Down-regulation of miR-515-5p contributes to the development of rhabdomyosarcoma through G3BP2

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 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.

Date of Award	2018
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology