In the present study, we have investigated IGF-II transcripts and protein in liver tissues from patients with hepatocarcinoma infected with hepatitis B virus, by using in situ hybridization and immunohistochemical techniques.
The level of insulin-like growth factor II messenger RNA transcripts in sections of hepatocellular carcinoma arising from cirrhotic and noncirrhotic tissues obtained from patients seronegative for hepatitis B virus was similar to that of normal liver.(ABSTRACT TRUNCATED AT 250 WORDS)
In tissue sections, cells with high expression of insulin-like growth factor II were observed not only in hepatocellular carcinoma (93%) but also in 95% of the pericancerous liver tissues, 72% of cirrhotic livers, 64% of chronic active hepatitis and 37% of chronic persistent hepatitis.
Extreme allelic-expression imbalance, leading to restoration of monoallelic IGF2 expression, was observed in 15 (100%) of 15 informative HCCs for the polymorphism with this monoallelic IGF2 expression appearing to be non-random from the paternal allele.
Since reactivation of fetal IGF-II transcripts has been observed in human HCC, we have analyzed the levels of adult P1 and fetal P3 and P4 IGF-II promoter-derived transcripts in the liver of patients with HCV-related chronic active hepatitis (CAH), cirrhosis, and HCC by means of a semiquantitative reverse-transcription polymerase chain reaction (RT-PCR) assay.
Interestingly, however, we found that restoration of allele-specific expression of the P1 promoter nonrandomly from the paternal allele was also frequent in HCC suggesting retention of an imprint for paternal expression from the P1 promoter of IGF2 in adult normal liver and altered availability of its modifying factor or factors in HCC.
To study whether the overexpression of IGF-II is significant for the growth of HCC or only a consequence of HCC development, we used antisense oligodeoxynucleotides (ATON) to arrest the translation of IGF-II mRNA, and then measured the effects on cell growth.
The frequent biallelic expression of H19 and IGF2 in hepatocellular carcinoma might play a causal role in the epigenetic mechanism involved in tumor development and/or process.
We now show that this VNTR also has effects on the nearby insulin-like growth factor II gene (IGF2) in human placenta in vivo and in the HepG2 hepatoma cell line in vitro.
However, little information is available on the transcriptional factors (TFs) controlling IGF-II gene expression in human liver cirrhosis (LC) and HCC tissues.
IGF II gene expression level, which was studied by a semiquantitative reverse-transcriptase polymerase chain reaction (RT-PCR), was significantly higher (3.6-fold) in the dysplastic nodules than the control livers, but a significant increase in the IGF II gene expression was not observed in well- and moderately differentiated HCCs as compared with the control livers.
Antisense oligonucleotides were used to demonstrate the importance of insulin-like growth factor II and alpha-fetoprotein for the growth of hepatoma cell lines.
Loss of maternal-specific methylation at the KvDMR1 locus in hepatocarcinoma correlated with abnormal expression of CDKN1C and IGF2, suggesting a function for KvDMR1 as a long-range imprinting center active in adult tissues.
Activation of the insulin-like growth factor II transcription by aflatoxin B1 induced p53 mutant 249 is caused by activation of transcription complexes; implications for a gain-of-function during the formation of hepatocellular carcinoma.
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.