from unaffected women. The DNA regions studied were promoters (BRCA1, CD44, ESR1, GSTM2, GSTP1, MAGEA1, MSI1, NFE2L3, RASSF1A, RUNX3, SIX3 and TFF1), far-upstream regions (EN1, PAX3, PITX2, and SGK1), introns (APC, EGFR, LHX2, RFX1 and SOX9) and the LINE-1 and satellite 2 DNA repeats. These choices were based upon previous literature or publicly available DNA methylome profiles. The percent methylation was averaged across neighboring CpG sites.
RESULTS: Most of the assayed gene regions displayed hypermethylation in cancer vs. adjacent tissue but the TFF1 and MAGEA1 regions were significantly hypomethylated (p ≤0.001). Importantly, six of the 16 regions examined in a large collection of patients (105 - 129) and in 15-18 reduction mammoplasty samples were already aberrantly methylated in adjacent, histologically normal tissue vs. non-cancerous mammoplasty samples (p ≤0.01). In addition, examination of transcriptome and DNA methylation databases indicated that methylation at three non-promoter regions (far-upstream EN1 and PITX2 and intronic LHX2) was associated with higher gene expression, unlike the inverse associations between cancer DNA hypermethylation and cancer-altered gene expression usually reported. These three non-promoter regions also exhibited normal tissue-specific hypermethylation positively associated with differentiation-related gene expression (in muscle progenitor cells vs. many other types of normal cells). The importance of considering the exact DNA region analyzed and the gene structure was further illustrated by bioinformatic analysis of an alternative promoter/intron gene region for APC.
CONCLUSIONS: We confirmed the frequent DNA methylation changes in invasive breast cancer at a variety of genome locations and found evidence for an extensive field effect in breast cancer. In addition, we illustrate the power of combining publicly available whole-genome databases with a candidate gene approach to study cancer epigenetics.

Nahas GR, Murthy RG, Patel SA, et al.
The RNA-binding protein Musashi 1 stabilizes the oncotachykinin 1 mRNA in breast cancer cells to promote cell growth.
FASEB J. 2016; 30(1):149-59 [PubMed] Related Publications
Substance P and its truncated receptor exert oncogenic effects. The high production of substance P in breast cancer cells (BCCs) is caused by the enhancement of tachykinin (TAC)1 translation by cytosolic factor. In vitro translational studies and mRNA stabilization analyses indicate that BCCs contain the factor needed to increase TAC1 translation and to stabilize the mRNA. Prediction of protein folding, RNA-shift analysis, and proteomic analysis identified a 40 kDa molecule that interacts with the noncoding exon 7. Western blot analysis and RNA supershift identified Musashi 1 (Msi1) as the binding protein. Ectopic expression of TAC1 in nontumorigenic breast cells (BCs) indicates that TAC1 regulates its stability by increasing Msi1. Using a reporter gene system, we showed that Msi1 competes with microRNA (miR)130a and -206 for the 3' UTR of exon 7/TAC1. In the absence of Msi1 and miR130a and -206, reporter gene activity decreased, indicating that Msi1 expression limits TAC1 expression. Tumor growth was significantly decreased when nude BALB/c mice were injected with Msi1-knockdown BCCs. In summary, the RNA-binding protein Msi1 competes with miR130a and -206 for interaction with TAC1 mRNA, to stabilize and increase its translation. Consequently, these interactions increase tumor growth.

Moghbeli M, Forghanifard MM, Sadrizadeh A, et al.
Role of Msi1 and MAML1 in Regulation of Notch Signaling Pathway in Patients with Esophageal Squamous Cell Carcinoma.
J Gastrointest Cancer. 2015; 46(4):365-9 [PubMed] Related Publications
PURPOSE: Developmental pathways such as Wnt and Notch are involved in different cellular functions from the cell cycle regulation to self-renewal. Therefore, aberrations in these pathways may cause tumorigenesis. Msi1 has a critical regulatory role for the Wnt and Notch pathways. In the present study, we have assessed the probable correlation between the Msi1 and MAML1 in esophageal squamous cell carcinoma (ESCC) progression and metastasis.
METHODS: Levels of Msi1 and MAML1 mRNA expression in 51 ESCC patients were compared to the normal tissues using real-time polymerase chain reaction (PCR).
RESULTS: Nine out of 51 (17.6 %) cases had Msi1/MAML1 overexpression, and there was a significant correlation between such overexpressed cases and tumor location (p = 0.013).
CONCLUSIONS: We showed that there is not any direct correlation and feedback between the Msi1 and MAML1 in ESCC patients.

