title: Expression of an IL-1 receptor antagonist during mouse hepatocarcinogenesis demonstrated by differential display analysis.
abstract: 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.
authors.affiliation: Department of Pathology, School of Medicine, Asahikawa Medical College, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Yamada
authors.forename: H
authors.initials: H
authors.lastname: Karasaki
authors.forename: K
authors.initials: K
authors.lastname: Matsushima
authors.forename: G H
authors.initials: GH
authors.lastname: Lee
authors.forename: K
authors.initials: K
authors.lastname: Ogawa
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D003001:Cloning, Molecular; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D053590:Interleukin 1 Receptor Antagonist Protein; D008114:Liver Neoplasms, Experimental / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011506:Proteins / Q000235:genetics; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000235:genetics*
chemical_list: C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D018809:Proliferating Cell Nuclear Antigen; D011506:Proteins; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins; C035737:major urinary proteins; D003577:Cytochrome P-450 Enzyme System; C110333:Cyp2f2 protein, mouse