Coordinated Regulation of Cell Cycle Transcripts by p53-Inducible microRNAs, miR-192 and miR-215

Georges, Sara A.; Biery, Matthew C.; Kim, Soo-Yeon; Schelter, Janell M.; Guo, Jane; Chang, Aaron N.; Jackson, Aimee L.; Carleton, Michael; Linsley, Peter S.; Cleary, Michele A.; Chau, B. Nelson

doi:10.1158/0008-5472.can-08-1846

Cited by 316 publications

(250 citation statements)

References 39 publications

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“…miR-215 is also reduced in metastatic renal cell carcinomas and over-expression is able to decrease cell migration and invasion in vitro (White et al 2011). Interestingly, miR-215 functions as a tumour suppressor with its activation inducing cell cycle arrest in a p53-dependent manner (Georges et al 2008). We also found that miR-31-5p (miR-31) was significantly downregulated in SBNETs compared with NSB mucosae in both profiling experiments ( Supplementary Fig.…”

Section: Global Mirna Profiling Reveals a Signature Specific For Smalmentioning

confidence: 61%

MicroRNAs associated with small bowel neuroendocrine tumours and their metastases

Miller¹,

Frampton²,

Malczewska³

et al. 2016

Endocrine-Related Cancer

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Novel molecular analytes are needed in small bowel neuroendocrine tumours (SBNETs) to better determine disease aggressiveness and predict treatment response. In this study, we aimed to profile the global miRNome of SBNETs, and identify microRNAs (miRNAs) involved in tumour progression for use as potential biomarkers. Two independent miRNA profiling experiments were performed (n = 90), including primary SBNETs (n = 28), adjacent normal small bowel (NSB; n = 14), matched lymph node (LN) metastases (n = 24), normal LNs (n = 7), normal liver (n = 2) and liver metastases (n = 15). We then evaluated potentially targeted genes by performing integrated computational analyses. We discovered 39 miRNAs significantly deregulated in SBNETs compared with adjacent NSB. The most upregulated (miR-204-5p, miR-7-5p and miR-375) were confirmed by qRT-PCR. Two miRNAs (miR-1 and miR-143-3p) were significantly downregulated in LN and liver metastases compared with primary tumours. Furthermore, we identified upregulated gene targets for miR-1 and miR-143-3p in an existing SBNET dataset, which could contribute to disease progression, and show that these miRNAs directly regulate FOSB and NUAK2 oncogenes. Our study represents the largest global miRNA profiling of SBNETs using matched primary tumour and metastatic samples. We revealed novel miRNAs deregulated during SBNET disease progression, and important miRNA-mRNA interactions. These miRNAs have the potential to act as biomarkers for patient stratification and may also be able to guide treatment decisions. Further experiments to define molecular mechanisms and validate these miRNAs in larger tissue cohorts and in biofluids are now warranted.

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Section: Global Mirna Profiling Reveals a Signature Specific For Smalmentioning

confidence: 61%

MicroRNAs associated with small bowel neuroendocrine tumours and their metastases

Miller¹,

Frampton²,

Malczewska³

et al. 2016

Endocrine-Related Cancer

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“…Although the miR-194-215 primary transcript has previously been implicated in the p53-mediated DNA damage response (29)(30)(31), the exact location of the 5′ end of the transcript has thus far eluded efforts to characterize the transcription start site (TSS). The standard method for identifying a TSS, 5′ rapid amplification of cDNA ends (5′RACE) (Fig.…”

