Surprisingly, LOI of LIT1 was not linked to LOI of insulin-like growth factor II (IGF2), which was found in 2 of 10 (20%) BWS patients, even though LOI of IGF2 occurs frequently in Wilms and other tumors, and in some patients with BWS.
By immunohistochemistry we were able to confirm increased IGF-II peptide levels within the tumor tissue in 10 pediatric patients, including the 4 patients described above.
Genomic or pharmacological strategies targeting STAT3 diminished the HDI-induced IGF2 mRNA expression and overcame the resistance to HDI treatment in HDI-resistant NSCLC- or patient-derived tumor xenograft models.
Our results showed that insulin-like growth factor-1 and insulin-like growth factor-2 mRNA levels were higher in tumor tissues and tumor-adjacent tissues than those in control cells, and were inversely correlated with the malignancy of the tumor with a positive correlation with ERα and ERβ expression.
While intense efforts are being made to explore the genetic basis of the other two-thirds of tumor cases, it is worth noting that, epigenetic changes, particularly the loss of imprinting of the DNA region encoding the major fetal growth factor IGF2, which results in its biallelic over-expression, are closely associated with the development of many Wilms tumors.
Further in vivo studies demonstrated that the stable overexpression of miR-663b or knock-down of HOTAIR inhibited tumor growth and was associated with IGF2 expression.
These findings indicate that reduced expression of the WT-1 tumor suppressor gene and elevated IGF-1R and IGF-II gene expression may be involved in the pathophysiology of prostatic hyperplasia, implying a new role for the Wilms' tumor gene in nonmalignant states.
The present study suggests that the disorganized expression of steroidogenic enzymes and the overexpression of IGF-II by the tumor are hallmarks of ACC, which could be used as biochemical and molecular markers for ACC.
BI 885578 significantly delayed the growth of IGF2-high colorectal cancer xenograft tumors in mice, while combination with a VEGF-A antibody increased efficacy and induced tumor regression.
In this study, semi-quantitative RT-PCR analyses of 48 paired, colorectal cancer patient samples showed significant overexpression of tumor IGF-1R and IGF-2 mRNA.
Activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway by insulin-like growth factor-II, inactivation of the p53 tumor suppressor protein, loss of DNA damage repair mechanisms, and ectopic expression of Myc oncoproteins cooperate with Shh/Patched signaling to enhance tumor formation in mice.
Expression of IGF-1 and IGF-2 in tumor tissues but not in cancer cell cultures indicates an IGF expression located predominantly in stromal parts of cancer tissues.
Accumulating evidence suggests that deregulation of the insulin-like growth factor II (IGF2) and H19 genes at 11p15, due to loss of imprinting (LOI), plays a role in the oncogenesis of Wilms' tumors.
The total level of circulating IGF-II was within the normal range, but Biogel P-60 gel filtration of patient serum revealed that 77% of the IGF-II was present in high molecular weight forms (normal: 10-15%), which decreased to 53% after partial removal of the tumour.
DNA extracted from tumor tissues was analyzed for IGF-II promoter methylation with seven methylation specific PCR (MSP) assays: three for promoter 2 (P2) and two assays each for promoters 3 and 4 (P3 and P4).
Sections of normal liver and tumor and non-tumor-bearing liver disease tissue were hybridized in situ with [35S]-labeled insulin-like growth factor II oligonucleotide probe.
To ascertain if LOI occurs in endometrial malignancies, the allelic expression of the IGF-II gene was examined in samples of normal human endometrium (n=22) and endometrial tumors (n=12) by assessing the ApaI polymorphism in cDNA segments amplified by RT-PCR.
To understand the autoimmune response and immunogenicity of a tumour-associated antigen (TAA) and IGF2 mRNA-binding protein (IMP2/62) in colon cancer, autoantibody to this TAA was evaluated by enzyme-linked immunosorbent assay (ELISA), Western blotting and indirect immunofluorescence assay in sera from patients with colon cancer.
IGF2 LOI was present in Wilms' tumours from predominantly white children from New Zealand (13 of 41 tumours) but absent in tumours from Japanese children (0 of 21 tumours; difference in proportions 0.32, 95% CI 0.07-0.52).
We propose a model in which incomplete gain or loss of methylation at this CTCF-binding site during tumorigenesis explains the complex and often conflicting expression patterns of IGF2 and H19 in tumors.
Although loss of imprinting (LOI) at fetal promoters contributes to increased IGF2 in tumors, the magnitude of IGF2 expression suggests the involvement of additional regulatory mechanisms.