Zhang Jianying, Chan Edward K L
Department of Molecular and Experimental Medicine, W.M. Keck Autoimmune Disease Center, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Autoimmun Rev. 2002 May;1(3):146-53. doi: 10.1016/s1568-9972(02)00030-7.
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.
对系统性风湿性疾病中自身抗体的研究提供了大量证据，表明自身免疫反应是由抗原驱动的，并且自身抗体通常可被视为免疫系统的报告物，揭示了可能在疾病进程的病理生理学中起作用的抗原的身份。我们实验室最近的数据表明，在某些癌症如肝细胞癌（HCC）中，体液免疫反应可能涉及类似的机制过程。HCC的独特之处在于，可以追踪一组慢性肝病患者，他们可能在10年或更长时间内发展为恶性肿瘤。据观察，在从慢性肝病转变为HCC的过程中，会出现新的自身抗体，而在癌前状态之前并未检测到这些抗体。假说是这些新的抗体反应可能由参与致癌作用的细胞蛋白所刺激。通过免疫筛选表达文库以分离自身抗原的cDNA克隆，最近在HCC中鉴定出一种RNA结合自身抗原p62，并且在一组HCC患者中有21%发现了针对p62的自身抗体。p62是一种细胞质蛋白，它与编码胰岛素样生长因子II（IGF-II）的mRNA结合，IGF-II是一种已知在HCC中过表达且在转基因动物中具有致瘤性的生长因子。p62的表达受发育调控，在胎儿肝脏中表达，但在成体肝脏中不表达。我们最近的观察结果表明，在未经选择的HCC中有30%异常表达p62，这表明它可能通过在其他致癌因素的环境中上调生长因子IGF-II的表达而在HCC和其他肿瘤中发挥作用。
