Cancer Genetics and Epigenetics 2018, Vol.6, No.4, 25-32
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Sequence analysis showed that the transcription originated from exon 7 of IGF2 gene. In vitro translation results
showed that it was an 84-amino acid peptide with an apparent molecular weight of 8.3 kD.
Monk et al. identified five IGF2 transcripts, which differed only in the untranslated region of their 5’primers.
RNA imprinting analysis revealed that the transcript was initiated by the P1 promoter and existed only in the liver,
known as the P1 transcript. P0 transcripts are diverse in most tissues except the brain and early placenta. High
expression exists in fetal skeletal muscle, full-term embryo and kidney. In contrast, the mouse P0 transcript was
only expressed in the placenta. Monk et al. also identified two combined read-through transcripts containing INS2
gene exons from upstream mixed with IGF2 exons. Later in the study, it was generally named INSIGF.
3 Study on IGF2 in Breast Cancer
Breast cancer is a systemic disease, and its occurrence and development is a complex process involving multiple
factors. Many bioactive substances are involved in the carcinogenesis and metastasis of breast cells. Abnormal
signal transduction pathways mediated by these bioactive substances can cause excessive amplification of some
genes, which can lead normal cells to accept abnormal proliferation, differentiation and growth signals, and
ultimately promote the carcinogenesis of breast cells. IGF2 gene plays a role in the development of breast cancer
through its unique signaling pathway (Li et al., 2018).
3.1 Stimulating effect of IGF2 on breast cancer cells
Margit Pacher’s experiment (Pacher et al., 2007) used an Afymetrix gene chip containing 45,000 probes to screen
the whole genome of long-term IGF1/2 target genes. The up-regulation of IGF signal composition is closely
related to amino acid transport and metabolism, protein biosynthesis and stability, nucleic acid base and
glutathione synthesis of most genes. All these processes are also based on the absolute requirement of maintaining
accelerated growth and value-added rates, which are exactly the survival markers of cancer cells. These combined
metabolic effects, together with their strong mitotic activity, can make IGF signal abnormally activated into an
extremely powerful oncogenic switch. It has been proved that overexpression of IGF1/2 alone can accelerate cell
cycle progression and induce MCF7 breast cancer cell growth. It can also significantly promote cell growth during
normal development.
3.2 IGF2 gene hypomethylation and breast cancer
IGF2 gene is mainly expressed in paternal lines. Previous studies have shown that LOI of IGF2 gene is observed
in 30-70% of breast cancer patients. LOI of IGF2 promoter proximal sequence (DMRO) such as low
methylation-related imprinting deletion (LOI) is considered as a susceptible biomarker of colorectal cancer. The
Yoko Ito (Ito et al., 2008) study assessed whether DMRO methylation of IGF2 gene occurred before or after the
onset of cancer by pyrophosphatic acid sequencing. The study analyzed DNA samples from 22 cases of breast
cancer and 42 cases of colorectal cancer from cancer and non-cancer tissues, as well as peripheral blood samples
from patients with colorectal cancer (n=192, control 96), breast cancer patients (n=364, control 96) and
prospective European cancer survey [EPIC-96]. Norfolk (n=228 in breast cancer group, 225 in colorectal cancer
group and 895 in control group). The results showed that the methylation level of IGF2 gene DMRO in tumors
was lower than that in non-tumorous tissues. The detection rate of DMRO hypomethylation in breast (33%) and
colorectal cancer (80%) tissues is higher than that in LOI. DMRO hypomethylation reaction of IGF2 gene is
related to the risk of breast cancer, and can be used in the diagnosis of breast cancer.
Another Preetha J. experiment (Shetty et al., 2011; Creemers et al., 2016) was designed to discuss the role of
methylation in the transcription and protein expression of IGF2. The methylation of IGF2 gene in the CpG region
of allele-specific DNA can be called methylation differential regions (DMRs). This study revealed a significant
deletion of methylation (P<0.000,1) in exon 9CpG cluster of IGF2 gene in 85% breast cancer tissues and adjacent
3% normal breast tissues. This study focused on the methylation of exon 9GpG cluster, which can be used as a
biomarker to enhance the expression of IGF2 in breast cancer tissues in DMR2 region. The results suggest that
IGF2 may also play a role in the transcription and expression of breast cancer.
