Understanding the mechanisms of hepatitis C virus (HCV) pathogenesis and persistence has been hampered by the lack of small, convenient animal models. GB virus B (GBV-B) is phylogenetically the closest related virus to HCV. It causes generally acute and occasionally chronic hepatitis in small primates and is used as a surrogate model for HCV. It is not known, however, whether GBV-B has evolved strategies to circumvent host innate defenses similar to those of HCV, a property that may contribute to HCV persistence in vivo. We show here in cultured tamarin hepatocytes that GBV-B NS3/4A protease, but not a related catalytically inactive mutant, effectively blocks innate intracellular antiviral responses signaled through the RNA helicase, retinoic acid-inducible gene I (RIG-I), an essential sensor molecule that initiates host defenses against many RNA viruses, including HCV. GBV-B NS3/4A protease specifically cleaves mitochondrial antiviral signaling protein (MAVS; also known as IPS-1/Cardif/VISA) and dislodges it from mitochondria, thereby disrupting its function as a RIG-I adaptor and blocking downstream activation of both interferon regulatory factor 3 and nuclear factor kappa B. MAVS cleavage and abrogation of virus-induced interferon responses were also observed in Huh7 cells supporting autonomous replication of subgenomic GBV-B RNAs. Our data indicate that, as in the case of HCV, GBV-B has evolved to utilize its major protease to disrupt RIG-I signaling and impede innate antiviral defenses. These data provide further support for the use of GBV-B infection in small primates as an accurate surrogate model for deciphering virus-host interactions in hepacivirus pathogenesis.Chronic hepatitis C virus (HCV) infection affects millions of people worldwide and poses a major threat to human health (42). However, efforts to understand HCV pathogenesis and identify specific HCV antivirals to supplement or substitute for current interferon (IFN)-based therapies have been impeded by the lack of a robust, fully permissive tissue culture system and the absence of small, convenient animal models of HCV infection. While the former problem has been partially solved recently by the development of systems allowing productive HCV infection in human hepatoma cells (25,45,49,51), the chimpanzee remains the only well-validated animal model that is susceptible to HCV infection. Several drawbacks, however, including availability, ethical considerations, and extraordinary cost, limit use of the chimpanzee for modeling HCV infection and confirming the activity of candidate antivirals.
Colorectal cancer (CRC) is a common malignant tumor of the digestive tract and one of the leading causes of cancer-associated mortality. Secreted phosphoprotein-1 (SPP-1) is overexpressed in CRC and promotes cancer progression, but the underlying mechanisms underlying SPP-1 function remain unclear. The present study aimed to explore the effects of Wnt/β-catenin signaling in SPP-1-induced CRC progression. The expression patterns of SPP-1 in CRC tissues were examined using reverse transcription-quantitative (RT-q)PCR, western blotting and immunohistochemistry. SPP-1 expression in cells was assessed using RT-qPCR and western blotting. Cell-Counting Kit-8, flow cytometry and tumor-burdened mice experiments were used to determine cell proliferation, apoptosis and in vivo tumor formation abilities. The results showed that SPP-1 expression was markedly elevated in CRC tissues and cells compared with that in normal colorectal tissues and cells. High expression of SPP-1 was associated with advanced clinical process and low overall survival rate in patients with CRC. Besides, SPP-1 could interact with β-catenin and positively regulated β-catenin protein expression, and enhanced its nuclear accumulation. Moreover, SPP-1-upregulation significantly enhanced cell proliferation and in vivo tumor formation ability, and reduced apoptosis, whereas these effects were all abolished when β-catenin was silenced. Overall, the present study revealed that SPP-1 promoted the progression of CRC in a β-catenin-dependent manner.
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