In the present study, we report a novel insulin-like growth factor 1 (IGF1) pathway that mediates de novo DNA methylation and TSG (such as DLC1 and CHD5) silencing by upregulation of the DNA methyltransferase 1 (DNMT1) via an AKT/β-transducin repeat-containing protein (βTrCP)-mediated ubiquitin-proteasome pathway in HCC.
We have investigated the expression of insulin-like growth factor I (IGF-I) receptor in human hepatocellular carcinoma cell lines using SNU368 cells containing HBx and SNU387 cells, which lack HBx gene transcript (J-G. Park et al., Int.J.
Moreover, the inhibition of PI3-kinase completely abolished the nuclear translocation of C/EBPbeta and the up-regulation of GSTalpha protein in IR-HCC treated with IGF-1.
Radiolabelled IGF-I incubated with serum-free conditioned media from the breast cancer cell line MDA-MB 231 eluted with an apparent M.W. of 35-40 kDa when analyzed by gel filtration chromatography at pH 7.4.The M.W. of this binding activity corresponded to that of BP-25, a binding protein cloned from the hepatocellular carcinoma cell line HepG2.
Long non-coding RNA deleted in lymphocytic leukaemia 1 promotes hepatocellular carcinoma progression by sponging miR-133a to regulate IGF-1R expression.
Only very high concentrations of insulin-like growth factor I and human proinsulin can compete for the insulin receptor binding and suppress HBsAg production, this suggests that insulin may act through its receptor binding to suppress HBsAg expression in human hepatoma Hep3B cells.
Klotho is a tumor suppressor that, through the regulation of IGF-1R phosphorylation and subsequent activation of downstream Akt-p70S6K and ERK signaling, regulates HCC tumor cell proliferation, apoptosis, autophagy and invasion.
The poorly differentiated hepatoma cell lines PLC/PRF/5 and SK-Hep-1 either did not express or constitutively expressed low basal levels of IGF I, IGF II, and TGF beta, whose mRNA synthesis and abundance showed no response to any heparin-hormone combination.
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.
The pathophysiology underlying development of hepatocellular carcinoma in this context is complex and is likely to involve increased proinflammatory mediators, oxidative stress, JNK-1 activation, increased IGF-1 activity, altered gut microbiota and immunomodulation.
The biological consequence of TCF-4J isoform expression was upregulation of genes associated with tripartite Wnt/β-catenin, insulin/IGF-1/IRS1 and Notch signal transduction pathway activation, which contribute to the pathogenesis of HCC.
Together, our results defined miR-28-5p as a critical regulator of IGF1 mRNA translation function, down-regulated miR-28-5p in HCC was associated with tumor growth through PI3K/AKT pathway by targeting IGF1. miR-28-5p-IGF1-PI3K/AKT pathway may play an important role in the development of HCC.
Therefore, this study highlights a potential role of IGF-1 in modulating cytolytic potential of NK cells of HCC patients. miR-486-5p acts in a cell-specific manner, differentially modulating IGF-1 expression in NK cells and their target hepatocytes with a contemporary inhibitory impact on HCC progression.
In multivariate models comparing the first, second, and third quartiles with the fourth quartile of IGF-1, the levels of IGF-1 in Q1 and Q2 were associated with HCC recurrence, with an increased risk of 216% [hazard ratios (HR) = 3.16 (95% CI: 1.79-4.28)] and 106% [3.02 (1.36-3.11)].
The results of the present study demonstrated that miR‑187 acted as a tumor suppressor in HCC progression via direct targeting of IGF‑1R. miR‑187 may therefore exhibit the potential to act as a novel and therapeutic target for HCC treatment in the future.
IGF-1R might be a potential prognostic biomarker for HCC (hazard ratio [HR] = 1.912, 95% confidence interval [CI]: 1.023-3.572, P = .042).The IGF-1R expression level is upregulated in HCC tissues and may act as a prognostic biomarker for the disease.