The critical role of LIN28B in the pathogenesis of a subset of Ewing Sarcomas


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A Master's thesis.
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Master (thesis) (master)
The critical role of LIN28B in the pathogenesis of a subset of Ewing Sarcomas
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Université de Lausanne, Faculté de biologie et médecine
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Ewing Sarcoma is the second most frequent bone malignancy in children. It mainly affects children and young adults with a peak incidence at age 15. It remains associated with bad prognosis, not responding well to the current treatment protocols (chemotherapy and surgery). About 85% of Ewing Sarcomas are characterized by the chromosomal translocation t(11;22) (q24;q12), which leads to the formation of a fusion protein, namely EWS-FLI-1. EWS-FLI-1’s oncogenicity stems from the fact that it functions as an aberrant transcription factor leading to transcriptional activation and repression of crucial oncogenes and tumor suppressor genes. Recently, a particularly aggressive subset has been uncovered and found to be associated with the onco-fetal RNA binding protein LIN28. LIN28 is normally expressed during embryogenesis. During this time, it inhibits the maturation of the differentiation-inducing Let- 7 microRNA family and thereby promotes pluripotency. In Ewing sarcoma it seems to act at different levels. It binds directly to EWS-FLI-1 transcripts ensuring their stability. It also appears to promote tumor aggressiveness, partly by silencing Let-7 and partly by mechanisms that remain to be defined. Interestingly, in this subset of Ewing sarcoma LIN28 depletion leads to loss of self-renewal and tumorigenic properties. These observations lead to a clear and hopeful conclusion that LIN28 is a potential therapeutic target worthy of investigating. The main goals of the present study are to review the current literature on Ewing sarcoma and LIN28, to understand how LIN28B stabilizes EWS-FLI-1 transcripts and why EWS-FLI-1 stability depends on LIN28B in some Ewing sarcomas but not in others. In addition, we will strive to gain better understanding of LIN28 as a potential therapeutic target. It should be noted that the current epidemiological situation limited laboratory time. In this context, although we were not able to explore all paths, we hope this manuscript will be useful for future research in the field of Ewing Sarcoma and LIN28 as it includes a literature review and troubleshooting.
Ewing Sarcoma, LIN28, literature review, fundamental research, troubleshooting
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09/09/2021 9:56
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09/09/2022 6:38
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