THESIS
2013
x, 68 p. : ill. (some col.) ; 30 cm
Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children
and young adults. It is characterized by the expression of one or several
muscle-specific genes including MyoD, myogenin, and desmin and thought to be
derived from deregulated muscle progenitor cells. microRNAs (miRNAs) are a class
of post-transcriptional regulators involved in various cellular processes and
developmental events. Dysregulated expression of miRNAs is associated with a
variety of diseases, including RMS. In our current study, we found that the expression
level of miR-203 was drastically reduced mainly due to promoter hypermethylation in
two RMS-derived cell lines (i.e., RD and Rh30) and a large fraction of RMS biopsies.
Re-expression of miR-203 in both RD and RH30 cells promoted partial myo...[
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Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children
and young adults. It is characterized by the expression of one or several
muscle-specific genes including MyoD, myogenin, and desmin and thought to be
derived from deregulated muscle progenitor cells. microRNAs (miRNAs) are a class
of post-transcriptional regulators involved in various cellular processes and
developmental events. Dysregulated expression of miRNAs is associated with a
variety of diseases, including RMS. In our current study, we found that the expression
level of miR-203 was drastically reduced mainly due to promoter hypermethylation in
two RMS-derived cell lines (i.e., RD and Rh30) and a large fraction of RMS biopsies.
Re-expression of miR-203 in both RD and RH30 cells promoted partial myogenic
differentiation and inhibited cell proliferation both in vitro and in vivo. p63, a member
of the p53 tumor suppressor family, and Leukemia inhibitory factor receptor (LIFR)
were found to be key direct targets of miR-203 in these RMS cells. We showed that
p63 positively regulated the Notch pathway by stimulating the expression of Jagged1,
while LIFR was required for the activation of the JAK1/STAT1/STAT3 pathway.
Re-expression of miR-203 in RMS cells led to the down regulation of both the Notch
and the JAK1/STAT1/STAT3 pathways, which promote myogenic differentiation.
To identify additional tumor suppressive miRNAs that are down regulated by
promoter hypermethylation in RMS, we treated both RD and Rh30 cells with
5'-azacytidine and performed quantitative PCR-based microRNA screening. Among
positive hits we identified, we selected miR-515-5p for further in-depth analysis. The
GTPase activating protein (SH3 domain) binding protein 2 (G3BP2) gene was found
to be a direct target of miR-515-5p.Although G3BP2 has been found to be
over-expressed in tumors, its role in tumorigenesis remains unclear. Work is underway
to further characterize its role in RMS.
Collectively, we have identified two new tumor suppressive miRNAs that are
down regulated in RMS mainly by promoter hypermethylation. They would serve as
new targets for therapeutic treatment of RMS in the future.
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