Recurrent Focal Copy-Number Changes and Loss of Heterozygosity Implicate Two Noncoding RNAs and One Tumor Suppressor Gene at Chromosome 3q13.31 in Osteosarcoma

Pašić, Ivan; Durbin, Adam D.; Stavropoulos, Dimitrios J.; Baskin, Berivan; Ray, Peter N.; Novokmet, Ana; Malkin, David

doi:10.1158/0008-5472.can-09-1902

Cited by 148 publications

(142 citation statements)

References 39 publications

(61 reference statements)

Supporting

Mentioning

124

Contrasting

Order By: Relevance

“…3). Notably, similar deletions at the 3q13.31 site are frequent in primary osteosarcomas (28)(29)(30) and cancer cell lines (31), whereas a small number of de novo CNVs in the AUTS2 gene have been reported in individuals with neurological disorders, including autism (32)(33)(34). It is possible that there is a selective advantage in culture for cells with CNVs in these regions.…”

Section: Resultsmentioning

confidence: 98%

Hydroxyurea induces de novo copy number variants in human cells

Arlt¹,

Ozdemir²,

Birkeland

et al. 2011

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

103

View full text Add to dashboard Cite

Copy number variants (CNVs) are widely distributed throughout the human genome, where they contribute to genetic variation and phenotypic diversity. Spontaneous CNVs are also a major cause of genetic and developmental disorders and arise frequently in cancer cells. As with all mutation classes, genetic and environmental factors almost certainly increase the risk for new and deleterious CNVs. However, despite the importance of CNVs, there is limited understanding of these precipitating risk factors and the mechanisms responsible for a large percentage of CNVs. Here we report that low doses of hydroxyurea, an inhibitor of ribonucleotide reductase and an important drug in the treatment of sickle cell disease and other diseases induces a high frequency of de novo CNVs in cultured human cells that resemble pathogenic and aphidicolin-induced CNVs in size and breakpoint structure. These CNVs are distributed throughout the genome, with some hotspots of de novo CNV formation. Sequencing revealed that CNV breakpoint junctions are characterized by short microhomologies, blunt ends, and short insertions. These data provide direct experimental support for models of replication-error origins of CNVs and suggest that any agent or condition that leads to replication stress has the potential to induce deleterious CNVs. In addition, they point to a need for further study of the genomic consequences of the therapeutic use of hydroxyurea.

show abstract

Section: Resultsmentioning

confidence: 98%

Hydroxyurea induces de novo copy number variants in human cells

Arlt¹,

Ozdemir²,

Birkeland

et al. 2011

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

103

View full text Add to dashboard Cite

show abstract

“…Researchers began to seek for related lncRNA in the occurrence and progression of osteosarcoma, so as to develop new diagnostic markers and therapeutic targets. But at present, researches in this field are still rarely reported (Pasic et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…But research of lncRNA effects on osteosarcoma is still in the preliminary stage, and the related reports are rare (Pasic et al, 2010). LncRNA Taurine Up -regulated Gene 1 (TUG1) was initially identified as a transcript up -regulated by taurine, siRNA -based depletion of TUG1 suppresses mouse retinal development (Young et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of Long Non-coding RNA TUG1 Inhibits Osteosarcoma Cell Proliferation and Promotes Apoptosis

Zhang¹,

Geng²,

Yin³

et al. 2013

Asian Pacific Journal of Cancer Prevention

177

137

View full text Add to dashboard Cite

Objective: To investigate the expression level of TUG1 and one of its transcript variants (n377360) in osteosarcoma cells and assess the role of TUG1 in proliferation and apoptosis in the U2OS cell line. Methods: TUG1 and n377360 expression levels in patients with osteosarcomas and the U2OS human osteosarcoma cell line were evaluated using real-time quantitative PCR. U2OS cells were transected with TUG1 and n377360 siRNA or non-targeting siRNA. MTS was performed to assess the cell proliferation and flow cytometry was applied to analyze apoptosis. Results: We found significantly higher TUG1 and n377360 expression levels in osteosarcoma tissues compared with matched non-tumorous tissues. In line with this, suppression of TUG1 and n377360 expression by siRNA significantly impaired the cell proliferation potential of osteosarcoma cells. Furthermore, inhibition of TUG1 expression significantly promoted osteosarcoma cell apoptosis. Conclusions: The overexpression of TUG1 and n377360 in osteosarcoma specimens and the functional role of TUG1 and n377360 regarding cell proliferation and apoptosis in an osteosarcoma cell line provided evidence that the use of TUG1 or n377360 may be a viable but an as yet unexplored therapeutic strategy in tumors that over express these factors.