Ma L, Xu YL, Ding WJ, et al.
Prognostic value of Musashi-1 in endometrioid adenocarcinoma.
Int J Clin Exp Pathol. 2015; 8(5):4564-72 [PubMed] Article available free on PMC after 18/11/2019 Related Publications
AIMS: Musashi-1, a RNA-binding protein, is suggested to be a cancer stem cell-related marker; its high level of protein expression is reported to be associated with high histological grade in some tumors. The aim of this study was to investigate the prognostic value of Musashi-1 in patients with endometrioid adenocarcinoma (EAC).
METHODS: We examined the Musashi-1 mRNA expression level in 35 fresh EAC tissue samples and 15 normal endometrium samples by real-time RT-PCR, and its protein expression level in 148 paraffin EAC tissue samples and 20 paraffin normal endometrium samples by immunohistochemistry. The correlation between Musashi-1 and overall survival (OS) used Cox proportional hazards regression. The prognostic accuracy of Musashi-1 compared with other clinicopathological risk factors by logistic regression. Furthermore, we examined whether Musashi-1 expression is correlated with another cancer stem cell marker CD133 by real-time RT-PCR.
RESULTS: Musashi-1 mRNA expression of EAC is 2.8-fold higher than that of normal endometrium (P=0.0009). Musashi-1 protein expression level is correlated with tumor stage, grade and vascular invasion. Patients with higher protein expression level of Musashi-1 are associated with poor survival rate than those with negative or low level of expression (HR=2.073, P=0.001). The area under the curve (AUC) for Musashi-1 is 0.8, which is higher than other clinicopathological factors (P=0.000). In addition, Musashi-1 mRNA expression seems to be closely correlated with CD133 expression (r=0.7167, P<0.0001).
CONCLUSIONS: Our results suggest high level of Musashi-1 protein expression is associated with poor survival in EAC patients, which may be an independent prognostic factor for EAC.

Uren PJ, Vo DT, de Araujo PR, et al.
RNA-Binding Protein Musashi1 Is a Central Regulator of Adhesion Pathways in Glioblastoma.
Mol Cell Biol. 2015; 35(17):2965-78 [PubMed] Article available free on PMC after 18/11/2019 Related Publications
The conserved RNA-binding protein Musashi1 (MSI1) has emerged as a key oncogenic factor in numerous solid tumors, including glioblastoma. However, its mechanism of action has not yet been established comprehensively. To identify its target genes comprehensively and determine the main routes by which it influences glioblastoma phenotypes, we conducted individual-nucleotide resolution cross-linking and immunoprecipitation (iCLIP) experiments. We confirmed that MSI1 has a preference for UAG sequences contained in a particular structural context, especially in 3' untranslated regions. Although numerous binding sites were also identified in intronic sequences, our RNA transcriptome sequencing analysis does not favor the idea that MSI1 is a major regulator of splicing in glioblastoma cells. MSI1 target mRNAs encode proteins that function in multiple pathways of cell proliferation and cell adhesion. Since these associations indicate potentially new roles for MSI1, we investigated its impact on glioblastoma cell adhesion, morphology, migration, and invasion. These processes are known to underpin the spread and relapse of glioblastoma, in contrast to other tumors where metastasis is the main driver of recurrence and progression.

Smith AR, Marquez RT, Tsao WC, et al.
Tumor suppressive microRNA-137 negatively regulates Musashi-1 and colorectal cancer progression.
Oncotarget. 2015; 6(14):12558-73 [PubMed] Article available free on PMC after 18/11/2019 Related Publications
Stem cell marker, Musashi-1 (MSI1) is over-expressed in many cancer types; however the molecular mechanisms involved in MSI1 over-expression are not well understood. We investigated the microRNA (miRNA) regulation of MSI1 and the implications this regulation plays in colorectal cancer. MicroRNA miR-137 was identified as a MSI1-targeting microRNA by immunoblotting and luciferase reporter assays. MSI1 protein was found to be highly expressed in 79% of primary rectal tumors (n=146), while miR-137 expression was decreased in 84% of the rectal tumor tissues (n=68) compared to paired normal mucosal samples. In addition to reduced MSI1 protein, exogenous expression of miR-137 inhibited cell growth, colony formation, and tumorsphere growth of colon cancer cells. Finally, in vivo studies demonstrated that induction of miR-137 can decrease growth of human colon cancer xenografts. Our results demonstrate that miR-137 acts as a tumor-suppressive miRNA in colorectal cancers and negatively regulates oncogenic MSI1.

Wang Y, Jiang CQ, Fan LF
Correlation of Musashi-1, Lgr5, and pEGFR expressions in human small intestinal adenocarcinomas.
Tumour Biol. 2015; 36(8):6075-82 [PubMed] Related Publications
Recent studies have revealed that Musashi-1 and Lgr5 (leucine-rich-repeat-containing G-protein-coupled receptor 5) were putative stem cell genes. The epidermal growth factor receptor (EGFR) has also been extensively studied; it was known as an oncogenic driver in cancers. Overexpressions of Musashi-1, EGFR, and Lgr5 have been reported in some tumor tissues and cell lines. In this study, we used immunohistochemical analysis to investigate the expression pattern of Musashi-1, Lgr5, and pEGFR in 38 small intestinal adenocarcinomas (SIAs) resection specimens, 20 matched normal specimens and tried to analyze the correlations among them. The positive rate of Musashi-1, Lgr5, and pEGFR in SIAs, respectively, was 71 % (27/38), 55 % (21/38), and 45 % (17/38). Compared with the adjacent normal small intestinal mucosa, Musashi-1, Lgr5, and pEGFR protein were overexpressed in SIAs (P< 0.05). Furthermore, Musashi-1 and Lgr5 expressions were significantly correlated with the depth of wall invasion (P = 0.0011, P = 0.0017, respectively). Musashi-1 expression was closely correlated with Lgr5 (P = 0.015, r = 0.392). However, pEGFR expression was not associated with age, gender, tumor size, differentiation, depth of invasion, lymphatic metastasis, TNM stage, and pEGFR expression was not correlated with Musashi-1 or Lgr5 (P > 0.05, r = 0.064; P > 0.05, r = 0.307, respectively). Thus, we suggest that Musashi-1, Lgr5, and pEGFR are overexpressed in human SIAs and may play roles in human SIA carcinogenesis and progression.

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