کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5890447 | 1568159 | 2014 | 15 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Mutant p53 gain of function can be at the root of dedifferentiation of human osteosarcoma MG63 cells into 3AB-OS cancer stem cells
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کلمات کلیدی
MmpsGOFCSCsHuman osteosarcoma - استئوسارکوم انسانیOsteosarcoma - استئوسارکوماGain of function - به دست آوردن عملکردMutant p53 - جهش p53Cancer stem cells - سلولهای بنیادی سرطانیfluorescent in situ hybridization - فلورسنت در محل hybridizationFish - ماهیMatrix metalloproteinases - متالوپروتئیناز ماتریکس
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شناسی تکاملی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
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 TRAIL-induced 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 stem-like 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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bone - Volume 60, March 2014, Pages 198-212
Journal: Bone - Volume 60, March 2014, Pages 198-212
نویسندگان
Riccardo Di Fiore, Michela Marcatti, Rosa Drago-Ferrante, Antonella D'Anneo, Michela Giuliano, Daniela Carlisi, Anna De Blasio, Francesca Querques, Lucio Pastore, Giovanni Tesoriere, Renza Vento,