Structural and functional studies of FKHR-PAX3, a reciprocal fusion gene of the t(2;13) chromosomal translocation in alveolar rhabdomyosarcoma.

Structural and functional studies of FKHR-PAX3, a reciprocal fusion gene of the t(2;13) chromosomal translocation in alveolar rhabdomyosarcoma.

Blog Article

Alveolar rhabdomyosarcoma (ARMS) is an aggressive pediatric cancer of skeletal muscle.More than 70% of ARMS tumors carry balanced t(2;13) chromosomal translocation that leads to the production of two novel fusion genes, PAX3-FKHR and FKHR-PAX3.While the PAX3-FKHR gene has been intensely studied, the reciprocal FKHR-PAX3 gene has rarely been described.We report here the cloning and functional characterization of the FKHR-PAX3 gene as the first step towards a better understanding of its potential impact on ARMS biology.

From RH30 ARMS cells, we detected and isolated three versions of Vehicle Alarm FKHR-PAX3 cDNAs whose C-terminal sequences corresponded to PAX3c, PAX3d, and PAX3e isoforms.Unlike the nuclear-specific localization of PAX3-FKHR, the reciprocal FKHR-PAX3 proteins stayed predominantly in the cytoplasm.FKHR-PAX3 potently inhibited myogenesis in both non-transformed myoblast cells and ARMS cells.We showed that FKHR-PAX3 was not a classic oncogene but could act as a facilitator in oncogenic pathways by stabilizing PAX3-FKHR expression, enhancing cell proliferation, clonogenicity, anchorage-independent growth, and matrix Vitamin E adhesion in vitro, and accelerating the onset of tumor formation in xenograft mouse model in vivo.

In addition to these pro-oncogenic behaviors, FKHR-PAX3 also negatively affected cell migration and invasion in vitro and lung metastasis in vivo.Taken together, these functional characteristics suggested that FKHR-PAX3 might have a critical role in the early stage of ARMS development.