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.
Collectively, these data support the concept for dual IGF-1R/IR targeting in HCC, where EMT status and expressions of IGF-2 and IR may be used to identify those patients who are most likely to benefit from treatment with an IGF-1R/IR dual inhibitor.
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.
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.
We found that sodium ascorbate blocked HCC-induced activation of sulfatase-2 leading to restoration of HSPGs receptors associated with reduction in IGF-2 and glypican-3.
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.
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.
The LINC01138 locus is frequently amplified in HCC; the LINC01138 transcript is stabilized by insulin like growth factor-2 mRNA-binding proteins 1/3 (IGF2BP1/IGF2BP3) and is associated with the malignant features and poor outcomes of HCC patients.
Abnormal expression of insulin-like growth factor II (IGF-II) is associated with the hepatocyte malignant transformation and hepatocellular carcinoma (HCC) progress.
In epidemiologic and clinicopathological studies on chronic liver disease (CLD), lowered serum levels, decreased tissue expression of IGF1, elevated production of IGF1R and variable IGF2 expression has been noted, from the start of preneoplastic alterations up to the developed hepatocellular carcinoma (HCC) stage.
Furthermore, inhibition of the menin/MLL interaction via MI-2/3 reduced IGF2 expression, inhibited the IGF1R-AKT pathway, and significantly repressed HCC with robust expression of IGF2.
In order to explore the effect of daintain/AIF-1 on the progression of hepatocellular carcinoma (HCC), enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR) were performed to examine the secretion and gene expression of (IGF)-1, IGF-2 and IGFBP-3.
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.
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.
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.
We focused our subsequent analyses on the Insulin-like growth factor 2 messenger RNA (mRNA)-binding protein 1 (IGF2BP1) representing the most strongly up-regulated RBP in HCC in our cohort.
The overexpression of 91H promotes tumour growth and metastasis, and is associated with a poor prognosis of HCC at least partially by positively regulating the expression of IGF2 through bivalent histone modification changes characterized by H3K4me3 and H3K27me3 at the P3 and P4 promoters.