[28-30] Furthermore, it has been hypothesized that this association between HCV and MTs may allow the virus to exploit selleck chemicals llc assembly dynamics and/or treadmilling mechanisms of MTs, which would allow for effective transport of the virus in infected cells.[29] Given these recent findings, and our observations showing that activated STAT3 may enhance MT dynamics in Huh-7 cells and that siRNA-mediated reduction of STMN1 results in a
partial reduction of HCV replication in the presence of STA-21, we hypothesize that HCV activates STAT3 directly by way of oxidative stress or indirectly by cytokines (EGF, LIF, IL-6) produced by bystander cells. This in turn may promote MT polymerization by way of STAT3-mediated attenuation of STMN1, leading to enhanced intracellular trafficking of the virus and increased RNA replication (Fig. 7). We postulate that this
may be another mechanism through which HCV uses cellular processes for its own replicative strategy. We have demonstrated that STAT3 is a proviral host cell factor and presented one potential molecular mechanism by which STAT3 promotes HCV replication, by way of positive regulation of MT dynamics. Further studies are required to ascertain other mechanisms, as it is likely that STAT3 will exert its effect in a multifaceted manner. Furthermore, the activation of STAT3 by HCV has significant clinical implications, in that activated STAT3 has been shown to play a role in HCC development.[31] One of the inhibitors used in our study, S31-201, has also been used in vivo to show HCC regression in mice CHIR-99021 solubility dmso and RNAi knockdown of STAT3 has also been demonstrated to cause suppression of HCC growth.[1, 30] STAT3 inhibitors have not currently been trialed in HCC patients; however, the tyrosine protein kinase inhibitor sorafenib that is approved for HCC treatment, and has been subsequently demonstrated MCE to inhibit STAT3.[32] Given our findings, it is possible that therapeutic intervention of STAT3 activation may have a place in the treatment
of CHC and HCV-related HCC in the future. We thank Stanley Lemon for the use of HCV replicons and Takaji Wakita for HCV JFH-1. We also thank Kate Pilkington for flow cytometry analysis and Tom Majerczak for graphic work. Additional Supporting Information may be found in the online version of this article. “
“Placental growth factor (PlGF) is associated selectively with pathological angiogenesis, and PlGF blockade does not affect the healthy vasculature. Anti-PlGF is therefore currently being clinically evaluated for the treatment of cancer patients. In cirrhosis, hepatic fibrogenesis is accompanied by extensive angiogenesis. In this paper, we evaluated the pathophysiological role of PlGF and the therapeutic potential of anti-PlGF in liver cirrhosis.