Fig. 7. Inhibition of MSI2-RNA interaction inhibited tumor growth in PDX mice, HCV replication and HCV-associated liver hyperplasia in humanized FRG mice.

A MSI2 inhibitors reduced tumor growth in PDX mice. NSG mice were used as xenograft recipients for treatment with GW7647 and Simvastatin. Tumor growth was recorded every eight days as tumor volume. Data points correspond to range of tumor volumes for each treatment cohort. (Inset) Representative tumor growth in mouse xenograft recipients from each treatment cohort. B Both GW7647 and Simvastatin suppressed MYC protein level of patient HCC xenografts as indicated by immunoblotting of MYC in xenograft tumors from drug treatment groups. C Inhibition of MSI2-RNA interaction inhibited HCV replication and HCV-associated liver hyperplasia. FRG mice were infected with HCV and fed alcohol western diet for six months. Treatment with GW7647 reduced incidence and size of liver hyperplasia in humanized FRG mice (Top panel). Treatment with GW7647 reduced HCV RNA levels, but did not affect the humanization process of livers in FRG mice (Bottom panel). D Approximately 60% of humanized FRG mice developed liver hyperplasia. Treatment with GW7647 inhibited MSI2-RNA interaction and reduced liver hyperplasia in humanized FRG mice (Top panel). Treatment with GW7647 reduced MYC protein level in liver of humanized FRG mice (Bottom panel). E A hypothetical model shows that MSI2 binds and activates MYC mRNA resulting in upregulated MYC translation and subsequent liver oncogenesis. Inhibitor of the interaction between MYC IRES and MSI2 reduces liver hyperplasia, viral mRNA translation and tumor formation.