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Abstract
Studies of autoantibodies in systemic rheumatic diseases have provided abundant evidence
suggesting that autoimmune responses are antigen-driven and that autoantibodies often
can be viewed as reporters of the immune system revealing the identity of antigens
which might be playing roles in the pathophysiology of the disease process. Recent
data from our laboratory suggest a similar mechanistic process may be involved in
humoral immune responses in certain cancers such as hepatocellular carcinoma (HCC).
HCC is unique in that one can follow a cohort of patients with chronic liver disease
who will likely progress to develop malignancy over a period of 10 or more years.
It has been observed that during transition from chronic liver disease to HCC, novel
autoantibodies can appear which are not detected prior to pre-malignant conditions.
The hypothesis is that these novel antibody responses may be stimulated by cellular
proteins which are involved in carcinogenesis. By immunoscreening an expression library
to isolate cDNA clones of autoantigens, a RNA-binding autoantigen p62 has been identified
in HCC recently and autoantibodies to p62 were found in 21% of a cohort of HCC patients.
p62 is a cytoplasmic protein which binds to mRNA encoding insulin-like growth factor
II (IGF-II), a growth factor which is known to be overexpressed in HCC and is tumorigenic
in transgenic animals. The expression of p62 is developmentally regulated, and expressed
in fetal, but not in adult liver. Our recent observations showing that p62 was aberrantly
expressed in 30% of unselected HCC suggest that it could play a role in HCC and other
tumors by upregulating expression of growth factor IGF-II in the milieu of other oncogenic
factors.