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.
Similar content being viewed by others
References
Holmdahl K. (1955) Cutaneous hemangiomas in premature and mature infants. Acta Paediatr. 44:370–9.
Mulliken JB. (1993) Cutaneous vascular anomalies. Semin. Vasc. Surg. 6:204–18.
Takahashi K, Mulliken JB, Kozakewich HP, Rogers RA, Folkman J, Ezekowitz RA. (1994) Cellular markers that distinguish the phases of hemangioma during infancy and childhood. J. Clin. Invest. 93:2357–64.
Yu Y, Flint AF, Mulliken JB, Wu JK, Bischoff J. (2004) Endothelial progenitor cells in infantile hemangioma. Blood 103:1373–5.
Boye E, Yu Y, Paranya G, Mulliken JB, Olsen BR, Bischoff J. (2001) Clonality and altered behavior of endothelial cells from hemangiomas. J. Clin. Invest. 107:745–52.
Walter JW et al. (2002) Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma. Genes Chromosomes Cancer 33:295–303.
Ezekowitz RA, Mulliken JB, Folkman J. (1992) Interferon alpha-2a therapy for life-threatening hemangiomas of infancy. N. Engl. J. Med. 326:1456–63.
Fawcett SL, Grant I, Hall PN, Kelsall AW, Nicholson JC. (2004) Vincristine as a treatment for a large haemangioma threatening vital functions. Br. J. Plast. Surg. 57:168–171.
Barlow CF et al. (1998) Spastic diplegia as a complication of interferon Alpha-2a treatment of hemangiomas of infancy. J. Pediatr. 132:527–30.
Worle H, Maass E, Kohler B, Treuner J. (1999) Interferon alpha-2a therapy in haemangiomas of infancy: spastic diplegia as a severe complication. Eur. J. Pediatr. 158:344.
Boon LM, MacDonald DM, Mulliken JB. (1999) Complications of systemic corticosteroid therapy for problematic hemangioma. Plast. Reconstr. Surg. 104: 1616–23.
Giannoukakis N, Deal C, Paquette J, Goodyer CG, Polychronakos C. (1993) Parental genomic imprinting of the human IGF2 gene. Nat. Genet. 4:98–101.
Arney KL. (2003) H19 and Igf2—enhancing the confusion? Trends Genet. 19: 17–23.
Rainier S et al. (1993) Relaxation of imprinted genes in human cancer. Nature 362:747–9.
Cui H et al. (2001) Loss of imprinting of insulin-like growth factor-II in Wilms’ tumor commonly involves altered methylation but not mutations of CTCF or its binding site. Cancer Res. 61:4947–50.
Yun K. (1998) Genomic imprinting and carcinogenesis. Histol. Histopathol. 13: 425–35.
Schneider DT et al. (2001) Multipoint imprinting analysis indicates a common precursor cell for gonadal and nongonadal pediatric germ cell tumors. Cancer Res. 61:7268–76.
Weksberg R, Smith AC, Squire J, Sadowski P. (2003) Beckwith-Wiedemann syndrome demonstrates a role for epigenetic control of normal development. Hum. Mol. Genet. 12 Spec No 1:R61–8.
Roy RN, Gerulath AH, Cecutti A, Bhavnani BR. (2000) Loss of IGF-II imprinting in endometrial tumors: overexpression in carcinosarcoma. CancerLett. 153:67–73.
Muller S, Zirkel D, Westphal M, Zumkeller W. (2000) Genomic imprinting of IGF2 and H19 in human meningiomas. Eur. J. Cancer 36:651–5.
Ogawa O et al. (1993) Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms’ tumor. Nature 362:749–51.
Ritter MR, Dorrell MI, Edmonds J, Friedlander SF, Friedlander M. (2002) Insulin-like growth factor 2 and potential regulators of hemangioma growth and involution identified by large-scale expression analysis. Proc. Natl. Acad. Sci. U.S.A. 99: 7455–60.
Tadokoro K, Fujii H, Inoue T, Yamada M. (1991) Polymerase chain reaction (PCR) for detection of ApaI polymorphism at the insulin like growth factor II gene (IGF2). Nucleic Acids Res. 19:6967.
Yu Y, Varughese J, Brown LF, Mulliken JB, Bischoff J. (2001) Increased Tie2 expression, enhanced response to angiopoietin-1, and dysregulated angiopoietin-2 expression in hemangioma-derived endothelial cells. Am. J. Pathol. 159: 2271–80.
Ginzinger DG. (2002) Gene quantification using real-time quantitative PCR: an emerging technology hits the mainstream. Exp. Hematol. 30:503–12.
Boon LM, Enjolras O, Mulliken JB. (1996) Congenital hemangioma: evidence of accelerated involution. J. Pediatr. 128:329–35.
Enjolras O, Mulliken JB. (1998) Vascular tumors and vascular malformations, new issues. In: Adv. Dermatol. Paller AS (ed.) Mosby-Year Book, Inc., St. Louis, Mo, pp. 375–422.
North PE, Waner M, Mizeracki A, Mihm Jr. MC. (2000) GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas. Hum. Pathol. 31:11–22.
North PE et al. (2001) Congenital nonprogressive hemangioma: a distinct clinicopathologic entity unlike infantile hemangioma. Arch. Dermatol. 137: 1607–20.
Cui H, Horon IL, Ohlsson R, Hamilton SR, Feinberg AP. (1998) Loss of imprinting in normal tissue of colorectal cancer patients with microsatellite instability. Nat. Med. 4:1276–80.
Jones JI, Clemmons DR. (1995) Insulin-like growth factors and their binding proteins: biological actions. Endocr. Rev. 16:3–34.
Le Roith D. (1997) Seminars in medicine of the Beth Israel Deaconess Medical Center. Insulin-like growth factors. N. Engl. J. Med. 336:633–40.
Li Q, Yu Y, Bischoff J, Mulliken JB, Olsen BR. (2003) Differential expression of CD146 in tissues and endothelial cells derived from infantile haemangioma and normal human skin. J. Pathol. 201:296–302.
Razon MJ, Kraling BM, Mulliken JB, Bischoff J. (1998) Increased apoptosis coincides with onset of involution in infantile hemangioma. Microcirculation 5: 189–95.
Kim KW et al. (1998) Insulin-like growth factor II induced by hypoxia may contribute to angiogenesis of human hepatocellular carcinoma. Cancer Res. 58:348–51.
Lee OH et al. (2000) Identification of angiogenic properties of insulin-like growth factor II in in vitro angiogenesis models. Br. J. Cancer 82:385–91.
Feldser D et al. (1999) Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. Cancer Res. 59:3915–8.
Chen C, Pore N, Behrooz A, Ismail-Beigi F, Maity A. (2001) Regulation of glut1 mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia. J. Biol. Chem. 276:9519–25.
Acknowledgments
This study is supported by grants from the NIH (P01 AR048564) and the John Butler Mulliken Foundation. We thank Drs. Zia Khan and Carmen Barnes, both members of the Vascular Biology Program, Children’s Hospital Boston, for advice on real-time PCR quantitative analysis and human placental RNA samples, respectively.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yu, Y., Wylie-Sears, J., Boscolo, E. et al. Genomic Imprinting of IGF2 Is Maintained in Infantile Hemangioma despite its High Level of Expression. Mol Med 10, 117–123 (2004). https://doi.org/10.2119/2004-00045.Bischoff
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.2119/2004-00045.Bischoff