Evaluation of paediatric osteosarcomas by classic cytogenetic and CGH analyses

Batanian, Jacqueline R.; Cavalli, Luciane R.; Aldosari, Naji; Ma, Esk; Sotelo‐Avila, Cirilo; Ramos, mariana Bastos; Rone, Janice D.; Thorpe, C M; Haddad, Bassem R.

doi:10.1136/mp.55.6.389

Cited by 42 publications

(34 citation statements)

References 24 publications

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“…Moreover, bioinformatic analyses selected 196 genes and 46 anticorrelated miRNAs involved in carcinogenesis and stemness [14]. Remarkably, the abnormalities evidenced in 3AB-OS cells appear to be strongly congruent with abnormalities described in a large number of pediatric and adult OS patients, where karyotype ranging from haploid to near hexaploid with chromosome number ranging from 15 to 120 were described; in addition, a great number of chromosomal regions with structural abnormalities among which 17p11.2-13 that contains TP53 gene were found [15][16][17].…”

Section: Introductionsupporting

confidence: 52%

Mutant p53 gain of function can be at the root of dedifferentiation of human osteosarcoma MG63 cells into 3AB-OS cancer stem cells

Fiore

Marcatti

Drago-Ferrante

et al. 2014

Bone

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Osteosarcoma is a highly metastatic tumor affecting adolescents, for which there is no second-line chemotherapy. As suggested for most tumors, its capability to overgrow is probably driven by cancer stem cells (CSCs), and finding new targets to kill CSCs may be critical for improving patient survival. TP53 is the most frequently mutated tumor suppressor gene in cancers and mutant p53 protein (mutp53) can acquire gain of function (GOF) strongly contributing to malignancy. Studies thus far have not shown p53-GOF in osteosarcoma. Here, we investigated TP53 gene status/role in 3AB-OS cells-a highly aggressive CSC line previously selected from human osteosarcoma MG63 cells-to evaluate its involvement in promoting proliferation, invasiveness, resistance to apoptosis and stemness. By RT-PCR, methylation-specific PCR, fluorescent in situ hybridization, DNA sequence, western blot and immunofluorescence analyses, we have shown that-in comparison with parental MG63 cells where TP53 gene is hypermethylated, rearranged and in single copy-in 3AB-OS cells, TP53 is unmethylated, rearranged and in multiple copies, and mutp53 (p53-R248W/P72R) is post-translationally modified and with nuclear localization. p53-R248W/P72R-knockdown by short-interfering RNA reduced the growth and replication rate of 3AB-OS cells, markedly increasing cell cycle inhibitor levels and sensitized 3AB-OS cells to TRAILinduced apoptosis by DR5 up-regulation; moreover, it strongly decreased the levels of stemness and invasiveness genes. We have also found that the ectopic expression of p53-R248W/P72R in MG63 cells promoted cancer stemlike features, as high proliferation rate, sphere formation, clonogenic growth, high migration and invasive ability; furthermore, it strongly increased the levels of stemness proteins. Overall, the findings suggest the involvement of p53-R248W/P72R at the origin of the aberrant characters of the 3AB-OS cells with the hypothesis that its GOF can be at the root of the dedifferentiation of MG63 cells into CSCs.

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Section: Introductionsupporting

confidence: 52%

Mutant p53 gain of function can be at the root of dedifferentiation of human osteosarcoma MG63 cells into 3AB-OS cancer stem cells

Fiore

Marcatti

Drago-Ferrante

et al. 2014

Bone

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“…Moreover, 3AB-OS cells show monosomies, trisomies and nullisomies, have 32 unidentifiable marker chromosomes, and exhibit -with respect to parental MG63 cells-49 copy number variations (gains/losses) affecting almost all the chromosomes [22] . Intriguingly, the abnormalities evidenced in 3AB-OS cells are very similar to those described in a large number of pediatric and adult osteosarcomas, where karyotypes ranging from haploid to near hexaploid have been shown [23][24][25] . Moreover, 3AB-OS cells showed losses/gains in agreement with those seen in osteosarcoma patients [23][24][25] .…”

Section: Research Highlightsupporting

confidence: 51%

“…Intriguingly, the abnormalities evidenced in 3AB-OS cells are very similar to those described in a large number of pediatric and adult osteosarcomas, where karyotypes ranging from haploid to near hexaploid have been shown [23][24][25] . Moreover, 3AB-OS cells showed losses/gains in agreement with those seen in osteosarcoma patients [23][24][25] . Comparing 3AB-OS cells to MG63 cells we reported the gene expression profile of 3AB-OS cells.…”

Section: Research Highlightsupporting

confidence: 51%

A short story of 3AB-OS Cancer Stem Cells, a possible model for studying cancer stemness

Fiore¹,

Drago-Ferrante

Marcatti

et al. 2014

Cancer Cell Microenviron

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“…The locus of paxillin, 17p8q, is not included in the areas where comparative genomic hybridization (CGH) analysis revealed that gene amplification is frequent in human osteosarcoma (Batanian et al, 2002;Squire et al, 2003;Lau et al, 2004). Paxillin mRNA in high-metastatic sublines is at most 1.7 times compared to that in low-metastatic sublines by cDNA microarray analysis (Nakano et al, personal communication).…”

Section: Discussionmentioning

confidence: 99%

Tyrosine phosphorylation of paxillin affects the metastatic potential of human osteosarcoma

Azuma

Tanaka²,

Uekita³

et al. 2005

Oncogene

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To acquire information on signal alteration corresponding to the changes in metastatic potential, we analysed protein tyrosine phosphorylation of low-and high-metastatic human osteosarcoma HuO9 sublines, which were recently established as the first metastatic model of human osteosarcoma. Tyrosine phosphorylation of proteins around 60, 70, and 120-130 kDa was enhanced in highmetastatic sublines. Among these proteins, the protein around 70 kDa, which was most remarkably phosphorylated, was identified as paxillin, a scaffold protein in integrin signaling. Activity of Src family kinase correlated well with metastatic potential, and a Src family kinase inhibitor, PP2, not only abolished tyrosine phosphorylation of paxillin but also impaired the motility of highmetastatic sublines. The expression of paxillin was also elevated in high-metastatic sublines, and knocking down of paxillin expression by RNAi method resulted in attenuated motility of high-metastatic cells. We also demonstrated that the phosphorylated form of paxillin is essential for the migration-promoting effect in human osteosarcoma. These findings suggest that enhanced activity of Src family kinases and overexpression of paxillin synergistically contribute to the high metastatic potential of human osteosarcoma through the hyperphosphorylation of paxillin.

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Evaluation of paediatric osteosarcomas by classic cytogenetic and CGH analyses

Cited by 42 publications

References 24 publications

Mutant p53 gain of function can be at the root of dedifferentiation of human osteosarcoma MG63 cells into 3AB-OS cancer stem cells

Mutant p53 gain of function can be at the root of dedifferentiation of human osteosarcoma MG63 cells into 3AB-OS cancer stem cells

A short story of 3AB-OS Cancer Stem Cells, a possible model for studying cancer stemness

Tyrosine phosphorylation of paxillin affects the metastatic potential of human osteosarcoma

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