Functional studies of Betaig-H3 in tumori-genesis

Our lab has identified a central role of c-Fos, a component of the AP-1 transcription factor complex, in at least two types of sarcoma formation, rhabdomyo- and osteo-sarcoma. Transgenic over-expression of c-Fos leads to transformation of the bone-forming osteoblasts and ultimately osteosarcoma (OS) formation, whereas complete loss of c-Fos in a p53 null background is sufficient for rhabdomyosarcoma (RMS) development in the extraocular muscles of the orbit. To identify the relevant genes in RMS formation, we employed microarray analysis of cells derived from the RMS tumors with or without the re-expression of c-Fos and identified Betaig H3 as a potential key component in RMS formation or progression. Expression of this protein is commonly suppressed in many types of human cancer including rhabdomyosarcoma and has been reported having regulatory properties regarding bone development, cellular migration, adherence, apoptosis, angiogenesis and tumor suppression. As most ot these studies were performed with in vitro methods we plan to investigate the role of this protein in vivo specifically in the context of these two c-Fos-linked sarcoma models. To this end, we will generate transgenic mice that over- express or utilize shRNA technology to silence expression of Betaig H3. These mice will be crossed into the sarcoma "prone" genetic backrounds and tumor parameters such as initiation, progression, angiogenesis and tumor- specific markers will be analyzed. These studies will provide novel molecular insights into the pathogenesis of these two important human cancers.

Our lab has identified a central role of c-Fos, a component of the AP-1 transcription factor complex, in at least two types of sarcoma formation, rhabdomyo- and osteo-sarcoma. Transgenic over-expression of c-Fos leads to transformation of the bone-forming osteoblasts and ultimately osteosarcoma (OS) formation, whereas complete loss of c-Fos in a p53 null background is sufficient for rhabdomyosarcoma (RMS) development in the extraocular muscles of the orbit. To identify the relevant genes in RMS formation, we employed microarray analysis of cells derived from the RMS tumors with or without the re-expression of c-Fos and identified Betaig H3 as a potential key component in RMS formation or progression. Expression of this protein is commonly suppressed in many types of human cancer including rhabdomyosarcoma and has been reported having regulatory properties regarding bone development, cellular migration, adherence, apoptosis, angiogenesis and tumor suppression. As most ot these studies were performed with in vitro methods we plan to investigate the role of this protein in vivo specifically in the context of these two c-Fos-linked sarcoma models. To this end, we will generate transgenic mice that over- express or utilize shRNA technology to silence expression of Betaig H3. These mice will be crossed into the sarcoma "prone" genetic backrounds and tumor parameters such as initiation, progression, angiogenesis and tumor- specific markers will be analyzed. These studies will provide novel molecular insights into the pathogenesis of these two important human cancers.