Nrf2 is a potential prognostic marker and promotes proliferation and invasion in human hepatocellular carcinoma

Abstract

BackgroundNuclear factor E2-related factor 2 (Nrf2 or NFE2L2) is abundantly expressed in cancer cells and relates to proliferation, invasion, and chemoresistance. Our early observations also found that expression of Nrf2 was up-regulated in kinds of cancer including human hepatocellular carcinoma (HCC) cells. But there are limited reports about the expression, significance, function of Nrf2 in HCC.MethodsFirst, Nrf2 expression was analyzed in HCC cell lines and tumor samples. Then, the relationship of Nrf2 with clinicopathological factors and survival were analyzed. Further, the effect of Nrf2 on cell proliferation, apoptosis, and metastasis was examined in vitro by modulating expression of Nrf2 through specific shRNA or expression plasmid. Last, the potential mechanisms were also investigated.ResultsNrf2 was up-regulated in HCC, and expression of Nrf2 was correlated with tumor differentiation, metastasis, and tumor size. Univariate and multivariate analyses indicated that high Nrf2 expression might be a poor prognostic factor. Further studies demonstrated that inhibition of Nrf2 expression inhibited proliferation by inducing apoptosis and repressed invasion, and up-regulation of Nrf2 expression resulted in opposite phenotypes. Moreover, there are positive correlation between Nrf2 expression and that of Bcl-xL and MMP-9.ConclusionNrf2 is a potential prognostic marker and promotes proliferation and invasion in human hepatocellular carcinoma partly through regulating expression of Bcl-xL and MMP-9.

Progression of Hepatic Adenoma to Carcinoma in Ogg1 Mutant Mice Induced by Phenobarbital

“…Furthermore, level of Ogg1 and nuclear translocation of Nrf2 protein were reported to be correlatively decreased upon treatment with PI3K or Akt inhibitors, indicating the existence of crosstalk between Ogg1 and Nrf2 [46]. Furthermore, increase of Nrf2 expression but not its activity was previously shown in human liver cancer samples [47]. However, increase of Nrf2 expression, which could be compensatory, does not necessarily mean elevation of its activity, which was reported to be increased due to phosphorylation by oxidative stress-activated different kinases such as ERK, JNK, PKC, and PI3K/AKT, and leads to dissociation of Nrf2 from Keap1 with subsequent nuclear transportation [48].…”

Suppression of radiation-induced migration of non-small cell lung cancer through inhibition of Nrf2-Notch Axis

“…Recent studies found that Nrf2 plays a critical role in invasion [16, 17] and that Nrf2 may regulate Notch1. For example, expression levels of Notch1 and its target genes were downregulated in Nrf2 − / − MEF cells and upregulation of Nrf2 produced excess Notch signaling [18].…”

Clinical implication of Keap1 and phosphorylated Nrf2 expression in hepatocellular carcinoma

“…In hepatocellular carcinoma, Zhang et al. reported that inhibition of Nrf2 expression inhibited proliferation by inducing apoptosis and repressed invasion, and upregulated expression of Nrf2 was correlated with tumor differentiation, metastasis, and tumor size . However, phosphorylated Nrf2, as an activated form of Nrf2 were rarely reported about its expression, significance, functional mechanism in HCC.…”

“…In gastric cancer, Kawasaki et al, immunohistochemically evaluated the expression of Nrf2 and assessed its clinical significance and claimed that Nrf2 expression was positively associated with aggressive tumor behavior in gastric cancer [8]. In hepatocellular carcinoma, Zhang et al reported that inhibition of Nrf2 expression inhibited proliferation by inducing apoptosis and repressed invasion, and upregulated expression of Nrf2 was correlated with tumor differentiation, metastasis, and tumor size [12]. However, phosphorylated Nrf2, as an activated form of Nrf2 were rarely reported about its expression, significance, functional mechanism in HCC.…”