Rig-I Maintains The Homeostasis Of Hematopoiesis By Regulating The DNA Damage Response Of Hematopoietic Stem Cells

Part Ⅰ Rig-I Maintains the Homeostasis of Hematopoiesis by Regulating the DNA Damage Response of Hematopoietic Stem CellsIn the past few decades,Retinoid acid inducible gene-I（Rig-I）has been well studied and acknowledged as a vital cytosolic recptor of extracellular virals.Nevertheless,the biological function of viral-RNA unprimed Rig-I failed to catch the attention of the broader research community.Our previous work have demonstrated that Rig-I is involved in the regulation of normal hematopoiesis and the differentiation of leukemic cells.Taken Rig-I^+/+and Rig-I^-/-as the mouse model,we analyzed the differences of DNA damage responses under stress or aging conditions.These results revealed that Rig-I is indispensable for maintaning the reconstitutive capacity of hematopoeitic stem cells（HSC）,as well as its genome stability.The deletion of Rig-I led to abnormal proportion of HSC,increased oxidative stress and impaired DNA repair ability,resulting in a shorter lifespan of the mice.Furthermore,the stability of FOXO3a protein plays a crucial role in HSC damage response.Mechanically,through competitively interacting with FOXO3a,Rig-I inhibits the ubiqutination and degradation of FOXO3a by excluding the E3 ligase MDM2 from FOXO3a,thus boost the DNA damage response of HSC.In summary,Rig-I plays an important role in protecting genomic stability of HSC,which presents a persuasive proof for the relationship between Rig-I and hematopoiesis.Part Two The Importance of Fibrotic Activity of FN in Osteosarcoma Cells to the Pulmonary Metastases of OsteosarcomaOsteosarcoma is the most common primary malignant bone tumor and occurs in Children and adolescents in general.Osteosarcoma is prone to form lung metastasis.Recently,with the application of modern neoadjuvant chemotherapy,the prognosis of patients with osteosarcoma was improved and the 5-year survival rate reaches 65%-70%.However,Once the osteosarcoma patient develops lung metastasis,the treatment is very limited and the prognosis is poor.Therefore,it is imminent to explore the mechanism of pulmonary metastasis.We revealed that both the model of sphere formation in osteosarcoma in vitro and lung metastasis model in vivo have the characteristics of fibrosis,wherein fibronection（FN）plays a key regulatory role.Further studies showed that the combination of FGF and its receptor FGFR promoted the formation of FN,which in turn activated downstream β3-Src-Paxillin pathway.The application of Nintedanib,an inhibitor of fibrosis,had significantly inhibited the development of sphere in vitro and the lung metastasis in vivo in osteosarcoma cells,and is expected to provide a new direction for the treatment of lung metastases in osteosarcoma patients.