The oncogenic RNA-binding protein Musashi1 is regulated by tumor suppressor miRNAs

Vo, Dat T.; Qiao, Mu; Smith, Andrew D.; Burns, Suzanne Perea; Brenner, Andrew; Penalva, Luiz O. F.

doi:10.4161/rna.8.5.16041

Cited by 66 publications

(62 citation statements)

References 92 publications

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“…Altogether, these results suggest that NOTCH3 could modulate MSI-1 levels by indirect mechanisms. In this regard, it was recently observed that several tumor suppressor microRNA (miR) act as direct regulators of MSI-1, affecting its expression pattern during tumorigenesis of brain tumors (39), opening the possibility that NOTCH3 controls MSI-1 expression by miR-mediated mechanisms. To test this hypothesis, future studies will address whether miRs involved in the regulation of MSI-1 are downstream on NOTCH3 in CRC cells.…”

Section: Discussionmentioning

confidence: 99%

NOTCH3 Signaling Regulates MUSASHI-1 Expression in Metastatic Colorectal Cancer Cells

et al. 2014

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MUSASHI-1 (MSI-1) is a well-established stem cell marker in both normal and malignant colon cells and it acts by positively regulating the NOTCH pathway through inactivation of NUMB, a NOTCH signaling repressor. To date, the mechanisms of regulation of MSI-1 levels remain largely unknown. Here, we investigated the regulation of MSI-1 by NOTCH signaling in colorectal cancer cell lines and in primary cultures of colorectal cancer metastases. Stimulation by the NOTCH ligand DLL4 was associated with an increase of MSI-1 mRNA and protein levels, and this phenomenon was prevented by the addition of an antibody neutralizing NOTCH2/3 but not NOTCH1. Moreover, forced expression of activated NOTCH3 increased MSI-1 levels, whereas silencing of NOTCH3 by short hairpin RNA reduced MSI-1 levels in both colorectal cancer cells and CRC tumor xenografts. Consistent with these findings, enforced NOTCH3 expression or stimulation by DLL4 increased levels of activated NOTCH1 in colorectal cell lines. Finally, treatment of colorectal cancer cells with anti-NOTCH2/3 antibody increased NUMB protein while significantly reducing formation of tumor cell spheroids. This novel feed-forward circuit involving DLL4, NOTCH3, MSI-1, NUMB, and NOTCH1 may be relevant for regulation of NOTCH signaling in physiologic processes as well as in tumor development. With regard to therapeutic implications, NOTCH3-specific drugs could represent a valuable strategy to limit NOTCH signaling in the context of colorectal cancers overexpressing this receptor. Cancer Res; 74(7); 2106-18. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

NOTCH3 Signaling Regulates MUSASHI-1 Expression in Metastatic Colorectal Cancer Cells

et al. 2014

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“…It can be regulated by ELAV or HuR by maintaining the stabilization of its mRNA or accumulation of mRNA translation (7,8), as well as by tumor suppressor microRNAs (9). It was first found in Drosophila as a determinant of sensory organ development (10) and highly conserved across species (11) with essential roles in the stem cell maintenance, nervous system development and tumorigenesis (12,13).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Msi1 suppresses the growth of human colon cancer by targeting p21cip1

Gao¹,

Han²,

Yu³

et al. 2014

International Journal of Oncology

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Abstract. Musashi1 (Msi1), a member of the RNA-binding protein (RBP) family, is highly expressed in neural progenitor or stem cells for the maintenance of stemness as well as in various cancers. Emerging studies have demonstrated that it regulates cell processes by translational activation or suppresses specifically bound mRNA. In the present study, we initially reported remarkably increased expression of Msi1 in colon cancer tissues compared with adjacent nontumor tissues. Knockdown of Msi1 significantly suppressed the proliferation, colony formation, tumorsphere formation and the progression of implanted colon cancers, and induced cell cycle attest at G 0 /G 1 phase, along with the upregulated expression of p21 cip1 . Reporter assays using a chimeric mRNA that combined luciferase and the 3'-UTR of p21 cip1 revealed that Msi1 decreased the reporter activity through the specific motif. Thus, the current results suggested that downregulation of Msi1 could inhibit the growth of colon cancers and Msi1 may be a promising therapeutic target molecule for human colon cancers.

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“…Many RNA-binding proteins have important roles in the initiation and progression of glioblastoma, including LIN28 (7), PCBP2 (8), HuR (9-11), Quaking (12), and Musashi1 (MSI1) (13)(14)(15)(16)(17)(18)(19)(20)(21). Among these, MSI1 stands out due to its evolutionary conservation, connection to neural stem cells, and role in balancing self-renewal and differentiation (18,(22)(23)(24)(25)(26).…”

mentioning

confidence: 99%

RNA-Binding Protein Musashi1 Is a Central Regulator of Adhesion Pathways in Glioblastoma

Uren

Araújo

et al. 2015

Molecular and Cellular Biology

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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 individualnucleotide 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.

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The oncogenic RNA-binding protein Musashi1 is regulated by tumor suppressor miRNAs

Cited by 66 publications

References 92 publications

NOTCH3 Signaling Regulates MUSASHI-1 Expression in Metastatic Colorectal Cancer Cells

NOTCH3 Signaling Regulates MUSASHI-1 Expression in Metastatic Colorectal Cancer Cells

Downregulation of Msi1 suppresses the growth of human colon cancer by targeting p21cip1

RNA-Binding Protein Musashi1 Is a Central Regulator of Adhesion Pathways in Glioblastoma

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