The differential display technique was applied for identification of genes that have altered expression in mouse
hepatocellular carcinomas relative to normal liver. Three genes were identified. The
IL-1 receptor antagonist (IL-1ra) was expressed in
hepatocellular carcinomas, whereas the major urinary
protein (MUP) and
cytochrome P-450 naphthalene hydroxylase (cyp2F2) genes were down-regulated. Because
IL-1ra is a natural antagonist of
IL-1, and because the latter has been reported to suppress the growth of hepatic cells, we also studied the expression of
IL-1ra in hepatocarcinogenesis.
IL-1ra was immunohistochemically detected in
tumor cells in approximately 70% of
hepatocellular adenomas and
carcinomas, whereas early preneoplastic hepatocytic foci, as well as normal hepatocytes surrounding the lesions, were negative. In addition, 20% of human
hepatocellular carcinomas were also partly positive for
IL-1ra. RT-PCR analysis demonstrated that mouse hepatic
tumors contain both secreted and intracellular forms of
IL-1ra. On the other hand, there were no differences in levels of IL-1alpha and IL-1beta between hepatic
tumors and normal liver in mice, suggesting that the majority of
tumors create a microenvironment that inhibits the actions of
IL-1. Furthermore, IL-1ra-positive
adenomas contained more
proliferating cell nuclear antigen-positive cells than IL-1ra-negative
adenomas, indicating a link with high proliferation activity, although this was no longer evident in
carcinomas. The observed altered gene expression may be related to
biological phenotypes of hepatic
tumors, and
IL-1ra in particular may positively influence
tumor cell growth through its antagonism of
IL-1.