The runx genes: gain or loss of function in cancer

Blyth, Karen; Cameron, Ewan R.; Neil, James C.

doi:10.1038/nrc1607

Cited by 418 publications

(435 citation statements)

References 173 publications

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“…(7,10) However, the RUNX genes have paradoxical roles in cancer, where they can function either as dominant oncogenes or as tumor suppressors based on the exact context. (48) In this study we present a novel mechanism of growth inhibition by RUNX2. Our data clearly show that transfection of hMSCs with siRNA able to inhibit RUNX2 expression and activity led to elevated expression of S-G 2 -M cyclins and a concomitant decrease in expression of the cyclin inhibitor p21 and the proapoptotic factor Bax.…”

Section: Discussionmentioning

confidence: 98%

TNF-α's effects on proliferation and apoptosis in human mesenchymal stem cells depend on RUNX2 expression

Ghali

Chauveau

Hardouin

et al. 2010

Journal of Bone and Mineral Research

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RUNX2 is a bone-specific transcription factor that plays a critical role in prenatal bone formation and postnatal bone development. It regulates the expression of genes that are important in committing cells into the osteoblast lineage. There is increasing evidence that RUNX2 is involved in osteoblast proliferation. RUNX2 expression increases during osteoblast differentiation, and recent data even suggest that it acts as a proapoptotic factor. The cytokine tumor necrosis factor a (TNF-a) is known to modulate osteoblast functions in a manner that depends on the differentiation stage. TNF-a affects the rate at which mesenchymal precursor cells differentiate into osteoblasts and induces apoptosis in mature osteoblasts. Thus we sought to establish whether or not the effects of TNF-a and fetal calf serum on proliferation and apoptosis in human mesenchymal stem cells (hMSCs) were dependent on RUNX2 level and activity. We transfected hMSCs with small interfering RNAs (siRNAs) directed against RUNX2 and found that they proliferated more quickly than control hMSCs transfected with a nonspecific siRNA. This increase in proliferation was accompanied by a rise in cyclin A1, B1, and E1 expression and a decrease in levels of the cyclin inhibitor p21. Moreover, we observed that RUNX2 silencing protected hMSCs from TNF-a's antiproliferative and apoptotic effects. This protection was accompanied by the inhibition of caspase-3 activity and Bax expression. Our results confirmed that RUNX2 is a critical link between cell fate, proliferation, and growth control. This study also suggested that, depending on the osteoblasts' differentiation stage, RUNX2 may control cell growth by regulating the expression of elements involved in hormone and cytokine sensitivity. ß

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Section: Discussionmentioning

confidence: 98%

TNF-α's effects on proliferation and apoptosis in human mesenchymal stem cells depend on RUNX2 expression

Ghali

Chauveau

Hardouin

et al. 2010

Journal of Bone and Mineral Research

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“…leukemia and lately in gastric cancer (Blyth et al, 2005;Sakakura et al, 2005). Adducin -a substrate of protein kinase C (PKC) -has been associated before with asbestos exposure (Shukla et al, 2003b).…”

Section: Discussionmentioning

confidence: 99%

Gene expression and copy number profiling suggests the importance of allelic imbalance in 19p in asbestos-associated lung cancer

et al. 2007

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Asbestos is a pulmonary carcinogen known to give rise to DNA and chromosomal damage, but the exact carcinogenic mechanisms are still largely unknown. In this study, gene expression arrays were performed on lung tumor samples from 14 heavily asbestos-exposed and 14 nonexposed patients matched for other characteristics. Using a two-step statistical analysis, 47 genes were revealed that could differentiate the tumors of asbestos-exposed from those of non-exposed patients. To identify asbestosassociated regions with DNA copy number and expressional changes, the gene expression data were combined with comparative genomic hybridization microarray data. As a result, a combinatory profile of DNA copy number aberrations and expressional changes significantly associated with asbestos exposure was obtained. Asbestosrelated areas were detected in 2p21-p16. 3, 3p21.31, 5q35.2-q35.3, 16p13.3, 19p13.3-p13.1 and 22q12.3-q13.1. The most prominent of these, 19p13, was further characterized by microsatellite analysis in 62 patients for the differences in allelic imbalance (AI) between the two groups of lung tumors. 79% of the exposed and 45% of the non-exposed patients (P ¼ 0.008) were found to be carriers of AI in their lung tumors. In the exposed group, AI in 19p was prevalent regardless of the histological tumor type. In adenocarcinomas, AI in 19p appeared to occur independently of the asbestos exposure.

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“…In the present study, a minimally deleted region in 1p36.31 -p36.11 was found. This region contains several genes including RUNX3, a transcription factor, which has been shown to be frequently deleted or transcriptionally silenced in a number of cancers, and it has been suggested to encode an important tumour suppressor (Blyth et al, 2005). Furthermore, this gene has been shown to be implicated in chondrocyte maturation, providing a biological link to the development of chordoma (Soung et al, 2007).…”

Section: Frequently Deleted Regionsmentioning

confidence: 99%

Frequent deletion of the CDKN2A locus in chordoma: analysis of chromosomal imbalances using array comparative genomic hybridisation

et al. 2007

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The initiating somatic genetic events in chordoma development have not yet been identified. Most cytogenetically investigated chordomas have displayed near-diploid or moderately hypodiploid karyotypes, with several numerical and structural rearrangements. However, no consistent structural chromosome aberration has been reported. This is the first array-based study characterising DNA copy number changes in chordoma. Array comparative genomic hybridisation (aCGH) identified copy number alterations in all samples and imbalances affecting 5 or more out of the 21 investigated tumours were seen on all chromosomes. In general, deletions were more common than gains and no high-level amplification was found, supporting previous findings of primarily losses of large chromosomal regions as an important mechanism in chordoma development. Although small imbalances were commonly found, the vast majority of these were detected in single cases; no small deletion affecting all tumours could be discerned. However, the CDKN2A and CDKN2B loci in 9p21 were homo-or heterozygously lost in 70% of the tumours, a finding corroborated by fluorescence in situ hybridisation, suggesting that inactivation of these genes constitute an important step in chordoma development.

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The runx genes: gain or loss of function in cancer

Cited by 418 publications

References 173 publications

TNF-α's effects on proliferation and apoptosis in human mesenchymal stem cells depend on RUNX2 expression

TNF-α's effects on proliferation and apoptosis in human mesenchymal stem cells depend on RUNX2 expression

Gene expression and copy number profiling suggests the importance of allelic imbalance in 19p in asbestos-associated lung cancer

Frequent deletion of the CDKN2A locus in chordoma: analysis of chromosomal imbalances using array comparative genomic hybridisation

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