show abstract

“…Although the underlying mechanism is generally unknown, it has been proposed that the expression of certain lncRNAs in CRC can be initiated or modulated by genetic (eg, SNPs in BA318C17.1, 66 sequence mutation of MALAT-1 67 ), epigenetic (eg, MIR211-dependent regulation of LOC285194, histone deacetylationinduced hypoxia-mediated downregulation of lncRNA-LET/NPTN-IT1 68 ), and transcriptional (eg, TCF7L2-dependent regulation of CCAT2, 58 TP53-dependent regulation of PVT1 69 ) regulatory factors and may allow for the exact execution of malignant transformation to some extent. 58,67,68 Intriguingly, in addition to being affected by MIR211, 64 LOC285194 was also found to be regulated by genetic deletion (copy number variation) and TP53, 64,65 suggesting that the expression of specific lncRNAs may be regulated by several regulatory mechanisms.…”

Section: Regulation Of Lncrna Expressionmentioning

confidence: 99%

Long non-coding RNAs in colorectal cancer: implications for pathogenesis and clinical application

Pan

2014

Modern Pathology

102

View full text Add to dashboard Cite

Long non-coding RNAs (lncRNAs) are a class of newly identified non-coding RNA molecules that are emerging as key regulators of tumor initiation and development. Colorectal cancer (CRC) remains a major health problem worldwide, and there remains a need to further refine the current screening approaches as well as provide tailored diagnostic and therapeutic approaches. Multiple dysregulated lncRNAs participate in tumorigenesis through a variety of molecular mechanisms, and various regulatory factors frequently contribute to the aberrant expression of lncRNAs in CRC, thereby allowing malignant transformation. Additionally, the association of dysregulated lncRNAs with specific developmental stages and clinical outcomes indicates their potential as strong diagnostic and prognostic predictors as well as therapeutic targets. Here we provide a brief overview of the known functions of CRC-associated lncRNAs, describe some potential molecular mechanisms that underlie changes in lncRNA expression in CRC, and attempt to uncover their clinical and therapeutic potential. Keywords: colorectal cancer; diagnosis; dysregulation; long non-coding RNA; prognosis High-throughput genome-scale studies have demonstrated that more than 93% of the DNA sequences in the human genome are actively transcribed. 1 However, only approximately 5-10% of the sequences are stably transcribed into mRNA or non-coding RNA (ncRNA). Genome tiling arrays have revealed that the amount of non-coding sequence is at least four times larger than the amount of coding sequence, which indicates that only 1% of the human genome is composed of protein-coding genes and the remaining 4-9% is transcribed into ncRNAs. 2 Therefore, ncRNAs constitute a very large proportion of the total RNA molecules.The function and clinical significance of short regulatory ncRNAs, such as microRNAs (miRNAs) and small interfering RNAs (siRNAs), were elucidated first, 3 and the regulatory roles of miRNAs have been broadly recognized in almost all physiological and pathological processes in the body, including carcinogenesis. 4 For example, we previously reported that MIR95 promotes cell proliferation and targets sorting nexin 1 in human colorectal carcinoma; 5 moreover, in colorectal cancer (CRC) patients, the plasma levels of MIR29a and MIR92a are significantly upregulated and the plasma levels of MIR601 and MIR760 are significantly downregulated; thus the levels of these miRNAs have good diagnostic value for CRC screening. 6,7 According to their transcript size, ncRNAs are grouped into two major classes: (i) small ncRNAs with transcripts o200 nucleotides (nt; eg, aforementioned siRNAs and miRNAs, Piwi-interacting RNAs, and some retrotransposon-derived RNAs) and (ii) long non-coding RNAs (lncRNAs), this class includes five broad categories: sense, antisense, bidirectional, intronic, and intergenic, based on the proximity between neighboring transcripts. 8 For a time, lncRNAs was commonly defined as a proteincoding transcripts that is 4200 nt. 9 However, this definition is arbitrary and ...

show abstract

Recurrent Focal Copy-Number Changes and Loss of Heterozygosity Implicate Two Noncoding RNAs and One Tumor Suppressor Gene at Chromosome 3q13.31 in Osteosarcoma

Cited by 148 publications

References 39 publications

Hydroxyurea induces de novo copy number variants in human cells

Hydroxyurea induces de novo copy number variants in human cells

Down-regulation of Long Non-coding RNA TUG1 Inhibits Osteosarcoma Cell Proliferation and Promotes Apoptosis

Long non-coding RNAs in colorectal cancer: implications for pathogenesis and clinical application

Contact Info

Product

Resources

About