Hepatitis C Virus Core Protein Activates the MAPK/ERK Cascade Synergistically With Tumor Promoter TPA, But Not With Epidermal Growth Factor or Transforming Growth Factor α

Abstract

Persistent hepatitis C virus (HCV) infection is

MEK1 promotes YAP and their interaction is critical for tumorigenesis in liver cancer

“…Cells were treated by PD98059 (15-50 lM, Cell Signaling Technology (CST), Boston, MA, USA) or U0126 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) lM, CST) 24 h before harvest. ShRNAs were cloned into pLKO.1 lentiviral vectors using primers as follows: MEK1-sh#1-Forward: CCGGAACTCTGGATCAAGTCCTGAACTCGAGTTCAGGACTTGATCCA-GAGTTTTTTTG and Reward: AATTCAAAAAAACTCTGGATCAAGTC C TGAACTCGAGTTCAGGACTTGATCCAGAGTT; MEK1-sh#2-Forward: CCGGAAGGACTCATTACTCTGTGCACTCGAGTGCACAGAGTAATGAGT CCTTTTTTTG and Reward: AATTCAAAAAAAGGACTCATTACTCTG TGCACTCGAGTGCACAGAGTAATGAGTCCTT.…”

“…There are several lines of evidence suggest an association between the MEK/ERK signaling pathway and liver cancers [12], and the two most common causes of HCC, hepatitis B and C, have viral proteins that activate MEK/ERK signaling [13,14]. Recently, YAP is reported involved in the hepatocarcinogenesis mediated by Hepatitis B virus X protein (HBx), providing evidence that YAP can be also activated by hepatitis viral infection [15].…”

Hepatitis C virus core proteins derived from different quasispecies of genotype 1b inhibit the growth of Chang liver cells

“…Several studies have established that HCV core protein can regulate cell signal transduction, such as MAPK-, JAK-STAT-, NF-κB-, AP-1-and SRE-associated pathways [6][7][8] . Hence, it plays important roles in the pathogenesis of HCV persistent infection, as well as HCC.…”

Sustained activation of the Raf/MEK/Erk pathway in response to EGF in stable cell lines expressing the Hepatitis C Virus (HCV) core protein

“…More interestingly, liver expression of HCV core in transgenic mice results in early steatosis (Moriya et al, 1997) and late HCC development (Moriya et al, 1998). A potential link between modulation of transcription and cell proliferation is provided by the reported ability of HCV core to activate the ERK/SRE signaling pathway in rodent ®broblasts (Tsuchihara et al, 1999), in human epithelial transformed cell lines (Shrivastava et al, 1998) and in a hepatoblastoma cell line Hayashi et al, 2000). Indeed, HCV core has been shown to bind 14-3-3 proteins and to activate Raf-1 .…”

“…This is particularly relevant in view of the recent demonstration that many HCV chronically infected patients also harbor an`occult' HBV coinfection (Cacciola et al, 1999;Shibata et al, 1999;Tamori et al, 1999) and that HBV-HCV co-infected cirrhotic patients seem to have an increased risk to develop HCC over time (Donato et al, 1998). Moreover, Hayashi et al (2000) have recently shown that Erk1/2 activation by HCV core is enhanced by TPA, that activates Raf1 through PKC and the phosphorylation of Ser 497 and Ser 499 in the Raf1 kinase domain, suggesting that HCV core may act synergistically with other stimuli that activate Raf1 with a di erent mechanism. The ability of HCV core proteins to activate the MAP kinase cascade may contribute, in concert with its ability to protect cells from various apoptotic stimuli (De Francesco, 1999) and with other genetic or environmental factors (Hayashi et al, 1999), to the neoplastic transformation of HCV infected liver cells.…”