These observations suggest a decrease of Igf2 methylation from cirrhosis to HCC in patients with HCV infection, which may be an additional risk factor for HCC.
Abnormal expression of insulin-like growth factor II (IGF-II) is associated with the hepatocyte malignant transformation and hepatocellular carcinoma (HCC) progress.
Potential mechanisms of augmented IGF-2 expression in HCC were also described and dysregulation of IGF signaling in HCC was concluded to occur predominantly at the level of IGF-2 bioavailability.
The IGF-II abnormality associates with HCC, and circulating IGF-II and IGF-II mRNA are useful molecular markers for HCC differential diagnosis and hematogenous metastasis.
Of the informative HCC samples 47.06% (8 of 17) demonstrated a gain of imprinting of IGF2, and 21.74% (5 of 23) of the informative HCC samples demonstrated a loss of imprinting of H19.
IRS-1, IRS-2, and IRS-4 were each overexpressed in 80% of the HCC samples, and IGF-I and IGF-2 receptors were overexpressed in 40% and 100% of the HCCs, respectively.
The positive frequency of circulating IGF-II mRNA was 34.2% in HCC, no amplified fragment was found in other liver diseases, extrahepatic tumors, and normal controls, respectively.
Our data suggest that PTEN blocks Sp1 phosphorylation in response to HBx, by inactivating PKC, MAPK and MAPK kinase which eventually downregulate IGF-II expression, during the formation of HCC.
These observations suggest that loss of parental-specific methylation at the IGF2 locus may be specifically associated with HCC, whether virus-associated or non-virus-associated, and arising in cirrhotic or non-cirrhotic livers.
This study demonstrates that a methylated sense oligonucleotide can be used to induce epigenetic changes in the IGF2 gene and that inhibition of IGF2 mRNA accumulation may lead to enhanced survival in a model of HCC.
Recently our laboratory identified a cytoplasmic RNA-binding protein p62 which binds to and regulates the expression of IGF II mRNA. p62 was initially shown to be recognized by auto-antibodies in hepatocellular carcinoma (HCC) but now anti-p62 has been described in diverse malignancies. p62 is uniformly expressed in fetal liver and prominently in 33% of HCC nodules, but not detectable in adult liver or normal tissue adjacent to HCC nodules.
The 31 genes up-regulated in HBV-associated HCC included imprinted genes (H19 and IGF2) and genes relating to signal transduction, transcription, and metastasis.
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.
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.
Antisense oligonucleotides were used to demonstrate the importance of insulin-like growth factor II and alpha-fetoprotein for the growth of hepatoma cell lines.