Section: Resultsmentioning

confidence: 99%

The CDX1–microRNA-215 axis regulates colorectal cancer stem cell differentiation

Jones

Hara²,

Francis

et al. 2015

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

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The transcription factor caudal-type homeobox 1 (CDX1) is a key regulator of differentiation in the normal colon and in colorectal cancer (CRC). CDX1 activates the expression of enterocyte genes, but it is not clear how the concomitant silencing of stem cell genes is achieved. MicroRNAs (miRNAs) are important mediators of gene repression and have been implicated in tumor suppression and carcinogenesis, but the roles of miRNAs in differentiation, particularly in CRC, remain poorly understood. Here, we identified microRNA-215 (miR-215) as a direct transcriptional target of CDX1 by using highthroughput small RNA sequencing to profile miRNA expression in two pairs of CRC cell lines: CDX1-low HCT116 and HCT116 with stable CDX1 overexpression, and CDX1-high LS174T and LS174T with stable CDX1 knockdown. Validation of candidate miRNAs identified by RNA-seq in a larger cell-line panel revealed miR-215 to be most significantly correlated with CDX1 expression. Quantitative ChIP-PCR and promoter luciferase assays confirmed that CDX1 directly activates miR-215 transcription. miR-215 expression is depleted in FACS-enriched cancer stem cells compared with unsorted samples. Overexpression of miR-215 in poorly differentiated cell lines causes a decrease in clonogenicity, whereas miR-215 knockdown increases clonogenicity and impairs differentiation in CDX1-high cell lines. We identified the genome-wide targets of miR-215 and found that miR-215 mediates the repression of cell cycle and stemness genes downstream of CDX1. In particular, the miR-215 target gene BMI1 has been shown to promote stemness and self-renewal and to vary inversely with CDX1. Our work situates miR-215 as a link between CDX1 expression and BMI1 repression that governs differentiation in CRC.T he caudal-type homeobox 1 (CDX1) transcription factor controls enterocyte differentiation in the colon, where its expression is excluded from the crypt-base stem cell compartment. CDX1 is also central to the capacity of a colorectal cancer (CRC) cell line to differentiate, and it is a negative marker of CRC stem cells (1-3). In 19% of CRC cell lines assayed in a large study, CDX1 expression was completely lost due to promoter methylation and was down-regulated in a further 13% as a result of hemimethylation of the promoter (4). Comparison of CDX1 expression in colorectal adenocarcinoma versus matched normal tissue showed downregulation of CDX1 in 73% of tumors, which was also attributable to promoter methylation (5). Expression of CDX1 also correlates inversely with that of the polycomb complex protein BMI1, which is necessary for the maintenance of quiescent injury-inducible stem cells in the normal crypt and is expressed in cancer stem cells (2, 6-8). The mechanism underlying this inverse correlation has not yet been elucidated.In addition to these correlative data, CDX1 has also been shown to promote directly the expression of structural proteins important for epithelial differentiation including cytokeratin 20 (KRT20) (1), villin (VIL) (9), and FABP1 (10). Introduction...

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“…A single administration of the miRNA inhibited multiple genes within oncogenic pathways of WnT/bCatenin, MapK, c-Met, Hedgehog, and VEGF and stimulated multiple genes within the p53 pathway. Hyperactivation of any of the five oncogenic pathways or suppression of the p53 pathway have proved to stimulate the development of hepatocellular carcinoma (HCC) in mice (16)(17)(18)(19)21) p53 is the most commonly mutated gene in patients with HCC (19,22) and reduced p53 activity appears to be a key early event in the development of liver tumors (23,24). Not surprisingly, the p53-regulated miR34a has reduced expression levels in liver tumors (4).…”

Section: Discussionmentioning

confidence: 99%

Systemic Delivery of a miR34a Mimic as a Potential Therapeutic for Liver Cancer

Daige

Wiggins

Priddy

et al. 2014

Molecular Cancer Therapeutics

144

103

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miR34a is a tumor-suppressor miRNA that functions within the p53 pathway to regulate cell-cycle progression and apoptosis. With apparent roles in metastasis and cancer stem cell development, miR34a provides an interesting opportunity for therapeutic development. A mimic of miR34a was complexed with an amphoteric liposomal formulation and tested in two different orthotopic models of liver cancer. Systemic dosing of the formulated miR34a mimic increased the levels of miR34a in tumors by approximately 1,000-fold and caused statistically significant decreases in the mRNA levels of several miR34a targets. The administration of the formulated miR34a mimic caused significant tumor growth inhibition in both models of liver cancer, and tumor regression was observed in more than one third of the animals. The antitumor activity was observed in the absence of any immunostimulatory effects or dose-limiting toxicities. Accumulation of the formulated miR34a mimic was also noted in the spleen, lung, and kidney, suggesting the potential for therapeutic use in other cancers. Mol Cancer Ther; 13(10); 2352-60. Ó2014 AACR.

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Coordinated Regulation of Cell Cycle Transcripts by p53-Inducible microRNAs, miR-192 and miR-215

Cited by 316 publications

References 39 publications

MicroRNAs associated with small bowel neuroendocrine tumours and their metastases

MicroRNAs associated with small bowel neuroendocrine tumours and their metastases

The CDX1–microRNA-215 axis regulates colorectal cancer stem cell differentiation

Systemic Delivery of a miR34a Mimic as a Potential Therapeutic for Liver Cancer

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