Aberrant Expression of Fetal RNA-Binding Protein p62 in Liver Cancer and Liver Cirrhosis

Abstract

p62 is a RNA-binding protein that was isolated by immunoscreening a cDNA expression library with autoantibodies from patients with hepatocellular carcinoma (HCC). This autoantigen binds to mRNA encoding insulin-like growth factor II, which has been found to be overexpressed in HCC and is tumorigenic in transgenic animals. Immunohistochemical analysis of HCC liver showed that 33% (9 of 27) exhibited readily detectable staining of p62 protein in the cytoplasm of all malignant cells in cancer nodules, whereas it was undetectable in adjacent nonmalignant liver cells. In addition one of two patients with cholangiocarcinoma expressed p62 in malignant bile duct epithelial cells. p62 expression was also detected in scattered cells in cirrhotic nodules in contrast to uniform expression in all cells in HCC nodules. In HCC nodules, p62 mRNA was also detected by reverse transcriptase-polymerase chain reaction analysis. Nine normal adult livers did not contain detectable p62 mRNA or p62 protein whereas five fetal livers were all positive for mRNA and protein. The observations show that p62 is developmentally regulated, expressed in fetal, but not in adult liver, and aberrantly expressed in HCC and could be playing a role in abnormal cell proliferation in HCC and cirrhosis by modulating expression of growth factors such as insulin-like growth factor II.

HMGA2 Regulates Transcription of the Imp2 Gene via an Intronic Regulatory Element in Cooperation with Nuclear Factor-κB

“…Online promoter prediction programs used included PromoterInspector and Gene2Promoter from GenomatixSuite, 5 grailEXP (Grail Experimental Gene Discovery Suite), 6 and PROSCAN. 7 Combination of the obtained predictions resulted in the identification of two putative gene-regulatory regions for the mouse Imp2 gene (Fig. 1B, light gray bars).…”

“…5,6), classifying them as oncofetal proteins. Concerning IMP2, Lu et al (7) detected overexpression of a splice variant of IMP2 (p62) in liver cancer (hepatocellular carcinoma and cholangiocarcinoma), and Zhang et al (8) found autoantibodies in sera of more than 10% of patients with esophageal, hepatocellular, lung, lymphoma, pharyngeal, or uterine cancer. Testing for the presence of such autoantibodies against a panel of autoantigens, including IMP proteins, has been proposed as a valuable tool for cancer detection and diagnosis (9).…”

Tumor-associated Antigen Arrays for the Serological Diagnosis of Cancer

“…proteolytic cleavage, phosphorylation, and oxidation) associated with aberrant cell death may enhance their immunogenicity under a proinflammatory environment (39 -43). Other possibilities are that specific autoantigens are fetal proteins aberrantly expressed in tumor cells (44) or expressed in abnormally high amounts in tissues affected by autoimmune disease, inflammatory disease, or cancer, contributing to loss of immune tolerance to these antigens (45).…”

Antibody detection using tumor-associated antigen mini-array in immunodiagnosing human hepatocellular carcinoma

“…The mechanism underlying the production of such autoantibodies are not completely understood but the available data show that many of the target antigens are cellular proteins whose aberrant regulation could lead to tumorigenesis, such as p53 [8], HER-2/neu and ras [9,10], or are proteins whose dysregulation could have tumorigenic potential including mRNA binding proteins such as p62 [5] and cell-cycle control proteins such as cyclin B1 [11,12]. In the case of p62 which is primarily expressed in fetal tissues and is absent in adult tissues, immunogenicity appears to be related to abnormal expression of p62 in tumor cells [13]. In previous studies, we have observed changes in autoantibody profiles predating or coincident with clinical detection of liver cancer in chronic liver disease patients [14,15].…”