Abstract
Glutathione S-transferase (GST) family members promote carcinogenesis and cancer progression. We assessed GST pi 1 (GSTP1) mRNA and protein levels in hepatocellular carcinoma (HCC) using genome databases and tissue microarray (TMA) technology. We found that in cancerous tissues, GSTP1 mRNA was down-regulated in genome databases, and immunohistochemical staining of GSTP1 in 237 HCC cases varied from negative to strongly positive. GSTP1 levels correlated negatively with tumor size and serum alpha-fetoprotein (AFP) in HCC patients, and higher GSTP1 levels associated with longer overall survival (OS) and disease-free survival (DFS). We also found that GSTP1 overexpression restrained HepG2 and Huh7 liver cancer cell proliferation in vivo and in vitro. GSTP1 arrested the cell cycle at G1/S by up-regulating p21 and p27 and down-regulating p-Akt. Interrupting GSTP1 gene expression promoted liver cancer cell proliferation and increased the percentage of cells in S phase by decreasing levels of p21 and p27 and increasing p-Akt. These results suggest high GSTP1 levels provide a better prognosis through suppression of tumorigenesis in HCC.
Highlights
Primary hepatic cancer is the second leading cause of cancer-related mortality worldwide [1]
We found that the expression in hepatocellular carcinoma (HCC) tissues of Glutathione S-transferase (GST) family members from The Cancer Genome Atlas (TCGA) was congruent with GEO: GSTA4 is up-regulated, while GSTA1, GSTM1, GSTM2, GSTM5, GST pi 1 (GSTP1), GSTT1, GSTT2, and GSTZ1 are down-regulated (Supplementary Tables 1 and 2; Supplementary Figures 1 and 2)
Multivariate analysis was performed using the Cox Proportional hazards model and the analysis revealed that AFP, tumor number, and tumor size were independent prognostic factors for HCC, while GSTP1 was not an independent prognostic factor for overall survival (OS) (HR: 0.715, 95% confidence interval. *P
Summary
Primary hepatic cancer is the second leading cause of cancer-related mortality worldwide [1]. The most frequently occurring hepatic cancer is hepatocellular carcinoma (HCC), which accounts for 75% of all primary liver cancers and causes more than 600,000 deaths each year [2]. Glutathione S-transferases (GSTs) are isoenzymes that have overlapping substrate specificities and protect cells from cytotoxic and carcinogenic agents [3]. Eight isoforms of cytosolic-soluble GSTs have been recognized in humans, including α, κ, μ, π, σ, θ, ζ, and ω [4]. CR450361) has shown both stimulatory [5,6,7] and inhibitory [8,9,10,11] effects on tumorigenesis and cancer prognosis, so we investigated GSTP1’s effect on HCC
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