Subset Of Human Hepatocellular Carcinomas Research Articles

Prognostic significance of glutamine synthetase expression in unifocal advanced hepatocellular carcinoma

Background/Aims: Glutamine synthetase (GS) catalyzes the synthesis of glutamine, a major energy source of cells, and is upregulated in a subset of human hepatocellular carcinomas (HCCs). GS expression may be related to tumor recurrence, since GS-expressing tumors have a growth advantage in that they are independent of the extracellular glutamine supply. However, there are no studies concerning the prognostic value of GS expression in patients with HCC.Methods: Seventy-three patients with a single advanced HCC nodule who underwent curative hepatectomy were included in the study. GS expression in the HCC nodules was analyzed immunohistochemically and was compared with clinicopathologic features and the behavior of the tumors. Survival curves were assessed according to the Kaplan-Meier productlimit method and multivariate analysis based on the Cox regression model was performed.Results: GS expression was strong in 26 cases (35.6%, high-GS group) and weak or absent in 47 cases (64.4%, low-GS group). Univariate analysis showed that the high-GS group had a significantly shorter disease-free survival time than the low-GS group (p=0.042). Multivariate analysis revealed that GS expression (p=0.021), as well as Child's classification (p=0.005) and portal invasion (p=0.039), was a significant and independent prognostic parameter that affected tumor recurrence.Conclusion: The results of this study indicate that GS expression may enhance the metastatic potential in HCC, and GS immunostaining may be helpful in identifying HCC patients at high risk for disease recurrence.

Transforming growth factor-beta receptors and mannose 6-phosphate/insulin-like growth factor-II receptor expression in human hepatocellular carcinoma.

The authors examined the expression of transforming growth factor-beta receptor (TGF-beta r) types I and II and the mannose 6-phosphate/insulin-like growth factor-II receptor (M6-P/IGF-IIr) in human hepatocellular carcinoma (HCC). Transforming growth factor-beta (TGF-beta) is part of a superfamily of peptide-signaling molecules that play an important role in modulating cell growth. It is secreted as a latent complex and therefore, must be activated to elicit a biological response. Bioactivation of the TGF-beta complex is facilitated by binding to the M6-P/IGF-IIr. Once activated, TGF-beta exerts its effects by binding to specific cell membrane TGF-beta receptors. The loss of responsiveness of hepatocytes to TGF-beta has been implicated in hepatocarcinogenesis and could result from a loss in the expression of either the TGF-beta receptors or the M6-P/IGF-IIr. Human hepatocellular carcinomas and surrounding normal tissue were collected from operating room samples and snap-frozen in liquid nitrogen (n = 13). Tissues from two tumors were fixed in Omni-fix for sectioning and immunohistochemistry staining for the M6-P/IGF-IIr and TGF-beta 1. RNA was extracted from both normal and malignant liver tissue and analyzed using an RNase protection assay. SDS-PAGE of purified membrane hybridized with 125I-TGF-beta 1 and 125I-IGF-II was used to determine the TGF-beta type I (TGF-betarI) and type II (TGF-beta rII) receptors and M6-P/IGF-IIr protein levels, respectively. Gels were quantitated by phosphorimager, and a paired t test was used for statistical analysis. In HCC, a 60% (p < 0.01) and 49% (p < 0.02) reduction in the mRNA levels for T beta rI and T beta rII, respectively, relative to the receptor levels in surrounding normal liver, was shown. A similar decrease in the receptor protein levels also was observed. The M6-P/IGF-IIr mRNA and protein levels were reduced in 7 of 11 hepatocellular carcinomas. Immunohistochemical staining demonstrated an absence of intracellular TGF-beta 1 and reduced M6-P/IGF-IIr in the hepatocellular carcinoma cells. These results demonstrate that human HCCs have a significantly reduced expression of both the TGF-beta rI- and TGF-beta rII-signaling receptors for TGF-beta. This may provide a selective growth advantage to the HCC by allowing them to escape the mito-inhibitory effects of activated TGF-beta. Furthermore, in the subset of HCC in which the expression of the M6-P/IGF-IIr is downregulated, the bioactivation of TGF-beta also may be impaired.