Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates the Rho GTPase Cdc42; FGD1 mutations result in Faciogenital Dysplasia (FGDY, Aarskog syndrome), an X-linked developmental disorder that adversely affects the formation of multiple skeletal structures. To further define the role of FGD1 in skeletal development, we examined its expression in developing mouse embryos and correlated this pattern with FGDY skeletal defects. In this study, we show that Fgd1, the mouse FGD1 ortholog, is initially expressed during the onset of ossification during embryogenesis. Fgd1 is expressed in regions of active bone formation in the trabeculae and diaphyseal cortices of developing long bones. The onset of Fgd1 expression correlates with the expression of bone sialo-protein, a protein specifically expressed in osteoblasts at the onset of matrix mineralization; an analysis of serial sections shows that Fgd1 is expressed in tissues containing calcified and mineralized extracellular matrix. Fgd1 protein is specifically expressed in cultured osteoblast and osteoblast-like cells including MC3T3-E1 cells and human osteosarcoma cells but not in other mesodermal cells; immunohistochemical studies confirm the presence of Fgd1 protein in mouse calvarial cells. Postnatally, Fgd1 is expressed more broadly in skeletal tissue with expression in the perichondrium, resting chondrocytes, and joint capsule fibroblasts. The data indicate that Fgd1 is expressed in a variety of regions of incipient and active endochondral and intramembranous ossification including the craniofacial bones, vertebrae, ribs, long bones and phalanges. The observed pattern of Fgd1 expression correlates with FGDY skeletal manifestations and provides an embryologic basis for the prevalence of observed skeletal defects. The observation that the induction of Fgd1 expression coincides with the initiation of ossification strongly suggests that FGD1 signaling plays a role in ossification and bone formation; it also suggests that FGD1 signaling does not play a role in the earlier phases of skeletogenesis. With the observation that FGD1 mutations result in the skeletal dysplasia FGDY, accumulated data indicate that FGD1 signaling plays a critical role in ossification and skeletal development.
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PMID:Skeletal-specific expression of Fgd1 during bone formation and skeletal defects in faciogenital dysplasia (FGDY; Aarskog syndrome). 1090 77

Rationale: Mesenchymal cell-derived osteosarcoma is a rare malignant bone tumor affecting children and adolescents. PTEN down-regulation or function-loss mutation is associated with the aggressive of osteosarcoma. Explicating the regulatory mechanism of PTEN might highlight new targets for improving the survival rate of osteosarcoma patients. Methods: The clinical relevance of FGD1 was examined by the TCGA data set, Western blotting and immunohistochemistry of osteosarcoma microarray slides. Functional assays, such as the MTS assay, colony formation assay and xenografts, were used to determine the biological role of FGD1 in osteosarcoma. The protein-protein interaction between FGD1 and PTEN was detected via co-immunoprecipitation. The relationship between FGD1 and PD-L1 was examined by Western blot analysis, RT-qPCR and immunohistochemistry. Results: In this study, analysis of the TCGA data set of sarcomas revealed that FGD1 was over-expressed with the highest P values. Then, we demonstrated that FGD1 was also abnormally up-regulated in osteosarcoma with unfavorable prognosis. Aberrant expressed FGD1 promoted the osteosarcoma tumor cell proliferation and invasion. Moreover, we found that FGD1 was participated in activating PI3K/AKT signaling pathway by interacting with PTEN. Finally, we showed that FGD1 was capable of regulating the tumor immune response via the PTEN/PD-L1 axis in osteosarcoma. Conclusions: Our data suggested that abnormally over-expressed FGD1 functions as an oncogenic protein to promote osteosarcoma progression through inhibiting PTEN activity and activating PI3K/AKT signaling. Notably, FGD1 increased PD-L1 expression in a PTEN dependent manner and modulated the sensitivity of immune checkpoint-based immunotherapy in osteosarcoma. Thus, FGD1 might be a potential target for improving the survival rate of osteosarcomas.
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PMID:FGD1 promotes tumor progression and regulates tumor immune response in osteosarcoma via inhibiting PTEN activity. 3219 40