Enhanced constitutive oxidative stress-mediated overexpression of hMTH1 and low expression of nm23 confer increased metastatic proclivity of human hepatocellular carcinoma cells

MK Shih, a CL Chern, a TZ Liu b

a Department of Medical Technology, Fooyin Institute of Technology, Kaohsiung, Taiwan; b Department of Medical Technology, School of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, Taiwan

AIM: To delineate how the constitutive oxidative stress status of a cancer cell can modulate its metastatic potential by evaluating the expression pattern of human Mut T homologue (hMTH1) and the anti-metastatic nm23 genes. METHODS: Five cell lines derived from human hepatocellular carcinoma (Hep G2, Hep 3B, J5, Mahl and SK-Hep-1), in which their differentiation status had been well characterized, were used as the experimental tool. Index of oxidative stress was evaluated using the expression profiles of antioxidant enzymes and GSH. Steady state mRNA for both hMTH1 and nm23 were performed by the RT-PCR techniques. In vitro assays for invasive activity of cells was performed by the transwell method. RESULTS: 1. These cells spontaneously and differentially expressed hMTH1 gene and the propensity of expression coincided inversely with the differentiation status, with order being SK-Hep-1> Mah1> J5> Hep 3B> Hep G2. A high level of hMTH1 gene expression was found to have a high in vitro invasive activity which correlated excellently with an enhanced oxidative stress status. 2. These cells could also express nm23 gene differentially and the extents of their expression increased with the differentiation status, with order being Hep G2> Hep 3B> J5> Mah1> SK-Hep-1. CONCLUSION: De-differentiation plays a pivotal role in the up-regulation of intracellular oxidative stress, which in turn increases the invasive propensity of a HCC cell via a mechanism involving an overexpression of hMTH1 in conjunction with lower expression of nm23 gene.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Gene Expression, Part 2.