Hypoglycemia from IGF2 overexpression associated with activation of fetal promoters and loss of imprinting in a metastatic hemangiopericytoma.

The mechanism of IGF2 overexpression in non-islet-cell tumor hypoglycemia is not understood.
We investigated the imprinting control and promoter usage for IGF2 expression to identify a mechanism for increased IGF-II production in non-islet-cell tumor hypoglycemia.
A patient with metastatic hemangiopericytoma was studied. Tissue from the original hemangiopericytoma, metastatic tumor, and uninvolved liver was analyzed for IGF-II immunohistochemistry. IGF2, a paternally imprinted gene, shares a control region with maternally imprinted H19, a putative tumor suppressor. IGF-II and H19 mRNA expression was compared in metastatic tumor and uninvolved liver by quantitative RT-PCR. Imprinting of IGF2/H19 genes and IGF2 promoter usage in metastatic tumor was investigated by RT-PCR and sequence analysis, and the methylation pattern in the IGF2/H19 imprinting control region was analyzed.
IGF-II protein expression was increased in metastatic tumor vs. uninvolved liver and original tumor. In the metastatic tumor, IGF-II mRNA was increased 60-fold, but H19 mRNA was comparable to uninvolved liver; loss of imprinting of IGF2, but not H19, was identified; no major change in methylation of the IGF2/H19 imprinting control regions was observed; and transcripts from four different IGF2 promoters were detected, compared to two in uninvolved liver.
IGF-2 overexpression, newly acquired in the metastatic tumor, was associated with loss of IGF2 gene imprinting and different promoter usage. The imprinting control mechanism governing the IGF2/H19 locus was intact, as evidenced by normal levels of H19, maintenance of H19 imprinting, and no major change in methylation of the imprinting control regions.
AuthorsElizabeth A Lawson, Xun Zhang, Jonathan T Crocker, Wei-Lien Wang, Anne Klibanski
JournalThe Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 94 Issue 7 Pg. 2226-31 (Jul 2009) ISSN: 1945-7197 [Electronic] United States
PMID19383775 (Publication Type: Case Reports, Journal Article)
Chemical References
  • H19 long non-coding RNA
  • RNA, Long Noncoding
  • RNA, Untranslated
  • Insulin-Like Growth Factor II
  • Fetus (metabolism)
  • Gene Expression Regulation, Neoplastic
  • Genomic Imprinting
  • Hemangiopericytoma (genetics, pathology)
  • Humans
  • Hypoglycemia (genetics)
  • Insulin-Like Growth Factor II (genetics)
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Promoter Regions, Genetic
  • RNA, Long Noncoding
  • RNA, Untranslated (genetics, metabolism)
  • Skin Neoplasms (genetics, pathology)
  • Up-Regulation

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