It becomes feasible to perform genome-wide differential gene or protein expression in the post genome era. However, little has been addressed on the effects of external stresses and microenvironment alterations on the outcomes of gene and protein expression. To identify downregulated genes during hepatoma development, we combined the cDNA representational difference analysis (RDA) and reverse Northern blot analysis identifying eight genes. Of interest, the expression of the clusterin gene was either down or upregulated in 8 and 7 out of the 20 hepatoma tissues, respectively. Further analysis revealed that its expression was independent of patients' age, gender, causes of liver disease, tumor size, tumor histological stage, or clinical outcome, but was strongly associated with the methods of hepatectomy procedures. In vitro studies disclosed that the clusterin mRNA was increased twofold in early exponential phase of cell proliferation followed by downregulation in the subsequent quiescence phase, whereas it was rapidly increased up to twelvefold upon UV-induced apoptosis. These results suggest that dys-regulation of the clusterin gene in human hepatoma was most likely due to cellular responses to external stresses especially during the procedures for sample collection rather than any correlation to hepatoma development or progression. Our findings that external stresses or microenvironmental changes could greatly affect gene or protein expression offer a general caution to all the studies conducted via genomic and proteomic approaches.