Hepatitis B viral HBx induces matrix metalloproteinase‐9 gene expression through activation of ERKs and PI‐3K/AKT pathways: Involvement of invasive potential

Abstract

Hepatitis B virus (HBV) X protein (HBx) has been shown to be essential for the development of hepatocellular carcinoma (HCC). Recently, we have found that HBx causes the progression of liver cancer through down-expression of PTEN, known as a tumor suppressor gene (1). The prognosis for HCC depends mainly on the clinicopathological characteristic regarding invasion and metastasis. The expression of matrix metalloproteinase (MMP)-9 has been implicated as playing an important role in HCC invasion and metastasis. We previously reported that HBV infection increased the invasiveness of hepatocytes and HCC cells through the transcriptional activation of MMP-9 (2). The HBx was shown to activate the mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase (PI-3K) signal cascade, which is essential for activation of transcription factors such as activating protein (AP)-1 and nuclear factor (NF)-kappaB. In this study, we show that the HBx protein stimulates the activities of the PI-3K-Akt/ protein kinase B (PKB) as well as extracellular signal-regulated kinase 1/2 (ERK 1/2) in HBx-transfected cells. Furthermore, we have shown that enhanced expression of MMP-9 in HBx-transfected cells mediated by not only activation of AP-1 transcriptional activity through ERKs pathway but also activation of NF-kappaB transcriptional activity through PI-3K-AKT/PKB pathway, and was associated with the invasive potential. However, treatment with U0126 (known as the ERKs inhibitor) or wortmannin (known as the PI-3K inhibitor), but not SB203580 (known as the p38 MAPK inhibitor), markedly inhibited the expression of MMP-9 induced by HBx in HBx-transfected cells. Seemingly, the invasiveness of HBx-transfected cells was decreased by treating with U0126 or wortmannin, but not SB203580. These results clearly suggest that the HBx contributed to the transcriptional regulation of MMP-9 through the ERKs and PI-3K-AKT/PKB pathway, and increased an invasive potential of cells.

Hyperforin Inhibits Cancer Invasion and Metastasis

“…In particular, up-regulation of MMP expression has been reported to be dependent on activation of the raf/MEK/ERK signaling pathway, which strictly regulates gene expression (31)(32)(33). Consistently, whereas the high expression of MMP-2 and MMP-9 in C-26 cells correlates with constitutive activation of ERK1/2 protein kinases (Fig.…”

“…Because the activation of the raf/MEK/ERK signaling pathway has been reported to induce the enhancement of MMP expression (32)(33)(34), the potential influence of Hyp-DCHA on the activity of ERK1/2 was tested. To this purpose, protein lysates of control and treated C-26 cells were subjected to Western blot analysis for phosphorylated (active) as well as total ERK1/2 protein kinases.…”

Radiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF-κB signal transduction pathway

“…Ruhul Amin et al (2003) reported PI3K-Akt was one of the signaling pathways to induce MMP-9 secretion. Recently, hepatitis B viral HBx was shown to induce MMP-9 gene expression through the activation of the ERK and PI3K/Akt pathways (Chung et al, 2004). More importantly, angiogenesis plays an essential role in tumor growth and metastasis.…”

Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis

“…An alternative mechanism for Wnt activation is the repression of E-cadherin transcription through hypermethylation of E-cadherin promoter by activation of DNA methyltranferase 1 (Kanai et al, 1997;Lee et al, 2005b). Recently, studies have shown that HBx may induce cellular migration through activation of matrix metalloproteinase 3 and 9 (Chung et al, 2004;Yu et al, 2005).…”