Gain-of-function mutant p53 downregulates miR-223 contributing to chemoresistance of cultured tumor cells

Masciarelli, Silvia; Fontemaggi, Giulia; Agostino, Silvia Di; Donzelli, Sara; Carcarino, Elena; Strano, Sabrina; Blandino, Giovanni

doi:10.1038/onc.2013.106

Cited by 120 publications

(102 citation statements)

References 57 publications

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“…MiRNAs are also frequently located near fragile sites in the genome, as well as commonly amplified regions or common breakpoints, indicating that genomic instability can also result in miRNA dysregulation (19). Aberrant expression or mutation of transcription factors may also result in dysregulation of miRNA expression in cancer, a phenomenon that has been extensively studied in relation to p53 (20)(21)(22)(23)(24). However, there is little information regarding the miRNAs regulated by CDX1 and how miRNAs contribute to the effects of CDX1 on stem cells and differentiation in CRC.…”

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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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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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“…[29][30][31] STMN1, which has a role in cell migration, was reported to be upregulated by mutp53. 32 It is possible that some of these genes mediate the promoting effect of Pontin on mutp53 GOF. Mutp53 often transcriptionally regulates genes through interacting with other transcription factors, including SREBP, NF-Y, VDR, NF-κB, and binding to the binding sites of their regulated genes.…”

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confidence: 99%

Pontin, a new mutant p53-binding protein, promotes gain-of-function of mutant p53

et al. 2015

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“…Transfecting miR-223 into these cells reduced the STMN1 protein and addition of an miR-223 blocker rescued STMN1 expression, suggesting that the suppressive effect was specifically caused by miR-223 (17). More recently, the interaction between miR-223 and STMN1 in p53 mutant breast and colon cancer cells was demonstrated (23). Mutant p53 was shown to upregulate STMN1 via miR-223 downregulation and as a consequence enhances the chemoresistance of these cells.…”

Section: Discussionmentioning

confidence: 94%

“…Recent evidence suggests that miR-223 may behave as an oncogene or tumor suppressor in a range of hematopoietic and solid tumors (16)(17)(18)(19)(20)(21) and can regulate functions, such as proliferation, migration (16,22), and chemoresistance (23) in these malignancies. The role of miR-223 in MPM is unknown.…”

Section: Introductionmentioning

confidence: 99%

Loss of miR-223 and JNK Signaling Contribute to Elevated Stathmin in Malignant Pleural Mesothelioma

Birnie

Yip

et al. 2015

Molecular Cancer Research

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Malignant pleural mesothelioma (MPM) is often fatal, and studies have revealed that aberrant miRNAs contribute to MPM development and aggressiveness. Here, a screen of miRNAs identified reduced levels of miR-223 in MPM patient specimens. Interestingly, miR-223 targets Stathmin (STMN1), a microtubule regulator that has been associated with MPM. However, whether miR-223 regulates STMN1 in MPM and the functions of miR-223 and STMN1 in this disease are yet to be determined. STMN1 is also regulated by c-Jun N-terminal kinase (JNK) signaling, but whether this occurs in MPM and whether miR-223 plays a role are unknown. The relationship between STMN1, miR-223, and JNK was assessed using MPM cell lines, cells from pleural effusions, and MPM tissue. Evidence indicates that miR-223 is decreased in all MPM tissue compared with normal/healthy tissue. Conversely, STMN1 expression was higher in MPM cell lines when compared with primary mesothelial cell controls. Following overexpression of miR-223 in MPM cell lines, STMN1 levels were reduced, cell motility was inhibited, and tubulin acetylation induced. Knockdown of STMN1 using siRNAs led to inhibition of MPM cell proliferation and motility. Finally, miR-223 levels increased while STMN1 was reduced following the re-expression of the JNK isoforms in JNK-null murine embryonic fibroblasts, and STMN1 was reduced in MPM cell lines following the activation of JNK signaling.Implications: miR-223 regulates STMN1 in MPM, and both are in turn regulated by the JNK signaling pathway. As such, miR-223 and STMN1 play an important role in regulating MPM cell motility and may be therapeutic targets.

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Gain-of-function mutant p53 downregulates miR-223 contributing to chemoresistance of cultured tumor cells

Cited by 120 publications

References 57 publications

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

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

Pontin, a new mutant p53-binding protein, promotes gain-of-function of mutant p53

Loss of miR-223 and JNK Signaling Contribute to Elevated Stathmin in Malignant Pleural Mesothelioma

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