Cloning of breakpoints in and downstream the IGF2 gene that are associated with overexpression of IGF2 transcripts in colorectal tumours

Hodzic, Didier; Frey, Bruno S.; Maréchal, Daniel; Scarcez, T; Grooteclaes, Madeleine; Winkler, Rosita

doi:10.1038/sj.onc.1202877

Cited by 6 publications

(6 citation statements)

References 26 publications

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“…However, the regulation of IGF2 by the SHH pathway is complex, and other not yet identified regulators may cooperate with the SHH pathway to induce IGF2 expression in HGNET-BCOR. Other mechanisms such as changes in the 3’ untranslated region of IGF2 [33] and altered methylation of the IGF2 promoter should be also considered [15]. Whether the SHH and IGF pathways act synergistically to support HGNET-BCOR proliferation remains to be evaluated.…”

Section: Discussionmentioning

confidence: 99%

IGF1R Is a Potential New Therapeutic Target for HGNET-BCOR Brain Tumor Patients

Vewinger

Huprich

Seidmann

et al. 2019

IJMS

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(1) Background: The high-grade neuroepithelial tumor of the central nervous system with BCOR alteration (HGNET-BCOR) is a highly malignant tumor. Preclinical models and molecular targets are urgently required for this cancer. Previous data suggest a potential role of insulin-like growth factor (IGF) signaling in HGNET-BCOR. (2) Methods: The primary HGNET-BCOR cells PhKh1 were characterized by western blot, copy number variation, and methylation analysis and by electron microscopy. The expression of IGF2 and IGF1R was assessed by qRT-PCR. The effect of chemotherapeutics and IGF1R inhibitors on PhKh1 proliferation was tested. The phosphorylation of IGF1R and downstream molecules was assessed by western blot. (3) Results: Phkh1 cells showed a DNA methylation profile compatible with the DNA methylation class “HGNET-BCOR” and morphologic features of cellular cannibalism. IGF2 and IGF1R were highly expressed by three HGNET-BCOR tumor samples and PhKh1 cells. PhKh1 cells were particularly sensitive to vincristine, vinblastine, actinomycin D (IC50 < 10 nM for all drugs), and ceritinib (IC50 = 310 nM). Ceritinib was able to abrogate the proliferation of PhKh1 cells and blocked the phosphorylation of IGF1R and AKT. (4) Conclusion: IGF1R is as an attractive target for the development of new therapy protocols for HGNET-BCOR patients, which may include ceritinib and vinblastine.

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Section: Discussionmentioning

confidence: 99%

IGF1R Is a Potential New Therapeutic Target for HGNET-BCOR Brain Tumor Patients

Vewinger

Huprich

Seidmann

et al. 2019

IJMS

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“…Igf2 expression may be induced due to mutation of its flanking regulatory sequences. Changes in the 3′ untranslated region of igf2 are associated with 100 to 1000-fold increases in igf2 transcript levels in colorectal cancer (33). Altered methylation of the igf2 promoter causes increased igf2 transcription in hepatoblastoma (34).…”

Section: Discussionmentioning

confidence: 99%

Insulin-like Growth Factor 2 Is Required for Progression to Advanced Medulloblastoma in patched1 Heterozygous Mice

et al. 2008

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Medulloblastoma (MB) can arise in the cerebellum due to genetic activation of the Sonic Hedgehog (Shh) signaling pathway. During normal cerebellum development, Shh spurs the proliferation of granule neuron precursors (GNP), the precursor cells of MB. Mutations in the Shh receptor gene patched1 (ptc1+/À) lead to increased MB incidence in humans and mice. MB tumorigenesis in mice heterozygous for ptc1+/À shows distinct steps of progression. Most ptc1+/À mice form clusters of preneoplastic cells on the surface of the mature cerebellum that actively transcribe Shh target genes. In f15% of mice, these preneoplastic cells will become fast-growing, lethal tumors. It was previously shown that the loss of function of insulin-like growth factor 2 (igf2) suppresses MB formation in ptc1+/À mice. We found that igf2 is not expressed in preneoplastic lesions but is induced as these lesions progress to more advanced MB tumors. Igf2 is not required for formation of preneoplastic lesions but is necessary for progression to advanced tumors. Exogenous Igf2 protein promoted proliferation of MB precursor cells (GNP) and a MB cell line, PZp53MED . Blocking igf2 signaling inhibited growth of PZp53 MED cells, implicating igf2 as a potential clinical target. [Cancer Res 2008;68(21):8788-95]

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“…One possibility for the tumorigenic effect of IGF2 is that some of the regulatory sequences responsible for regulating Igf2, located at the 3Ј end of the gene, were deleted on expression of the cDNA. Deletion of these sequences results in elevated IGF2 expression and increased proliferation (45).…”

Section: Discussionmentioning

confidence: 99%

Paternal and maternal genomes confer opposite effects on proliferation, cell-cycle length, senescence, and tumor formation

Hernandez

Kozlov

Piras

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Loss of imprinting is the silencing of active imprinted genes or the activation of silent imprinted genes, and it is one of the most common epigenetic changes associated with the development of a wide variety of tumors. Here, we have analyzed the effects that global imprinted gene expression has on cell proliferation and transformation. Primary mouse embryonic fibroblasts (MEFs), whose entire genome is either exclusively paternal (androgenetic) or maternal (parthenogenetic), exhibit dramatically contrasting patterns of growth. In comparison with biparental MEFs, androgenetic proliferation is characterized by a shorter cell cycle, increased saturation density, spontaneous transformation, and formation of tumors at low passage number. Parthenogenetic MEFs reach a lower saturation density, senesce, and die. The maternally expressed imprinted genes p57 kip2 and M6P͞Igf2r retard proliferation and reduce the long-term growth of MEFs. In contrast, the paternally expressed growth factor Igf2 is essential for the longterm proliferation of all genotypes. Increased Igf2 expression in primary MEFs not only stimulates proliferation, but also results in their rapid conversion to malignancy with tumor formation of short latency. Our results reveal that paternally expressed imprinted genes, in the absence of maternal imprinted genes, predispose fibroblasts to rapid transformation. A potent factor in their transformation is IGF2, which on increased expression results in the rapid conversion of primary cells to malignancy. These results reveal a route by which malignant choriocarcinoma may arise from molar pregnancies. They also suggest that the derivation of stem cells from parthenogenetic embryos, for the purposes of therapeutic cloning, may be ineffective.genomic imprinting ͉ uniparental ͉ Igf2 ͉ p57 kip2 ͉ cloning

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Cloning of breakpoints in and downstream the IGF2 gene that are associated with overexpression of IGF2 transcripts in colorectal tumours

Cited by 6 publications

References 26 publications

IGF1R Is a Potential New Therapeutic Target for HGNET-BCOR Brain Tumor Patients

IGF1R Is a Potential New Therapeutic Target for HGNET-BCOR Brain Tumor Patients

Insulin-like Growth Factor 2 Is Required for Progression to Advanced Medulloblastoma in patched1 Heterozygous Mice

Paternal and maternal genomes confer opposite effects on proliferation, cell-cycle length, senescence, and tumor formation

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