THESIS
2018
viii, 81 pages : color illustrations ; 30 cm
Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma found in children
and young adults. By screening for potential tumor suppressive microRNAs in two
RMS cell lines, we found that miR-515-5p exibited tumor suppressive functions: it is
downregulated in a large fraction of RMS biopsies; its overexpression inhibited tumor
growth in nude mice and cell proliferation and migration in cell culture. Our previous
work showed that the gene encoding GTPase activating protein (SH3 domain) binding
protein 2 (G3bp2), was a target of miR-515-5p. G3BP2 is overexpressed in several types
of human cancers and exhibits oncogenic properties: knocking down G3bp2 in RMS-derived
cells inhibited cell proliferation and migration.
It remains unclear how G3BP2 exerts its oncogenic activity. To f...[
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Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma found in children
and young adults. By screening for potential tumor suppressive microRNAs in two
RMS cell lines, we found that miR-515-5p exibited tumor suppressive functions: it is
downregulated in a large fraction of RMS biopsies; its overexpression inhibited tumor
growth in nude mice and cell proliferation and migration in cell culture. Our previous
work showed that the gene encoding GTPase activating protein (SH3 domain) binding
protein 2 (G3bp2), was a target of miR-515-5p. G3BP2 is overexpressed in several types
of human cancers and exhibits oncogenic properties: knocking down G3bp2 in RMS-derived
cells inhibited cell proliferation and migration.
It remains unclear how G3BP2 exerts its oncogenic activity. To further elucidate the
function of G3BP2, I conducted the yeast two-hybrid assays to search for G3BP2-interacting proteins. As a result, CAPRIN1, TROPHININ and RPS6KB2 were found to
be novel G3BP2 interacting proteins. We further demonstrated that G3BP2 formed a
complex with CAPRIN1 to regulate the translation of Myc and to promote RMS cell
proliferation. In addition, G3BP2 also formed complexes with TROPHININ or
RPS6KB2 to regulate the kinase activity of LIMK2, which is important for the
dynamics of actin cytoskeleton, and to promote RMS cell migration.
Collectively, we demonstrated that miR-515-5p is a tumor suppressor frequently
downregulated in RMS. It exerts its function by suppressing G3BP2, an oncogenic
protein that promotes the proliferation and migration of RMS cells.
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