IGF-II in Primary Human Colorectal Tumors: Peptide Level, Activated Promoters, Parental Imprinting and Gene Rearrangement

Abstract

IGF-II is a polypeptide growth factor with growth and differentiation promoting activities, involved in human development. We have reported previously IGF-II mRNA and peptide overexpression in primary human colon cancers. Here we show that the IGF-II peptide content is increased in six primary colon cancers compared to the corresponding healthy tissues. The IGF-II transcripts in healthy and cancerous colon tissues were identified by Northern blotting and RT-PCR. Promoters P3 and P4 were active in most tissues. Relaxation of parental imprinting was observed in two tumors and one healthy tissue, without any correlation with the IGF-II transcript levels. Rearrangements of the IGF-II gene in two tumors containing very high amounts of IGF-II mRNA are described. Fragments containing the breakpoints were cloned by the vectorette-PCR strategy. In both tumors, the breakpoints occurred in repetitive sequences. In one tumor (T11), the breakpoint was localized 2 kb downstream the end of exon 9. The second tumor (T18) contains two modified alleles. In one rearranged allele the breakpoint is located in exon 9. The exact position of the breakpoint in the second rearranged allele has not been identified. In future experiments, the correlation between the gene rearrangements and IGF-II mRNA overexpression will be studied.

New approaches to therapy of cancers of the stomach, colon and pancreas based on peptide analogs

“…Therefore, diet and associated factors may influence the risk of colorectal cancers [155], and circulating IGF-I levels may regulate colon cancer growth and metastasis [156]. IGF-II mRNA and IGF-II peptide are also overexpressed in primary human colon cancers [157]. The levels of circulating IGF-II are likewise elevated in patients with colorectal adenomas and colorectal cancer [158].…”

IGF-II promoter methylation and ovarian cancer prognosis

“…Additionally, human hepatocellular carcinoma and colon carcinoma derived cell lines were shown to express IGF-II transcripts from P3 and P4, respectively (Schneid et al 1993). When comparing primary colon cancers to corresponding healthy tissue, Winkler et al (1999) found that IGF-II was overexpressed, and that the transcripts were derived from P3 and P4. When ovarian tumors were analyzed, transcripts from P3 and P4 were found to be more frequent and abundant than transcripts from P1 and P2; further high levels of expression from P3 and P4 were associated with signiWcantly increased risks of death (Lu et al 2006a).…”

Overexpression of mature insulin-like growth factor (IGF)-II leads to growth arrest in Caco-2 human colon cancer cells

“…IGF-II is the single most overexpressed gene in colorectal cancer relative to normal colonic epithelial cells and elevated circulating levels of IGF-II is associated with the development of colorectal cancer [16,17]. In addition, the IGF-IR is overexpressed in colorectal cancer compared to normal tissues [6].…”