Genomic Imprinting of IGF2 Is Maintained in Infantile Hemangioma despite its High Level of Expression

Abstract

Hemangioma, the most common tumor of infancy, is characterized by rapid growth and slow regression. Increased mRNA expression of insulin-like growth factor 2 (IGF2) has been detected in the proliferating phase by cDNA microarray analysis, but the underlying mechanism causing the increase remains unknown. Here, using quantitative real-time polymerase chain reaction (PCR) and immunohistochemistry, we show that IGF2 is highly expressed in both proliferating and involuting phase hemangioma, but is not detectable in other vascular lesions such as pyogenic granuloma, venous malformation, lymphatic malformation, or in normal infant skin. Loss of imprinting of the Igf2 gene has been associated with IGF2 overexpression in a variety of childhood tumors. To determine if loss of imprinting and consequent bi-allelic expression might contribute to the increased expression of IGF2, we examined the genomic imprinting status of Igf2 in 48 individual hemangiomas. We determined allele-specific Igf2 expression using reverse transcriptase-PCR combined with analysis of an Apa I-sensitive restriction fragment length polymorphism. Similar to heterozygous normal skin controls, all 15 informative hemangiomas showed uniform mono-allelic expression of Igf2. Therefore, loss of imprinting is not involved in the increased expression of IGF2 in infantile hemangioma.

Elevated IGF2 prevents leptin induction and terminal adipocyte differentiation in hemangioma stem cells

“…bm-MPCs have been shown to express high levels of IGF2 as compared to mature fibroblasts (Brendel et al, 2005). Previous studies have shown almost undetectable mRNA and protein levels of IGF2 in venous and lymphatic malformations, congenital hemangiomas, pyogenic granulomas, and hemangioendotheliomas Yu et al, 2004). Therefore, we believe that bm-MPCs represent the most ideal positive control cell type for IGF2 studies in hemangioma.…”

“…Recent studies have shown that the self-sustaining nature of embryonic stem cells is established via endogenous regulators such as fibroblast growth factors (FGF) and insulin-like growth factor-2 (IGF2) (Bendall et al, 2007). IGF2 has been reported to be highly expressed during the proliferating phase of hemangiomas Ritter et al, 2002Ritter et al, , 2003Yu et al, 2004) implicating a role of IGF2 in hemSC activity.…”

Infantile Hemangiomas and Retinopathy of Prematurity: Possible Association

“…29 IGF-2 is known to play a role in the development of IHs. 30 Circulating endothelial progenitor cells have been identified as vascular stem cells with the capacity to contribute to postnatal vascular proliferation such as IHs. 31,32 A summary of the angiogenic factors putatively involved in IHs and ROP is shown in Table 2.…”

Rapidly involuting congenital haemangioma (RICH) of the liver

“…Positive immunohistochemical staining for GLUT1 reliably distinguishes IH in all its phases from CH, which are almost uniformly negative [4,8,9]. Similarly, IGF2 (the insulinlike growth factor 2 gene) is highly expressed in IH in its proliferative and involuting phases, but only weakly expressed in RICH and NICH [7,10,11]. These findings may be linked, since insulin-like growth factor 2 induces expression of hypoxia-induced factor 1α [12], which in turn increases levels of GLUT1 mRNA [13].…”